Archives: Cancer Types

Uterine Sarcoma Treatment (PDQ®)–Patient Version

Uterine Sarcoma Treatment (PDQ®)–Patient Version

General Information About Uterine Sarcoma

Go to Health Professional Version

Key Points

  • Uterine sarcoma is a disease in which malignant (cancer) cells form in the muscles of the uterus or other tissues that support the uterus.
  • Past treatment with radiation therapy to the pelvis can increase the risk of uterine sarcoma.
  • Signs of uterine sarcoma include abnormal bleeding.
  • Tests that examine the uterus are used to diagnose uterine sarcoma.
  • Certain factors affect prognosis (chance of recovery) and treatment options.

Uterine sarcoma is a disease in which malignant (cancer) cells form in the muscles of the uterus or other tissues that support the uterus.

The uterus is part of the female reproductive system. The uterus is the hollow, pear-shaped organ in the pelvis, where a fetus grows. The cervix is at the lower, narrow end of the uterus, and leads to the vagina.

EnlargeAnatomy of the female reproductive system; drawing shows the uterus, myometrium (muscular outer layer of the uterus), endometrium (inner lining of the uterus), ovaries, fallopian tubes, cervix, and vagina.
Anatomy of the female reproductive system. The organs in the female reproductive system include the uterus, ovaries, fallopian tubes, cervix, and vagina. The uterus has a muscular outer layer called the myometrium and an inner lining called the endometrium.

Uterine sarcoma is a very rare kind of cancer that forms in the uterine muscles or in tissues that support the uterus. For more information about other types of sarcomas, visit Soft Tissue Sarcoma Treatment.

Uterine sarcoma is different from endometrial cancer, a disease in which cancer forms in the tissue that lines the uterus. Carcinosarcoma is a subtype of endometrial cancer and is staged using endometrial cancer definitions. For more information, visit Endometrial Cancer Treatment.

Uterine sarcomas include leiomyosarcomas, endometrial stromal sarcomas, and adenosarcomas.

Past treatment with radiation therapy to the pelvis can increase the risk of uterine sarcoma.

Anything that increases a person’s chance of getting a disease is called a risk factor. Not every person with one or more of these risk factors will develop an uterine sarcoma, and it will develop in some people who don’t have any known risk factors. Talk with your doctor if you think you may be at risk. Risk factors for uterine sarcoma include:

Signs of uterine sarcoma include abnormal bleeding.

Abnormal bleeding from the vagina and other signs and symptoms may be caused by uterine sarcoma or by other conditions. Check with your doctor if you have:

Tests that examine the uterus are used to diagnose uterine sarcoma.

In addition to asking about your personal and family health history and doing a physical exam, your doctor may perform the following tests and procedures:

  • Pelvic exam: An exam of the vagina, cervix, uterus, fallopian tubes, ovaries, and rectum. A speculum is inserted into the vagina and the doctor or nurse looks at the vagina and cervix for signs of disease. A Pap test of the cervix is usually done. The doctor or nurse also inserts one or two lubricated, gloved fingers of one hand into the vagina and places the other hand over the lower abdomen to feel the size, shape, and position of the uterus and ovaries. The doctor or nurse also inserts a lubricated, gloved finger into the rectum to feel for lumps or abnormal areas.
    EnlargePelvic exam; drawing shows a side view of the female reproductive anatomy during a pelvic exam. The uterus, left fallopian tube, left ovary, cervix, vagina, bladder, and rectum are shown. Two gloved fingers of one hand of the doctor or nurse are shown inserted into the vagina, while the other hand is shown pressing on the lower abdomen. The inset shows a woman covered by a drape on an exam table with her legs apart and her feet in stirrups.
    Pelvic exam. A doctor or nurse inserts one or two lubricated, gloved fingers of one hand into the vagina and presses on the lower abdomen with the other hand. This is done to feel the size, shape, and position of the uterus and ovaries. The vagina, cervix, fallopian tubes, and rectum are also checked.
  • Pap test: A procedure to collect cells from the surface of the cervix and vagina. A piece of cotton, a brush, or a small wooden stick is used to gently scrape cells from the cervix and vagina. The cells are viewed under a microscope to find out if they are abnormal. This procedure is also called a Pap smear. Because uterine sarcoma begins inside the uterus, this cancer may not show up on the Pap test.
    EnlargePap test; drawing shows a side view of the female reproductive anatomy during a Pap test. A speculum is shown widening the opening of the vagina. A brush is shown inserted into the open vagina and touching the cervix at the base of the uterus. The rectum is also shown. One inset shows the brush touching the center of the cervix. A second inset shows a woman covered by a drape on an exam table with her legs apart and her feet in stirrups.
    Pap test. A speculum is inserted into the vagina to widen it. Then, a brush is inserted into the vagina to collect cells from the cervix. The cells are checked under a microscope for signs of disease.
  • Transvaginal ultrasound exam: A procedure used to examine the vagina, uterus, fallopian tubes, and bladder. An ultrasound transducer (probe) is inserted into the vagina and used to bounce high-energy sound waves (ultrasound) off internal tissues or organs and make echoes. The echoes form a picture of body tissues called a sonogram. The doctor can identify tumors by looking at the sonogram.
    EnlargeTransvaginal ultrasound; drawing shows a side view of the female reproductive anatomy during a transvaginal ultrasound procedure. An ultrasound probe (a device that makes sound waves that bounce off tissues inside the body) is shown inserted into the vagina. The bladder, uterus, right fallopian tube, and right ovary are also shown. The inset shows the diagnostic sonographer (a person trained to perform ultrasound procedures) examining a woman on a table, and a computer screen shows an image of the patient’s internal tissues.
    Transvaginal ultrasound. An ultrasound probe connected to a computer is inserted into the vagina and is gently moved to show different organs. The probe bounces sound waves off internal organs and tissues to make echoes that form a sonogram (computer picture).
  • Dilatation and curettage: A procedure to remove samples of tissue from the inner lining of the uterus. The cervix is dilated and a curette (spoon-shaped instrument) is inserted into the uterus to remove tissue. The tissue samples are checked under a microscope for signs of disease. This procedure is also called a D&C.
    EnlargeDilatation and curettage (D and C). Three-panel drawing showing a side view of the female reproductive anatomy during a D and C procedure. The first panel shows a speculum widening the opening of the vagina. The cervix, uterus with abnormal tissue, bladder, and rectum are also shown; an inset shows the lower half of a woman covered by a drape on an exam table with her legs apart and her feet in stirrups. The middle panel shows the uterus and a dilator inserted through the vagina into the cervix. The third panel shows a curette scraping out abnormal tissue from the uterus; an inset shows a close up of the curette with the abnormal tissue in it.
    Dilatation and curettage (D and C). A speculum is inserted into the vagina to widen it in order to look at the cervix (first panel). A dilator is used to widen the cervix (middle panel). A curette is put through the cervix into the uterus to scrape out abnormal tissue (last panel).
  • Endometrial biopsy: The removal of tissue from the endometrium (inner lining of the uterus) by inserting a thin, flexible tube through the cervix and into the uterus. The tube is used to gently scrape a small amount of tissue from the endometrium and then remove the tissue samples. A pathologist views the tissue under a microscope to look for cancer cells.

Certain factors affect prognosis (chance of recovery) and treatment options.

The prognosis and treatment options depend on:

  • The stage of the cancer.
  • The type and size of the tumor.
  • The patient’s general health.
  • Whether the cancer has just been diagnosed or has recurred (come back).

Stages of Uterine Sarcoma

Key Points

  • After uterine sarcoma has been diagnosed, tests are done to find out if cancer cells have spread within the uterus or to other parts of the body.
  • Uterine sarcoma may be diagnosed, staged, and treated in the same surgery.
  • There are three ways that cancer spreads in the body.
    • Cancer may spread from where it began to other parts of the body.
  • The following FIGO staging system is used for leiomyosarcomas and endometrial stromal sarcomas:
    • Stage I
    • Stage II
    • Stage III
    • Stage IV
  • The following FIGO staging system is used for adenosarcomas:
    • Stage I
    • Stage II
    • Stage III
    • Stage IV
  • Uterine sarcoma can recur (come back) after it has been treated.

After uterine sarcoma has been diagnosed, tests are done to find out if cancer cells have spread within the uterus or to other parts of the body.

The process used to find out if cancer has spread within the uterus or to other parts of the body is called staging. The information gathered from the staging process determines the stage of the disease. It is important to know the stage in order to plan treatment. The following procedures may be used in the staging process:

  • Blood chemistry studies: A procedure in which a blood sample is checked to measure the amounts of certain substances released into the blood by organs and tissues in the body. An unusual (higher or lower than normal) amount of a substance can be a sign of disease.
  • CA-125 assay: A test that measures the level of CA-125 in the blood. CA-125 is a substance released by cells into the bloodstream. An increased CA-125 level is sometimes a sign of cancer or other condition.
  • Chest x-ray: An x-ray of the organs and bones inside the chest. An x-ray is a type of energy beam that can go through the body and onto film, making a picture of areas inside the body.
  • Transvaginal ultrasound exam: A procedure used to examine the vagina, uterus, fallopian tubes, and bladder. An ultrasound transducer (probe) is inserted into the vagina and used to bounce high-energy sound waves (ultrasound) off internal tissues or organs and make echoes. The echoes form a picture of body tissues called a sonogram. The doctor can identify tumors by looking at the sonogram.
    EnlargeTransvaginal ultrasound; drawing shows a side view of the female reproductive anatomy during a transvaginal ultrasound procedure. An ultrasound probe (a device that makes sound waves that bounce off tissues inside the body) is shown inserted into the vagina. The bladder, uterus, right fallopian tube, and right ovary are also shown. The inset shows the diagnostic sonographer (a person trained to perform ultrasound procedures) examining a woman on a table, and a computer screen shows an image of the patient’s internal tissues.
    Transvaginal ultrasound. An ultrasound probe connected to a computer is inserted into the vagina and is gently moved to show different organs. The probe bounces sound waves off internal organs and tissues to make echoes that form a sonogram (computer picture).
  • CT scan (CAT scan): A procedure that makes a series of detailed pictures of areas inside the body, such as the abdomen and pelvis, taken from different angles. The pictures are made by a computer linked to an x-ray machine. A dye may be injected into a vein or swallowed to help the organs or tissues to show up more clearly. This procedure is also called computed tomography, computerized tomography, or computerized axial tomography.
  • Cystoscopy: A procedure to look inside the bladder and urethra to check for abnormal areas. A cystoscope is inserted through the urethra into the bladder. A cystoscope is a thin, tube-like instrument with a light and a lens for viewing. It may also have a tool to remove tissue samples, which are checked under a microscope for signs of cancer.
    EnlargeCystoscopy; drawing shows a side view of the lower pelvis containing the bladder, uterus, vagina, rectum, and anus. A cystoscope (a thin, tube-like instrument with a light and a lens for viewing) is shown passing through the urethra and into the bladder. Fluid is used to fill the bladder. An inset shows a woman lying on an examination table with her knees bent and legs apart. She is covered by a drape. The doctor is looking at an image of the inner wall of the bladder on a computer monitor to check for abnormal areas.
    Cystoscopy. A cystoscope (a thin, tube-like instrument with a light and a lens for viewing) is inserted through the urethra into the bladder. Fluid is used to fill the bladder. The doctor looks at an image of the inner wall of the bladder on a computer monitor to check for abnormal areas.

Uterine sarcoma may be diagnosed, staged, and treated in the same surgery.

Surgery is used to diagnose, stage, and treat uterine sarcoma. During this surgery, the doctor removes as much of the cancer as possible. The following procedures may be used to diagnose, stage, and treat uterine sarcoma:

  • Laparotomy: A surgical procedure in which an incision (cut) is made in the wall of the abdomen to check the inside of the abdomen for signs of disease. The size of the incision depends on the reason the laparotomy is being done. Sometimes organs are removed or tissue samples are taken and checked under a microscope for signs of disease.
  • Abdominal and pelvic washings: A procedure in which a saline solution is placed into the abdominal and pelvic body cavities. After a short time, the fluid is removed and viewed under a microscope to check for cancer cells.
  • Total abdominal hysterectomy: A surgical procedure to remove the uterus and cervix through a large incision (cut) in the abdomen.
    EnlargeHysterectomy; drawing shows the female reproductive anatomy, including the ovaries, uterus, vagina, fallopian tubes, and cervix. Dotted lines show which organs and tissues are removed in a total hysterectomy, a total hysterectomy with salpingo-oophorectomy, and a radical hysterectomy. An inset shows the location of two possible incisions on the abdomen: a low transverse incision is just above the pubic area and a vertical incision is between the navel and the pubic area.
    Hysterectomy. The uterus is surgically removed with or without other organs or tissues. In a total hysterectomy, the uterus and cervix are removed. In a total hysterectomy with salpingo-oophorectomy, (a) the uterus plus one (unilateral) ovary and fallopian tube are removed; or (b) the uterus plus both (bilateral) ovaries and fallopian tubes are removed. In a radical hysterectomy, the uterus, cervix, both ovaries, both fallopian tubes, and nearby tissue are removed. These procedures are done using a low transverse incision or a vertical incision.
  • Bilateral salpingo-oophorectomy: Surgery to remove both ovaries and both fallopian tubes.
  • Lymphadenectomy: A surgical procedure in which lymph nodes are removed and checked under a microscope for signs of cancer. For a regional lymphadenectomy, some of the lymph nodes in the tumor area are removed. For a radical lymphadenectomy, most or all of the lymph nodes in the tumor area are removed. This procedure is also called lymph node dissection.

Treatment in addition to surgery may be given, as described in the Treatment Option Overview section of this summary.

There are three ways that cancer spreads in the body.

Cancer may spread from where it began to other parts of the body.

When cancer spreads to another part of the body, it is called metastasis. Cancer cells break away from where they began (the primary tumor) and travel through the lymph system or blood.

  • Lymph system. The cancer gets into the lymph system, travels through the lymph vessels, and forms a tumor (metastatic tumor) in another part of the body.
  • Blood. The cancer gets into the blood, travels through the blood vessels, and forms a tumor (metastatic tumor) in another part of the body.

The metastatic tumor is the same type of cancer as the primary tumor. For example, if uterine sarcoma spreads to the lung, the cancer cells in the lung are actually uterine sarcoma cells. The disease is metastatic uterine sarcoma, not lung cancer.

Many cancer deaths are caused when cancer moves from the original tumor and spreads to other tissues and organs. This is called metastatic cancer. This animation shows how cancer cells travel from the place in the body where they first formed to other parts of the body.

Cancer can spread through tissue, the lymph system, and the blood:

  • Tissue. The cancer spreads from where it began by growing into nearby areas.
  • Lymph system. The cancer spreads from where it began by getting into the lymph system. The cancer travels through the lymph vessels to other parts of the body.
  • Blood. The cancer spreads from where it began by getting into the blood. The cancer travels through the blood vessels to other parts of the body.

The following FIGO staging system is used for leiomyosarcomas and endometrial stromal sarcomas:

Stage I

In stage I, the tumor is found in the uterus only. Stage I is divided into stages IA and IB:

  • In stage IA, the tumor is 5 centimeters or smaller.
  • In stage IB, the tumor is larger than 5 centimeters.
EnlargeDrawing shows different sizes of a tumor in centimeters (cm) compared to the size of a pea (1 cm), a peanut (2 cm), a grape (3 cm), a walnut (4 cm), a lime (5 cm), an egg (6 cm), a peach (7 cm), and a grapefruit (10 cm). Also shown is a 10-cm ruler and a 4-inch ruler.
Tumor sizes are often measured in centimeters (cm) or inches. Common food items that can be used to show tumor size in cm include: a pea (1 cm), a peanut (2 cm), a grape (3 cm), a walnut (4 cm), a lime (5 cm or 2 inches), an egg (6 cm), a peach (7 cm), and a grapefruit (10 cm or 4 inches).

Stage II

In stage II, the tumor has spread beyond the uterus but has not spread beyond the pelvis. Stage II is divided into stages IIA and IIB:

Stage III

In stage III, the tumor has spread into tissues in the abdomen. Stage III is divided into stages IIIA, IIIB, and IIIC:

  • In stage IIIA, the tumor has spread to one site in the abdomen.
  • In stage IIIB, the tumor has spread to more than one site in the abdomen.
  • In stage IIIC, the tumor has spread to lymph nodes in the pelvis and/or around the abdominal aorta (the largest blood vessel in the abdomen).

Stage IV

Stage IV is divided into stages IVA and IVB:

  • In stage IVA, the tumor has spread into the bladder and/or the rectum.
  • In stage IVB, the tumor has spread to distant parts of the body.

The following FIGO staging system is used for adenosarcomas:

Stage I

In stage I, the tumor is found in the uterus only. Stage I is divided into stages IA, IB, and IC:

  • In stage IA, the tumor is found in the endometrium or endocervix (the inner part of the cervix that forms a canal connecting the vagina to the uterus).
  • In stage IB, the tumor has spread halfway or less into the myometrium (the muscular outer layer of the uterus).
  • In stage IC, the tumor has spread more than halfway into the myometrium.

Stage II

In stage II, the tumor has spread outside the uterus into the pelvis. Stage II is divided into stages IIA and IIB:

Stage III

In stage III, the tumor has spread into tissues in the abdomen. Stage III is divided into stages IIIA, IIIB, and IIIC:

  • In stage IIIA, the tumor has spread to one site in the abdomen.
  • In stage IIIB, the tumor has spread to more than one site in the abdomen.
  • In stage IIIC, the tumor has spread to lymph nodes in the pelvis and/or around the abdominal aorta (the largest blood vessel in the abdomen).

Stage IV

Stage IV is divided into stages IVA and IVB:

  • In stage IVA, the tumor has spread into the bladder and/or the rectum.
  • In stage IVB, the tumor has spread to distant parts of the body.

Uterine sarcoma can recur (come back) after it has been treated.

The cancer may come back in the uterus, the pelvis, or in other parts of the body.

Treatment Option Overview

Key Points

  • There are different types of treatment for patients with uterine sarcoma.
  • The following types of treatment are used:
    • Surgery
    • Radiation therapy
    • Chemotherapy
    • Hormone therapy
  • New types of treatment are being tested in clinical trials.
  • Treatment for uterine sarcoma may cause side effects.
  • Patients may want to think about taking part in a clinical trial.
  • Patients can enter clinical trials before, during, or after starting their cancer treatment.
  • Follow-up care may be needed.

There are different types of treatment for patients with uterine sarcoma.

Different types of treatments are available for patients with uterine sarcoma. Some treatments are standard (the currently used treatment), and some are being tested in clinical trials. A treatment clinical trial is a research study meant to help improve current treatments or obtain information on new treatments for patients with cancer. When clinical trials show that a new treatment is better than the standard treatment, the new treatment may become the standard treatment. Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.

The following types of treatment are used:

Surgery

Surgery is the most common treatment for uterine sarcoma, as described in the Stages of Uterine Sarcoma section of this summary.

After the doctor removes all the cancer that can be seen at the time of the surgery, some patients may be given chemotherapy or radiation therapy after surgery to kill any cancer cells that are left. Treatment given after the surgery, to lower the risk that the cancer will come back, is called adjuvant therapy.

Radiation therapy

Radiation therapy is a cancer treatment that uses high energy x-rays or other types of radiation to kill cancer cells or keep them from growing. There are two types of radiation therapy:

The way the radiation therapy is given depends on the type and stage of the cancer being treated. External and internal radiation therapy are used to treat uterine sarcoma, and may also be used as palliative therapy to relieve symptoms and improve quality of life.

Chemotherapy

Chemotherapy is a cancer treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. When chemotherapy is taken by mouth or injected into a vein or muscle, the drugs enter the bloodstream and can reach cancer cells throughout the body (systemic chemotherapy).

Hormone therapy

Hormone therapy is a cancer treatment that removes hormones or blocks their action and stops cancer cells from growing. Hormones are substances produced by glands in the body and circulated in the bloodstream. Some hormones can cause certain cancers to grow. If tests show the cancer cells have places where hormones can attach (receptors), drugs, surgery, or radiation therapy is used to reduce the production of hormones or block them from working.

New types of treatment are being tested in clinical trials.

Information about clinical trials is available from the NCI website.

Treatment for uterine sarcoma may cause side effects.

For information about side effects caused by treatment for cancer, visit our Side Effects page.

Patients may want to think about taking part in a clinical trial.

For some patients, taking part in a clinical trial may be the best treatment choice. Clinical trials are part of the cancer research process. Clinical trials are done to find out if new cancer treatments are safe and effective or better than the standard treatment.

Many of today’s standard treatments for cancer are based on earlier clinical trials. Patients who take part in a clinical trial may receive the standard treatment or be among the first to receive a new treatment.

Patients who take part in clinical trials also help improve the way cancer will be treated in the future. Even when clinical trials do not lead to effective new treatments, they often answer important questions and help move research forward.

Patients can enter clinical trials before, during, or after starting their cancer treatment.

Some clinical trials only include patients who have not yet received treatment. Other trials test treatments for patients whose cancer has not gotten better. There are also clinical trials that test new ways to stop cancer from recurring (coming back) or reduce the side effects of cancer treatment.

Clinical trials are taking place in many parts of the country. Information about clinical trials supported by NCI can be found on NCI’s clinical trials search webpage. Clinical trials supported by other organizations can be found on the ClinicalTrials.gov website.

Follow-up care may be needed.

As you go through treatment, you will have follow-up tests or check-ups. Some tests that were done to diagnose or stage the cancer may be repeated to see how well the treatment is working. Decisions about whether to continue, change, or stop treatment may be based on the results of these tests.

Some of the tests will continue to be done from time to time after treatment has ended. The results of these tests can show if your condition has changed or if the cancer has recurred (come back).

Treatment of Stage I Uterine Sarcoma

For information about the treatments listed below, visit the Treatment Option Overview section.

Treatment of stage I leiomyosarcoma of the uterus, stage I endometrial stromal sarcoma, and stage I adenosarcoma of the uterus may include:

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

Treatment of Stage II Uterine Sarcoma

For information about the treatments listed below, visit the Treatment Option Overview section.

Treatment of stage II leiomyosarcoma of the uterus, stage II endometrial stromal sarcoma, and stage II adenosarcoma of the uterus may include:

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

Treatment of Stage III Uterine Sarcoma

For information about the treatments listed below, visit the Treatment Option Overview section.

Treatment of stage III leiomyosarcoma of the uterus, stage III endometrial stromal sarcoma, and stage III adenosarcoma of the uterus may include:

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

Treatment of Stage IV Uterine Sarcoma

There is no standard treatment for patients with stage IV leiomyosarcoma of the uterus, stage IV endometrial stromal sarcoma, or stage IV adenosarcoma of the uterus. Treatment may include a clinical trial using chemotherapy.

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

Treatment of Recurrent Uterine Sarcoma

For information about the treatments listed below, visit the Treatment Option Overview section.

There is no standard treatment for recurrent uterine sarcoma. Treatment may include a clinical trial using chemotherapy.

For patients with recurrent carcinosarcoma (a certain type of tumor), treatment may include:

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

To Learn More About Uterine Sarcoma

For more information from the National Cancer Institute about uterine sarcoma, visit the Uterine Cancer Home Page.

For general cancer information and other resources from the National Cancer Institute, visit:

About This PDQ Summary

About PDQ

Physician Data Query (PDQ) is the National Cancer Institute’s (NCI’s) comprehensive cancer information database. The PDQ database contains summaries of the latest published information on cancer prevention, detection, genetics, treatment, supportive care, and complementary and alternative medicine. Most summaries come in two versions. The health professional versions have detailed information written in technical language. The patient versions are written in easy-to-understand, nontechnical language. Both versions have cancer information that is accurate and up to date and most versions are also available in Spanish.

PDQ is a service of the NCI. The NCI is part of the National Institutes of Health (NIH). NIH is the federal government’s center of biomedical research. The PDQ summaries are based on an independent review of the medical literature. They are not policy statements of the NCI or the NIH.

Purpose of This Summary

This PDQ cancer information summary has current information about the treatment of uterine sarcoma. It is meant to inform and help patients, families, and caregivers. It does not give formal guidelines or recommendations for making decisions about health care.

Reviewers and Updates

Editorial Boards write the PDQ cancer information summaries and keep them up to date. These Boards are made up of experts in cancer treatment and other specialties related to cancer. The summaries are reviewed regularly and changes are made when there is new information. The date on each summary (“Updated”) is the date of the most recent change.

The information in this patient summary was taken from the health professional version, which is reviewed regularly and updated as needed, by the PDQ Adult Treatment Editorial Board.

Clinical Trial Information

A clinical trial is a study to answer a scientific question, such as whether one treatment is better than another. Trials are based on past studies and what has been learned in the laboratory. Each trial answers certain scientific questions in order to find new and better ways to help cancer patients. During treatment clinical trials, information is collected about the effects of a new treatment and how well it works. If a clinical trial shows that a new treatment is better than one currently being used, the new treatment may become “standard.” Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.

Clinical trials can be found online at NCI’s website. For more information, call the Cancer Information Service (CIS), NCI’s contact center, at 1-800-4-CANCER (1-800-422-6237).

Permission to Use This Summary

PDQ is a registered trademark. The content of PDQ documents can be used freely as text. It cannot be identified as an NCI PDQ cancer information summary unless the whole summary is shown and it is updated regularly. However, a user would be allowed to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks in the following way: [include excerpt from the summary].”

The best way to cite this PDQ summary is:

PDQ® Adult Treatment Editorial Board. PDQ Uterine Sarcoma Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/uterine/patient/uterine-sarcoma-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389379]

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Endometrial Cancer Screening (PDQ®)–Health Professional Version

Endometrial Cancer Screening (PDQ®)–Health Professional Version

Summary of Evidence

Go to Patient Version

Note: The Summary of Evidence section summarizes the published evidence on this topic. The rest of the summary describes the evidence in more detail.

Other PDQ summaries on Endometrial Cancer Prevention; Endometrial Cancer Treatment; and Uterine Sarcoma Treatment are also available.

Transvaginal Ultrasound: Benefits

There is no evidence that screening by ultrasonography (e.g., endovaginal ultrasound or transvaginal ultrasound) reduces mortality from endometrial cancer. Most cases of endometrial cancer (85%) are diagnosed at low stage because of symptoms, and survival rates are high.

Transvaginal Ultrasound: Harms

Based on solid evidence, screening asymptomatic women will result in unnecessary additional biopsies because of false-positive test results. Risks associated with false-positive tests include anxiety and complications from biopsies.

  • Study Design: Evidence obtained from cohort studies.
  • Internal Validity: Fair.
  • Consistency: One study for endometrial biopsy and one study for hysteroscopy.
  • Magnitude of Effects on Health Outcomes: Small negative magnitude.
  • External Validity: Fair.

Endometrial Sampling (Biopsy): Benefits

There is inadequate evidence that screening by endometrial sampling (i.e., biopsy) reduces mortality from endometrial cancer. Most cases of endometrial cancer (85%) are diagnosed at low stage because of symptoms, and survival rates are high.

Endometrial Sampling (Biopsy): Harms

Based on solid evidence, endometrial biopsy may result in discomfort, bleeding, infection, and rarely, uterine perforation.

  • Study Design: Evidence obtained from cohort studies.
  • Internal Validity: Fair.
  • Consistency: One study for endometrial biopsy and one study for hysteroscopy.
  • Magnitude of Effects on Health Outcomes: Small negative magnitude.
  • External Validity: Fair.

Significance

Epidemiology of Endometrial Cancer

Incidence and mortality

Endometrial cancer is the most common invasive gynecologic cancer in U.S. women, with an estimated 69,120 new cases expected to occur in 2025 and an estimated 13,860 women expected to die of the disease.[1] Endometrial cancer is primarily a disease of postmenopausal women, with a mean age at diagnosis of 60 years.[2] Age-adjusted endometrial cancer incidence in the United States increased from the mid-1960s to 1975 and then declined from 1975 to 1980, with a transient increase in incidence occurring from 1973 to 1978, which was associated with estrogen therapy, also known as hormone therapy.[3] There was no associated increase in mortality. Continuing with more recent trends, incidence rates increased by 0.6% per year in White women and by 2% to 3% per year in women of all other racial and ethnic groups. Between 2013 and 2022, death rates for endometrial cancer increased by 1.5% per year.[1] Most cases of endometrial cancer are diagnosed because of symptoms and typically at an early stage.

Risk Factors

Estrogen therapy unopposed by progesterone therapy is a cause of endometrial cancer in women with an intact uterus. However, women taking combination estrogen-progesterone therapy (hormone therapy) exhibit similar risk to women who do not take postmenopausal hormone therapy.[4–8] Tamoxifen therapy is also a cause of endometrial cancer. Results from the National Surgical Adjuvant Breast and Bowel Project P-1 trial, report a doubling of the risk of endometrial cancer associated with an annual rate of 2.30 per 1,000 for women taking tamoxifen compared with 0.91 per 1,000 for women receiving placebo; the increased risk was seen primarily in postmenopausal women.[9]

In addition to the increased risk of developing endometrial cancer that is observed in women who use unopposed estrogen therapy or tamoxifen, a number of additional risk factors have been identified, and most appear to be related to estrogenic effects. Among these factors are obesity, a high-fat diet, and reproductive factors such as nulliparity, polycystic ovary syndrome, early menarche, and late menopause. Hereditary nonpolyposis colorectal cancer (HNPCC) syndrome is associated with a markedly increased risk of endometrial cancer compared with women in the general population. Among women who are HNPCC carriers, the estimated cumulative incidence of endometrial cancer ranges from 20% to 60% by age 70 years (for more information, see Genetics of Colorectal Cancer).[10–12] This risk appears to differ slightly based on the germline mutation; for MLH1 carriers the lifetime risk at age 70 years is 25%, while MSH2 mutation carriers have a 35% to 40% lifetime risk of endometrial cancer by age 70 years. The mean age of diagnosis for MLH1 or MSH2 carriers is 47 years compared with 60 years for noninherited forms of endometrial cancer.[13] The prognosis and survival are similar between HNPCC-related and noninherited forms of endometrial cancer.[14]

Major differences exist between Black and White women in stages of endometrial cancer at detection and at subsequent survival. Although the incidence of endometrial cancer is lower among Black women, mortality is higher. The National Cancer Institute initiated a Black/White Cancer Survival Study [15] and concluded that higher-grade and more aggressive histologies appear to be related to excess risk of advanced-stage disease in Black women. It is difficult to disentangle the effects that biology and socioeconomic status may have on the lower survival rates of Black women with endometrial cancer. Evidence suggests that lower income is associated with advanced-stage disease, lower probability of undergoing a hysterectomy, and lower survival rates.[16] Others, however, assert that there is no Black/White racial difference in the interval from patient-reported symptoms to initial medical consultation, making it unlikely that patient delay after onset of symptoms could explain much of the excess of advanced-stage disease found in Black women.[17] Further research is necessary to understand why Black women tend to be diagnosed with more aggressive disease and have a higher probability of dying than White women, despite their lower incidence of endometrial cancer.

References
  1. American Cancer Society: Cancer Facts and Figures 2025. American Cancer Society, 2025. Available online. Last accessed January 16, 2025.
  2. American Cancer Society: Detailed Guide: Endometrial Cancer: What are the Risk Factors for Endometrial Cancer? Atlanta, Ga: American Cancer Society, 2005. Available online. Last accessed April 8, 2025.
  3. Jick H, Walker AM, Rothman KJ: The epidemic of endometrial cancer: a commentary. Am J Public Health 70 (3): 264-7, 1980. [PUBMED Abstract]
  4. Pike MC, Peters RK, Cozen W, et al.: Estrogen-progestin replacement therapy and endometrial cancer. J Natl Cancer Inst 89 (15): 1110-6, 1997. [PUBMED Abstract]
  5. Persson I, Weiderpass E, Bergkvist L, et al.: Risks of breast and endometrial cancer after estrogen and estrogen-progestin replacement. Cancer Causes Control 10 (4): 253-60, 1999. [PUBMED Abstract]
  6. Heiss G, Wallace R, Anderson GL, et al.: Health risks and benefits 3 years after stopping randomized treatment with estrogen and progestin. JAMA 299 (9): 1036-45, 2008. [PUBMED Abstract]
  7. Doherty JA, Cushing-Haugen KL, Saltzman BS, et al.: Long-term use of postmenopausal estrogen and progestin hormone therapies and the risk of endometrial cancer. Am J Obstet Gynecol 197 (2): 139.e1-7, 2007. [PUBMED Abstract]
  8. Barakat RR, Bundy BN, Spirtos NM, et al.: Randomized double-blind trial of estrogen replacement therapy versus placebo in stage I or II endometrial cancer: a Gynecologic Oncology Group Study. J Clin Oncol 24 (4): 587-92, 2006. [PUBMED Abstract]
  9. Cuzick J, Forbes JF, Sestak I, et al.: Long-term results of tamoxifen prophylaxis for breast cancer–96-month follow-up of the randomized IBIS-I trial. J Natl Cancer Inst 99 (4): 272-82, 2007. [PUBMED Abstract]
  10. Watson P, Vasen HF, Mecklin JP, et al.: The risk of endometrial cancer in hereditary nonpolyposis colorectal cancer. Am J Med 96 (6): 516-20, 1994. [PUBMED Abstract]
  11. Aarnio M, Mecklin JP, Aaltonen LA, et al.: Life-time risk of different cancers in hereditary non-polyposis colorectal cancer (HNPCC) syndrome. Int J Cancer 64 (6): 430-3, 1995. [PUBMED Abstract]
  12. Aarnio M, Sankila R, Pukkala E, et al.: Cancer risk in mutation carriers of DNA-mismatch-repair genes. Int J Cancer 81 (2): 214-8, 1999. [PUBMED Abstract]
  13. Berends MJ, Wu Y, Sijmons RH, et al.: Toward new strategies to select young endometrial cancer patients for mismatch repair gene mutation analysis. J Clin Oncol 21 (23): 4364-70, 2003. [PUBMED Abstract]
  14. Boks DE, Trujillo AP, Voogd AC, et al.: Survival analysis of endometrial carcinoma associated with hereditary nonpolyposis colorectal cancer. Int J Cancer 102 (2): 198-200, 2002. [PUBMED Abstract]
  15. Barrett RJ, Harlan LC, Wesley MN, et al.: Endometrial cancer: stage at diagnosis and associated factors in black and white patients. Am J Obstet Gynecol 173 (2): 414-22; discussion 422-3, 1995. [PUBMED Abstract]
  16. Madison T, Schottenfeld D, James SA, et al.: Endometrial cancer: socioeconomic status and racial/ethnic differences in stage at diagnosis, treatment, and survival. Am J Public Health 94 (12): 2104-11, 2004. [PUBMED Abstract]
  17. Coates RJ, Click LA, Harlan LC, et al.: Differences between black and white patients with cancer of the uterine corpus in interval from symptom recognition to initial medical consultation (United States). Cancer Causes Control 7 (3): 328-36, 1996. [PUBMED Abstract]

Evidence of Benefit

Measuring endometrial thickness (ET) with transvaginal ultrasound (TVU) and endometrial sampling with cytological examination have been proposed as possible screening modalities for endometrial cancer. The Papanicolaou (Pap) test, used successfully for screening for cervical cancer, is too insensitive to be used as a screening technique for the detection of endometrial cancer,[1] although occasionally the Pap test may fortuitously identify endometrial abnormalities, such as endometrial cancer.

Routine screening of asymptomatic women for endometrial cancer has not been evaluated for its impact on endometrial cancer mortality.[2,3] Although high-risk groups can be identified, the benefit of screening in reducing endometrial cancer mortality in these high-risk groups has not been evaluated. Using the same cutoffs to define an abnormal ET in asymptomatic women [4] as used in symptomatic women [5] would result in large numbers of false-positive test results and larger numbers of unnecessary referrals for cytological evaluations. Published recommendations for screening certain groups of women at high risk of endometrial carcinoma are based on opinion regarding presumptive benefit.[6]

Modalities of Endometrial Cancer Screening

Ultrasonography in women with vaginal bleeding

TVU is used as a diagnostic tool to evaluate symptomatic women with vaginal bleeding. Among women with postmenopausal uterine bleeding and cancer, 96% will have an abnormal ET (>6 mm). The specificity varies by whether women used hormone therapy. Among nonusers, the specificity was 92%.[5] Much less work has been done to evaluate the accuracy of TVU among asymptomatic women. If the same ET cutoff is used among asymptomatic women, the false positives will be extremely high, resulting in a very low positive predictive value.[4] No studies have evaluated the efficacy of screening with TVU in reducing mortality from endometrial cancer.

A group of researchers used dilation and curettage (D&C) as a gold standard, to evaluate TVU measurement of ET as a predictor of endometrial cancer in women reporting postmenopausal bleeding (PMB) (estrogen-progestin therapy [hormone therapy] and nonhormone therapy users). Of the 339 participants, 39 (11.5%) were diagnosed with endometrial cancer (four had an ET of 5–7 mm and 35 had an ET >8 mm) based on histopathology from curettage. No cancers were detected in women with an ET of less than 4 mm. Using a cutoff point of 4 mm, TVU has 100% sensitivity and 60% specificity.[7] In this population, 46% (156) of the women had an ET greater than 4 mm.

Ultrasonography in women without vaginal bleeding

A comparison of TVU and endometrial aspiration was conducted among asymptomatic postmenopausal women potentially eligible for an osteoporosis prevention trial [8] as part of determination of eligibility for randomization. TVU was performed on 1,926 women. Of these, 93 women had ET greater than 6 mm. Among the 93 women with abnormal ET, 42 had endometrial aspiration with one finding of abnormal pathology (defined as adenocarcinoma or atypical hyperplasia). Of the 1,833 women with ET measuring 6 mm or less, 1,750 women had endometrial aspiration and five of these women had an abnormal pathological biopsy. Among this population of asymptomatic postmenopausal women, the estimated sensitivity for TVU with a threshold value of 6 mm was 17% and 33% for a threshold value of 5 mm.

One study assessed the usefulness of TVU among a cohort of postmenopausal, asymptomatic women receiving hormone therapy. Using the Postmenopausal Estrogen and Progestin Interventions Trial participants who had undergone both TVU and endometrial biopsy, sensitivity, specificity, positive predictive value, and negative predictive value were determined for women who received placebo, estrogen alone, and estrogen-progestin therapy. At a threshold value of 5 mm for ET, TVU had 90% sensitivity and 48% specificity. Using this threshold, more than half the women would receive a biopsy while only 4% of them had serious disease.[9]

Another study obtained endometrial biopsy specimens from 801 asymptomatic perimenopausal and postmenopausal women before enrollment in a hormone therapy study. Of the specimens, 75% of the samples contained sufficient tissue for diagnosis. Among these women, one case of endometrial cancer was diagnosed, illustrating the low yield of screening among asymptomatic women and the difficulty with endometrial cavity access.[10]

Although TVU can be used to evaluate asymptomatic and occult endometrial pathology, the technique has not been evaluated as a screening method for reducing mortality in asymptomatic women.

Ultrasonography in women using tamoxifen

Tamoxifen is widely used as part of adjuvant therapy for breast cancer and as chemoprevention for women at increased risk of breast cancer. In addition to the protective effects for breast cancer, the biological and endocrine effects of tamoxifen increase patients’ risk of developing endometrial pathology, including endometrial polyps, endometrial hyperplasia, and endometrial carcinoma.

There is interest in trying to reduce the morbidity from endometrial cancer through early detection, and there has been interest in using endovaginal ultrasound as a method to screen women to detect endometrial cancer.

In a prospective, observational study of 304 women using tamoxifen over 6 years, women underwent annual endovaginal ultrasound screening. Women with abnormal ultrasound findings and women who were symptomatic with bleeding all underwent endometrial biopsy. Thirty-two percent of the ultrasound examinations had associated significant uterine abnormalities identified that required further medical or surgical investigation and treatment. However, most abnormalities (80%) represented benign polyps for which no treatment was needed. Six cases of primary endometrial cancer were detected, and all cases presented with irregular bleeding. The sensitivity of ultrasound was only 63.3%, with a specificity of 60.4%, and had a low positive predictive value for cancer of only 1%.[11]

Other reports have noted similar results. Routine ultrasound surveillance in asymptomatic women using tamoxifen is not useful because of its low specificity and low positive predictive value. Evaluation of the endometrium in women taking tamoxifen should be limited to women symptomatic with vaginal bleeding.

Sonohysterography

Sonohysterography (hydrosonography) is a diagnostic test used to help guide biopsies in asymptomatic women that is able to separate space occupied by endometrial lesions from an abnormal endometrial-myometrial junction. There is no evidence that routine screening sonohysterography will confer clinical benefit.

Endometrial sampling in women with uterine bleeding

In the setting of abnormal uterine bleeding, endometrial sampling has gained favor largely as an alternative to more invasive procedures such as fractional D&C. Several methods of biopsy exist (e.g., Pipelle, Tao Brush, and Uterine Explora Curette) to identify endometrial pathology. Although endometrial sampling has largely replaced D&C as the first choice in the evaluation of women with bleeding, issues of access to the endometrial cavity and sampling error limit the clinical significance of a negative result. In the Arimidex, Tamoxifen, Alone or in Combination trial, 36% of biopsies had insufficient tissue for diagnosis. A meta-analysis of PMB reported that 91% (95% confidence interval [CI], 87%–93%) of women with endometrial cancer reported PMB. However, among women with PMB, only 9% (95% CI, 8%–11%) were diagnosed with endometrial cancer. This report is limited by a lack of histology-specific estimates.[12,13]

No studies have evaluated the use of endometrial sampling as routine screening in reducing endometrial cancer mortality.

Hysteroscopy

Hysteroscopy is used in the office setting to directly visualize the uterine cavity. A group of researchers noted that hysteroscopy is not as useful in detecting endometrial cancer as biopsy or D&C.[14] It has not been evaluated as a screening tool.[15]

References
  1. Burk JR, Lehman HF, Wolf FS: Inadequacy of papanicolaou smears in the detection of endometrial cancer. N Engl J Med 291 (4): 191-2, 1974. [PUBMED Abstract]
  2. Pritchard KI: Screening for endometrial cancer: is it effective? Ann Intern Med 110 (3): 177-9, 1989. [PUBMED Abstract]
  3. Eddy D: ACS report on the cancer-related health checkup. CA Cancer J Clin 30 (4): 193-240, 1980 Jul-Aug. [PUBMED Abstract]
  4. Smith-Bindman R, Weiss E, Feldstein V: How thick is too thick? When endometrial thickness should prompt biopsy in postmenopausal women without vaginal bleeding. Ultrasound Obstet Gynecol 24 (5): 558-65, 2004. [PUBMED Abstract]
  5. Smith-Bindman R, Kerlikowske K, Feldstein VA, et al.: Endovaginal ultrasound to exclude endometrial cancer and other endometrial abnormalities. JAMA 280 (17): 1510-7, 1998. [PUBMED Abstract]
  6. Burke W, Petersen G, Lynch P, et al.: Recommendations for follow-up care of individuals with an inherited predisposition to cancer. I. Hereditary nonpolyposis colon cancer. Cancer Genetics Studies Consortium. JAMA 277 (11): 915-9, 1997. [PUBMED Abstract]
  7. Gull B, Karlsson B, Milsom I, et al.: Can ultrasound replace dilation and curettage? A longitudinal evaluation of postmenopausal bleeding and transvaginal sonographic measurement of the endometrium as predictors of endometrial cancer. Am J Obstet Gynecol 188 (2): 401-8, 2003. [PUBMED Abstract]
  8. Fleischer AC, Wheeler JE, Lindsay I, et al.: An assessment of the value of ultrasonographic screening for endometrial disease in postmenopausal women without symptoms. Am J Obstet Gynecol 184 (2): 70-5, 2001. [PUBMED Abstract]
  9. Langer RD, Pierce JJ, O’Hanlan KA, et al.: Transvaginal ultrasonography compared with endometrial biopsy for the detection of endometrial disease. Postmenopausal Estrogen/Progestin Interventions Trial. N Engl J Med 337 (25): 1792-8, 1997. [PUBMED Abstract]
  10. Archer DF, McIntyre-Seltman K, Wilborn WW, et al.: Endometrial morphology in asymptomatic postmenopausal women. Am J Obstet Gynecol 165 (2): 317-20; discussion 320-2, 1991. [PUBMED Abstract]
  11. Fung MF, Reid A, Faught W, et al.: Prospective longitudinal study of ultrasound screening for endometrial abnormalities in women with breast cancer receiving tamoxifen. Gynecol Oncol 91 (1): 154-9, 2003. [PUBMED Abstract]
  12. Clarke MA, Long BJ, Del Mar Morillo A, et al.: Association of Endometrial Cancer Risk With Postmenopausal Bleeding in Women: A Systematic Review and Meta-analysis. JAMA Intern Med 178 (9): 1210-1222, 2018. [PUBMED Abstract]
  13. Duffy S, Jackson TL, Lansdown M, et al.: The ATAC adjuvant breast cancer trial in postmenopausal women: baseline endometrial subprotocol data. BJOG 110 (12): 1099-106, 2003. [PUBMED Abstract]
  14. Bradley WH, Boente MP, Brooker D, et al.: Hysteroscopy and cytology in endometrial cancer. Obstet Gynecol 104 (5 Pt 1): 1030-3, 2004. [PUBMED Abstract]
  15. Gumus II, Keskin EA, Kiliç E, et al.: Diagnostic value of hysteroscopy and hysterosonography in endometrial abnormalities in asymptomatic postmenopausal women. Arch Gynecol Obstet 278 (3): 241-4, 2008. [PUBMED Abstract]

Special Populations

Hormone Therapy

There is no evidence to suggest that screening women before or during estrogen-progestin therapy, also known as hormone therapy, would decrease endometrial cancer mortality.[1,2] Thus, women on hormone therapy should have a prompt diagnostic work-up for abnormal bleeding. Although women using certain hormone regimens have an increased risk of endometrial cancer, most women who develop cancer will have vaginal bleeding. There is no evidence that screening these women would decrease mortality from endometrial cancer.

Hereditary Nonpolyposis Colorectal Cancer

The lifetime risk of endometrial cancer for women with hereditary nonpolyposis colorectal cancer (HNPCC) and for women who are at high risk for HNPCC is as high as 60%. These cases are often diagnosed in the fifth decade, 10 to 20 years earlier than sporadic cases.[3–7] Based on limited evidence, it appears that 5-year survival among women with HNPCC diagnosed with endometrial cancer is similar to that of nonhereditary cases in the general population.[8] Because the risk of endometrial cancer is so high among these women, international guidelines suggest gynecologic surveillance including annual transvaginal ultrasound with endometrial biopsy for women aged 25 to 35 years.[9,10] The most recent American Cancer Society Cancer Detection Guidelines (updated January 2005) recommend annual screening with endometrial biopsy beginning at age 35 years.[11]

Women Treated With Tamoxifen

The risk of endometrial cancer is increased in women who are treated with tamoxifen and is even greater in the subset of women who have a history of prior estrogen therapy.[12] Beyond a routine gynecologic examination eliciting any history of abnormal bleeding, it has been recommended that screening studies and procedures for detecting endometrial pathology in women taking tamoxifen should be left to the discretion of the individual gynecologist.[13] Commonly, there are endometrial abnormalities in women taking tamoxifen, especially in false-positive endovaginal ultrasound screening tests. More importantly, any abnormal uterine bleeding should be completely evaluated.

Endometrial cancers that occur in tamoxifen-treated women are very similar to those cancers occurring in the general population, with respect to stage, grade, and histology.[14–16] Prognosis is good and not affected by early detection.[17]

There have been no published studies evaluating the effect of endometrial cancer-screening modalities on mortality among women taking tamoxifen for breast cancer treatment or prevention.

References
  1. ACOG committee opinion. Routine cancer screening. Number 185, September 1997 (replaces no. 128, October 1993). Committee on Gynecologic Practice. American College of Obstetricians and Gynecologists. Int J Gynaecol Obstet 59 (2): 157-61, 1997. [PUBMED Abstract]
  2. Korhonen MO, Symons JP, Hyde BM, et al.: Histologic classification and pathologic findings for endometrial biopsy specimens obtained from 2964 perimenopausal and postmenopausal women undergoing screening for continuous hormones as replacement therapy (CHART 2 Study). Am J Obstet Gynecol 176 (2): 377-80, 1997. [PUBMED Abstract]
  3. Watson P, Vasen HF, Mecklin JP, et al.: The risk of endometrial cancer in hereditary nonpolyposis colorectal cancer. Am J Med 96 (6): 516-20, 1994. [PUBMED Abstract]
  4. Aarnio M, Sankila R, Pukkala E, et al.: Cancer risk in mutation carriers of DNA-mismatch-repair genes. Int J Cancer 81 (2): 214-8, 1999. [PUBMED Abstract]
  5. Vasen HF, Wijnen JT, Menko FH, et al.: Cancer risk in families with hereditary nonpolyposis colorectal cancer diagnosed by mutation analysis. Gastroenterology 110 (4): 1020-7, 1996. [PUBMED Abstract]
  6. Dunlop MG, Farrington SM, Carothers AD, et al.: Cancer risk associated with germline DNA mismatch repair gene mutations. Hum Mol Genet 6 (1): 105-10, 1997. [PUBMED Abstract]
  7. Lancaster JM, Powell CB, Kauff ND, et al.: Society of Gynecologic Oncologists Education Committee statement on risk assessment for inherited gynecologic cancer predispositions. Gynecol Oncol 107 (2): 159-62, 2007. [PUBMED Abstract]
  8. Boks DE, Trujillo AP, Voogd AC, et al.: Survival analysis of endometrial carcinoma associated with hereditary nonpolyposis colorectal cancer. Int J Cancer 102 (2): 198-200, 2002. [PUBMED Abstract]
  9. Burke W, Petersen G, Lynch P, et al.: Recommendations for follow-up care of individuals with an inherited predisposition to cancer. I. Hereditary nonpolyposis colon cancer. Cancer Genetics Studies Consortium. JAMA 277 (11): 915-9, 1997. [PUBMED Abstract]
  10. Vasen HF, Mecklin JP, Khan PM, et al.: The International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer (ICG-HNPCC). Dis Colon Rectum 34 (5): 424-5, 1991. [PUBMED Abstract]
  11. Smith RA, Cokkinides V, Eyre HJ: American Cancer Society Guidelines for the Early Detection of Cancer, 2005. CA Cancer J Clin 55 (1): 31-44; quiz 55-6, 2005 Jan-Feb. [PUBMED Abstract]
  12. Barakat RR: Tamoxifen and endometrial neoplasia. Clin Obstet Gynecol 39 (3): 629-40, 1996. [PUBMED Abstract]
  13. ACOG committee opinion. Tamoxifen and endometrial cancer. Number 169, February 1996. Committee on Gynecologic Practice. American College of Obstetricians and Gynecologists. Int J Gynaecol Obstet 53 (2): 197-9, 1996. [PUBMED Abstract]
  14. Fisher B, Costantino JP, Wickerham DL, et al.: Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 90 (18): 1371-88, 1998. [PUBMED Abstract]
  15. Barakat RR, Wong G, Curtin JP, et al.: Tamoxifen use in breast cancer patients who subsequently develop corpus cancer is not associated with a higher incidence of adverse histologic features. Gynecol Oncol 55 (2): 164-8, 1994. [PUBMED Abstract]
  16. Fornander T, Hellström AC, Moberger B: Descriptive clinicopathologic study of 17 patients with endometrial cancer during or after adjuvant tamoxifen in early breast cancer. J Natl Cancer Inst 85 (22): 1850-5, 1993. [PUBMED Abstract]
  17. Barakat RR, Gilewski TA, Almadrones L, et al.: Effect of adjuvant tamoxifen on the endometrium in women with breast cancer: a prospective study using office endometrial biopsy. J Clin Oncol 18 (20): 3459-63, 2000. [PUBMED Abstract]

Evidence of Harms

Abnormal ultrasound typically requires further investigation including endometrial biopsy (sampling). The evidence is solid that endometrial sampling may result in discomfort, bleeding, infection, and rarely uterine perforation. A study designed to evaluate performance, patient acceptance, and cost-effectiveness of blind biopsy, hysteroscopy with biopsy, and ultrasound in 683 women with vaginal bleeding, reported that minor events, including discomfort and distress, occurred in 16% of women who had hysteroscopy with biopsy, and in 10% of the women who had a blind biopsy.[1] A group of researchers studied 13,600 diagnostic and operative hysteroscopic procedures and found a lower complication rate among diagnostic procedures (0.13%) compared with operative procedures (0.28%).[2] Risks associated with false-positive test results include anxiety and additional diagnostic testing and surgery. Endometrial cancers may be missed on endometrial sampling and ultrasound.

References
  1. Critchley HO, Warner P, Lee AJ, et al.: Evaluation of abnormal uterine bleeding: comparison of three outpatient procedures within cohorts defined by age and menopausal status. Health Technol Assess 8 (34): iii-iv, 1-139, 2004. [PUBMED Abstract]
  2. Jansen FW, Vredevoogd CB, van Ulzen K, et al.: Complications of hysteroscopy: a prospective, multicenter study. Obstet Gynecol 96 (2): 266-70, 2000. [PUBMED Abstract]

Latest Updates to This Summary (04/10/2025)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Significance

Updated statistics with estimated new cases and deaths for 2025 (cited American Cancer Society as reference 1). Also revised text to state that between 2013 and 2022, death rates for endometrial cancer increased by 1.5% per year.

This summary is written and maintained by the PDQ Screening and Prevention Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about endometrial cancer screening. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Screening and Prevention Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

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Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Screening and Prevention Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

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PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”

The preferred citation for this PDQ summary is:

PDQ® Screening and Prevention Editorial Board. PDQ Endometrial Cancer Screening. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/uterine/hp/endometrial-screening-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389229]

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Genetics of Prostate Cancer (PDQ®)–Health Professional Version

Genetics of Prostate Cancer (PDQ®)–Health Professional Version

Executive Summary

This executive summary reviews the topics covered in Genetics of Prostate Cancer and provides hyperlinks to detailed sections that describe available evidence on each topic.

  • Introduction

    Prostate cancer is highly heritable. Up to 60% of prostate cancer risk is caused by inherited factors. This inherited risk is comprised of risk from common genetic variants and risk from pathogenic variants in moderate-risk and high-risk genes.

  • Risk Factors for Prostate Cancer

    Risk factors for prostate cancer include age, a family history of prostate cancer and other cancers, genetics, and ancestry (such as West African ancestry).

  • Risk Assessment for Prostate Cancer

    Risk assessment for prostate cancer primarily includes intake of an individual’s personal cancer history, family cancer history, and ancestry. These factors are then incorporated into recommendations for prostate cancer screening.

  • Indications for Prostate Cancer Germline Genetic Testing

    Hereditary prostate cancer genetic testing criteria are based on one or more of the following: an individual’s family history and/or genetic test results, personal/disease characteristics, and tumor sequencing results. Criteria for prostate cancer genetic testing vary based on current guidelines and expert opinion.

  • Genetic Testing Approach for Prostate Cancer

    Since next-generation sequencing (NGS) has become readily available and patent restrictions have been eliminated, several clinical laboratories offer multigene panel testing at a cost that is comparable to that of single-gene testing.

  • Germline Genetics for Prostate Cancer

    The bulk of inherited prostate cancer risk is conferred by hundreds of genetic polymorphisms, which are common in the general population. Each of these polymorphisms provides a slight increase in prostate cancer risk. For a subset of individuals, prostate cancer risk is caused by rare, deleterious variants located in specific genes.

  • Prostate Cancer Genetics: Screening, Surveillance, and Treatment

    This section focuses on the impacts of genetics on prostate cancer screening, surveillance, and treatment. Genetic test results are increasingly driving targeted therapy options and strategies for treatment in oncology.

Introduction

Prostate cancer is highly heritable. Up to 60% of prostate cancer risk is caused by inherited factors.[1,2] The inherited risk is comprised of risk from common genetic variants and risk from pathogenic variants in moderate-risk and high-risk genes. As with breast and colon cancers, familial clustering of prostate cancer has been reported frequently.[3]

Prostate cancer clusters with particular intensity in some families. Highly to moderately penetrant genetic variants are thought to be associated with prostate cancer risk in these families. Members of these families may benefit from genetic counseling. Additionally, polygenic risk scores derived from combinations of single nucleotide polymorphisms, in addition to other risk factors like family history, race, and age/stage of prostate cancer diagnosis, have also been developed.[4,5] Recommendations and guidelines for genetic counseling referrals are based on an individual’s age at prostate cancer diagnosis, prostate cancer stage at diagnosis, and specific patterns of cancer in the family history.[6,7] However, uptake of genetic testing based on an individual’s family history of prostate cancer and/or a diagnosis of prostate cancer is variably implemented across practice settings and geographical regions.[8–10] For more information about genetic testing criteria for prostate cancer, see Table 2.

References
  1. Houlahan KE, Livingstone J, Fox NS, et al.: A polygenic two-hit hypothesis for prostate cancer. J Natl Cancer Inst 115 (4): 468-472, 2023. [PUBMED Abstract]
  2. Mucci LA, Hjelmborg JB, Harris JR, et al.: Familial Risk and Heritability of Cancer Among Twins in Nordic Countries. JAMA 315 (1): 68-76, 2016. [PUBMED Abstract]
  3. Seibert TM, Garraway IP, Plym A, et al.: Genetic Risk Prediction for Prostate Cancer: Implications for Early Detection and Prevention. Eur Urol 83 (3): 241-248, 2023. [PUBMED Abstract]
  4. Pagadala MS, Lynch J, Karunamuni R, et al.: Polygenic risk of any, metastatic, and fatal prostate cancer in the Million Veteran Program. J Natl Cancer Inst 115 (2): 190-199, 2023. [PUBMED Abstract]
  5. Huynh-Le MP, Karunamuni R, Fan CC, et al.: Prostate cancer risk stratification improvement across multiple ancestries with new polygenic hazard score. Prostate Cancer Prostatic Dis 25 (4): 755-761, 2022. [PUBMED Abstract]
  6. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic. Version 2.2024. Plymouth Meeting, Pa: National Comprehensive Cancer Network, 2023. Available online with free registration. Last accessed September 18, 2024.
  7. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer Early Detection. Version 2.2023. Plymouth Meeting, Pa: National Comprehensive Cancer Network, 2023. Available online with free registration. Last accessed November 30, 2023.
  8. Clark NM, Flanagan MR: ASO Author Reflections: Low Genetic Testing Utilization Among Patients with Breast, Ovarian, Pancreatic, and Prostate Cancers. Ann Surg Oncol 30 (3): 1327-1328, 2023. [PUBMED Abstract]
  9. Giri VN, Morgan TM, Morris DS, et al.: Genetic testing in prostate cancer management: Considerations informing primary care. CA Cancer J Clin 72 (4): 360-371, 2022. [PUBMED Abstract]
  10. Russo J, Giri VN: Germline testing and genetic counselling in prostate cancer. Nat Rev Urol 19 (6): 331-343, 2022. [PUBMED Abstract]

Risk Factors for Prostate Cancer

Age

Prostate cancer risk correlates with age. Prostate cancer is rarely seen in men younger than 40 years. The incidence rises rapidly with each decade thereafter. For example, the probability of being diagnosed with prostate cancer is 1 in 468 for men aged 49 years or younger, 1 in 26 for men aged 50 through 64 years, 1 in 9 for men aged 65 through 84 years, and 1 in 31 for men aged 85 years and older. Lifetime risk of developing prostate cancer is 1 in 8.[1] Approximately 10% of prostate cancer cases are diagnosed in men younger than 56 years and represent early-onset prostate cancer. Data from the Surveillance, Epidemiology, and End Results (SEER) Program show that early-onset prostate cancer diagnosis rates are increasing, and there is evidence that cases may be more aggressive in this subpopulation.[2]

Ancestry

The risk of developing prostate cancer is dramatically higher in Black American individuals, who predominantly have West African ancestry (191.5 cases/100,000 men) when compared with other racial and ethnic groups in the United States:

  • White: 114.5 cases/100,000 men.
  • Asian American or Pacific Islander: 63.1 cases/100,000 men.
  • American Indian or Alaska Native: 99.1 cases/100,000 men.
  • Hispanic or Latino: 92.9 cases/100,000 men.[1]

Prostate cancer mortality rates in Black individuals (37.2 deaths/100,000 men) are higher than those in other racial and ethnic groups in the United States:

  • White: 18.1 deaths/100,000 men.
  • Asian American or Pacific Islander: 8.8 deaths/100,000 men.
  • American Indian or Alaska Native: 21.2 deaths/100,000 men.
  • Hispanic or Latino: 15.4 deaths/100,000 men.[1]

Globally, prostate cancer incidence and mortality rates also vary widely from country to country.[3] The etiology of this variation in prostate cancer risk is likely multifactorial and may be due to biological factors, access to health care, and other social determinants of health.[4,5]

Family History of Prostate Cancer and Other Cancers

Results from several large case-control studies and cohort studies representing various populations suggest that family history is a major risk factor in prostate cancer.[6–10] A family history of a brother or father with prostate cancer increases the risk of prostate cancer, and the risk is inversely related to the age of the affected relative.[7,8,11–13] Risk is increased when a first-degree relative (FDR) was diagnosed with prostate cancer before age 65 years.

A meta-analysis of 33 epidemiological case-control and cohort-based studies has provided detailed information regarding risk ratios related to family history of prostate cancer (for more information, see Table 1).[14]

Table 1. Relative Risk (RR) Related to Family History of Prostate Cancera
Risk Group RR for Prostate Cancer (95% CI)
CI = confidence interval; FDR = first-degree relative.
aAdapted from Kiciński et al.[14]
Brother(s) with prostate cancer diagnosed at any age 3.14 (2.37–4.15)
Father with prostate cancer diagnosed at any age 2.35 (2.02–2.72)
One affected FDR diagnosed at any age 2.48 (2.25–2.74)
Affected FDRs diagnosed <65 y 2.87 (2.21–3.74)
Affected FDRs diagnosed ≥65 y 1.92 (1.49–2.47)
Second-degree relatives diagnosed at any age 2.52 (0.99–6.46)
Two or more affected FDRs diagnosed at any age 4.39 (2.61–7.39)

A family history of breast cancer is also associated with increased prostate cancer risk. In the Health Professionals Follow-up Study (HPFS), comprising over 40,000 men, those with a family history of breast cancer had a 21% higher risk of developing prostate cancer overall and a 34% increased risk of developing a lethal form of prostate cancer.[10] This is consistent with findings from previous cohorts,[15] though, notably, not all series have detected this association.[16,17] The HPFS and other studies have also shown that men with a family history of both prostate and breast/ovarian cancers were at an even higher risk of prostate cancer compared with men with a family history of either prostate or breast/ovarian cancer alone.[10,16] A proportion of the increased prostate cancer risk associated with family history of breast cancer is likely due to pathogenic variants in the DNA damage repair pathway, most commonly BRCA2.[18–21] For more information, see the BRCA1 and BRCA2 section. The association between prostate and breast cancers in families appears bidirectional. Among women, a family history of prostate cancer is likewise associated with increased risk of breast cancer.[22,23]

An association also exists between prostate cancer risk and colon cancer. Men with germline variants in DNA mismatch repair genes are at increased risk of developing prostate cancer.[24] One study reported an approximately twofold increased risk of prostate cancer among first- and second-degree relatives of probands with colorectal cancer meeting Amsterdam I or Amsterdam II criteria for Lynch syndrome.[25] For more information on Amsterdam criteria, see the Defining Lynch syndrome families section in Genetics of Colorectal Cancer.

Family history has been shown to be a risk factor for men of different races and ethnicities. In a population-based case-control study of prostate cancer among African American, White, and Asian American individuals in the United States (Los Angeles, San Francisco, and Hawaii) and Canada (Vancouver and Toronto),[26] 5% of controls and 13% of all cases reported a father, brother, or son with prostate cancer. These prevalence estimates were somewhat lower among Asian American individuals than among African American or White individuals. A positive family history was associated with a twofold to threefold increase in relative risk (RR) in each of the three ethnic groups. The overall odds ratio (OR) associated with a family history of prostate cancer was 2.5 (95% confidence interval [CI], 1.9–3.3) with adjustment for age and ethnicity.[26]

Evidence shows that a family history of prostate cancer can be associated with inferior clinical outcomes. When patients were referred for prostate biopsy (typically due to elevated prostate-specific antigen [PSA]), men with a family history of the disease were at increased risk for high-grade prostate cancer when compared with patients without a family history.[27] A large population-based study from Utah reported that men with either of the following were at an increased risk for early-onset prostate cancer: 1) three or more FDRs diagnosed with prostate cancer, or 2) two or more FDRs or second-degree relatives with prostate cancer.[28]

Genetics

There are multiple germline pathogenic variants and single nucleotide variants that are associated with prostate cancer risk. For more information about these genetic variants, see the National Human Genome Research Institute’s GWAS catalog. Germline genetic testing may be indicated to assess prostate cancer risk and/or inform therapeutic decision-making in men diagnosed with prostate cancer. Prostate cancer risks vary depending on the specific gene and pathogenic variant involved.[29] Prostate cancer heritability (when considering low, moderate, and high-penetrant genetic factors) can be as high 57% (95% CI, 51%–63%).[30] Genetic variants that contribute to this risk are continuously being identified.[28] Prostate cancer heritability rates may also vary in different racial and ethnic populations.[31] For more information, see the Germline Genetics for Prostate Cancer section.

References
  1. American Cancer Society: Cancer Facts and Figures 2025. American Cancer Society, 2025. Available online. Last accessed January 16, 2025.
  2. Salinas CA, Tsodikov A, Ishak-Howard M, et al.: Prostate cancer in young men: an important clinical entity. Nat Rev Urol 11 (6): 317-23, 2014. [PUBMED Abstract]
  3. Sung H, Ferlay J, Siegel RL, et al.: Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 71 (3): 209-249, 2021. [PUBMED Abstract]
  4. Krimphove MJ, Cole AP, Fletcher SA, et al.: Evaluation of the contribution of demographics, access to health care, treatment, and tumor characteristics to racial differences in survival of advanced prostate cancer. Prostate Cancer Prostatic Dis 22 (1): 125-136, 2019. [PUBMED Abstract]
  5. Fletcher SA, Marchese M, Cole AP, et al.: Geographic Distribution of Racial Differences in Prostate Cancer Mortality. JAMA Netw Open 3 (3): e201839, 2020. [PUBMED Abstract]
  6. Carter BS, Beaty TH, Steinberg GD, et al.: Mendelian inheritance of familial prostate cancer. Proc Natl Acad Sci U S A 89 (8): 3367-71, 1992. [PUBMED Abstract]
  7. Grönberg H, Damber L, Damber JE: Familial prostate cancer in Sweden. A nationwide register cohort study. Cancer 77 (1): 138-43, 1996. [PUBMED Abstract]
  8. Cannon L, Bishop DT, Skolnick M, et al.: Genetic epidemiology of prostate cancer in the Utah Mormon genealogy. Cancer Surv 1 (1): 47-69, 1982.
  9. Saarimäki L, Tammela TL, Määttänen L, et al.: Family history in the Finnish Prostate Cancer Screening Trial. Int J Cancer 136 (9): 2172-7, 2015. [PUBMED Abstract]
  10. Barber L, Gerke T, Markt SC, et al.: Family History of Breast or Prostate Cancer and Prostate Cancer Risk. Clin Cancer Res 24 (23): 5910-5917, 2018. [PUBMED Abstract]
  11. Ghadirian P, Howe GR, Hislop TG, et al.: Family history of prostate cancer: a multi-center case-control study in Canada. Int J Cancer 70 (6): 679-81, 1997. [PUBMED Abstract]
  12. Stanford JL, Ostrander EA: Familial prostate cancer. Epidemiol Rev 23 (1): 19-23, 2001. [PUBMED Abstract]
  13. Matikaine MP, Pukkala E, Schleutker J, et al.: Relatives of prostate cancer patients have an increased risk of prostate and stomach cancers: a population-based, cancer registry study in Finland. Cancer Causes Control 12 (3): 223-30, 2001. [PUBMED Abstract]
  14. Kiciński M, Vangronsveld J, Nawrot TS: An epidemiological reappraisal of the familial aggregation of prostate cancer: a meta-analysis. PLoS One 6 (10): e27130, 2011. [PUBMED Abstract]
  15. Cerhan JR, Parker AS, Putnam SD, et al.: Family history and prostate cancer risk in a population-based cohort of Iowa men. Cancer Epidemiol Biomarkers Prev 8 (1): 53-60, 1999. [PUBMED Abstract]
  16. Kalish LA, McDougal WS, McKinlay JB: Family history and the risk of prostate cancer. Urology 56 (5): 803-6, 2000. [PUBMED Abstract]
  17. Damber L, Grönberg H, Damber JE: Familial prostate cancer and possible associated malignancies: nation-wide register cohort study in Sweden. Int J Cancer 78 (3): 293-7, 1998. [PUBMED Abstract]
  18. Agalliu I, Karlins E, Kwon EM, et al.: Rare germline mutations in the BRCA2 gene are associated with early-onset prostate cancer. Br J Cancer 97 (6): 826-31, 2007. [PUBMED Abstract]
  19. Edwards SM, Kote-Jarai Z, Meitz J, et al.: Two percent of men with early-onset prostate cancer harbor germline mutations in the BRCA2 gene. Am J Hum Genet 72 (1): 1-12, 2003. [PUBMED Abstract]
  20. Ford D, Easton DF, Bishop DT, et al.: Risks of cancer in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Lancet 343 (8899): 692-5, 1994. [PUBMED Abstract]
  21. Gayther SA, de Foy KA, Harrington P, et al.: The frequency of germ-line mutations in the breast cancer predisposition genes BRCA1 and BRCA2 in familial prostate cancer. The Cancer Research Campaign/British Prostate Group United Kingdom Familial Prostate Cancer Study Collaborators. Cancer Res 60 (16): 4513-8, 2000. [PUBMED Abstract]
  22. Beebe-Dimmer JL, Yee C, Cote ML, et al.: Familial clustering of breast and prostate cancer and risk of postmenopausal breast cancer in the Women’s Health Initiative Study. Cancer 121 (8): 1265-72, 2015. [PUBMED Abstract]
  23. Sellers TA, Potter JD, Rich SS, et al.: Familial clustering of breast and prostate cancers and risk of postmenopausal breast cancer. J Natl Cancer Inst 86 (24): 1860-5, 1994. [PUBMED Abstract]
  24. Dominguez-Valentin M, Sampson JR, Seppälä TT, et al.: Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database. Genet Med 22 (1): 15-25, 2020. [PUBMED Abstract]
  25. Samadder NJ, Smith KR, Wong J, et al.: Cancer Risk in Families Fulfilling the Amsterdam Criteria for Lynch Syndrome. JAMA Oncol 3 (12): 1697-1701, 2017. [PUBMED Abstract]
  26. Whittemore AS, Wu AH, Kolonel LN, et al.: Family history and prostate cancer risk in black, white, and Asian men in the United States and Canada. Am J Epidemiol 141 (8): 732-40, 1995. [PUBMED Abstract]
  27. Clements MB, Vertosick EA, Guerrios-Rivera L, et al.: Defining the Impact of Family History on Detection of High-grade Prostate Cancer in a Large Multi-institutional Cohort. Eur Urol 82 (2): 163-169, 2022. [PUBMED Abstract]
  28. Beebe-Dimmer JL, Kapron AL, Fraser AM, et al.: Risk of Prostate Cancer Associated With Familial and Hereditary Cancer Syndromes. J Clin Oncol 38 (16): 1807-1813, 2020. [PUBMED Abstract]
  29. Seibert TM, Garraway IP, Plym A, et al.: Genetic Risk Prediction for Prostate Cancer: Implications for Early Detection and Prevention. Eur Urol 83 (3): 241-248, 2023. [PUBMED Abstract]
  30. Mucci LA, Hjelmborg JB, Harris JR, et al.: Familial Risk and Heritability of Cancer Among Twins in Nordic Countries. JAMA 315 (1): 68-76, 2016. [PUBMED Abstract]
  31. Bree KK, Hensley PJ, Pettaway CA: Germline Predisposition to Prostate Cancer in Diverse Populations. Urol Clin North Am 48 (3): 411-423, 2021. [PUBMED Abstract]

Risk Assessment for Prostate Cancer

Risk assessment for prostate cancer primarily involves the intake of a patient’s family cancer history. Family history intake includes the following:

  • Information about cancers* in male and female blood relatives on maternal and paternal sides of the family.
  • Ages at cancer diagnoses.
  • Ages of death from cancer.
  • The number of relatives with metastatic prostate cancer.
  • The number of relatives who died of prostate cancer.
  • Information on relatives who are undergoing cancer screening, if known.

*Cancers include, but are not limited to, the following: prostate, breast, pancreas, colorectal, uterine, ovarian, upper gastrointestinal (GI), and skin cancers.

Ancestry is also an important component of the family history. Ashkenazi Jewish ancestry on either side of the family may prompt greater suspicion for founder pathogenic variants in BRCA1 and BRCA2, which could lead to increased cancer risk in a family. Men of African descent (Black men) also have a higher risk for prostate cancer. Within the United States, Black men (191.5 cases/100,000 men) have approximately a 67% higher incidence rate of prostate cancer than White men (114.5 cases/100,000 men).[1] Black men also have more than twice the rate of prostate cancer–specific death (37.2 deaths/100,000 men) than White men (18.1 deaths/100,000 men).[1] This increased prostate cancer risk may be due to challenges, including the following: 1) access to care, 2) limited awareness of prostate cancer screening programs, 3) limited engagement in prostate cancer screening/genetic testing, and 4) the presence of specific genetic markers that can increase prostate cancer risk.[2–6]

These familial risk factors are then incorporated into recommendations for prostate cancer screening. National guidelines recommend discussing prostate cancer screening with prostate-specific antigen (PSA) and digital rectal exam between the ages of 45 and 75 years for individuals at average risk for prostate cancer.

In contrast, prostate cancer screening is recommended to start at age 40 years for individuals in these high-risk groups:

Men of Black/African descent.

Men with germline pathogenic variants that increase prostate cancer risk.

Men who have family histories with features suggestive of hereditary cancer syndromes like the following:

  • Hereditary breast and ovarian cancer syndrome: Family members with ovarian cancer, pancreatic cancer, metastatic/high-risk prostate cancer, male breast cancer, and/or breast cancer diagnosed at or before age 50 years.
  • Lynch syndrome: Family members with colorectal or endometrial cancer diagnosed at or before age 50 years, ovarian cancer, pancreatic cancer, urothelial cancer, and/or upper GI cancer.
  • Hereditary prostate cancer: Multiple generations with prostate cancer, deaths from prostate cancer, and/or family members with metastatic prostate cancer.[4–6]

The role of additional markers, such as polygenic risk scores, in prostate cancer risk assessment is evolving. Additional screening strategies, like multiparametric magnetic resonance imaging (mpMRI), are also being studied.

References
  1. American Cancer Society: Cancer Facts and Figures 2025. American Cancer Society, 2025. Available online. Last accessed January 16, 2025.
  2. Liadi Y, Campbell T, Dike P, et al.: Prostate cancer metastasis and health disparities: a systematic review. Prostate Cancer Prostatic Dis 27 (2): 183-191, 2024. [PUBMED Abstract]
  3. Nair SS, Chakravarty D, Dovey ZS, et al.: Why do African-American men face higher risks for lethal prostate cancer? Curr Opin Urol 32 (1): 96-101, 2022. [PUBMED Abstract]
  4. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic. Version 2.2024. Plymouth Meeting, Pa: National Comprehensive Cancer Network, 2023. Available online with free registration. Last accessed September 18, 2024.
  5. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer Early Detection. Version 2.2023. Plymouth Meeting, Pa: National Comprehensive Cancer Network, 2023. Available online with free registration. Last accessed November 30, 2023.
  6. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer. Version 4.2023. Plymouth Meeting, Pa: National Comprehensive Cancer Network, 2023. Available online with free registration. Last accessed November 30, 2023.

Indications for Prostate Cancer Germline Genetic Testing

The criteria for consideration of genetic testing for prostate cancer varies depending on the current guidelines and expert opinion consensus, as summarized in Table 2.[1–5] Hereditary prostate cancer genetic testing criteria are based on an individual’s family history, personal/disease characteristics, and tumor sequencing results. The genes recommended for genetic testing vary based on national guidelines and consensus conference recommendations. Precision therapy has emerged as a major driver for germline genetic testing and may be a separate reason to pursue testing beyond the criteria stated in Table 2. The National Comprehensive Cancer Network (NCCN) Prostate Cancer guidelines recommend testing for at least BRCA1, BRCA2, ATM, CHEK2, PALB2, HOXB13, MLH1, MSH2, MSH6, and PMS2 for men meeting specific testing indications.[4] A consensus conference in 2019 addressed the role of genetic testing for inherited prostate cancer.[6] Family history–based indications for genetic testing included testing for BRCA1/BRCA2, HOXB13, DNA mismatch repair (MMR) genes, and ATM. Tumor sequencing that identifies variants that may be germline in origin, like variants in BRCA1/BRCA2, DNA MMR genes, or ATM and other genes, warrants confirmatory germline testing. Somatic findings for which germline testing is considered include the following:

  • Somatic variants that are associated with germline susceptibility.
  • Hypermutated tumors, which are indicative of DNA MMR.
  • Chromosome rearrangements in specific tumors.
  • High-variant allele frequency (percent of sequence reads that have the identified variant). Variant allele frequency can be altered for reasons not associated with germline variants such as loss of heterozygosity, ploidy (copy number variants), tumor heterogeneity, and tumor sample purity.[7]

It is recommended that germline genetic testing candidates undergo genetic education and counseling before participating in testing. Genetic counseling provides information about genetic testing and possible testing outcomes (including risks, benefits, limitations, and familial, psychological, and health care–based implications that vary depending on results). Genetic education and counseling help individuals make informed decisions about whether they should undergo germline genetic testing. For more information on genetic education and genetic counseling, see Cancer Genetics Risk Assessment and Counseling.

Table 2. Indications for Prostate Cancer Genetic Testing
  Philadelphia Prostate Cancer Consensus Conference (Giri et al. 2020)a [6] Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic (Version 2.2024)b [3] NCCN Prostate Cancer (Version 4.2023)c [4] European Advanced Prostate Cancer Consensus Conference (Gillessen et al. 2017 [2] and Gillessen 2020 [8])d
dMMR = mismatch repair deficient; FDR = first-degree relative; HBOC = hereditary breast and ovarian cancer; MMR = mismatch repair; MSI = microsatellite instability; NCCN = National Comprehensive Cancer Network; SDR= second-degree relative; TDR= third-degree relative.
aGiri et al.: Specific genes to test include BRCA1/BRCA2, DNA MMR genes, ATM, and HOXB13 depending on various testing indications.
bNCCN Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic guidelines state that prostate cancer risk management is indicated for BRCA1 and BRCA2 carriers, but evidence for risk management is insufficient for other genes.
cNCCN Prostate Cancer guidelines specify that germline multigene testing includes at least the following genes: BRCA1, BRCA2, ATM, PALB2, CHEK2, MLH1, MSH2, MSH6, and PMS2. Including additional genes may be appropriate based on clinical context.
dGillessen et al. endorsed the use of large panel testing including homologous recombination and DNA MMR genes.
Family History Criteria All men with prostate cancer from families meeting established testing or syndromic criteria for HBOC, hereditary prostate cancer, or Lynch syndrome Men affected with prostate cancer who have a family history of the following: ≥1 FDR, SDR, or TDR (on the same side of the family) with breast cancer at age ≤50 y or with any of the following: triple-negative breast cancer, ovarian cancer, pancreatic cancer, high- or very-high-risk prostate cancer, male breast cancer, or metastatic prostate cancer at any age Men affected with prostate cancer who have the following: ≥1 FDR, SDR, or TDR (on the same side of the family) with breast cancer at age ≤50 y, colorectal or endometrial cancer at age ≤50 y, male breast cancer at any age, ovarian cancer at any age, exocrine pancreatic cancer at any age, or metastatic, regional, very-high-risk, high-risk prostate cancer at any age Men with a positive family history of prostate cancer [2]
Men affected with prostate cancer who have >2 close biological relatives with a cancer associated with HBOC, hereditary prostate cancer, or Lynch syndrome Men affected with prostate cancer who have ≥3 FDRs, SDRs, or TDRs (on the same side of the family) with breast cancer or prostate cancer (any grade) at any age Men affected with prostate cancer who have ≥1 FDR with prostate cancer at age ≤60 y (exclude relatives with clinically localized Grade Group 1 disease) Men with a positive family history of other cancer syndromes (HBOC and/or pancreatic cancer and/or Lynch syndrome) [2]
Men with an FDR who was diagnosed with prostate cancer at <60 y Men with or without prostate cancer with an FDR who meets any of the criteria listed above (except when a man without prostate cancer has relatives who meet the above criteria solely for systemic therapy decision-making; these criteria may also be extended to an affected TDR if he/she is related to the patient through two male relatives) Men affected with prostate cancer who have ≥2 FDRs, SDRs, or TDRs (on the same side of the family) with breast cancer or prostate cancer at any age (exclude relatives with clinically localized Grade Group 1 disease)  
Men with relatives who died of prostate cancer   Men affected with prostate cancer who have ≥3 FDRs or SDRs (on the same side of the family) with the following Lynch syndrome-related cancers, especially if diagnosed at age <50 y: colorectal, endometrial, gastric, ovarian, exocrine pancreas, upper tract urothelial, glioblastoma, biliary tract, and small intestine  
Men with a metastatic prostate cancer in an FDR      
Consider genetic testing in men with prostate cancer and Ashkenazi Jewish ancestry Men with prostate cancer and Ashkenazi Jewish ancestry Men with prostate cancer and Ashkenazi Jewish ancestry  
    Men with prostate cancer and a known family history of a pathogenic or likely pathogenic variant in one of the following genes: BRCA1, BRCA2, ATM, PALB2, CHEK2, MLH1, MSH2, MSH6, PMS2, or EPCAM  
Clinical/Pathological Features Men with metastatic prostate cancer Men with metastatic prostate cancer Men with metastatic prostate cancer Men with newly diagnosed metastatic prostate cancer (62% of panel voted in favor of genetic counseling/testing in a minority of selected patients) [8]
Men with stage T3a or higher prostate cancer Men with high- or very-high-risk prostate cancer Men with high-risk prostate cancer, very-high-risk prostate cancer, high-risk localized prostate cancer, or regional (node-positive) prostate cancer  
Men with prostate cancer that has intraductal/ductal histology Testing may be considered in men who have intermediate-risk prostate cancer with intraductal/cribriform histology at any age Germline testing may be considered in men who have intermediate-risk prostate cancer with intraductal/cribriform histology at any age  
    Germline testing may be considered in men with prostate cancer AND a prior personal history of any of the following cancers: exocrine pancreatic, colorectal, gastric, melanoma, upper tract urothelial, glioblastoma, biliary tract, and small intestinal Men with prostate cancer diagnosed at age <60 y [2]
Tumor Sequencing Characteristics Men with prostate cancer whose somatic testing reveals the possibility of a germline variant in a cancer risk gene, especially BRCA2, BRCA1, ATM, and DNA MMR genes Men with a pathogenic variant found on tumor genomic testing that may have clinical implications if it is also identified in the germline Recommend tumor testing for pathogenic variants in homologous recombination genes in men with metastatic disease; consider tumor testing in men with regional prostate cancer  
    Recommend MSI-high or dMMR tumor testing in men with metastatic castration-resistant prostate cancer; consider testing in men with regional or castration-sensitive metastatic prostate cancer  
References
  1. Giri VN, Knudsen KE, Kelly WK, et al.: Role of Genetic Testing for Inherited Prostate Cancer Risk: Philadelphia Prostate Cancer Consensus Conference 2017. J Clin Oncol 36 (4): 414-424, 2018. [PUBMED Abstract]
  2. Gillessen S, Attard G, Beer TM, et al.: Management of Patients with Advanced Prostate Cancer: The Report of the Advanced Prostate Cancer Consensus Conference APCCC 2017. Eur Urol 73 (2): 178-211, 2018. [PUBMED Abstract]
  3. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic. Version 2.2024. Plymouth Meeting, Pa: National Comprehensive Cancer Network, 2023. Available online with free registration. Last accessed September 18, 2024.
  4. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer. Version 4.2023. Plymouth Meeting, Pa: National Comprehensive Cancer Network, 2023. Available online with free registration. Last accessed November 30, 2023.
  5. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer Early Detection. Version 2.2023. Plymouth Meeting, Pa: National Comprehensive Cancer Network, 2023. Available online with free registration. Last accessed November 30, 2023.
  6. Giri VN, Knudsen KE, Kelly WK, et al.: Implementation of Germline Testing for Prostate Cancer: Philadelphia Prostate Cancer Consensus Conference 2019. J Clin Oncol 38 (24): 2798-2811, 2020. [PUBMED Abstract]
  7. Raymond VM, Gray SW, Roychowdhury S, et al.: Germline Findings in Tumor-Only Sequencing: Points to Consider for Clinicians and Laboratories. J Natl Cancer Inst 108 (4): , 2016. [PUBMED Abstract]
  8. Gillessen S, Attard G, Beer TM, et al.: Management of Patients with Advanced Prostate Cancer: Report of the Advanced Prostate Cancer Consensus Conference 2019. Eur Urol 77 (4): 508-547, 2020. [PUBMED Abstract]

Genetic Testing Approach for Prostate Cancer

Since next-generation sequencing (NGS) has become readily available and patent restrictions have been eliminated, several clinical laboratories offer multigene panel testing at a cost that is comparable to that of single-gene testing. Three types of genetic test results can be reported: 1) pathogenic/likely pathogenic variants, 2) variants of uncertain significance (VUS), or 3) negative results. Patients need pretest genetic counseling or informed consent to understand germline genetic testing results. For example, patients should understand that VUS can be reported, that VUS do not immediately impact care/inform cancer risk, and that VUS may be reclassified as either pathogenic/likely pathogenic or benign/likely benign when more data are acquired. For more information on genetic counseling considerations and research associated with multigene testing, see the Multigene (panel) testing section in Cancer Genetics Risk Assessment and Counseling.

Germline Genetics for Prostate Cancer

Prostate cancer is highly heritable. More than half of an individual’s prostate cancer risk is inherited from one’s parents.[1] Considerable work has been performed to identify and characterize inherited germline variants that contribute to the genetic portion of prostate cancer risk. For most patients, the bulk of inherited risk is conferred by hundreds of genetic polymorphisms, which are common in the general population. Each of these polymorphisms slightly increases prostate cancer risk. For a small subset of patients, prostate cancer risk is generated by rare, deleterious variants located in specific genes. In this section, we will describe the specific genes implicated in inherited prostate cancer risk and the many common polymorphisms (which are typically located in the genomic space between genes) that create a risk profile for most patients.

EnlargeGraph shows relative risk on the x-axis and allele frequency on the y-axis. A line depicts the general finding of a low relative risk associated with common, low-penetrance genetic variants and a higher relative risk associated with rare, high-penetrance genetic variants.
Genetic architecture of cancer risk. This graph depicts the general finding of a low relative risk associated with common, low-penetrance genetic variants, such as single-nucleotide polymorphisms identified in genome-wide association studies, and a higher relative risk associated with rare, high-penetrance genetic variants, such as mutations in the BRCA1/ BRCA2 genes associated with hereditary breast and ovarian cancer and the mismatch repair genes associated with Lynch syndrome.

Clinically Relevant Genes for Prostate Cancer

BRCA1 and BRCA2

Studies of male carriers of BRCA1 and BRCA2 pathogenic variants demonstrate that these individuals have a higher risk of prostate cancer and other cancers.[2,3] Prostate cancer, in particular, has been observed at higher rates in male carriers of BRCA2 pathogenic variants than in the general population.[4] For more information about BRCA1 and BRCA2 pathogenic variants, see BRCA1 and BRCA2: Cancer Risks and Management.

BRCA–associated prostate cancer risk

The risk of prostate cancer in carriers of BRCA pathogenic variants has been studied in various settings.

In an effort to clarify the relationship between BRCA pathogenic variants and prostate cancer risk, findings from a systematic review and meta-analysis are summarized in Table 3 .

Table 3. BRCA Pathogenic Variants in Prostate Cancera
Population Number of Studies Fixed-Effect Pooled Prostate Cancer RR (95% CI) Random-Effect Pooled Prostate Cancer RR (95% CI) I2
CI = confidence interval; RR = relative risk.
aAdapted from Nyberg et al.
BRCA1
All 20 1.57 (1.30–1.91) 1.69 (1.30–2.20) 30%
Unselected for age, aggressive prostate cancer, or prostate cancer family history 15 1.43 (1.71–1.75) 1.47 (1.13–1.91) 25%
Unselected for age, aggressive prostate cancer, or prostate cancer family history and did not use historical controls 13 1.32 (1.07–1.64) 1.33 (1.05–1.69) 8%
Prostate cancer diagnosed <65 y 4 2.21 (1.47–3.30) 2.19 (1.21–3.98) 57%
Prostate cancer diagnosed >65 y 3 1.18 (0.83–1.70) 1.43 (0.71–2.87) 65%
BRCA2
All 21 5.24 (4.63–5.49) 3.94 (2.79–5.56) 83%
Unselected for age, aggressive prostate cancer, or prostate cancer family history 15 3.87 (3.34–4.47) 3.33 (2.57–4.33) 58%
Prostate cancer diagnosed <65 y 5 6.37 (4.81–8.43) 5.28 (3.10–9.00) 63%
Prostate cancer diagnosed >65 y 3 3.74 (2.82–4.96) 3.74 (2.82–4.96) 0%
Prevalence of BRCA founder pathogenic variants in men with prostate cancer
Ashkenazi Jewish population

Several studies in Israel and in North America have analyzed the frequency of BRCA founder pathogenic variants among Ashkenazi Jewish (AJ) men with prostate cancer.[5–7] Two specific BRCA1 pathogenic variants (185delAG and 5382insC) and one BRCA2 pathogenic variant (6174delT) are common in individuals of AJ ancestry. Carrier frequencies for these pathogenic variants in the general Jewish population are 0.9% (95% CI, 0.7%–1.1%) for the 185delAG pathogenic variant, 0.3% (95% CI, 0.2%–0.4%) for the 5382insC pathogenic variant, and 1.3% (95% CI, 1.0%–1.5%) for the BRCA2 6174delT pathogenic variant.[8–11] In these studies, the relative risks (RRs) were commonly greater than 1, but only a few were statistically significant. Many of these studies were not sufficiently powered to rule out a lower, but clinically significant, risk of prostate cancer in carriers of Ashkenazi BRCA founder pathogenic variants.

Table 4 summarizes the findings from a systemic review and meta-analysis, which help clarify the relationship between BRCA pathogenic variants and prostate cancer risk in individuals of Ashkenazi Jewish heritage.

Table 4. BRCA Pathogenic Variants in Ashkenazi Jewish Populations with Prostate Cancera
Population Number of Studies Fixed-Effect Pooled Prostate Cancer RR (95% CI) Random-Effect Pooled Prostate Cancer RR (95% CI) I2
CI = confidence interval; RR = relative risk.
aAdapted from Nyberg et al.
BRCA1
All 3 1.12 (0.55–2.31) 1.12 (0.55–2.31) 0%
BRCA2
All 6 2.08 (1.38–3.12) 2.08 (1.38–3.12) 0%

This systematic review and meta-analysis provide further evidence that prostate cancer occurs more often in Ashkenazi Jewish BRCA founder variant carriers and suggests that prostate cancer risk may be greater in men with BRCA2 6174delT founder pathogenic variants than in men with BRCA1 85delAG or BRCA1 5382insC founder pathogenic variants.

Other populations

The association between prostate cancer and pathogenic variants in BRCA1 and BRCA2 has also been studied in other populations. Table 5 summarizes studies from a systematic review and meta-analysis. This table reports the prevalence of BRCA pathogenic variants in men with prostate cancer from other varied populations.

Table 5. Case-Control Studies in Varied Populations With BRCA1/BRCA2 Pathogenic Variants and Prostate Cancer Riska
Population Number of Studies Fixed-Effect Pooled Prostate Cancer RR (95% CI) Random-Effect Pooled Prostate Cancer RR (95% CI) I2
CI = confidence interval; RR = relative risk.
aAdapted from Nyberg et al.
BRCA1
Non-Ashkenazi European Ancestry 8 1.30 (1.03–1.64) 1.30 (0.95–1.79) 30%
African Ancestry 1 1.11 (0.09–13.61) 1.11 (0.09–13.61) –
Asian Ancestry 1 2.27 (0.92–5.59) 2.27 (0.92–5.59) –
BRCA2
Non-Ashkenazi European Ancestry 7 4.07 (3.45–4.80) 3.69 (2.71–5.04) 66%
African Ancestry 1 10.30 (1.28–82.73) 10.30 (1.28–82.73) –
Asian Ancestry 1 5.65 (3.49–9.15) 5.65 (3.49–9.15) –
Prostate cancer aggressiveness in carriers of BRCA pathogenic variants

A systematic review and meta-analysis found that BRCA1 and BRCA2 showed differences in prostate cancer aggressiveness.[3] The pooled, random-effects RRs of aggressive prostate cancer (using any definition of aggressiveness) were the following for BRCA1 and BRCA2:

  • BRCA1: RR, 1.98 (1.35–2.90; I² = 0%).
  • BRCA2: RR, 6.08 (3.44–10.8; I² = 82%).

Men harboring pathogenic variants in the United Kingdom and Ireland were prospectively followed for prostate cancer diagnoses (BRCA1 [n = 16/376] and BRCA2 [n = 26/447]; median follow-up, 5.9 y and 5.3 y, respectively).[12] The prostate cancers identified covered the spectrum of Gleason scores from less than 6 to greater than 8; however, they differed by gene:

  • BRCA1 Gleason score less than 6; standardized incidence ratio (SIR), 3.50 (95% CI, 1.67–7.35) and Gleason score greater than 7; SIR, 1.80 (95% CI, 0.89–3.65).
  • BRCA2 Gleason score less than 6; SIR, 3.03 (95% CI, 1.24–7.44) and Gleason score greater than 7; SIR, 5.07 (95% CI, 3.20–8.02).

This study was followed by a large, retrospective, international study of men diagnosed with prostate cancer who had pathogenic variants in BRCA1 (n = 3,453) and BRCA2 (n = 3,051).[13] In BRCA1, there were no statistically significant associations between overall prostate cancer risk/prostate cancer with a Gleason score of 8 or higher and pathogenic sequence variant types, pathogenic variant function, or the region of the gene in which a pathogenic variant occurred, such as RING or BRCA1 C-terminal (BRCT) domains. In contrast, two prostate cancer cluster regions were identified in BRCA2: 1) 3’ of BRCA2 c.7914 (hazard ratio [HR],1.78; 95% confidence interval [CI], 1.25–2.52; P = .001), and 2) BRCA2 c.756–c.1000 (HR, 2.83; 95% CI, 1.71–4.68; P = 4.0 x 10-5).

These studies suggest that prostate cancer in BRCA carriers is associated with aggressive disease features including a high Gleason score, and a high tumor stage and/or grade at diagnosis. This is a finding that warrants consideration when patients undergo cancer risk assessment and genetic counseling.[14] Research is under way to gain insight into the biological basis of aggressive prostate cancer in carriers of BRCA pathogenic variants. One study of 14 BRCA2 germline pathogenic variant carriers reported that BRCA2-associated prostate cancers harbor increased genomic instability and a mutational profile that more closely resembles metastatic prostate cancer than localized disease, with genomic and epigenomic dysregulation of the MED12L/MED12 axis similar to metastatic castration-resistant prostate cancer.[15]

BRCA1/BRCA2 and survival outcomes

Analyses of prostate cancer cases in families with known BRCA1 or BRCA2 pathogenic variants have been examined for survival. A meta-analysis that examined BRCA1/BRCA2 prostate cancer risk, BRCA1/BRCA2 frequency in patients with prostate cancer, and prostate cancer mortality found that BRCA1/BRCA2 carriers who were diagnosed with prostate cancer had decreased cancer-specific survival (HR, 2.53; 95% CI, 1.98–3.22; P < .0001) when compared with noncarriers.[16] Similarly, prostate cancer overall survival (OS) was lower in men with BRCA1/BRCA2 pathogenic variants (HR, 2.08; 95% CI, 1.55–2.79; P < .0001). BRCA2 carriers had decreased cancer-specific survival (HR, 2.63; 95% CI, 2.00–3.47; P < .0001) and OS (HR, 2.21; 95% CI, 1.64–2.99; P < .0001) values when compared with noncarriers. BRCA2 carriers (BRCA2, 71.1%; 95% CI, 31.4%–93.0%) were also more likely to have prostate cancer with a Gleason score of 7 or greater than BRCA1 carriers (BRCA1, 36.3%; 95% CI, 20.0%–56.5%).

HOXB13

Key points

HOXB13 was the first gene found to be associated with hereditary prostate cancer. The HOXB13 G84E variant has been extensively studied because of its association with prostate cancer risk.

  • Overall risk of prostate cancer with the G84E variant ranges from 3- to 5-fold, with a higher risk of early-onset prostate cancer with the G84E variant of up to 10-fold.
  • Penetrance for carriers of the G84E variant is an approximate 60% lifetime risk of prostate cancer by age 80 years.
  • There is no clear association of the G84E variant with aggressive prostate cancer or other cancers.
  • Preliminary studies suggest additional variants in HOXB13 may be relevant for prostate cancer risk in diverse populations.
Background

Linkage to 17q21-22 was initially reported by the UM-PCGP from 175 pedigrees of families with hereditary prostate cancer.[17] Fine-mapping of this region provided strong evidence of linkage (LOD score, 5.49) and a narrow candidate interval (15.5 Mb) for a putative susceptibility gene among 147 families with four or more affected men and average age at diagnosis of 65 years or younger.[18] The exons of 200 genes in the 17q21-22 region were sequenced in DNA from 94 unrelated patients from hereditary prostate cancer families (from the UM-PCGP and Johns Hopkins University).[19] Probands from four families were discovered to have a recurrent pathogenic variant (G84E) in HOXB13, and 18 men with prostate cancer from these four families carried the pathogenic variant. The pathogenic variant status was determined in 5,083 additional cases and 2,662 controls. Carrier frequencies and ORs for prostate cancer risk were as follows:

  • Men with a positive family history of prostate cancer, 2.2% versus negative, 0.8% (OR, 2.8; 95% CI, 1.6–5.1; P = 1.2 × 10-4).
  • Men younger than 55 years at diagnosis, 2.2% versus older than 55 years, 0.8% (OR, 2.7; 95% CI, 1.6–4.7; P = 1.1 × 10-4).
  • Men with a positive family history of prostate cancer and younger than 55 years at diagnosis, 3.1% versus a negative family history of prostate cancer and age at diagnosis older than 55 years, 0.6% (OR, 5.1; 95% CI, 2.4–12.2; P = 2.0 × 10-6).
  • Men with a positive family history of prostate cancer and older than 55 years at diagnosis, 1.2%.
  • Controls, 0.1% to 0.2%.[19]

The clinical utility of genetic testing for the HOXB13 G84E variant is evolving.[20,21]

Validation and confirmatory studies

A validation study from the International Consortium of Prostate Cancer Genetics confirmed HOXB13 as a susceptibility gene for prostate cancer risk.[22] Within carrier families, the G84E pathogenic variant was more common among men with prostate cancer than among unaffected men (OR, 4.42; 95% CI, 2.56–7.64). The G84E pathogenic variant was also significantly overtransmitted from parents to affected offspring (P = 6.5 × 10-6).

Additional studies have emerged that better define the carrier frequency and prostate cancer risk associated with the HOXB13 G84E pathogenic variant.[19,23–28] This pathogenic variant appears to be restricted to White men, primarily of European descent.[19,23–25] The highest carrier frequency of 6.25% was reported in Finnish early-onset cases.[26] A pooled analysis of European Americans that included 9,016 cases and 9,678 controls found an overall G84E pathogenic variant frequency of 1.34% among cases and 0.28% among controls.[27]

Risk of prostate cancer by HOXB13 G84E pathogenic variant status has been reported to vary by age of onset, family history, and geographical region. A validation study in an independent cohort of 9,988 cases and 61,994 controls from six studies of men of European ancestry, including 4,537 cases and 54,444 controls from Iceland whose genotypes were largely imputed, reported an OR of 7.06 (95% CI, 4.62–10.78; P = 1.5 × 10−19) for prostate cancer risk by G84E carrier status.[29] A pooled analysis reported a prostate cancer OR of 4.86 (95% CI, 3.18–7.69; P = 3.48 × 10-17) in men with HOXB13 pathogenic variants compared with noncarriers; this increased to an OR of 8.41 (95% CI, 5.27–13.76; P = 2.72 ×10-22) among men diagnosed with prostate cancer at age 55 years or younger. The OR was 7.19 (95% CI, 4.55–11.67; P = 9.3 × 10-21) among men with a positive family history of prostate cancer and 3.09 (95% CI, 1.83–5.23; P = 6.26 × 10-6) among men with a negative family history of prostate cancer.[27] A meta-analysis that included 24,213 cases and 73,631 controls of European descent revealed an overall OR for prostate cancer by carrier status of 4.07 (95% CI, 3.05–5.45; P < .00001). Risk of prostate cancer varied by geographical region: United States (OR, 5.10; 95% CI, 3.21–8.10; P < .00001), Canada (OR, 5.80; 95% CI, 1.27–26.51; P = .02), Northern Europe (OR, 3.61; 95% CI, 2.81–4.64; P < .00001), and Western Europe (OR, 8.47; 95% CI, 3.68–19.48; P < .00001).[24] In addition, the association between the G84E pathogenic variant and prostate cancer risk was higher for early-onset cases (OR, 10.11; 95% CI, 5.97–17.12). There was no significant association with aggressive disease in the meta-analysis.

Another meta-analysis that included 11 case-control studies also reported higher risk estimates for prostate cancer in HOXB13 G84E carriers (OR, 4.51; 95% CI, 3.28–6.20; P < .00001) and found a stronger association between HOXB13 G84E and early-onset disease (OR, 9.73; 95% CI, 6.57–14.39; P < .00001).[30] An additional meta-analysis of 25 studies that included 51,390 cases and 93,867 controls revealed an OR for prostate cancer of 3.248 (95% CI, 2.121–3.888). The association was most significant in White individuals (OR, 2.673; 95% CI, 1.920–3.720), especially those of European descent. No association was found for breast or colorectal cancer.[31] One population-based, case-control study from the United States confirmed the association of the G84E pathogenic variant with prostate cancer (OR, 3.30; 95% CI, 1.21–8.96) and reported a suggestive association with aggressive disease.[32] In addition, one study identified no men of AJ ancestry who carried the G84E pathogenic variant.[33] A case-control study from the United Kingdom that included 8,652 cases and 5,252 controls also confirmed the association of HOXB13 G84E with prostate cancer (OR, 2.93; 95% CI, 1.94–4.59; P = 6.27 × 10-8).[34] The risk was higher among men with a family history of the disease (OR, 4.53; 95% CI, 2.86–7.34; P = 3.1 × 10−8) and in early-onset prostate cancer (diagnosed at age 55 y or younger) (OR, 3.11; 95% CI, 1.98–5.00; P = 6.1 × 10−7). No association was found between carrier status and Gleason score, cancer stage, OS, or cancer-specific survival.

However, a 2018 publication of a study combining multiple prostate cancer cases and controls of Nordic origin along with functional analysis reported that simultaneous presence of HOXB13 (G84E) and CIP2A (R229Q) predisposes men to an increased risk of prostate cancer (OR, 21.1; P = .000024).[35] Furthermore, dual carriers had elevated risk for high Gleason score (OR, 2.3; P = .025) and worse prostate cancer–specific survival (hazard ratio [HR], 3.9; P = .048). Clinical validation is needed.

HOXB13 pathogenic variants in diverse populations

A study of Chinese men with and without prostate cancer failed to identify the HOXB13 G84E pathogenic variant; however, there was an excess of a novel variant, G135E, in cases compared with controls.[36] A large study of approximately 20,000 Japanese men with and without prostate cancer identified another novel HOXB13 variant, G132E, which was associated with prostate cancer with an OR of 6.08 (95% CI, 3.39–11.59).[37]

Two studies confirmed the association between the HOXB13 X285K variant and increased prostate cancer risk in African American men after this variant was identified in Martinique.[38] One of these was a single-institution study, which sequenced HOXB13 in a clinical patient population of 1,048 African American men undergoing prostatectomy for prostate cancer.[39] The HOXB13 X285K variant was identified in eight patients. In a case–case analysis, X285K variant carriers were at increased risk of developing clinically significant prostate cancer (1.2% X285K carrier rate in prostate cancers with a Gleason score ≥7 vs. 0% X285K carrier rate in prostate cancers with Gleason score <7; P = .028). Similarly, X285K variant carriers also had an increased chance of developing prostate cancer at an early age (2.4% X285K carrier rate in patients <50 years vs. 0.5% X285K carrier rate in patients ≥50 years; OR, 5.25; 95% CI, 1.00–28.52; P = .03). A second study included 11,688 prostate cancer cases and 10,673 controls from multiple large consortia.[40] The HOXB13 X285K variant was only present in men of West African ancestry and was associated with a 2.4-fold increased chance of developing prostate cancer (95% CI, 1.5–3.9; P = 2 x 10-4). Individuals with the X285K variant were also more likely to have aggressive and advanced prostate cancer (Gleason score ≥8: OR, 4.7; 95% CI, 2.3–9.5; P = 2 x 10-5; stage T3/T4: OR, 4.5; 95% CI, 2.0–10.0; P = 2 x 10-4; metastatic disease: OR, 5.1; 95% CI, 1.9–13.7; P = .001). This information is important to consider when developing genetic tests for HOXB13 pathogenic variants in broader populations.

Penetrance

Penetrance estimates for prostate cancer development in carriers of the HOXB13 G84E pathogenic variant are also being reported. One study from Sweden estimated a 33% lifetime risk of prostate cancer among G84E carriers.[41] Another study from Australia reported an age-specific cumulative risk of prostate cancer of up to 60% by age 80 years.[42] A study in the United Kingdom that included HOXB13 genotype data from nearly 12,000 men with prostate cancer enrolled between 1993 and 2014 reported that the average predicted risk of prostate cancer by age 85 years is 62% (95% CI, 47%–76%) for carriers of the G84E pathogenic variant. The risk of developing prostate cancer in variant carriers increased if the men had affected family members, especially those diagnosed at an early age.[43]

Biology

HOXB13 plays a role in prostate cancer development and interacts with the androgen receptor; however, the mechanism by which it contributes to the pathogenesis of prostate cancer remains unknown. This is the first gene identified to account for a fraction of hereditary prostate cancer, particularly early-onset prostate cancer. The clinical utility and implications for genetic counseling regarding HOXB13 G84E or other pathogenic variants have yet to be defined.

DNA mismatch repair genes (Lynch syndrome)

Five genes are implicated in mismatch repair (MMR), namely MLH1, MSH2, MSH6, PMS2, and EPCAM. Germline pathogenic variants in these five genes have been associated with Lynch syndrome, which manifests by cases of nonpolyposis colorectal cancer and a constellation of other cancers in families, including endometrial, ovarian, duodenal cancers, and transitional cell cancers of the ureter and renal pelvis. For more information about other cancers that are associated with Lynch syndrome, see the Lynch syndrome section in Genetics of Colorectal Cancer. Reports have suggested that prostate cancer may be observed in men harboring an MMR gene pathogenic variant.[44,45] The first quantitative study described nine cases of prostate cancer occurring in a population-based cohort of 106 Norwegian male carriers of MMR gene pathogenic variants or obligate carriers.[46] The expected number of cases among these 106 men was 1.52 (P < .01); the men were younger at the time of diagnosis (60.4 y vs. 66.6 y; P = .006) and had more evidence of Gleason score of 8 to 10 (P < .00001) than the cases from the Norwegian Cancer Registry. Kaplan-Meier analysis revealed that the cumulative risk of prostate cancer diagnosis by age 70 years was 30% in carriers of MMR gene pathogenic variants and 8% in the general population. This finding awaits confirmation in additional populations. A population-based case-control study examined haplotype-tagging SNVs in three MMR genes (MLH1, MSH2, and PMS2). This study provided some evidence supporting the contribution of genetic variation in MLH1 and overall risk of prostate cancer.[47] To assess the contribution of prostate cancer as a feature of Lynch syndrome, one study performed microsatellite instability (MSI) testing on prostate cancer tissue blocks from families enrolled in a prostate cancer family registry who also reported a history of colon cancer. Among 35 tissue blocks from 31 distinct families, two tumors from families with MMR gene pathogenic variants were found to be MSI-high. The authors conclude that MSI is rare in hereditary prostate cancer.[48] Other studies are attempting to characterize rates of prostate cancer in Lynch syndrome families and correlate molecular features with prostate cancer risk.[49]

One study that included two familial cancer registries found an increased cumulative incidence and risk of prostate cancer among 198 independent families with MMR gene pathogenic variants and Lynch syndrome.[50] The cumulative lifetime risk of prostate cancer (to age 80 y) was 30.0% (95% CI, 16.54%–41.30%; P = .07) in carriers of MMR gene pathogenic variants, whereas it was 17.84% in the general population, according to the Surveillance, Epidemiology, and End Results (SEER) Program estimates. There was a trend of increased prostate cancer risk in carriers of pathogenic variants by age 50 years, where the risk was 0.64% (95% CI, 0.24%–1.01%; P = .06), compared with a risk of 0.26% in the general population. Overall, the HR (to age 80 y) for prostate cancer in carriers of MMR gene pathogenic variants in the combined data set was 1.99 (95% CI, 1.31–3.03; P = .0013). Among men aged 20 to 59 years, the HR was 2.48 (95% CI, 1.34–4.59; P = .0038).

A systematic review and meta-analysis that included 23 studies (6 studies with molecular characterization and 18 risk studies, of which 12 studies quantified risk for prostate cancer) reported an association of prostate cancer with Lynch syndrome.[51] In the six molecular studies included in the analysis, 73% (95% CI, 57%–85%) of prostate cancers in carriers of MMR gene pathogenic variants were MMR deficient. The RR of prostate cancer in carriers of MMR gene pathogenic variants was estimated to be 3.67 (95% CI, 2.32–6.67). Of the twelve risk studies, the RR of prostate cancer ranged from 2.11 to 2.28, compared with that seen in the general population depending on carrier status, prior diagnosis of colorectal cancer, or unknown male carrier status from families with a known pathogenic variant.

A study from three sites participating in the Colon Cancer Family Registry examined 32 cases of prostate cancer (mean age at diagnosis, 62 y; standard deviation, 8 y) in men with a documented MMR gene pathogenic variant (23 MSH2 carriers, 5 MLH1 carriers, and 4 MSH6 carriers).[52] Seventy-two percent (n = 23) had a previous diagnosis of colorectal cancer. Immunohistochemistry was used to assess MMR protein loss, which was observed in 22 tumors (69%); the pattern of loss of protein expression was 100% concordant with the germline pathogenic variant. The RR of prostate cancer was highest in carriers of MSH2 pathogenic variants (RR, 5.8; 95% CI, 2.6–20.9); the RRs in carriers of MLH1 and MSH6 pathogenic variants were 1.7 (95% CI, 1.1–6.7) and 1.3 (95% CI, 1.1–5.3), respectively. Gleason scores ranged from 5 to 10; two tumors had a Gleason score of 5; 22 tumors had a Gleason score of 6 or 7; and eight tumors had a Gleason score higher than 8. Sixty-seven percent (12 of 18) of the tumors were found to have perineural invasion, and 47% (9 of 19) had extracapsular invasion. A large observational cohort study, which included more than 6,000 MMR-variant carriers, reported an increased cumulative incidence of prostate cancer by age 70 years for specific MMR genes, as follows: MLH1 (7.0; 95% CI, 4.2–11.9), MSH2 (15.9; 95% CI, 11.2–22.5), and PMS2 (4.6; 95% CI, 0.8–67.5). No significant increase in prostate cancer incidence was reported for MSH6.[53]

Although the risk of prostate cancer appears to be elevated in families with Lynch syndrome, strategies for germline testing for MMR gene pathogenic variants in index prostate cancer patients remain to be determined.

A study of 1,133 primary prostate adenocarcinomas and 43 neuroendocrine prostate cancers (NEPC) conducted screening by MSH2 immunohistochemistry with confirmation by NGS.[54] MSI was assessed by polymerase chain reaction and NGS. Of primary adenocarcinomas and NEPC, 1.2% (14/1,176) had MSH2 loss. Overall, 8% (7/91) of adenocarcinomas with primary Gleason pattern 5 (Gleason score 9–10) had MSH2 loss compared with 0.4% (5/1,042) of tumors with any other Gleason scores (P < .05). Three patients had germline variants in MSH2, of whom two had a primary Gleason score of 5. Pending further confirmation, these findings may support universal MMR screening of prostate cancer with a Gleason score of 9 to 10 to identify men who may be eligible for immunotherapy and germline testing.

EPCAM testing has been included in some multigene panels likely due to EPCAM variants silencing MSH2. Specific large genomic rearrangement variants at the 3’ end of EPCAM (which lies near the MSH2 gene) induce methylation of the MSH2 promoter, resulting in MSH2 protein loss.[55] Pathogenic variants in MSH2 are associated with Lynch syndrome and an increase in prostate cancer risk.[52] For more information on EPCAM and MSH2, see the Gene-specific considerations and associated CRC risk section or the Lynch Syndrome section in Genetics of Colorectal Cancer. Thus far, studies have not found an association between increased prostate cancer risk and EPCAM pathogenic variants.[56]

ATM

Ataxia telangiectasia (AT) is an autosomal recessive disorder characterized by neurological deterioration, telangiectasias, immunodeficiency states, and hypersensitivity to ionizing radiation. It is estimated that 1% of the general population may be heterozygous carriers of ATM pathogenic variants.[57] In the presence of DNA damage, the ATM protein is involved in mediating cell cycle arrest, DNA repair, and apoptosis.[58] Given evidence of other cancer risks in heterozygous ATM carriers, evidence of an association with prostate cancer susceptibility continues to emerge. A prospective case series of 10,317 Danish individuals who had a 36-year follow-up period, during which 2,056 individuals developed cancer, found that the ATM Ser49Cys variant was associated with increased prostate cancer risk (HR, 2.3; 95% CI, 1.1–5.0).[58] A retrospective case series of 692 men with metastatic prostate cancer, who were not selected based on a family history of cancer or the patient’s age at cancer diagnosis, found that 1.6% of participants (11 of 692) had an ATM pathogenic variant.[56] Multiple independent reports have shown that the ATM P1054R variant, which is found in 2% of Europeans, is associated with increased prostate cancer risk.[37,59,60] For example, the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium found an OR of 1.16 (95% CI, 1.10–1.22) for the ATM P1054 variant’s association with prostate cancer risk.[61] A subsequent PRACTICAL consortium study had 14 groups (five from North America, six from Europe, and two from Australia) and 8,913 participants (5,560 cases and 3,353 controls). Next-generation ATM sequencing data were standardized and ClinVar classifications were used to categorize the variants as Tier 1 (likely pathogenic) or Tier 2 (potentially deleterious). Prostate cancer risk in Tier 1 variants had an OR of 4.4 (95% CI, 2.0–9.5).[62]

CHEK2

CHEK2 has also been investigated for a potential association with prostate cancer risk. For more information on other cancers associated with CHEK2 pathogenic variants, see the CHEK2 section in Genetics of Breast and Gynecologic Cancers and the CHEK2 section in Genetics of Colorectal Cancer. A retrospective case series of 692 men with metastatic prostate cancer unselected for cancer family history or age at diagnosis found 1.9% (10 of 534 [men with data]) were found to have a CHEK2 pathogenic variant.[56] A systematic review and meta-analysis from eight retrospective cohort studies examining the relationship between CHEK2 variants (1100delC, IVS2+1G>A, I157T) and prostate cancer confirmed the association of the 1100delC (OR, 3.29; 95% CI, 1.85–5.85; P = .00) and I157T (OR, 1.80; 95% CI, 1.51–2.14; P = .00) variants with prostate cancer susceptibility.[63] A genome-wide association study (GWAS) focusing on African American cases and controls identified a missense variant, I448S, which is associated with prostate cancer (risk allele frequency, 1.5%; OR, 1.62; 95% CI, 1.39–1.89, P = 7.50 × 10-10).[64] Further studies of CHEK2 in large diverse populations are warranted.

TP53

TP53 has also been investigated for a potential association with prostate cancer risk. For more information about other cancers associated with TP53 pathogenic variants, see the Li-Fraumeni Syndrome section in Genetics of Breast and Gynecologic Cancers. In a case series of 286 individuals from 107 families with a deleterious TP53 variant, 403 cancer diagnoses were reported, of which 211 were the first primary cancer including two prostate cancers diagnosed after age 45 years. Prostate cancer was also reported in 4 of 61 men with a second primary cancer.[65] In a Dutch case series of 180 families meeting either classic Li-Fraumeni syndrome (LFS) or Li-Fraumeni–like (LFL) family history criteria, a deleterious TP53 variant was identified in 24 families with one case of prostate cancer found in each group (LFS or LFL). Prostate cancer risks varied on the basis of the family history criteria with LFS (RR, 0.50; 95% CI, 0.01–3.00) and LFL (RR, 4.90; 95% CI, 0.10–27.00).[66] In a French case series of 415 families with a deleterious TP53 variant, four prostate cancers were reported, with a mean age at diagnosis of 63 years (range, 57–71 y).[67]

Germline TP53 pathogenic variants have also been identified in men with prostate cancer who have undergone tumor testing. A prospective case series of 42 men with either localized, biochemically recurrent, or metastatic prostate cancer unselected for cancer family history or age at diagnosis undergoing tumor-only somatic testing found that 2 of 42 men (5%) were found to have a suspected TP53 germline pathogenic variant.[68]

Further evidence supports an association between prostate cancer and germline TP53 pathogenic variants.[69–71] A retrospective study of 163 men (>18 y) with TP53 pathogenic/likely pathogenic variants from 132 known TP53 families found that 19% (n = 31/163) of participants had diagnoses of prostate cancer.[72] Of these participants, 48% (n = 31) were older than age 50 years. The median age of prostate cancer diagnosis was 56 years (range, 50–64 y). Locally advanced prostate cancer or de novo metastatic disease was found in 19% (n = 4) of men. Additionally, 40% (n = 8/20) of participants had high-grade prostate cancer (Gleason score, >8) at the time of diagnosis. This study also combined the existing cohort with a prostate cancer cohort that had documented germline TP53 pathogenic/likely pathogenic variants. This combined cohort had a prostate cancer relative risk of 9.1 (95% CI, 6.2–14; P < .0001).

NBN

NBN, which is also known as NBS1, has been investigated due to a potential association with prostate cancer risk, with the literature constantly evolving. Studies mostly from Polish populations reported that the NBN 657del5 variant is associated with prostate cancer risk (OR, 2.5; P < .001), mortality (HR, 1.6; P = .001), and familial prostate cancer (OR, 4.6; P < .0001).[73,74] One of these studies (from Poland) reported adverse survival when individuals with the NBN 657del5 variant also carried the NBN E185Q GG genotype (HR,1.9; P = .0004).[73] In the metastatic setting, a retrospective case series of 692 men with metastatic prostate cancer (unselected for cancer family history or age at diagnosis) found that 0.3% (2 of 692 men) had an NBN pathogenic variant.[56] Some clinical genetic testing laboratories do not include NBN on their prostate cancer panels, since NBN‘s association with prostate cancer is based on preliminary evidence. Further data will be required to fully understand the role and generalizability of NBN and its association with prostate cancer.

Multigene testing studies in prostate cancer

Prevalence of pathogenic variants with prostate cancer risk on multigene panel testing

The following section gives information about additional genes that may be on hereditary prostate cancer panel tests.

One retrospective case series of 692 men with metastatic prostate cancer unselected for cancer family history or age at diagnosis assessed the incidence of germline pathogenic variants in 16 DNA repair genes. Pathogenic variants were identified in 11.8% (82 of 692), a rate higher than in men with localized prostate cancer (4.6%, P < .001), suggesting that genetic aberrations are more commonly observed in men with aggressive forms of disease.[56] Two studies were published using data from a clinical testing laboratory database. The first study evaluated 1,328 men with prostate cancer and reported an overall pathogenic variant rate of 15.6%, including 10.9% in DNA repair genes.[75] A second study involved a larger cohort of 3,607 men with prostate cancer, some of whom had been included in the prior publication.[76] The reported pathogenic variant rate was 17.2%. Overall, pathogenic variant rates by gene were consistently reported between the two studies and were as follows: BRCA2, 4.74%; CHEK2, 2.88%; ATM, 2.03%; and BRCA1, 1.25%.[76] The most commonly aberrant gene in this cohort was BRCA2. The first publication reported associations between family history of breast cancer and high Gleason score (≥8).[75] The second publication focused on the percentage of men with pathogenic variants who met National Comprehensive Cancer Network national guidelines for genetic testing and found that 229 individuals (37%) with pathogenic variants in this cohort did not meet guidelines for genetic testing.[76] A systematic evidence review examined the median prevalence of pathogenic germline variants in the DNA damage-response pathway, including ATM, ATR, BRCA1, BRCA2, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, and RAD51C. The overall prevalence was 18.6% (range, 17.2%–19%; n = 1,712) for general prostate cancer, 11.6% (range, 11.4%–11.8%; n = 1,261) for metastatic prostate cancer, 8.3% (range, 7.5%–9.1%; n = 738) for metastatic castration-resistant prostate cancer, and 29.3% (range, 7.3%–92.67%; n = 327) for familial prostate cancer.[77]

A case-control study in a Japanese population of 7,636 men with prostate cancer and 12,366 men without prostate cancer evaluated pathogenic variants in eight genes (BRCA1, BRCA2, CHEK2, ATM, NBN, PALB2, HOXB13, and BRIP1) for an association with prostate cancer.[37] The study found strong associations for BRCA2 (OR, 5.65; 95% CI, 3.55–9.32), HOXB13 (OR, 4.73; 95% CI, 2.84–8.19), and ATM (OR, 2.86; 95% CI, 1.63–5.15). The study supports a population-specific assessment of the genetic contribution to prostate cancer risk.

Germline pathogenic variants associated with metastatic prostate cancer

The metastatic prostate cancer setting is also contributing insights into the germline pathogenic variant spectrum of prostate cancer. Clinical sequencing of 150 metastatic tumors from men with castrate-resistant prostate cancer identified alterations in genes involved in DNA repair in 23% of men.[78] Interestingly, 8% of these variants were pathogenic and present in the germline. Another study focused on tumor-normal sequencing of advanced and metastatic cancers identified germline pathogenic variants in 19.6% of men (71 of 362) with prostate cancer.[79] Germline pathogenic variants were found in BRCA1, BRCA2, MSH2, MSH6, PALB2, PMS2, ATM, BRIP1, NBN, as well as other genes. These and other studies are summarized in Table 6. The contribution of germline variants identified from large sequencing efforts to inherited prostate cancer predisposition requires molecular confirmation of genes not classically linked to prostate cancer risk.

Table 6. Summary of Tumor Sequencing Studies With Germline Findings
Study Cohort Germline Results for Prostate Cancer Comments
mCRPC = metastatic castration-resistant prostate cancer.
aPotential overlap of cohorts.
Robinson et al. (2015)a [78] Whole-exome and transcriptome sequencing of bone or soft tissue tumor biopsies from a cohort of 150 men with mCRPC 8% had germline pathogenic variants:  
— BRCA2: 9/150 (6.0%)
— ATM: 2/150 (1.3%)
— BRCA1: 1/150 (0.7%)
Pritchard et al. (2016)a [56] 692 men with metastatic prostate cancer, unselected for family history; analysis focused on 20 genes involved in maintaining DNA integrity and associated with autosomal dominant cancer–predisposing syndromes 82/692 (11.8%) had germline pathogenic variants: Frequency of germline pathogenic variants in DNA repair genes among men with metastatic prostate cancer significantly exceeded the prevalence of 4.6% among 499 men with localized prostate cancer in the Cancer Genome Atlas (P < .001)
— BRCA2: 37/692 (5.3%)
— ATM: 11/692 (1.6%)
— BRCA1: 6/692 (0.9%)
Schrader et al. (2016) [80] 1,566 patients undergoing tumor profiling (341 genes) with matched normal DNA at a single institution; 97 cases of prostate cancer included 10/97 (10.3%) had germline pathogenic variants:  
— BRCA2: 6/97 (6.2%)
— BRCA1: 1/97 (1.0%)
— MSH6: 1/97 (1.0%)
— MUTYH: 1/97 (1.0%)
— PMS2: 1/97 (1.0%)

Common Risk Variants and Polygenic Risk Scores for Prostate Cancer

The most prevalent prostate cancer risk variants in the human genome were discovered in genome-wide association studies (GWAS). GWAS evaluate the millions of common single nucleotide polymorphisms (SNPs) in the human population (typically >5% prevalence) and ask if each variant is enriched in individuals with a given disease. With great statistical rigor, GWAS have revealed over 250 prostate cancer risk variants. Each single SNP confers a very modest prostate cancer risk. However, when compounded, these SNPs comprise a substantial portion of inherited prostate cancer risk. Research continues to translate these discoveries into clinical practice, with use in tools like polygenic risk scores (PRS).

GWAS and SNPs

  • GWAS can identify inherited genetic variants that influence a specific phenotype, such as risk of a particular disease.
  • For complex diseases, such as prostate cancer, risk of developing the disease is the product of multiple genetic and environmental factors; each individual factor contributes relatively little to overall risk.
  • To date, GWAS have discovered more than 250 common genetic variants associated with prostate cancer risk.
  • Individuals can be genotyped for all known prostate cancer risk markers relatively easily; but, to date, studies have not demonstrated that this information substantially refines risk estimates from commonly used variables, such as family history.
  • The clinical relevance of variants identified from GWAS remains unclear.

Although the statistical evidence for an association between genetic variation at these loci and prostate cancer risk is overwhelming, the clinical relevance of the variants and the mechanism(s) by which they lead to increased risk are unclear and will require further characterization. Additionally, these loci are associated with very modest risk estimates and explain only a fraction of overall inherited risk. However, when combined into a PRS, these confirmed genetic risk variants may prove to be useful for prostate cancer risk stratification and to identify men for targeted screening and early detection. Further work will include genome-wide analysis of rarer alleles catalogued via sequencing efforts. Disease-associated alleles with frequencies of less than 1% in the population may prove to be more highly penetrant and clinically useful. In addition, further work is needed to describe the landscape of genetic risk in non-European populations. Finally, until the individual and collective influences of genetic risk alleles are evaluated prospectively, their clinical utility will remain difficult to fully assess.

Beginning in 2006, multiple genome-wide studies seeking associations with prostate cancer risk converged on the same chromosomal locus, 8q24.[81–94] Since that time, more than ten genetic polymorphisms, all independently associated with disease, reside within five distinct 8q24 risk regions. The population-attributable risk of prostate cancer from the 8q24 risk alleles reported to date is 9.4%.[95]

Since prostate cancer risk loci have been discovered at 8q24, more than 250 variants have been identified at other chromosomal risk loci. These chromosomal risk loci were detected by multistage GWAS, which were comprised of thousands of cases and controls and were validated in independent cohorts.[96] The most convincing associations reported to date for men of European ancestry are annotated in the National Human Genome Research Institute GWAS catalog.

Most prostate cancer GWAS data generated to date have been derived from populations of European descent. This shortcoming is profound, considering that linkage disequilibrium structure, SNV frequencies, and incidence of disease differ across ancestral groups. To provide meaningful genetic data to all patients, well-designed, adequately powered GWAS must be aimed at specific ethnic groups.[97] Most work in this regard has focused on African American, Chinese, and Japanese men. The most convincing associations reported to date for men of non-European ancestry are annotated in the National Human Genome Research Institute GWAS catalog.

The African American population is of particular interest because American men with West African ancestry are at higher risk of prostate cancer than any other group. A handful of studies have sought to determine whether GWAS findings in men of European ancestry are applicable to men of African ancestry.[64,98,99] The majority of risk alleles (approximately 83%) are shared across African American and European American populations. Three independent associations were subsequently replicated. All three variants were within or near long noncoding RNAs (lncRNAs) previously associated with prostate cancer, and two of the variants were unique to men of African ancestry.[100]

Statistically well-powered GWAS have also been launched to examine inherited cancer risk in Japanese and Chinese populations. Investigators discovered that these populations share many risk regions observed in African American men.[101–104] Additionally, risk regions that are unique to these ancestral groups were identified (for more information, see the National Human Genome Research Institute GWAS catalog). Ongoing work in larger cohorts will validate and expand upon these findings.

Polygenic risk scores for prostate cancer

Current GWAS findings account for an estimated 58% of heritable prostate cancer risk. Another 6% of familial prostate cancer risk is attributed to rare genetic variants.[105] Efforts have been made to translate these discoveries into clinically useful metrics for risk stratification and early detection. PRS were devised to measure prostate cancer risk based on the burden of genetic risk variants that an individual inherits. Associations between PRS and disease risk clearly exist. However, it remains unclear whether screening PRS can appreciably influence long-term outcomes.

In a 2023 study, PRS were created for a multi-ethnic cohort of over 150,000 prostate cancer cases and over 750,000 controls.[106] A PRS was based on 451 prostate cancer risk variants validated via GWAS. The study accounted for genetic dose (i.e., homozygosity vs. heterozygosity). When focusing on men in the top quintile of PRS scores and comparing them to men in the middle of the distribution, men of European ancestry had an OR of greater than 2-fold for developing prostate cancer when compared with men who had average PRS scores. In men of African ancestry, those who belonged to the upper 16% of the PRS had a greater than 2-fold increased risk to develop prostate cancer before age 66 years when compared with those who had average PRS scores. Men in the upper quintile of the PRS represented over 50% of prostate cancer cases, including clinically aggressive cases. In contrast, those in the lowest quintile of the PRS represented fewer than 5% of prostate cancer cases. These data suggest that PRS could inform prostate cancer screening.[107,108] Studies that were conducted prior to this 2023 study analyzed multi-ethnic cohorts and began validating models.[109–120] Further research is needed to determine whether a PRS devised using prostate cancer risk SNPs can help identify clinically aggressive disease.[121]

As GWAS elucidate these networks, it is hoped that new therapies and chemopreventive strategies will follow.[122–130]

Germline SNPs associated with prostate cancer aggressiveness

Prostate cancer is biologically and clinically heterogeneous. Many tumors are indolent and are successfully managed with observation alone. Other tumors are quite aggressive and prove deadly. Several variables are used to determine prostate cancer aggressiveness at the time of diagnosis, such as Gleason score and PSA, but these are imperfect. Additional markers are needed because sound treatment decisions depend on accurate prognostic information. Germline genetic variants are attractive markers because they are present, easily detectable, and static throughout life.

Findings regarding inherited risk of aggressive disease are considered preliminary. Further work is needed to validate findings and assess these associations prospectively.

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Prostate Cancer Genetics: Screening, Surveillance, and Treatment

This section addresses the impact of genetics on prostate cancer screening, surveillance, and treatment. For more information about prostate cancer screening, surveillance, and treatment, see Prostate Cancer Screening and Prostate Cancer Treatment.

Prostate Cancer Screening

Background

Decisions about risk-reducing interventions for patients with an inherited predisposition to prostate cancer, as with any disease, are best guided by randomized controlled clinical trials and knowledge of the underlying natural history of the process. However, existing studies of screening for prostate cancer in high-risk men (men with a positive family history of prostate cancer and African American men) are predominantly based on retrospective case series or retrospective cohort analyses. Because awareness of a positive family history can lead to more frequent work-ups for cancer and result in apparently earlier prostate cancer detection, assessments of disease progression rates and survival after diagnosis are subject to selection, lead time, and length biases. This section focuses on screening and risk reduction of prostate cancer among men predisposed to the disease; data relevant to screening in high-risk men are primarily extracted from studies performed in the general population.

Screening

Information is limited about the efficacy of commonly available screening tests such as the digital rectal exam (DRE) and serum prostate-specific antigen (PSA) in men genetically predisposed to developing prostate cancer. Furthermore, comparing the results of studies that have examined the efficacy of screening for prostate cancer is difficult because studies vary with regard to the cutoff values chosen for an elevated PSA test. For a given sensitivity and specificity of a screening test, the positive predictive value (PPV) increases as the underlying prevalence of disease rises. Therefore, it is theoretically possible that the PPV and diagnostic yield will be higher for the DRE and for PSA in men with a genetic predisposition than in average-risk populations.[1,2]

Most retrospective analyses of prostate cancer screening cohorts have reported PPV for PSA, with or without DRE, among high-risk men in the range of 23% to 75%.[2–6] Screening strategies (frequency of PSA measurements or inclusion of DRE) and PSA cutoff for biopsy varied among these studies, which may have influenced this range of PPV. Cancer detection rates among high-risk men have been reported to be in the range of 4.75% to 22%.[2,5,6] Most cancers detected were of intermediate Gleason score (5–7), with Gleason scores of 8 or higher being detected in some high-risk men. Overall, there is limited information about the net benefits and harms of screening men at higher risk of prostate cancer. In addition, there is little evidence to support specific screening approaches in prostate cancer families at high risk. Risks and benefits of routine screening in the general population are discussed in Prostate Cancer Screening. On the basis of the available data, most professional societies and organizations recommend that high-risk men engage in shared decision-making with their health care providers and develop individualized plans for prostate cancer screening based on their risk factors. A summary of prostate cancer screening recommendations for high-risk men by professional organizations is shown in Table 7 and Table 8.

Table 7. Available Recommendations for Prostate Cancer Screening in BRCA1, BRCA2, and HOXB13 Carriersa
  Age to Begin PSA Screening Screening Interval
PSA = prostate-specific antigen.
aFor germline pathogenic variants other than BRCA2 (including ATM and Lynch syndrome genes), it is reasonable to consider beginning shared decision-making about PSA screening at age 40 years and to consider screening at annual intervals, rather than every other year.[7]
BRCA1 Carriers Consider screening [8] or shared-decision making about screening [7] at age 40 years or 10 years before the youngest prostate cancer diagnosis in the family [8] Consider annual screening rather than screening every other year [7]
BRCA2 Carriers Recommend screening at age 40 years [7,8] or 10 years before the youngest prostate cancer diagnosis in the family [8] Consider annual screening rather than screening every other year [7]
HOXB13 Carriers Consider shared-decision making about screening at age 40 years [7] Consider annual screening rather than screening every other year [7]
Table 8. Summary of Prostate Cancer Screening Recommendations for Men Based on Family History, Race, and Ethnicity
Screening Recommendation Source Population Test Age Screening Initiated Frequency Comments
DRE = digital rectal exam; FDR = first-degree relative; NCCN = National Comprehensive Cancer Network; PSA = prostate-specific antigen; SDR = second-degree relative.
aDRE is recommended in addition to PSA test for men with hypogonadism.
bA suspicious family history includes, but is not limited to, an FDR or SDR with metastatic prostate cancer, ovarian cancer, male breast cancer, female breast cancer at age ≤45 y, colorectal or endometrial cancer at age ≤50 y, or pancreatic cancer; this may also include two or more FDRs or SDRs with breast, prostate (excluding clinically localized Grade Group 1 disease), colorectal, or endometrial cancer at any age.
United States Preventive Services Task Force (2018) [9] Men aged 55–69 y PSA N/A N/A In determining whether PSA-based screening is appropriate in individual cases, patients and clinicians should consider the benefits and harms of PSA screening based on family history, race and ethnicity, comorbid medical conditions, patient values about the benefits and harms of screening and treatment-specific outcomes, and other health needs
American Urological Association (2023) [10] African American men, men with germline pathogenic variants in hereditary prostate cancer genes, and men with strong family histories of prostate cancer PSA 40 to 45 y Screening is individualized based on the patient’s personal preferences and an informed discussion regarding the uncertainty of benefit and associated harms  
American Cancer Society (2023) [11] African American men PSA with or without DREa ≥45 y Screen every 2 y if PSA is <2.5 ng/mL; screen annually if PSA level is ≥2.5 ng/mL; if PSA levels are between 2.5–4.0 ng/mL, an individualized risk assessment can be performed, which incorporates other prostate cancer risk factors (particularly for high-grade cancer, which may be used for a referral recommendation) Counseling consists of a review of the benefits and limitations of testing so that a clinician-assisted, informed decision about testing can be made. It is recommended that prostate cancer screening be accompanied by an informed decision-making process
Men with an FDR who was diagnosed with prostate cancer at <65 y PSA with or without DREa ≥45 y
Men with multiple FDRs who were diagnosed with prostate cancer at <65 y PSA with or without DREa ≥40 y
NCCN Prostate Cancer Early Detection (Version 2.2023) [7] African American men Baseline PSA 40 y Consider screening at annual intervals rather than every other year The panel states that it is reasonable for African American men to consider beginning shared decision-making about PSA screening with their providers at age 40 y
Men with a suspicious family historyb Baseline PSA 40 y Screen every 2–4 y if PSA level <1 ng/mL, DRE normal; if the family history is concerning, NCCN recommends shared decision-making to determine the frequency of PSA screening Referral to a cancer genetics professional is recommended for those with a known or suspected pathogenic variant in a cancer susceptibility gene [7]
Screen every 1–2 y if PSA level ≤3 ng/mL, DRE normal (if done)

Level of evidence: 5

Screening in carriers of BRCA pathogenic variants

IMPACT (Identification of Men with a genetic predisposition to ProstAte Cancer) is an international study focused on prostate cancer screening in carriers of BRCA1/BRCA2 pathogenic variants versus noncarriers.[12] The study recruited 2,481 men (791 BRCA1 carriers, 531 BRCA1 noncarriers; 731 BRCA2 carriers, 428 BRCA2 noncarriers). A total of 199 men (8%) presented with PSA levels higher than 3.0 ng/mL, which was the study PSA cutoff for recommending a biopsy. The overall cancer detection rate was 36.4% (59 prostate cancers diagnosed among 162 biopsies). Prostate cancer by BRCA pathogenic variant status was as follows: BRCA1 carriers (n = 18), BRCA1 noncarriers (n = 10); BRCA2 carriers (n = 24), BRCA2 noncarriers (n = 7). Using published stage and grade criteria for risk classification,[13] intermediate- or high-risk tumors were diagnosed in 11 of 18 BRCA1 carriers (61%), 8 of 10 BRCA1 noncarriers (80%), 17 of 24 BRCA2 carriers (71%), and 3 of 7 BRCA2 noncarriers (43%). The PPV of PSA with a biopsy threshold of 3.0 ng/mL was 48% in carriers of BRCA2 pathogenic variants, 33.3% in BRCA2 noncarriers, 37.5% in BRCA1 carriers, and 23.3% in BRCA1 noncarriers. Ninety-five percent of the men were White; therefore, the results cannot be generalized to all ethnic groups.

Interim results from the IMPACT study (now comprising 2,932 participants including 919 BRCA1 carriers and 902 BRCA2 carriers) demonstrated a cancer incidence rate (per 1,000 person-years) that was higher in BRCA2 carriers compared with noncarriers (19 vs. 12; P = .03). There was no statistical difference in the cancer incidence rates between BRCA1 carriers and noncarriers. Cancer in BRCA2 carriers, but not in BRCA1 carriers, was diagnosed at an earlier age and was more likely to be clinically significant.[14]

Level of evidence (screening in carriers of BRCA pathogenic variants): 3

Impact of Germline Genetics on Management and Treatment of Metastatic Prostate Cancer

Targeted therapies on the basis of genetic results are increasingly driving options and strategies for treatment in oncology. These therapeutic approaches include candidacy for targeted therapy (such as poly [ADP-ribose] polymerase [PARP] inhibitors or immune checkpoint inhibitors), use of platinum-based chemotherapy, and sequencing of androgen-signaling therapy versus chemotherapy. Multiple genetically informed clinical trials are under way for men with prostate cancer.[15] Table 9 summarizes some of the published precision oncology and precision management studies.

Table 9. Summary of Precision Oncology or Precision Management Studies Involving Germline Pathogenic Variant Status
Study Cohort Germline Results Intervention Outcomes and Comments
ADT = androgen deprivation therapy; AR = androgen receptor; CI = confidence interval; CSS = cause-specific survival; DDR = DNA damage repair; FDA = U.S. Food and Drug Administration; HR = hazard ratio; HRR = homologous recombination repair; mCRPC = metastatic castration-resistant prostate cancer; mPC = metastatic prostate cancer; ORR = objective response rate; OS = overall survival; PARP = poly (ADP-ribose) polymerase; PC = prostate cancer; PFS = progression-free survival; PSA = prostate-specific antigen; RR = relative risk.
aThis study reported both germline and somatic genetic test results.
Retrospective
Annala et al. (2017) [16] 319 men with mCRPC; performed germline sequencing of 22 DNA repair genes; all participants previously received ADT and their PCs progressed 24/319 (7.5%) had DDR germline pathogenic variants: Patients with mCRPC and a germline pathogenic variant received the following as a first-line AR-targeted therapy: docetaxel/cabazitaxel (41%), enzalutamide (23%), or abiraterone (36%) Patients with DNA repair defects had decreased responses to ADT:
— BRCA2: 16/319 (5.0%)
— ATM: 1/319 (0.3%) — Time from ADT initiation to mCRPC: Germline positive, 11.8 mo (n = 22) vs. germline negative, 19.0 mo (n = 113) (P = .031)
— BRCA1: 1/319 (0.3%) Patients with mCRPC but without a germline pathogenic variant received the following as a first-line AR-targeted therapy: docetaxel/cabazitaxel (33%), enzalutamide (18%), abiraterone (39%), or other (10%)
— PALB2: 2/319 (0.6%) — PFS on first-line AR-targeted therapy: Germline positive, 3.3 mo vs. germline negative, 6.2 mo (P = .01)
Pomerantz et al. (2017) [17] 141 men with mCRPC treated with docetaxel 8/141 (5.7%) had BRCA2 germline pathogenic variants Patients received at least two doses of carboplatin and docetaxel 6/8 men with BRCA2 germline pathogenic variants (75%) had PSA levels that declined by 50% vs. 23/133 in men without BRCA2 germline pathogenic variants (17%) (P < .001)
A small case series (n = 3) showed a response to platinum chemotherapy with biallelic inactivation of BRCA2, defined as either biallelic somatic BRCA2 pathogenic variants or a germline pathogenic variant plus a somatic BRCA2 pathogenic variant [18]
Mateo et al. (2018) [19] 390 men with mPC; retrospective review 60/390 (15.4%) had DDR germline pathogenic variants: Patients received abiraterone, enzalutamide, and docetaxel; an exploratory subgroup analysis was done for PARP inhibitors/platinum chemotherapy Similar findings were observed for DDR pathogenic variant carriers and noncarriers for several outcome measures:
— Median OS from castration resistance (3.2 y in carriers vs 3.0 y in noncarriers; P = .73)
— Median docetaxel PFS (6.8 mo in carriers vs. 5.1 mo in noncarriers)
— BRCA2: 37/390 (9.5%) — RRs for PC (61% in carriers vs. 54% in noncarriers)
— Median PFS on first-line abiraterone/enzalutamide (8.3 mo in both carriers and noncarriers)
— RR of PC on first-line abiraterone/enzalutamide (46% in carriers vs. 56% in noncarriers)
Carter et al. (2019) [20] 1,211 men with PC on active surveillance 2.1% of patients had germline pathogenic variants in BRCA1/BRCA2/ATM Patients were put on active surveillance 289 patients had their PC tumor grades reclassified: 11/26 patients had pathogenic variants in BRCA1/BRCA2/ATM and 278/1,185 patients did not have a pathogenic variant in BRCA1/BRCA2/ATM (noncarriers); adjusted HR, 1.96 (95% CI, 1.004–3.84; P = .04)
Tumor reclassification occurred in 6/11 BRCA2 carriers and 283/1,200 noncarriers; adjusted HR, 2.74 (95% CI, 1.26–5.96; P = .01)
Of the men who had their PCs reclassified, 3.8% had a BRCA1, BRCA2, or ATM pathogenic variant, and 2.1% only had a BRCA2 pathogenic variant. Of the men whose PCs were not reclassified, 1.6% had a BRCA1, BRCA2, or ATM pathogenic variant, and 0.5% only had a BRCA2 pathogenic variant. The P value for BRCA1/BRCA2/ATM carriers with PCs reclassified versus those without PCs reclassified was .04. The P value for BRCA2 carriers with PCs reclassified versus those without PCs reclassified was .03
Marshall et al. (2019) [21] 46 men with mCRPC were offered olaparib; 23 men had germline pathogenic variants (13 men were not tested) 23 men had germline pathogenic variants in BRCA1/BRCA2/ATM; 2 men had BRCA1 pathogenic variants, 15 men had BRCA2 pathogenic variants, and 6 men had ATM pathogenic variants Patients received olaparib When patients were given olaparib, PSA levels were reduced by 50% in 13/17 (76%) men with BRCA1/BRCA2 pathogenic variants and in 0/6 (0%) men with ATM pathogenic variants (Fisher’s exact test; P = .002)
Patients with BRCA1/BRCA2 pathogenic variants had a median PFS of 12.3 mo, while patients with ATM pathogenic variants had a median PFS of 2.4 mo (HR, 0.17; 95% CI, 0.05–0.57; P = .004)
Sokolova et al. (2021) [22] 90 men with PC; 76/90 had metastatic disease when their PC was diagnosed; participants were matched for PC stage and year of germline testing; participants had similar ages, Gleason grades, and PSA levels at diagnosis 45 men with ATM germline pathogenic variants; 45 men with BRCA2 germline pathogenic variants Patients received various systemic therapies No changes were observed when different groups were given abiraterone, enzalutamide, or docetaxel
When patients were given PARP inhibitors, PSA levels were reduced by 50% in 0/7 men with ATM germline pathogenic variants and in 12/14 men with BRCA2 germline pathogenic variants (P < .001); this response was significant
Study limitations included the following: retrospective study, no zygosity data
Prospective
Antonarakis et al. (2018) [23] 172 men with mCRPC began treatment with abiraterone or enzalutamide 22/172 (12.8%) had DDR germline pathogenic variants: Patients received first-line hormonal therapy (abiraterone or enzalutamide) In propensity score–weighted multivariable analyses, outcomes were superior in men with germline BRCA1/BRCA2/ATM variants with respect to PSA-PFS (HR, 0.48; 95% CI, 0.25–0.92; P = .027), PFS (HR, 0.52; 95% CI, 0.28–0.98; P = .044), and OS (HR, 0.34; 95% CI, 0.12–0.99; P = .048). These results were not observed for men with non-BRCA1/BRCA2/ATM germline variants (P > .10)
— BRCA1/BRCA2/ATM: 9/172 (5.2%) Study limitations included the following: only 9 patients with BRCA1/BRCA2/ATM pathogenic variants
Castro et al. (2019) [24] 419 men with mCRPC were enrolled when they were diagnosed with mPC 68/419 (16.2%) had DDR germline pathogenic variants: Patients received an androgen-signaling inhibitor (abiraterone or enzalutamide) as a first-line therapy and a taxane (docetaxel was given in 96.3% of patients) as a second-line therapy or patients received a taxane as a first-line therapy and an androgen-signaling inhibitor (abiraterone or enzalutamide) as a second-line therapy CSS between ATM/BRCA1/BRCA2/PALB2 carriers and noncarriers was not statistically significant (23.3 mo vs. 33.2 mo; P = .264)
— BRCA2: 14/419 (3.3%)
— ATM: 8/419 (1.9%) CSS was halved in BRCA2 carriers (17.4 mo vs. 33.2 mo; P = .027), and BRCA2 pathogenic variants were identified as an independent prognostic factor for CSS (HR, 2.11; P = .033)
— BRCA1: 4/419 (1%) Significant interactions between BRCA2 status and treatment type (androgen-signaling inhibitor vs. taxane therapy) were observed (CSS-adjusted P = .014; PFS-adjusted P = .005)
— PALB2: None CSS (24.0 mo vs. 17.0 mo) and PFS (18.9 mo vs. 8.6 mo) were greater in BRCA2 carriers treated with first-line abiraterone or enzalutamide when compared with first-line taxanes
de Bono et al. (2020) [25] 387 men in the PROfound study who had mCRPC with disease progression while receiving a new hormonal agent (e.g., enzalutamide or abiraterone) Currently, the FDA has approved olaparib for use in patients with mCRPC who have a somatic or germline pathogenic variant in an HRR gene. The PROfound study cited data from Mateo et al. 2015, which discovered that about half of the HRR gene variants in patient tumors were germline in nature. Results in this study reported on olaparib response in individuals with somatic variants. Data on germline pathogenic variants will be reported in the future Randomized, open-label, phase III trial in which patients received olaparib (300 mg twice per day) or the physician’s choice of enzalutamide (160 mg once per day) or abiraterone (1,000 mg once per day) plus prednisone (5 mg twice per day) In cohort A, imaging-based PFS was significantly longer in the olaparib group than in the control group (median, 7.4 mo vs. 3.6 mo; HR for progression or death, 0.34; 95% CI, 0.25–0.47; P < .001). The median OS in cohort A was 18.5 mo in the olaparib group and 15.1 mo in the control group; 81% of the patients in the control group who had disease progression crossed over to receive olaparib
Cohort A: 245 men with >1 somatic variant in BRCA1, BRCA2, or ATM
Cohort B: 142 men with >1 somatic variant in any of the following genes: BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, or RAD54L
Hussain et al. (2020) [26] 387 men with mCRPC in the PROfound study; PC progressed when taking enzalutamide, abiraterone, or both Currently, the FDA has approved olaparib for use in patients with mCRPC who have a somatic or germline pathogenic variant in an HRR gene. The PROfound study cited data from Mateo et al. 2015, which discovered that about half of the HRR gene variants in patient tumors were germline in nature. Results in this study reported on olaparib response in individuals with somatic variants. Data on germline pathogenic variants will be reported in the future Patients received treatment that was randomly assigned in a 2:1 ratio for olaparib versus control therapy; control therapy consisted of the provider’s choice of enzalutamide or abiraterone, plus prednisone. Crossover to olaparib was permitted when PC progressed on imaging The median OS in cohort A was 19.1 mo with olaparib and 14.7 mo with control therapy. The HR for death (adjusted for crossover from control therapy) was 0.42 (95% CI, 0.19–0.91)
Cohort A: 245 men with >1 somatic variant in BRCA1, BRCA2, or ATM The median OS in cohort B was 14.1 mo for olaparib and 11.5 mo for control therapy. The HR for death (adjusted for crossover from control therapy) was 0.83 (95% CI, 0.11–5.98)
Cohort B: 142 men with >1 somatic variant in any of the following genes: BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, or RAD54L
Abida et al. (2020)a [27] 115 men with mCRPC from the TRITON2 study with a deleterious somatic or germline pathogenic variant in BRCA1/BRCA2; patients had mCRPCs that progressed after treatment with one to two lines of next-generation AR-directed therapy and one taxane-based chemotherapy 44/115 (38%) had BRCA1/BRCA2 germline pathogenic variants: Patients received one or more doses of rucaparib (600 mg) The ORR was 43.5% in men with measurable disease and 50.8% in men without measurable disease. ORRs were similar for men with germline and somatic variants and for men with BRCA1/BRCA2 pathogenic variants
— BRCA1: 5/115 (4%)
— BRCA2: 39/115 (34%)
71/115 (62%) had BRCA1/BRCA2 somatic variants: 63/115 men had a confirmed PSA response (54.8%), which differed by gene; however, the BRCA1 group was small:
— BRCA1: 8/115 (7%) — BRCA1: 2/13 (15.4%)
— BRCA2: 63/115 (55%) —BRCA2: 61/102 (59.8%)
De Bono et al. (2021)a[28] 104 men with progressive mCRPC and pathogenic variants in DDR-HRR genes; patients received at least one dose of talazoparib 25/71 (25%) patients had germline pathogenic variants: 13 in BRCA2, 4 in ATM, and 8 in other genes Patients received one or more doses of talazoparib per day (received 1 mg per day or 0.75 mg per day if the patient had moderate renal impairment) The ORR was observed in 7/28 (25%) men with germline pathogenic variants
Patients also had somatic variants in the following genes: 61 in BRCA1/2, 57 in BRCA2, 4 in PALB2, 17 in ATM, 22 in other genes (ATR, CHEK2, FANCA, MLH1, MRE11A, NBN, and RAD51C) After a median follow-up period of 16.4 mo (range, 11.1–22.1), the ORR for patients with somatic variants was 29.8% (31 of 104 patients; 95% CI, 21.2%–39.6%). Clinical benefit (defined as patients with complete response, partial response, or stable disease for ≥6 months from treatment start) varied between individuals with different pathogenic variants: BRCA1/2 (56%), BRCA2 (56%), PALB2 (25%), ATM (24%), other (0%)
References
  1. Sartor O: Early detection of prostate cancer in African-American men with an increased familial risk of disease. J La State Med Soc 148 (4): 179-85, 1996. [PUBMED Abstract]
  2. Matikainen MP, Schleutker J, Mörsky P, et al.: Detection of subclinical cancers by prostate-specific antigen screening in asymptomatic men from high-risk prostate cancer families. Clin Cancer Res 5 (6): 1275-9, 1999. [PUBMED Abstract]
  3. Catalona WJ, Antenor JA, Roehl KA, et al.: Screening for prostate cancer in high risk populations. J Urol 168 (5): 1980-3; discussion 1983-4, 2002. [PUBMED Abstract]
  4. Valeri A, Cormier L, Moineau MP, et al.: Targeted screening for prostate cancer in high risk families: early onset is a significant risk factor for disease in first degree relatives. J Urol 168 (2): 483-7, 2002. [PUBMED Abstract]
  5. Narod SA, Dupont A, Cusan L, et al.: The impact of family history on early detection of prostate cancer. Nat Med 1 (2): 99-101, 1995. [PUBMED Abstract]
  6. Giri VN, Beebe-Dimmer J, Buyyounouski M, et al.: Prostate cancer risk assessment program: a 10-year update of cancer detection. J Urol 178 (5): 1920-4; discussion 1924, 2007. [PUBMED Abstract]
  7. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer Early Detection. Version 2.2023. Plymouth Meeting, Pa: National Comprehensive Cancer Network, 2023. Available online with free registration. Last accessed November 30, 2023.
  8. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic. Version 2.2024. Plymouth Meeting, Pa: National Comprehensive Cancer Network, 2023. Available online with free registration. Last accessed September 18, 2024.
  9. U.S. Preventative Services Task Force: Screening for prostate cancer: U.S. Preventive Services Task Force recommendation statement. Rockville, Md: U.S. Preventative Services Task Force, 2018. Available online. Last accessed May 8, 2025.
  10. Wei JT, Barocas D, Carlsson S, et al.: Early Detection of Prostate Cancer: AUA/SUO Guideline Part I: Prostate Cancer Screening. J Urol 210 (1): 46-53, 2023. [PUBMED Abstract]
  11. American Cancer Society: American Cancer Society Recommendations for Prostate Cancer Early Detection. American Cancer Society, 2023. Available online. Last accessed May 8, 2025.
  12. Bancroft EK, Page EC, Castro E, et al.: Targeted prostate cancer screening in BRCA1 and BRCA2 mutation carriers: results from the initial screening round of the IMPACT study. Eur Urol 66 (3): 489-99, 2014. [PUBMED Abstract]
  13. National Collaborating Centre for Cancer (UK): Prostate Cancer: Diagnosis and Treatment. Cardiff, UK: National Collaborating Centre for Cancer, 2008. Available online. Last accessed May 8, 2025.
  14. Page EC, Bancroft EK, Brook MN, et al.: Interim Results from the IMPACT Study: Evidence for Prostate-specific Antigen Screening in BRCA2 Mutation Carriers. Eur Urol 76 (6): 831-842, 2019. [PUBMED Abstract]
  15. Carlo MI, Giri VN, Paller CJ, et al.: Evolving Intersection Between Inherited Cancer Genetics and Therapeutic Clinical Trials in Prostate Cancer: A White Paper From the Germline Genetics Working Group of the Prostate Cancer Clinical Trials Consortium. JCO Precis Oncol 2018: , 2018. [PUBMED Abstract]
  16. Annala M, Struss WJ, Warner EW, et al.: Treatment Outcomes and Tumor Loss of Heterozygosity in Germline DNA Repair-deficient Prostate Cancer. Eur Urol 72 (1): 34-42, 2017. [PUBMED Abstract]
  17. Pomerantz MM, Spisák S, Jia L, et al.: The association between germline BRCA2 variants and sensitivity to platinum-based chemotherapy among men with metastatic prostate cancer. Cancer 123 (18): 3532-3539, 2017. [PUBMED Abstract]
  18. Cheng HH, Pritchard CC, Boyd T, et al.: Biallelic Inactivation of BRCA2 in Platinum-sensitive Metastatic Castration-resistant Prostate Cancer. Eur Urol 69 (6): 992-5, 2016. [PUBMED Abstract]
  19. Mateo J, Cheng HH, Beltran H, et al.: Clinical Outcome of Prostate Cancer Patients with Germline DNA Repair Mutations: Retrospective Analysis from an International Study. Eur Urol 73 (5): 687-693, 2018. [PUBMED Abstract]
  20. Carter HB, Helfand B, Mamawala M, et al.: Germline Mutations in ATM and BRCA1/2 Are Associated with Grade Reclassification in Men on Active Surveillance for Prostate Cancer. Eur Urol 75 (5): 743-749, 2019. [PUBMED Abstract]
  21. Marshall CH, Sokolova AO, McNatty AL, et al.: Differential Response to Olaparib Treatment Among Men with Metastatic Castration-resistant Prostate Cancer Harboring BRCA1 or BRCA2 Versus ATM Mutations. Eur Urol 76 (4): 452-458, 2019. [PUBMED Abstract]
  22. Sokolova AO, Marshall CH, Lozano R, et al.: Efficacy of systemic therapies in men with metastatic castration resistant prostate cancer harboring germline ATM versus BRCA2 mutations. Prostate 81 (16): 1382-1389, 2021. [PUBMED Abstract]
  23. Antonarakis ES, Lu C, Luber B, et al.: Germline DNA-repair Gene Mutations and Outcomes in Men with Metastatic Castration-resistant Prostate Cancer Receiving First-line Abiraterone and Enzalutamide. Eur Urol 74 (2): 218-225, 2018. [PUBMED Abstract]
  24. Castro E, Romero-Laorden N, Del Pozo A, et al.: PROREPAIR-B: A Prospective Cohort Study of the Impact of Germline DNA Repair Mutations on the Outcomes of Patients With Metastatic Castration-Resistant Prostate Cancer. J Clin Oncol 37 (6): 490-503, 2019. [PUBMED Abstract]
  25. de Bono J, Mateo J, Fizazi K, et al.: Olaparib for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med 382 (22): 2091-2102, 2020. [PUBMED Abstract]
  26. Hussain M, Mateo J, Fizazi K, et al.: Survival with Olaparib in Metastatic Castration-Resistant Prostate Cancer. N Engl J Med 383 (24): 2345-2357, 2020. [PUBMED Abstract]
  27. Abida W, Patnaik A, Campbell D, et al.: Rucaparib in Men With Metastatic Castration-Resistant Prostate Cancer Harboring a BRCA1 or BRCA2 Gene Alteration. J Clin Oncol 38 (32): 3763-3772, 2020. [PUBMED Abstract]
  28. de Bono JS, Mehra N, Scagliotti GV, et al.: Talazoparib monotherapy in metastatic castration-resistant prostate cancer with DNA repair alterations (TALAPRO-1): an open-label, phase 2 trial. Lancet Oncol 22 (9): 1250-1264, 2021. [PUBMED Abstract]

Psychosocial Issues in Familial Prostate Cancer

Introduction

The psychological impact of a family history of prostate cancer and/or a positive genetic test for hereditary prostate cancer may influence well-being and screening/prevention behaviors. Important psychosocial issues that have been investigated include perceived risk of prostate cancer, distress, and prostate cancer screening behaviors. Most of this evidence is based on hereditary risk from family history, rather than the results of genetic testing. If known, this section includes data from studies of men who tested positive for hereditary prostate cancer genes. The presence of a prostate cancer family history is important, since most cases of hereditary prostate cancer have unknown etiologies, are polygenic, or cannot be explained by clinical multigene panel tests.[1] For more information about polygenic risk, see the Polygenic risk scores for prostate cancer section.

Prostate Cancer Risk Perception

Understanding drivers of prostate cancer risk perception is important because it can influence other psychological characteristics and is widely regarded as a predictor of health behaviors. Studies that have analyzed the influence of a family history of prostate cancer on perceived cancer risk have had mixed results.

Although family histories of prostate cancer can increase perceived prostate cancer risk in some men,[2] other studies found that men with family histories of prostate cancer considered their risk to be the same as, or less than, that of the average man.[3,4] Other factors, including being married, were associated with increased prostate cancer risk perception.[5] Perceived risk may be positively correlated with levels of concern about developing prostate cancer,[3] depression,[6] and/or the number of relatives who were diagnosed with prostate cancer in a family.[2,3] Confusion regarding the differences between benign prostatic hyperplasia and prostate cancer are confounders in prostate cancer risk perception.[6]

An international study of men with personal and/or family histories of BRCA1/BRCA2 pathogenic variants found that risk perception was associated with intrusive thoughts, avoidance coping, prostate cancer–related anxiety, and worry about prostate cancer.[7]

Psychological Distress

Although up to 50% of first-degree relatives (FDRs) of prostate cancer patients expressed concern about developing prostate cancer in some studies,[3] the level of anxiety reported by these individuals was relatively low and was related to lifetime risk, rather than short-term risk.[3,6] This concern was higher in men who were younger than their FDRs when their prostate cancers were diagnosed.[3] Unmarried FDRs may have worried more about developing prostate cancer than married men did.[3] In a Swedish study, only 3% of participants (n = 110) said that worry about prostate cancer affected their daily lives fairly much, and 28% said that it affected their daily lives slightly.[6]

In men who self-referred for free prostate cancer screening, general– and prostate cancer–related distress did not differ significantly between men who were FDRs of prostate cancer patients and men who were not.[2] In a Swedish study, male FDRs who reported higher levels of worry about developing prostate cancer had higher Hospital Anxiety and Depression Scale (HADS) scores than men with lower levels of worry. In FDRs, the average HADS score was in the 75th percentile.[6]

A study measured anxiety and general quality-of-life in 220 men with family histories of prostate cancer who were undergoing prostate cancer screening with prostate-specific antigen (PSA) tests.[8] In this group, 20% of participants experienced a moderate deterioration in their anxiety scores, and 20% experienced a minimal deterioration in health-related quality-of-life (HRQOL) scores. The average period between assessments was 35 days, which encompassed PSA testing and a wait for results that averaged 15.6 days. Only men with normal PSA values (4 ng/mL or less) were assessed. Factors associated with HRQOL deterioration included being 50 to 60 years old, having more than two relatives with prostate cancer, having an anxious personality, being well-educated, and not having children living at home. The authors stressed that analysis of prostate cancer screening impact on FDRs should not rely solely on mean changes in HRQOL scores. Since a subset of men who received normal results experienced screening-associated distress, interventions may be needed to encourage men with increased hereditary risk to comply with repeated screening requests.

Screening for Prostate Cancer

For more information about prostate cancer screening in the general population, see Prostate Cancer Screening, and for more information about screening individuals with hereditary prostate cancer syndromes, see the Prostate Cancer Screening section.

For most cancer types, knowing that an individual has hereditary risk leads to recommendations for approved (if not proven) screening. This complicates prostate cancer screening, because there is a lack of clear recommendations for many high-risk men and men in the general population. This creates uncertainty about the clinical and psychosocial factors related to prostate cancer screening.

Several small studies have examined the behavioral correlates of prostate cancer screening at average and increased prostate cancer risk, based on family history.[4,6,8–14] In general, results differed regarding whether men with a family histories of prostate cancer were more likely to be screened than those without hereditary prostate cancer risk. It is unclear if the prostate cancer screening implemented in each group was appropriate for its risk status. Most studies had a relatively small numbers of subjects, and the prostate cancer screening criteria were not uniform across studies, making generalizations difficult. Notably, all of these studies predate the era of hereditary cancer testing, and there is a paucity of research about prostate cancer screening behaviors in males who have undergone hereditary prostate cancer genetic testing.

References
  1. Ni Raghallaigh H, Eeles R: Genetic predisposition to prostate cancer: an update. Fam Cancer 21 (1): 101-114, 2022. [PUBMED Abstract]
  2. Taylor KL, DiPlacido J, Redd WH, et al.: Demographics, family histories, and psychological characteristics of prostate carcinoma screening participants. Cancer 85 (6): 1305-12, 1999. [PUBMED Abstract]
  3. Beebe-Dimmer JL, Wood DP, Gruber SB, et al.: Risk perception and concern among brothers of men with prostate carcinoma. Cancer 100 (7): 1537-44, 2004. [PUBMED Abstract]
  4. Miller SM, Diefenbach MA, Kruus LK, et al.: Psychological and screening profiles of first-degree relatives of prostate cancer patients. J Behav Med 24 (3): 247-58, 2001. [PUBMED Abstract]
  5. Montgomery GH, Erblich J, DiLorenzo T, et al.: Family and friends with disease: their impact on perceived risk. Prev Med 37 (3): 242-9, 2003. [PUBMED Abstract]
  6. Bratt O, Damber JE, Emanuelsson M, et al.: Risk perception, screening practice and interest in genetic testing among unaffected men in families with hereditary prostate cancer. Eur J Cancer 36 (2): 235-41, 2000. [PUBMED Abstract]
  7. Bancroft EK, Saya S, Page EC, et al.: Psychosocial impact of undergoing prostate cancer screening for men with BRCA1 or BRCA2 mutations. BJU Int 123 (2): 284-292, 2019. [PUBMED Abstract]
  8. Cormier L, Reid K, Kwan L, et al.: Screening behavior in brothers and sons of men with prostate cancer. J Urol 169 (5): 1715-9, 2003. [PUBMED Abstract]
  9. Vadaparampil ST, Jacobsen PB, Kash K, et al.: Factors predicting prostate specific antigen testing among first-degree relatives of prostate cancer patients. Cancer Epidemiol Biomarkers Prev 13 (5): 753-8, 2004. [PUBMED Abstract]
  10. Bock CH, Peyser PA, Gruber SB, et al.: Prostate cancer early detection practices among men with a family history of disease. Urology 62 (3): 470-5, 2003. [PUBMED Abstract]
  11. Jacobsen PB, Lamonde LA, Honour M, et al.: Relation of family history of prostate cancer to perceived vulnerability and screening behavior. Psychooncology 13 (2): 80-5, 2004. [PUBMED Abstract]
  12. Roumier X, Azzouzi R, Valéri A, et al.: Adherence to an annual PSA screening program over 3 years for brothers and sons of men with prostate cancer. Eur Urol 45 (3): 280-5; author reply 285-6, 2004. [PUBMED Abstract]
  13. Weinrich SP: Prostate cancer screening in high-risk men: African American Hereditary Prostate Cancer Study Network. Cancer 106 (4): 796-803, 2006. [PUBMED Abstract]
  14. Ross LE, Uhler RJ, Williams KN: Awareness and use of the prostate-specific antigen test among African-American men. J Natl Med Assoc 97 (7): 963-71, 2005. [PUBMED Abstract]

Latest Updates to This Summary (05/09/2025)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Risk Factors for Prostate Cancer

Updated statistics with new cancer cases and deaths for 2025 (cited American Cancer Society as reference 1).

Updated statistics with estimated new cancer cases and deaths for different racial and ethnic groups in 2025.

Risk Assessment for Prostate Cancer

Updated statistics with estimated new cancer cases and deaths for different racial and ethnic groups in 2025 (cited American Cancer Society as reference 1).

This summary is written and maintained by the PDQ Cancer Genetics Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the genetics of prostate cancer. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Cancer Genetics Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Genetics of Prostate Cancer are:

  • Kathleen A. Calzone, PhD, RN, AGN-BC, FAAN (National Cancer Institute)
  • Veda N. Giri, MD (Yale University)
  • Suzanne C. O’Neill, PhD (Georgetown University)
  • Mark Pomerantz, MD (Dana-Farber Cancer Institute)
  • John M. Quillin, PhD, MPH, MS (Virginia Commonwealth University)
  • Charite Ricker, MS, CGC (University of Southern California)
  • Catharine Wang, PhD, MSc (Boston University School of Public Health)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website’s Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Cancer Genetics Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”

The preferred citation for this PDQ summary is:

PDQ® Cancer Genetics Editorial Board. PDQ Genetics of Prostate Cancer. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/prostate/hp/prostate-genetics-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389227]

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Liver (Hepatocellular) Cancer Prevention (PDQ®)–Health Professional Version

Liver (Hepatocellular) Cancer Prevention (PDQ®)–Health Professional Version

Overview

Note: The Overview section summarizes the published evidence on this topic. The rest of the summary describes the evidence in more detail.

Other PDQ summaries containing information related to liver (hepatocellular) cancer prevention include the following:

Who Is at Risk?

The critical etiologic agent in at least 80% of hepatocellular cancer (HCC) cases worldwide is chronic hepatitis B virus (HBV) infection or chronic hepatitis C virus (HCV) infection.[1] Both viruses, either alone or when present with other risk factors, are responsible for staggering increases in the risk of HCC, relative to the absence of these hepatitis viruses. Men with chronic HBV or HCV infection are more likely to develop HCC than are women with the same chronic infection, with some, but not the entire difference explained by varying prevalence of other risk factors.[2] Cirrhosis, regardless of its etiology, predisposes patients to HCC [3] and is present in 70% to 90% of HCC patients at the time of diagnosis.[4] Heavy alcohol use is a strong etiologic agent for HCC because it can cause cirrhosis and the presence of HBV or HCV increases risk even more.[5] Exposure to aflatoxin B1 strongly increases HCC risk in individuals with chronic HBV infection and may do so, but to a much lesser extent, in individuals without chronic HBV infection.[1] Nonalcoholic steatohepatitis (NASH) increases risk of HCC among patients who have accompanying cirrhosis [6] and may modestly increase risk in patients without cirrhosis.[7,8] Cigarette smoking modestly increases the risk.[9] Untreated hereditary hemochromatosis and certain other rare medical and genetic conditions are responsible for large increases in HCC risk but are responsible for only a small percentage of cases.[1] The future HCC incidence among patients newly diagnosed with nonalcoholic fatty liver (NAFL) is not known, and because NAFL can progress to NASH, and NAFL patients can develop cirrhosis, there is reason to believe that NAFL patients are at elevated risk.[10] A diagnosis of metabolic syndrome (MetS) is associated with an increased risk of HCC,[11] as are obesity and type 2 diabetes, which are common component conditions of MetS.[11] Those three conditions also can occur concurrently with NAFL.[12] The frequent coexistence of these four conditions makes the interpretation of condition-specific risk measures difficult. Decreases in HCC incidence rates have occurred after implementation of HBV vaccination programs,[13] and treatment with nucleos(t)ide analog therapy reduces but does not eliminate the risk of HCC in patients with chronic HBV infection.[14] Replacement of a food supply that was heavily contaminated with aflatoxin B1 with one that contained much lower levels resulted in a more than 50% reduction in primary liver cancer.[15] HCV treatment with direct-acting antivirals that results in sustained virologic response may reduce HCC risk.[16]

Factors With Adequate Evidence of Increased Risk of Hepatocellular Cancer (HCC)

Chronic hepatitis B virus (HBV) infection

Based on solid evidence, chronic HBV infection causes HCC.

Magnitude of Effect: Chronic HBV infection is the leading cause of HCC in Asia and Africa.[17] HBV, either alone or in the presence of other risk factors, is responsible for large increases in the risk of developing HCC. Although degree of increase in risk varies by the presence of other factors or characteristics of infection, it is reasonable to assume that, on average, relative risks (RRs) of HBV are at least fivefold.[2]

  • Study Design: Prospective cohort studies; case-control studies.
  • Internal Validity: Good.
  • Consistency: Good.
  • External Validity: Good.

Chronic hepatitis C virus (HCV) infection

Based on solid evidence, chronic HCV infection causes HCC.

Magnitude of Effect: HCV infection is the leading cause of HCC in North America, Europe, and Japan.[17] HCV, either alone or in the presence of other risk factors, is responsible for staggering increases in the risk of developing HCC. Although degree of increase in risk varies by the presence of other factors or characteristics of infection, it is reasonable to assume that, on average, relative risks of HCV are at least 15-fold.[18]

  • Study Design: Prospective cohort studies; case-control studies.
  • Internal Validity: Good.
  • Consistency: Good.
  • External Validity: Good.

Cirrhosis

Based on solid evidence, cirrhosis, regardless of its etiology, predisposes patients to HCC.[3] HCC develops in the presence of a cirrhotic liver in most instances.[3]

Magnitude of Effect: In autopsy studies, 80% to 90% of individuals who die of HCC have cirrhotic livers.[3] The risk of HCC varies by cause of cirrhosis; patients with HCV-related cirrhosis are at greater risk than those with HBV-related cirrhosis, and those with HBV-related cirrhosis are at greater risk than those with alcohol-related cirrhosis.[17,18] The 5-year cumulative risk of developing HCC for patients with cirrhosis ranges between 5% and 30%.[18]

  • Study Design: Autopsy studies, prospective cohort studies, case-control studies.
  • Internal Validity: Good.
  • Consistency: Good.
  • External Validity: Good.

Heavy alcohol use

Based on solid evidence, heavy alcohol use increases HCC risk.[2] Heavy alcohol use causes cirrhosis, and the development of most alcohol-related HCC is thought to occur via that pathway.[3] However, heavy alcohol users who do not develop cirrhosis are also at elevated risk of developing HCC.[3]

Magnitude of Effect: Heavy alcohol consumption increases HCC risk at least twofold; some studies suggest at least a fivefold increase.[17] Among individuals with HBV or HCV infection, the magnitude of the association is about the same.[19] However, heavy alcohol consumption and chronic HCV infection appear to act synergistically on HCC risk, resulting in perhaps a 100-fold increase in risk relative to individuals who are not infected and not heavy consumers of alcohol. The existence of a synergistic effect with HBV is less consistent, although one study observed a 50-fold increase in risk.[19]

  • Study Design: Case-control study, case series, cohort studies.
  • Internal Validity: Fair.
  • Consistency: Good.
  • External Validity: Good.

Aflatoxin B1

Aflatoxin B1 is a mycotoxin that can contaminate corn and peanuts stored in warm, humid environments.[1] Based on solid evidence, aflatoxin B1 exposure increases HCC risk.[18]

Magnitude of Effect: In individuals with chronic HBV infection, aflatoxin B1 exposure is estimated to increase risk 60-fold.[18] Because chronic HBV infection is highly prevalent in areas where exposure to aflatoxin B1 is an environmental concern, it is difficult to assess the magnitude of effect in individuals without HBV, although the available limited data suggest that the increase in risk may be fourfold.[20]

  • Study Design: Ecological studies, prospective cohort studies.
  • Internal Validity: Good.
  • Consistency: Good.
  • External Validity: Good.

Nonalcoholic steatohepatitis (NASH)

Based on fair evidence, NASH increases risk of HCC.

Magnitude of Effect: In a study of 195 patients with NASH and cirrhosis, 13% were diagnosed with HCC after a median follow-up of 3.2 years.[6] In patients with NASH without cirrhosis, HCC occurs infrequently; however, these patients are thought to have a modestly elevated risk of HCC.[7,8]

  • Study Design: Prospective cohort studies, medical record abstraction, case series.
  • Internal Validity: Fair.
  • Consistency: Good.
  • External Validity: Fair.

Cigarette smoking

Based on fair evidence, cigarette smoking increases HCC risk.

Magnitude of Effect: Cigarette smoking in the absence of viral infection is associated with a modest (up to twofold) increase in HCC risk. Cigarette smoking and presence of chronic HBV or HCV infection results in at least an additive effect on HCC risk.[9]

  • Study Design: Case-control and cohort studies.
  • Internal Validity: Fair.
  • Consistency: Fair.
  • External Validity: Fair.

Certain rare genetic and medical conditions (untreated hereditary hemochromatosis [HH], alpha-1-antitrypsin deficiency, glycogen storage disease, porphyria cutanea tarda, and Wilson disease)

Based on solid evidence, untreated HH, alpha-1-antitrypsin deficiency (AAT), glycogen storage disease, porphyria cutanea tarda, and Wilson disease increase the risk of HCC, but account for few cases.[1] In the absence of treatment, HH leads to cirrhosis, although there are reports of HCC developing in patients with noncirrhotic livers.[1]

Magnitude of Effect: Untreated HH confers at least a 20-fold increase in risk,[17] although risk varies according to other factors (including HBV and HCV infection). Treatment to reduce iron stores can greatly reduce risk. AAT deficiency, glycogen storage disease, porphyria cutanea tarda, and Wilson disease confer large but varied increases in risk of HCC.[1]

  • Study Design: Prospective cohort studies (HH), case series (other conditions).
  • Internal Validity: Fair (HCC), not applicable (N/A; other conditions).
  • Consistency: Fair (HCC), good (other conditions).
  • External Validity: Fair (HCC), N/A (other conditions).

Factors With Inadequate Evidence of Increased Risk of HCC

Nonalcoholic fatty liver

Based on limited evidence, some patients with NAFL will develop NASH or cirrhosis.[10] Therefore, NAFL is assumed to increase HCC risk.

Magnitude of Effect: A small clinical study suggested that between 20% and 50% of NAFL patients may develop NASH.[10] Up to 4% of NAFL patients may develop cirrhosis.[21] The observation that NAFL patients have developed these conditions, which are known to increase HCC risk, leads to the conclusion that NAFL increases HCC risk, even though the future incidence of HCC among patients newly diagnosed with NAFL is not known.

  • Study Design: Biopsy studies, case series.
  • Internal Validity: Poor.
  • Consistency: N/A.
  • External Validity: N/A.

Metabolic syndrome (MetS)

Based on fair evidence, a diagnosis of MetS is associated with an increased risk of HCC.[22]

Magnitude of Effect: A meta-analysis of more than 7,000 HCC cases from four studies produced a risk ratio of 1.8 (95% confidence interval [CI], 1.37–2.40) for a diagnosis of MetS. The combined risk ratios were varied (range, 1.2 [95% CI, 0.55–2.53] to 3.7 [95% CI, 1.78–7.58]).[23]

  • Study Design: Case-control studies and cohort studies.
  • Internal Validity: Fair.
  • Consistency: Good.
  • External Validity: Good.

Obesity

Based on fair evidence, obesity is associated with an increase in HCC risk.

Magnitude of Effect: Numerous large epidemiological studies suggest about a twofold increase in HCC risk for individuals who are obese.[11]

  • Study Design: Case-control studies, retrospective and prospective cohort studies.
  • Internal Validity: Fair.
  • Consistency: Good.
  • External Validity: Good.

Type 2 diabetes

Based on fair evidence, type 2 diabetes is associated with an increase in HCC risk.

Magnitude of Effect: Numerous large epidemiological studies suggest a twofold to fourfold increase in HCC risk for individuals with type 2 diabetes.[11]

  • Study Design: Case-control studies, retrospective and prospective cohort studies.
  • Internal Validity: Fair.
  • Consistency: Good.
  • External Validity: Good.

Interventions With Adequate Evidence of Decreased Risk of HCC

HBV vaccination

Based on solid evidence, neonatal HBV vaccination or catch-up vaccination at young ages reduces HCC incidence in young adults.[24]

Magnitude of Effect: Reductions in pediatric and young adult HCC risk of at least 50% have been observed in cohorts immunized at birth or during early childhood. It is predicted that universal neonate immunization will ultimately eliminate 70% to 85% of global HCC cases.[24,25]

  • Study Design: Cluster randomized controlled trial (RCT), historical trends, mathematical modeling.
  • Internal Validity: Good.
  • Consistency: Good.
  • External Validity: Good.

Treatment for chronic HBV infection

Based on solid evidence, chronic HBV treatment with nucleos(t)ide analog therapy reduces the risk of HCC.[14]

Magnitude of Effect: About a 50% reduction in incidence.

  • Study Design: Meta-analysis of clinical trials (some randomized, some blinded), retrospective cohort studies.
  • Internal Validity: Good.
  • Consistency: Good.
  • External Validity: Good.

Availability of food not contaminated with aflatoxin B1

Based on solid evidence, replacement of food highly contaminated with aflatoxin B1 with food that harbors much lower levels of aflatoxin B1 leads to a reduction in liver cancer mortality.[15]

Magnitude of Effect: A more-than-50% reduction in liver cancer mortality.

  • Study Design: Historical trends.
  • Internal Validity: Good.
  • Consistency: N/A.
  • External Validity: N/A.

Interventions With Inadequate Evidence of Decreased Risk of HCC

HCV treatment with direct-acting antivirals (DAAs)

Based on fair evidence, HCV treatment with DAAs that results in sustained virologic response (SVR) may reduce HCC risk.

Magnitude of Effect: Patients treated with DAAs who attained SVR had an approximately 75% reduction in HCC risk relative to those who did not attain SVR.[16] Reduction in relative risk with SVR was similar in patients with cirrhosis (hazard ratio [HR], 0.31; 95% CI, 0.23–0.44) and patients without cirrhosis (HR, 0.18; 95% CI, 0.11–0.30). There does not appear to be an increased risk of HCC among individuals, with or without cirrhosis, who received DAAs as opposed to those who received interferon.[26,27]

  • Study Design: Retrospective cohort, case series.
  • Internal Validity: Fair.
  • Consistency: Fair.
  • External Validity: Fair.

Statin use among adults with HBV or HCV

Based on fair evidence, statin use may be associated with a reduced risk of developing HCC in patients with HBV or HCV infection.[28] Statin use may be associated with a reduced risk of developing HCC in all adults.

Magnitude of Effect: Relative reductions in HCC risk in adults with HBV or HCV infection of approximately 50% was found in a systematic review of observational studies (kappa statistic, 13). A statistically significant effect was observed with lipophilic statin use (HR, 0.52; P < .001; kappa statistic, 2) but not with hydrophilic statin use (RR, 0.89; P = .21; kappa statistic, 2) (P for subgroup difference < .001).[28] However, there was moderate heterogeneity in the two studies that reported on hydrophilic statin use, with one study [29,30] showing a 49% statistically significant relative reduction and the other study [31,32] showing a nonsignificant 5% relative reduction.

  • Study Design: Systematic review and meta-analysis of observational study.
  • Internal Validity: Good.
  • Consistency: Good across patient characteristics, including possibly HBV/HCV status but possibly inconsistent for the type of statin use (lipophilic vs. hydrophilic).
  • External Validity: Unclear. A systematic review and meta-analysis of observational and randomized studies in adults with and without HBV/HCV infection (kappa statistic, 10) reported that statin use was associated with a 37% relative reduction in developing HCC (odds ratio [OR], 0.63; 95% CI, 0.52–0.76). Five studies did not report the baseline prevalence of HBV/HCV in individuals; one study noted that 100% of individuals had HBV infection, another study noted that HBV/HCV was present in 23.9%/25.1% at baseline while another study noted 1.9%/14.7%, respectively. Two other studies reported that HBV/HCV was present in less than 10% of the population. In sensitivity analyses, the association between statin use and HCC was observed in observational studies (kappa statistic, 7; adjusted OR, 0.60; 95% CI, 0.49–0.73) but not in RCTs (kappa statistic, 3; OR, 0.95; 95% CI, 0.62–1.45 [although CIs were wide]).[33]
References
  1. London WT, McGlynn K: Liver cancer. In: Schottenfeld D, Fraumeni JF Jr, eds.: Cancer Epidemiology and Prevention. 3rd ed. Oxford University Press, 2006, pp 763-86.
  2. El-Serag HB, Kanwal F: Epidemiology of hepatocellular carcinoma in the United States: where are we? Where do we go? Hepatology 60 (5): 1767-75, 2014. [PUBMED Abstract]
  3. Fattovich G, Stroffolini T, Zagni I, et al.: Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology 127 (5 Suppl 1): S35-50, 2004. [PUBMED Abstract]
  4. Hartke J, Johnson M, Ghabril M: The diagnosis and treatment of hepatocellular carcinoma. Semin Diagn Pathol 34 (2): 153-159, 2017. [PUBMED Abstract]
  5. Donato F, Tagger A, Gelatti U, et al.: Alcohol and hepatocellular carcinoma: the effect of lifetime intake and hepatitis virus infections in men and women. Am J Epidemiol 155 (4): 323-31, 2002. [PUBMED Abstract]
  6. Ascha MS, Hanouneh IA, Lopez R, et al.: The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. Hepatology 51 (6): 1972-8, 2010. [PUBMED Abstract]
  7. White DL, Kanwal F, El-Serag HB: Association between nonalcoholic fatty liver disease and risk for hepatocellular cancer, based on systematic review. Clin Gastroenterol Hepatol 10 (12): 1342-1359.e2, 2012. [PUBMED Abstract]
  8. Perumpail RB, Wong RJ, Ahmed A, et al.: Hepatocellular Carcinoma in the Setting of Non-cirrhotic Nonalcoholic Fatty Liver Disease and the Metabolic Syndrome: US Experience. Dig Dis Sci 60 (10): 3142-8, 2015. [PUBMED Abstract]
  9. Chuang SC, Lee YC, Hashibe M, et al.: Interaction between cigarette smoking and hepatitis B and C virus infection on the risk of liver cancer: a meta-analysis. Cancer Epidemiol Biomarkers Prev 19 (5): 1261-8, 2010. [PUBMED Abstract]
  10. Calzadilla Bertot L, Adams LA: The Natural Course of Non-Alcoholic Fatty Liver Disease. Int J Mol Sci 17 (5): , 2016. [PUBMED Abstract]
  11. Streba LA, Vere CC, Rogoveanu I, et al.: Nonalcoholic fatty liver disease, metabolic risk factors, and hepatocellular carcinoma: an open question. World J Gastroenterol 21 (14): 4103-10, 2015. [PUBMED Abstract]
  12. Kim D, Touros A, Kim WR: Nonalcoholic Fatty Liver Disease and Metabolic Syndrome. Clin Liver Dis 22 (1): 133-140, 2018. [PUBMED Abstract]
  13. Kao JH: Hepatitis B vaccination and prevention of hepatocellular carcinoma. Best Pract Res Clin Gastroenterol 29 (6): 907-17, 2015. [PUBMED Abstract]
  14. Singal AK, Salameh H, Kuo YF, et al.: Meta-analysis: the impact of oral anti-viral agents on the incidence of hepatocellular carcinoma in chronic hepatitis B. Aliment Pharmacol Ther 38 (2): 98-106, 2013. [PUBMED Abstract]
  15. Chen JG, Egner PA, Ng D, et al.: Reduced aflatoxin exposure presages decline in liver cancer mortality in an endemic region of China. Cancer Prev Res (Phila) 6 (10): 1038-45, 2013. [PUBMED Abstract]
  16. Kanwal F, Kramer J, Asch SM, et al.: Risk of Hepatocellular Cancer in HCV Patients Treated With Direct-Acting Antiviral Agents. Gastroenterology 153 (4): 996-1005.e1, 2017. [PUBMED Abstract]
  17. Lafaro KJ, Demirjian AN, Pawlik TM: Epidemiology of hepatocellular carcinoma. Surg Oncol Clin N Am 24 (1): 1-17, 2015. [PUBMED Abstract]
  18. El-Serag HB: Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology 142 (6): 1264-1273.e1, 2012. [PUBMED Abstract]
  19. Grewal P, Viswanathen VA: Liver cancer and alcohol. Clin Liver Dis 16 (4): 839-50, 2012. [PUBMED Abstract]
  20. Bosetti C, Turati F, La Vecchia C: Hepatocellular carcinoma epidemiology. Best Pract Res Clin Gastroenterol 28 (5): 753-70, 2014. [PUBMED Abstract]
  21. Rinella ME: Nonalcoholic fatty liver disease: a systematic review. JAMA 313 (22): 2263-73, 2015. [PUBMED Abstract]
  22. Mittal S, El-Serag HB, Sada YH, et al.: Hepatocellular Carcinoma in the Absence of Cirrhosis in United States Veterans is Associated With Nonalcoholic Fatty Liver Disease. Clin Gastroenterol Hepatol 14 (1): 124-31.e1, 2016. [PUBMED Abstract]
  23. Jinjuvadia R, Patel S, Liangpunsakul S: The association between metabolic syndrome and hepatocellular carcinoma: systemic review and meta-analysis. J Clin Gastroenterol 48 (2): 172-7, 2014. [PUBMED Abstract]
  24. Qu C, Chen T, Fan C, et al.: Efficacy of neonatal HBV vaccination on liver cancer and other liver diseases over 30-year follow-up of the Qidong hepatitis B intervention study: a cluster randomized controlled trial. PLoS Med 11 (12): e1001774, 2014. [PUBMED Abstract]
  25. McGlynn KA, Petrick JL, London WT: Global epidemiology of hepatocellular carcinoma: an emphasis on demographic and regional variability. Clin Liver Dis 19 (2): 223-38, 2015. [PUBMED Abstract]
  26. Li DK, Ren Y, Fierer DS, et al.: The short-term incidence of hepatocellular carcinoma is not increased after hepatitis C treatment with direct-acting antivirals: An ERCHIVES study. Hepatology 67 (6): 2244-2253, 2018. [PUBMED Abstract]
  27. Carrat F, Fontaine H, Dorival C, et al.: Clinical outcomes in patients with chronic hepatitis C after direct-acting antiviral treatment: a prospective cohort study. Lancet 393 (10179): 1453-1464, 2019. [PUBMED Abstract]
  28. Li X, Sheng L, Liu L, et al.: Statin and the risk of hepatocellular carcinoma in patients with hepatitis B virus or hepatitis C virus infection: a meta-analysis. BMC Gastroenterol 20 (1): 98, 2020. [PUBMED Abstract]
  29. Tsan YT, Lee CH, Wang JD, et al.: Statins and the risk of hepatocellular carcinoma in patients with hepatitis B virus infection. J Clin Oncol 30 (6): 623-30, 2012. [PUBMED Abstract]
  30. Tsan YT, Lee CH, Ho WC, et al.: Statins and the risk of hepatocellular carcinoma in patients with hepatitis C virus infection. J Clin Oncol 31 (12): 1514-21, 2013. [PUBMED Abstract]
  31. Simon TG, Duberg AS, Aleman S, et al.: Lipophilic Statins and Risk for Hepatocellular Carcinoma and Death in Patients With Chronic Viral Hepatitis: Results From a Nationwide Swedish Population. Ann Intern Med 171 (5): 318-327, 2019. [PUBMED Abstract]
  32. Simon TG, Bonilla H, Yan P, et al.: Atorvastatin and fluvastatin are associated with dose-dependent reductions in cirrhosis and hepatocellular carcinoma, among patients with hepatitis C virus: Results from ERCHIVES. Hepatology 64 (1): 47-57, 2016. [PUBMED Abstract]
  33. Singh S, Singh PP, Singh AG, et al.: Statins are associated with a reduced risk of hepatocellular cancer: a systematic review and meta-analysis. Gastroenterology 144 (2): 323-32, 2013. [PUBMED Abstract]

Incidence, Mortality, and Survival

Liver cancer, regardless of histology, accounts for about 2% of cancer diagnoses and 5% of cancer deaths in the United States, and is not among the top ten diagnosed cancers in the United States.[1] It is, however, the sixth-leading cause of cancer deaths in the United States.[1] About 41,630 new cases of liver cancer are expected to occur in the United States in 2024; the expected number of deaths is 29,840 individuals.[2] Hepatocellular cancer (HCC) accounts for about 71% of all liver cancers in the United States.[2] In 1975, liver cancer incidence in the United States was 2.64 per 100,000. In 2021, the rate had risen more than threefold to 8.39 per 100,000.[3] Five-year survival rates varies by stage, from a high of 37.3% for localized disease to a low of 3.3% for distant disease.[1] In the United States, rates of liver cancer incidence are lowest in White individuals and highest in American Indian or Alaska Native individuals. Rates of liver cancer death are lowest in White individuals and highest in American Indian or Alaska Native individuals. Rates are also higher in Hispanic individuals, as compared with non-Hispanic individuals.[1]

Worldwide, liver cancer is the sixth most common cancer and the third leading cause of cancer-related death.[4] HCC results in about 905,677 new cases and 830,180 deaths worldwide each year;[4] in most countries, the HCC annual incidence and mortality rates are nearly identical.[4] It is the fifth most frequently diagnosed cancer in adult men and the ninth most commonly diagnosed cancer in women.[4] The incidence of HCC varies widely according to geographic location.[4] High-incidence regions include Northern and Western Africa (Egypt, the Gambia, Guinea) and Eastern and South-Eastern Asia (Mongolia, Cambodia, and Vietnam). HCC incidence is low in North and South America, most of Europe, Australia, and parts of the Middle East.[4,5] In all parts of the world, HCC is more common in men than in women.[4,5]

References
  1. National Cancer Institute: SEER Stat Fact Sheets: Liver and Intrahepatic Bile Duct Cancer. Bethesda, Md: National Cancer Institute. Available online. Last accessed December 5, 2024.
  2. American Cancer Society: Cancer Facts and Figures 2024. American Cancer Society, 2024. Available online. Last accessed December 30, 2024.
  3. Surveillance Research Program, National Cancer Institute: SEER*Explorer: An interactive website for SEER cancer statistics. Bethesda, MD: National Cancer Institute. Available online. Last accessed December 30, 2024.
  4. Sung H, Ferlay J, Siegel RL, et al.: Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 71 (3): 209-249, 2021. [PUBMED Abstract]
  5. Jemal A, Bray F, Center MM, et al.: Global cancer statistics. CA Cancer J Clin 61 (2): 69-90, 2011 Mar-Apr. [PUBMED Abstract]

Factors With Adequate Evidence of Increased Risk of HCC

Chronic HBV Infection

Chronic hepatitis B virus (HBV) infection is the leading cause of hepatocellular cancer (HCC) in Asia and Africa.[1] Hepatitis B is transmitted through contact with infected blood, semen, or other body fluids. In areas with high incidence of chronic HBV infection and HCC, about 70% of infections are acquired in the perinatal period or in early childhood.[2] In addition to maternal-to-child transmission, HBV can be spread through sexual contact and contact with infected blood.[3] In the United States, the most common route of transmission is sharing drug-injecting needles.[4] It is estimated that 850,000 to 2.2 million people in the United States have chronic HBV infection [3] and that the infection is responsible for 10% to 15% of HCC cases.[5] The World Health Organization (WHO) estimates that 240 million people are infected worldwide.[4]

Evidence for a causal relationship between chronic HBV infection and HCC comes from etiologic studies, case series, case-control studies, and prospective epidemiological studies.[2] Ecological studies demonstrate a strong positive correlation between the prevalence of chronic HBV and HCC incidence and mortality. HBV is present in liver tissue in nearly all patients who are seropositive for the virus and have HCC,[2] and HBV DNA has been found in 10% to 20% of HCC tumors in patients who are seronegative but are positive for HBV antibodies.[2] Case-control studies and prospective studies have observed odds ratios or relative risks (RRs) of at least 5 for chronic HBV infection.[2] Some prospective studies have observed RRs exceeding 50.[2] The lifetime risk of HCC in individuals chronically infected with HBV is estimated to be between 10% and 25%.[2] Clinical factors that have been reported to increase risk in individuals with chronic HBV infection include higher levels of HBV replication; certain HBV genotypes; longer duration of infection; and coinfection with hepatitis C virus (HCV), HIV, or hepatitis D virus.[6] The presence of cirrhosis increases risk, although HBV can cause HCC in the absence of cirrhosis.[7]

Coinfection with HCV appears to have an additive effect on risk.[8] In addition, degree of increased risk of chronic HBV varies with the presence of other factors and is discussed in sections of this summary that cover those specific factors.

Chronic HCV Infection

Chronic HCV infection is the leading cause of HCC in North America, Europe, and Japan.[1] Chronic HCV infection accounts for about one-third of HCC cases in the United States.[4] HCV is a blood-borne pathogen; before screening of the blood supply or donated human organs (1992), HCV infection often was acquired during blood transfusions or organ transplants. Today, most new infections are caused by the sharing of drug-injecting needles. HCV can be transmitted during sexual contact, although this occurs infrequently. An estimated 2.7 to 3.9 million people in the United States have chronic hepatitis C.[9] In the United States, more cases are attributable to chronic HCV infection than to any other risk factor.[10]

Even though the mechanisms through which HCV increases HCC risk are unclear, chronic HCV infection is accepted as playing a causal role in the development of HCC. Evidence of a strong association comes primarily from cross-sectional and case-control studies, which suggest that individuals with HCV infection have at least a 15-fold increase in HCC risk, relative to individuals without HCV infection.[6] A prospective study of more than 23,000 residents of Taiwan observed a cumulative lifetime HCC incidence of 24% in men and 17% in women;[11] other prospective studies, including cases series of individuals accidently infected with HCV through blood transfusion, have produced a wide range of incidence estimates.[2] The reason for such variability is likely the variation in prevalence of advanced fibrosis and cirrhosis in the groups being studied. Chronic HCV infection typically leads to liver fibrosis, but HCC is rare in HCV-positive individuals with minimal or no fibrosis.[6] Once HCV-related cirrhosis develops, HCC develops annually in 1% to 8% of patients.[6] Other clinical factors that have been reported to increase risk in individuals with chronic HCV infection include coinfection with HBV or HIV, HCV genotype 1b, and steatosis.[6]

Coinfection with HBV appears to have an additive effect on risk.[8] In addition, degree of increased risk of chronic HCV varies with the presence of other factors and is discussed in sections of this summary that cover those specific factors.

Cirrhosis

The prevalence of cirrhosis in the United States is estimated to be 0.3%, which corresponds to more than 600,000 adults.[12] Because cirrhosis is present in 70% to 90% of HCC patients at the time of diagnosis,[13] cirrhosis is considered a predisposing factor for HCC.[14] In autopsy studies, 80% to 90% of individuals who die of HCC have cirrhotic livers.[14] A standardized incidence ratio of 60 was observed in a prospective 16-year study of 11,065 Danish individuals with cirrhosis (more than one-half of cases caused by alcohol consumption).[2] The 5-year cumulative risk of developing HCC for patients with cirrhosis is 5% to 30%, with risk dependent on cause of cirrhosis and stage of cirrhosis.[6]

With perhaps the exception of aflatoxin B1, all HCC risk factors are also risk factors for cirrhosis.[1] In patients with established cirrhosis, HCC risk may be modifiable with elimination of the factor responsible for cirrhosis.[15] However, evidence to support that possibility is limited, and reduction in risk is likely to occur only in patients with precirrhotic changes or very early-stage cirrhosis.[15]

Patients with HCV-related cirrhosis are at greater risk of developing HCC than are those with cirrhosis related to HBV and alcohol-related cirrhosis.[14] Using data from several prospective studies, 5-year cumulative HCC incidence rates for individuals with cirrhosis and specific risk factors were estimated as follows: HCV, 30% in Japan and 17% in Western countries; HBV, 15% in endemic areas and 10% in Western countries; and alcohol, 8%.[14]

Heavy Alcohol Use

Heavy alcohol use causes cirrhosis; between 8% and 20% of chronic alcoholics develop the condition.[1] HCC also occurs in heavy alcohol users who do not have cirrhosis. Some data exist to suggest a synergistic effect on HCC risk by heavy alcohol use and tobacco use, fatty liver disease, and metabolic syndrome (MetS) components.[16]

Many epidemiological studies have examined the association of alcohol use and HCC; those that could examine the impact of increasing exposure typically have seen a positive correlation between consumption and risk. The following RRs (95% confidence intervals [CIs]) were generated by using models derived from a meta-analysis: 1.19 (1.12–1.27) for 25 g of alcohol per day; 1.40 (1.25–1.56) for 50 g/d; and 1.81 (1.50–2.19) for 100 g/d.[1] While there is agreement that alcohol consumption, especially heavy consumption, is an important HCC risk factor, the magnitude of the increase in risk varies across studies.[16] Some studies report a twofold increase in risk with heavy consumption, while others observe a greater increase, at least fivefold. Variability is likely caused by many factors, including choice of control subjects, choice of referent categories, definition of heavy alcohol use, and presence of cofactors.

Alcoholics with cirrhosis appear to have a roughly tenfold risk of developing HCC, relative to alcoholics without cirrhosis.[14,16] In a cohort study of alcoholics, the summary incidence rate was 0.2 per 100 person-years in people with cirrhosis, and 0.01 per 100 person-years in those without cirrhosis.[14] The evidence for a twofold to threefold increase in risk with heavy alcohol use is more consistent for individuals with chronic HCV infection than for individuals with chronic HBV infection.[16] An Italian case-control study observed synergistic effects of heavy alcohol use and HBV or HCV infection: heavy alcohol use and HBV infection led to a 50-fold increase in risk, and heavy alcohol use and HCV infection led to a 100-fold increase in risk, relative to absence of heavy alcohol use and HBV or HCV infection.[17]

Aflatoxin B1

Aflatoxin B1 is a mycotoxin that can contaminate corn and peanuts stored in warm, humid environments.[2] The highest levels of aflatoxin B1 exposure are found in sub-Saharan Africa, Southeast Asia, and China.[18]

Aflatoxin B1 was deemed a carcinogen by the International Agency for Research on Cancer (IARC) in 1987.[2] The population-attributable risk of aflatoxin B1 to HCC is estimated to be 20% in the Western Pacific (including China), 27% in southeast Asia, and 40% in Africa.[19] Exposure may be responsible for up to 155,000 HCC cases worldwide.[19]

Prospective cohort studies established aflatoxin B1 as an etiologic agent for HCC, and demonstrated that magnitude of risk varies by presence or absence of chronic HBV infection. A nested case-control study comprising about 18,000 men who resided in Shanghai in the 1980s indicated that aflatoxin exposure increases risk 4-fold among individuals without chronic HBV infection, but exposure increases risk 60-fold among individuals with chronic HBV infection.[20] A subsequent cohort study in Taiwan observed a similar multiplicative or more-than-multiplicative increase in risk with the presence of both factors, relative to the presence of neither factor.[20]

NASH

Nonalcoholic steatohepatitis (NASH) is an aggressive yet dynamic condition; it can regress, persist at a relatively constant level of activity, or cause progressive fibrosis that leads to cirrhosis. It is estimated that 6% of the U.S. adult population has NASH and that 2% of U.S. adults will develop NASH-related cirrhosis at some time in their lives.[21]

At least 17 prospective cohort studies have examined HCC risk in patients with either NASH or nonalcoholic fatty liver disease (NAFLD), but few have examined NASH patients alone.[22] The most frequently referenced study of NASH patients is a prospective study conducted in the United States that examined HCC experience in 195 patients with NASH-related cirrhosis. After a median follow-up of 3.2 years, 13% of the patients had been diagnosed with HCC.[23] Yearly cumulative incidence in this case series was 2.6%. A case series of HCV patients was conducted concurrently; that group experienced higher rates (20% had an HCC diagnosis, and yearly cumulative incidence was 4%).

HCC has been observed in patients with NASH who do not have cirrhosis. Reliable risk estimates are not available, but most researchers believe that these individuals are at elevated risk, albeit lower than in those with cirrhosis.[22]

MetS, obesity, type 2 diabetes, insulin resistance, hypertension, and hyperlipidemia or dyslipidemia, are suspected risk factors for HCC and are associated with NASH. A study of 8.5 million people from 22 countries reported prevalence estimates for NASH patients with the following diagnoses: overweight or obesity, 80%; hyperlipidemia or dyslipidemia, 72%; type 2 diabetes, 44%; and MetS, 71%.[24]

Cigarette Smoking

The relationship between tobacco use and liver cancer has been studied extensively for many years.[25] Early epidemiological studies produced positive associations, but doubt regarding the legitimacy of tobacco use as an independent risk factor existed because of the possibility of residual confounding by HBV status, HCV status, and alcohol consumption. In addition, some studies also suggested that the increase in risk might exist only in subgroups, particularly in patients with chronic HBV infection. In 2004, the IARC reported that tobacco use was causally associated with HCC; that conclusion was on the basis of studies that had consistently shown increased risk with increased duration or intensity of tobacco use after careful consideration of potential confounders.[25] In 2014, the U.S. Surgeon General concluded a causal relationship on the basis of study results published after 2004.[26]

An extensive meta-analysis published in 2009 examined 38 cohort and 58 case-control studies that evaluated the relationship between cigarette smoking and liver cancer.[25] Studies varied in their degree of adjustment for possible confounders, though most adjusted for age and about one-third adjusted for alcohol consumption. Relative to never-smokers, the summary RR (SRR) for current smokers was 1.51 (95% CI, 1.37–1.67) and for former smokers, 1.12 (95% CI, 0.78–1.60). The point estimate was similar when restricted to five high-quality studies that adjusted for alcohol use (RR, 1.45; 95% CI, 1.14–1.80); the point estimates were similar but not significant when restricted to three studies that adjusted for chronic HBV infection and three studies that adjusted for chronic HCV infection. A dose-response relationship for the number of cigarettes smoked per day was observed, even though there was substantial statistical heterogeneity in the eight studies that were analyzed together for that analysis. A prospective cohort study published after the meta-analysis observed significant linear increases in risk with increasing number of cigarettes smoked per day, years smoked, and pack-years; analyses were adjusted for grams of alcohol consumed per day, and significant linear increases also were observed when daily drinkers were excluded.[27]

A meta-analysis that examined the relationship of cigarette smoking in the presence and absence of chronic HBV or HCV infection observed the following:[28] in the absence of viral infection, cigarette smoking was associated with an RR of about 1.5 to 2; in the presence of HBV, the increase in risk appeared additive; and in the presence of HCV, the increase in risk appeared to be more than multiplicative. Relative to persons who were negative for HBV and did not smoke cigarettes, the adjusted random effects estimate was 21.7 (11.8–40) for those with HBV who smoked cigarettes. Relative to individuals who were negative for HCV and did not smoke cigarettes, the adjusted random effects estimate was 19.6 (1.55–247) for those with HCV who smoked cigarettes.[28]

Certain Rare Medical and Genetic Conditions (Untreated HH, Alpha-1-Antitrypsin Deficiency, Glycogen Storage Disease, Porphyria Cutanea Tarda, and Wilson Disease)

Untreated hereditary hemochromatosis (HH), alpha-1-antitrypsin (AAT) deficiency, glycogen storage disease, porphyria cutanea tarda (PCT), and Wilson disease are known to increase the risk of developing HCC. While increases in risk are known or believed to be large, these conditions contribute little to the burden of HCC.

Hemochromatosis is an autosomal recessive disorder that leads to excessive absorption of dietary iron and subsequent iron loading in certain organs, including the liver.[2] Between 1 in 200 and 1 in 400 individuals of northern European descent carry the most common genetic mutation, although many of these individuals do not develop progressive iron overload.[29] Patients with untreated hemochromatosis may develop cirrhosis. The annual incidence of HCC in patients with hemochromatosis is 4% once cirrhosis has been established.[30] In cohorts of patients with untreated hemochromatosis and cirrhosis, the observed number of HCC cases is at least 20-fold higher than expected.[29] HCC is seen, albeit rarely, in hemochromatosis patients who do not have cirrhosis.[29] Between 25% and 45% of premature deaths in hemochromatosis patients are caused by HCC.[29] Hemochromatosis can be treated successfully through phlebotomy, repeated at necessary intervals.[30] Treatment before the development of cirrhosis appears to greatly reduce the risk of HCC.[30] It is hypothesized that the presence of other HCC risk factors, particularly chronic HBV infection, chronic HCV infection, and heavy alcohol use, could increase risk among patients with untreated hemochromatosis in a more-than-additive manner,[29] but appropriate data in which to explore this possibility are not available.

AAT deficiency is an inherited disorder affecting the lungs, liver, and rarely, the skin. It is estimated that about 100,000 individuals in the United States have AAT deficiency.[31] Liver disease results from the accumulation within hepatocytes of unsecreted variant AAT proteins.[32] Individuals with certain AAT deficiency genotypes are at high risk of developing HCC.[33]

Glucose-6-phosphatase deficiency (G6PD) is an autosomal-recessive disorder. It also is known as von Gierke disease and is more commonly known as glycogen storage disease, or GSD1. The defective enzymes involved are mainly active in the liver and kidneys. The incidence of GSD1 is 1 per 100,000 live births. HCC is recognized as a late complication of GSD1.[34] No estimates of increase in HCC risk are available.

PCT is the result of deficient activity of hepatic uroporphyrinogen; acute intermittent porphyria (AIP, also known as Swedish porphyria) is characterized by deficient activity of porphobilinogen. The prevalence of PCT in the United States is 1 in 25,000.[35] PCT and AIP are associated with increases in HCC risk.[2] A prospective study in Sweden of individuals with porphyria observed a standardized incidence ratio of 21 for PCT and 70 for AIP.[36]

Wilson disease (hepatolenticular degeneration) is caused by a genetic abnormality inherited in an autosomal recessive manner that leads to impairment of cellular copper transport. Worldwide prevalence is approximately 1 in 30,000 live births.[37] Wilson disease causes progressive liver damage, including cirrhosis. The association between Wilson disease and HCC is uncertain but suspected given that tumors of the liver, including HCC, are observed in Wilson disease patients.[38]

References
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  4. U.S. Department of Health and Human Services: Hepatitis B Basic Information. Washington, DC: U.S. Department of Health and Human Services, 2017. Available online. Last accessed December 5, 2024.
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  9. Centers for Disease Control and Prevention: Hepatitis C FAQs for Health Professionals. Atlanta, GA: Centers for Disease Control and Prevention, Division of Viral Hepatitis, 2017. Available online. Last accessed December 5, 2024.
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  12. Scaglione S, Kliethermes S, Cao G, et al.: The Epidemiology of Cirrhosis in the United States: A Population-based Study. J Clin Gastroenterol 49 (8): 690-6, 2015. [PUBMED Abstract]
  13. Hartke J, Johnson M, Ghabril M: The diagnosis and treatment of hepatocellular carcinoma. Semin Diagn Pathol 34 (2): 153-159, 2017. [PUBMED Abstract]
  14. Fattovich G, Stroffolini T, Zagni I, et al.: Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology 127 (5 Suppl 1): S35-50, 2004. [PUBMED Abstract]
  15. Saffioti F, Pinzani M: Development and Regression of Cirrhosis. Dig Dis 34 (4): 374-81, 2016. [PUBMED Abstract]
  16. Grewal P, Viswanathen VA: Liver cancer and alcohol. Clin Liver Dis 16 (4): 839-50, 2012. [PUBMED Abstract]
  17. Donato F, Tagger A, Gelatti U, et al.: Alcohol and hepatocellular carcinoma: the effect of lifetime intake and hepatitis virus infections in men and women. Am J Epidemiol 155 (4): 323-31, 2002. [PUBMED Abstract]
  18. McGlynn KA, Petrick JL, London WT: Global epidemiology of hepatocellular carcinoma: an emphasis on demographic and regional variability. Clin Liver Dis 19 (2): 223-38, 2015. [PUBMED Abstract]
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  20. Chen JG, Egner PA, Ng D, et al.: Reduced aflatoxin exposure presages decline in liver cancer mortality in an endemic region of China. Cancer Prev Res (Phila) 6 (10): 1038-45, 2013. [PUBMED Abstract]
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  23. Ascha MS, Hanouneh IA, Lopez R, et al.: The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. Hepatology 51 (6): 1972-8, 2010. [PUBMED Abstract]
  24. Younossi ZM, Koenig AB, Abdelatif D, et al.: Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 64 (1): 73-84, 2016. [PUBMED Abstract]
  25. Lee YC, Cohet C, Yang YC, et al.: Meta-analysis of epidemiologic studies on cigarette smoking and liver cancer. Int J Epidemiol 38 (6): 1497-511, 2009. [PUBMED Abstract]
  26. Cancer. In: U.S. Department of Health and Human Services: The Health Consequences of Smoking—50 Years of Progress: A Report of the Surgeon General. U.S. Department of Health and Human Services, CDC, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, 2014, pp 139-351. Also available online. Last accessed December 5, 2024.
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  28. Chuang SC, Lee YC, Hashibe M, et al.: Interaction between cigarette smoking and hepatitis B and C virus infection on the risk of liver cancer: a meta-analysis. Cancer Epidemiol Biomarkers Prev 19 (5): 1261-8, 2010. [PUBMED Abstract]
  29. Harrison SA, Bacon BR: Relation of hemochromatosis with hepatocellular carcinoma: epidemiology, natural history, pathophysiology, screening, treatment, and prevention. Med Clin North Am 89 (2): 391-409, 2005. [PUBMED Abstract]
  30. Villanueva A, Newell P, Hoshida Y: Inherited hepatocellular carcinoma. Best Pract Res Clin Gastroenterol 24 (5): 725-34, 2010. [PUBMED Abstract]
  31. Campos MA, Wanner A, Zhang G, et al.: Trends in the diagnosis of symptomatic patients with alpha1-antitrypsin deficiency between 1968 and 2003. Chest 128 (3): 1179-86, 2005. [PUBMED Abstract]
  32. Lomas DA, Evans DL, Finch JT, et al.: The mechanism of Z alpha 1-antitrypsin accumulation in the liver. Nature 357 (6379): 605-7, 1992. [PUBMED Abstract]
  33. Nelson DR, Teckman J, Di Bisceglie AM, et al.: Diagnosis and management of patients with α1-antitrypsin (A1AT) deficiency. Clin Gastroenterol Hepatol 10 (6): 575-80, 2012. [PUBMED Abstract]
  34. Limmer J, Fleig WE, Leupold D, et al.: Hepatocellular carcinoma in type I glycogen storage disease. Hepatology 8 (3): 531-7, 1988 May-Jun. [PUBMED Abstract]
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  36. Linet MS, Gridley G, Nyrén O, et al.: Primary liver cancer, other malignancies, and mortality risks following porphyria: a cohort study in Denmark and Sweden. Am J Epidemiol 149 (11): 1010-5, 1999. [PUBMED Abstract]
  37. Huster D: Wilson disease. Best Pract Res Clin Gastroenterol 24 (5): 531-9, 2010. [PUBMED Abstract]
  38. Pfeiffenberger J, Mogler C, Gotthardt DN, et al.: Hepatobiliary malignancies in Wilson disease. Liver Int 35 (5): 1615-22, 2015. [PUBMED Abstract]

Factors With Inadequate Evidence of Increased Risk of HCC

NAFL

Nonalcoholic fatty liver (NAFL) is diagnosed when hepatic steatosis cannot be explained by alcohol use or viral infection.[1] It generally is an asymptomatic, benign condition and is often detected incidentally.[2] NAFL can progress to cirrhosis or nonalcoholic steatohepatitis (NASH). Up to 4% of NAFL patients may develop cirrhosis,[3] and a small clinical study suggested that between 20% and 50% of NAFL patients may develop NASH.[4] The observation that NAFL patients have developed these conditions, which are known to increase hepatocellular cancer (HCC) risk, leads to the conclusion that NAFL increases HCC risk.

Even though NAFL and NASH have different clinical relevance, they often are combined into one clinical entity known as NAFLD (nonalcoholic fatty liver disease). While prevalence estimates and measures of relative risk (RR) are available for NAFLD and NASH, they are unavailable for NAFL. NAFLD estimates can provide an upper bound for NAFL, however.

In the United States, NAFLD prevalence is estimated at 25%.[5] NAFLD prevalence has more than doubled in the last 30 years [1] and is now the most common liver disorder in the United States.[1] NAFLD is sometimes referred to as the hepatic presentation of metabolic syndrome (MetS);[5] increases in NAFLD rates parallel those of MetS, including obesity and type 2 diabetes.[1] MetS, obesity, and type 2 diabetes are frequent NAFLD comorbidities. Estimates of global prevalence of MetS, obesity, and type 2 diabetes in individuals with NAFLD are as follows: MetS, 43%; obesity, 51%; and type 2 diabetes, 23%.[1] A meta-analysis that considered data from countries around the world reported that the HCC incidence rate ratio for NAFLD versus non-NAFLD patients was 1.94 (95% confidence interval [CI], 1.28–2.92).[1] HCC has been diagnosed in patients with both cirrhotic and noncirrhotic NAFLD.[6] A study of 1,500 U.S. Veterans’ Administration patients with NAFLD, 107 patients developed HCC. Of the 107 patients, 6 patients had level 1 evidence (histological) of no cirrhosis, and 31 patients had level 2 evidence (imaging or biospecimen) of no cirrhosis.[7] Furthermore, the percentage of noncirrhotic HCC patients among those with NAFLD was greater than was observed for other known HCC risk factors.[7]

MetS

MetS is diagnosed when at least three of five metabolic risk factors (central adiposity, high triglyceride levels, low levels of high-density lipoprotein, high fasting glucose levels, and hypertension) are present.[8] The prevalence of MetS has been rising for at least the last 30 years, and by 2012, more than one-third of U.S. adults met the criteria for MetS.[9]

A meta-analysis of more than 7,000 HCC cases from five studies produced a risk ratio of 1.8 (95% CI, 1.37–2.40) for a diagnosis of MetS.[10] The combined risk ratios were varied (range, 1.2 [95% CI, 0.55–2.53] to 3.7 [96% CI, 1.78–7.58]).

MetS and NAFLD are frequently comorbid conditions. The prevalence of MetS among patients with NAFLD was estimated to be 42.5% in a meta-analysis that included studies from around the world.[1] Given that obesity and type 2 diabetes, two suspected HCC risk factors, are component causes of MetS and also prevalent in patients with NAFLD, attempts to disentangle the independent impact on HCC risk of MetS using epidemiological data is not warranted. Observed associations should not be interpreted as causal relationships.

Only a few studies have examined insulin resistance, hypertension, and dyslipidemia, yet there is a suggestion that the first two are associated with an increase in HCC risk.[11] These factors will not be discussed further.

Obesity

Obesity has been considered extensively as a risk factor for HCC, and in most instances, a positive association has been observed. A European multicenter prospective cohort study with 177 HCC cases examined central obesity, as measured by waste-to-hip ratio, and observed a more-than-threefold increase in HCC risk for the highest tertile (males, ≥ 27.81; females, ≥ 26.65), relative to the lowest (RR, 3.51; 95% CI, 2.09–5.87), after adjustment for several potential confounders, including alcohol consumption.[12] A meta-analysis of 26 prospective studies (25,337 HCC cases) reported that obesity (BMI ≥ 30 kg/m2) was associated with an increased risk of primary liver cancer (SRR, 1.83; 95% CI, 1.59–2.11). Of note is that the included studies varied in their control for confounding, with 11 not controlling for alcohol consumption and 15 not controlling for history of diabetes; furthermore, not all studies were population based. Nevertheless, point estimates were somewhat consistently suggestive of a modest increase in risk, and associations of a similar magnitude have been seen in Japanese and U.S. populations.[13,14]

NAFLD is estimated to be present in up to 90% of individuals with obesity.[15] Obesity is a component cause of MetS, another suspected HCC risk factor; obesity also is a frequent comorbidity to type 2 diabetes, yet another suspected HCC risk factor. Attempts to disentangle the independent impact on HCC risk of obesity using epidemiological data is not warranted. Observed associations should not be interpreted as causal relationships.

Type 2 Diabetes

Type 2 diabetes has been considered extensively as a risk factor for HCC, and in most instances, positive associations have been observed. The most recent meta-analysis of diabetes and HCC was published in 2012.[16] Seventeen case-control studies and 32 cohort studies were included, and a summary RR of 2.31 (95% CI, 1.87–2.84) for either type 1 or type 2 diabetes was observed. Of the 49 studies used to produce the summary RR, only 19 adjusted for alcohol use and 13 for obesity, and not all were population based. The summary risk estimate for type 2 diabetes alone, based on data from 13 studies, was 2.18 (95% CI, 1.58–3.01). Studies published since the meta-analysis produced estimates similar to those of the summary measure.[17]

NAFLD is estimated to be present in up to 70% of type 2 diabetics.[15] Type 2 diabetes is a component cause of MetS, another suspected HCC risk factor; type 2 diabetes is a frequent comorbidity to obesity, yet another suspected HCC risk factor. An additional complexity is that diabetes can be caused by cirrhosis.[18] With the exception of cirrhosis, attempts to disentangle the independent impact on HCC risk of type 2 diabetes using epidemiological data is not warranted. Observed associations should not be interpreted as causal relationships.

References
  1. Younossi ZM, Stepanova M, Afendy M, et al.: Changes in the prevalence of the most common causes of chronic liver diseases in the United States from 1988 to 2008. Clin Gastroenterol Hepatol 9 (6): 524-530.e1; quiz e60, 2011. [PUBMED Abstract]
  2. Dyson JK, Anstee QM, McPherson S: Non-alcoholic fatty liver disease: a practical approach to diagnosis and staging. Frontline Gastroenterol 5 (3): 211-218, 2014. [PUBMED Abstract]
  3. Rinella ME: Nonalcoholic fatty liver disease: a systematic review. JAMA 313 (22): 2263-73, 2015. [PUBMED Abstract]
  4. Calzadilla Bertot L, Adams LA: The Natural Course of Non-Alcoholic Fatty Liver Disease. Int J Mol Sci 17 (5): , 2016. [PUBMED Abstract]
  5. Younossi ZM, Koenig AB, Abdelatif D, et al.: Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 64 (1): 73-84, 2016. [PUBMED Abstract]
  6. Baffy G, Brunt EM, Caldwell SH: Hepatocellular carcinoma in non-alcoholic fatty liver disease: an emerging menace. J Hepatol 56 (6): 1384-91, 2012. [PUBMED Abstract]
  7. Mittal S, El-Serag HB, Sada YH, et al.: Hepatocellular Carcinoma in the Absence of Cirrhosis in United States Veterans is Associated With Nonalcoholic Fatty Liver Disease. Clin Gastroenterol Hepatol 14 (1): 124-31.e1, 2016. [PUBMED Abstract]
  8. Kim D, Touros A, Kim WR: Nonalcoholic Fatty Liver Disease and Metabolic Syndrome. Clin Liver Dis 22 (1): 133-140, 2018. [PUBMED Abstract]
  9. Aguilar M, Bhuket T, Torres S, et al.: Prevalence of the metabolic syndrome in the United States, 2003-2012. JAMA 313 (19): 1973-4, 2015. [PUBMED Abstract]
  10. Jinjuvadia R, Patel S, Liangpunsakul S: The association between metabolic syndrome and hepatocellular carcinoma: systemic review and meta-analysis. J Clin Gastroenterol 48 (2): 172-7, 2014. [PUBMED Abstract]
  11. Rahman R, Hammoud GM, Almashhrawi AA, et al.: Primary hepatocellular carcinoma and metabolic syndrome: An update. World J Gastrointest Oncol 5 (9): 186-94, 2013. [PUBMED Abstract]
  12. Schlesinger S, Aleksandrova K, Pischon T, et al.: Abdominal obesity, weight gain during adulthood and risk of liver and biliary tract cancer in a European cohort. Int J Cancer 132 (3): 645-57, 2013. [PUBMED Abstract]
  13. Welzel TM, Graubard BI, Zeuzem S, et al.: Metabolic syndrome increases the risk of primary liver cancer in the United States: a study in the SEER-Medicare database. Hepatology 54 (2): 463-71, 2011. [PUBMED Abstract]
  14. Chen Y, Wang X, Wang J, et al.: Excess body weight and the risk of primary liver cancer: an updated meta-analysis of prospective studies. Eur J Cancer 48 (14): 2137-45, 2012. [PUBMED Abstract]
  15. Streba LA, Vere CC, Rogoveanu I, et al.: Nonalcoholic fatty liver disease, metabolic risk factors, and hepatocellular carcinoma: an open question. World J Gastroenterol 21 (14): 4103-10, 2015. [PUBMED Abstract]
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  17. Wainwright P, Scorletti E, Byrne CD: Type 2 Diabetes and Hepatocellular Carcinoma: Risk Factors and Pathogenesis. Curr Diab Rep 17 (4): 20, 2017. [PUBMED Abstract]
  18. Ferlay J, Soerjomataram I, Dikshit R, et al.: Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 136 (5): E359-86, 2015. [PUBMED Abstract]

Interventions With Adequate Evidence of Decreased Risk of HCC

HBV Vaccination

Hepatitis B virus (HBV) vaccines became available for the prevention of HBV infection in the early 1980s.[1] The World Health Organization recommends that all infants receive the hepatitis B vaccine as soon as possible after birth, preferably within 24 hours.[2] By 2011, 180 countries had introduced infant HBV vaccination, and the global HBV vaccination coverage rate for the final dose was estimated to be about 78%.[1] It is estimated that in 2015, the worldwide prevalence of HBV infection in children younger than 5 years was about 1.3%, compared with about 4.7% in the prevaccination era.[2]

Epidemiological evidence regarding the ability of hepatitis B vaccination to reduce hepatocellular cancer (HCC) comes from follow-up studies of children and risk of childhood liver cancer. In a cluster randomized controlled trial of HBV immunization of 75,000 newborns in Qidong, China (an area where HBV is endemic), the incidence ratio of primary liver cancer in the vaccination-at-birth group compared with the control group (68% of whom received catch-up vaccinations at ages 10–14 years) was 0.16 (95% confidence interval [CI], 0.03–0.77).[3] A registry study conducted in Taiwan identified 1,509 patients aged 6 to 26 years with HCC, and observed that HCC incidence per 100,000 person-years was 0.92 in the unvaccinated cohort and 0.23 in the vaccinated birth cohorts.[4]

It is too soon to know if neonate vaccination also will reduce HCC risk in later adulthood, and no data have been published on the impact of vaccination in adulthood. Nevertheless, vaccination at any age before infection should reduce HCC risk. Mathematical modeling suggests that neonatal HBV vaccination ultimately will lead to the elimination of 70% to 85% of HBV-related HCC cases worldwide.[5] Booster immunizations currently are not recommended for those who are not immunocompromised.[6]

Treatment for Chronic HBV Infection

The presence of hepatitis B surface antigen for more than 6 months identifies patients with chronic HBV infection. Expanded and sustained HBV vaccination ultimately will decrease the prevalence of individuals with chronic HBV infection, but the need to minimize downstream consequences of chronic infection, including the risk of HCC, exists for the foreseeable future. Anti-HBV treatment options for chronic HBV carriers are interferon and nucleos(t)ide analogues (NAs). Interferon is used in young patients who want a short course of therapy and have well-compensated liver disease,[7] although it is not consistently associated with a reduction in HCC incidence. There are several NAs that are preferred because of their low risk of viral resistance (e.g., entecavir, tenofovir disoproxil fumarate, and tenofovir alafenamide). Other NAs (e.g., lamivudine, adefovir, and telbivudine) are available, although they are less preferred because of the emergence of viral resistance, which may lead to hepatic decompensation.[8] Reductions in HCC risk, when observed for interferon therapy, have typically been among treatment responders with preexisting liver cirrhosis.[9] A reduction in HCC risk has been consistently observed for patients treated with NA therapy, regardless of cirrhosis status.[9]

The decision to initiate anti-HBV therapy depends on several factors, including the presence or absence of hepatitis B e antigen (HBeAg), a relative increase of alanine transaminase (ALT) compared with the upper limit of normal (ULN), HBV DNA level, degree of fibrosis, and age. It has been recommended that patients in the immune-active phase of chronic HBV be treated with anti-HBV therapy. Patients are considered to be in the immune-active phase if they have evidence of liver inflammation and are either: (1) HBeAg-positive with an HBV DNA level of more than 20,000 IU/mL and an ALT level more than two times the ULN, or (2) HBeAg-negative with an HBV DNA level of more than 2,000 IU/mL and an ALT level more than two times the ULN.[8] Patients with inactive HBV, in general, have normal ALT levels and HBV DNA levels of more than 2,000 IU/mL.[8]

Antiviral therapy has not been routinely recommended for patients who are not in the immune-active phase. Patients who are neither in the immune-active phase nor in one of the other standard phases of chronic HBV (immune-tolerant phase or inactive phase) are considered to be in an indeterminate phase, representing approximately 40% of patients with chronic HBV.[10] The 10-year cumulative incidence of HCC was higher among patients in the indeterminate phase of chronic HBV (4.6%; 95% CI, 3.0%–7.2%) compared with patients in the inactive phase (0.5%; 95% CI, 0.2%–1.3%).[10] However, their risk may be reduced if anti-HBV therapy is initiated.

In a multicenter, international, retrospective cohort study of 819 patients with chronic HBV who had no fibrosis or liver cirrhosis in the indeterminate phase, anti-HBV therapy was associated with a 70% reduction in HCC risk (hazard ratio [HR], 0.30; 95% CI, 0.10–0.60).[10] The cumulative incidence of HCC was significantly lower in those treated with anti-HBV therapy compared with those who were not, with proportions as follows:

  • At 10 years, 3.9% (95% CI, 1.9%–7.8%) versus 14.7% (95% CI, 9.6%–22.0%).
  • At 15 years, 9.4% (95% CI 4.5%–19.3%) versus 19.1% (95% CI, 12.9%–27.6%).

While these findings suggest a significant benefit of anti-HBV therapy in reducing HCC incidence, several limitations should be noted. Firstly, the study did not specify details on HCC surveillance or the HCC diagnostic criteria used, although it was reported that diagnoses were made according to the American Association for the Study of Liver Diseases (AASLD) guidelines, using either pathology or noninvasive imaging. Additionally, the study did not provide information about the specific types or doses of anti-HBV therapy administered, although it was noted that patients in the treatment group remained on therapy throughout follow-up.[11]

The degree of HCC risk reduction with NA therapy has been nearly consistent across studies, with treated patients experiencing about half the risk of those who are not treated with NA therapy.[9,12] Most studies have been conducted in countries outside North America, yet the two studies conducted in North America observed similarly-sized, statistically significant reductions. A Canadian cohort of 322 patients with chronic HBV infection experienced lower than expected rates of HCC with a standardized incidence ratio of 0.46 (95% CI, 0.23–0.82) for patients treated with NA therapy, relative to those who were not.[13] A U.S. cohort of more than 2,000 patients with chronic HBV infection observed an HR of 0.39 (95% CI, 0.27–0.56) with treatment, although the cohort included patients treated with interferon.[14]

Potential harms of treatment for chronic HBV infection

NA-based therapy is generally considered safe with limited side effects. Lactic acidosis has been reported along with renal toxicity and osteomalacia. In patients with chronic HBV infection and known renal or bone disease, tenofovir alafenamide may be considered as it has been found to be more stable in the plasma and delivers active metabolite to hepatocytes efficiently, allowing a lower dose and less risk of bone and renal toxicity. Interferon-based therapy has been associated with flu-like symptoms, fatigue, mood disturbances, cytopenias, and autoimmune disorders.[8]

Availability of Food Not Contaminated With Aflatoxin B1

Qidong, China, historically has had exceptionally high rates of primary liver cancer, due to endemic chronic HBV infection and a food supply (predominately corn) with high levels of aflatoxin B1 contamination. Agricultural reforms in the 1980s led to greater availability of rice, which typically harbors much lower levels of aflatoxin B1. A population-based cancer registry was used to examine primary liver cancer mortality in Qidong in residents born before 2002, the year that universal HBV vaccination of newborns was achieved. For that group, a higher-than-50% reduction in mortality from primary liver cancer was observed following the availability of rice. About 80% of the benefit was estimated to be among those infected with HBV.[15]

References
  1. Kao JH: Hepatitis B vaccination and prevention of hepatocellular carcinoma. Best Pract Res Clin Gastroenterol 29 (6): 907-17, 2015. [PUBMED Abstract]
  2. World Health Organization: Hepatitis B Fact Sheet. Geneva, Switzerland: World Health Organization, 2017. Available online. Last accessed December 5, 2024.
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  4. Chang MH, You SL, Chen CJ, et al.: Long-term Effects of Hepatitis B Immunization of Infants in Preventing Liver Cancer. Gastroenterology 151 (3): 472-480.e1, 2016. [PUBMED Abstract]
  5. McGlynn KA, Petrick JL, London WT: Global epidemiology of hepatocellular carcinoma: an emphasis on demographic and regional variability. Clin Liver Dis 19 (2): 223-38, 2015. [PUBMED Abstract]
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  13. Coffin CS, Rezaeeaval M, Pang JX, et al.: The incidence of hepatocellular carcinoma is reduced in patients with chronic hepatitis B on long-term nucleos(t)ide analogue therapy. Aliment Pharmacol Ther 40 (11-12): 1262-9, 2014. [PUBMED Abstract]
  14. Gordon SC, Lamerato LE, Rupp LB, et al.: Antiviral therapy for chronic hepatitis B virus infection and development of hepatocellular carcinoma in a US population. Clin Gastroenterol Hepatol 12 (5): 885-93, 2014. [PUBMED Abstract]
  15. Chen JG, Egner PA, Ng D, et al.: Reduced aflatoxin exposure presages decline in liver cancer mortality in an endemic region of China. Cancer Prev Res (Phila) 6 (10): 1038-45, 2013. [PUBMED Abstract]

Interventions with Inadequate Evidence of Decreased Risk of HCC

HCV Treatment With DAAs

Treatment with direct-acting antivirals (DAAs) leads to elimination of hepatitis C virus (HCV) infection in almost all patients.[1] The goal of therapy is to eradicate HCV RNA and attain a sustained virologic response (SVR), which is defined as an undetectable RNA level 12 weeks after the completion of therapy. Attainment of an SVR is associated with a 97% to 100% chance of being HCV RNA negative during 5-year follow-up, and patients can therefore be considered cured of the HCV infection.[1]

Results from studies of hepatocellular cancer (HCC) risk after attaining SVR have produced conflicting results; some have observed increases in risk after treatment.[2] Most studies have included small numbers of patients, and some had insufficient follow-up time.[2] Some studies did not consider that the presence or absence of cirrhosis could affect the impact of DAAs on HCC risk.[3]

The strongest evidence to date regarding DAA treatment and HCC risk comes from a cohort study of more than 22,000 U.S. veterans receiving DAA treatment for HCV infection.[2] In that cohort, 271 HCC diagnoses occurred. Patients treated with DAAs who attained an SVR had an approximately 75% reduction in the HCC risk, relative to those who did not attain an SVR. Reduction relative risk with SVR was similar in patients with cirrhosis (hazard ratio [HR], 0.31; 95% CI, 0.23–0.44) and patients without cirrhosis (HR, 0.18; 95% CI, 0.11–0.30). Nevertheless, among patients who achieved an SVR, those with cirrhosis had an almost fivefold increase in HCC risk, relative to those without cirrhosis (HR, 4.73; 95% CI, 3.34–6.68).

Statin Use Among Adults With HBV or HCV

Statins, also known as 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase inhibitors, are cholesterol-lowering medications. Statins have been implicated in the regulation of cell proliferation, apoptosis, and tumor progression in cancer patients, and statin use at the time of cancer diagnosis has been reported to be associated with reduced cancer risk and improved survival. A systematic review and meta-analysis noted that statin use was associated with lower cancer mortality and progression overall and in patients who initiated statin use after cancer diagnosis.[4] Another meta-analysis indicated that statin use may be associated with a 37% reduced risk of HCC (odds ratio [OR], 0.63; 95% CI, 0.52– 0.76).[5] However, this meta-analysis included a patient population with and without HBV/HCV infection, making the results difficult to interpret for HBV- or HCV-infected individuals.[6] In a U.K. study of 3,719 liver cancer cases and 14,876 controls, the authors observed a 35% lower risk (OR, 0.65; 95% CI, 0.58–0.74) of liver cancer among patients who received one or more statin prescriptions before a liver cancer diagnosis date for cases and corresponding date for matched controls after adjusting for factors including HBV infection, HCV infection, alcohol-related disorders, and diabetes mellitus.[7]

Nonstatin Cholesterol-Lowering Medication Use Among Adults

Although several studies have shown that statin use lowers liver cancer risk, many patients are not able to tolerate statin therapy because of its side effects. It is unclear whether other cholesterol-lowering medications reduce the risk of liver cancer. Cholesterol-absorption inhibitors work in the small intestine to prevent cholesterol reabsorption and reduce the level of circulating cholesterol, which may regulate key signaling factors for angiogenesis and liver tumor growth. In the U.K.-based, nested case-control study, receiving one or more prescriptions for cholesterol-absorption inhibitors was associated with a lower risk of liver cancer overall (OR, 0.69; 95% CI, 0.50–0.95) and among patients with liver disease (OR, 0.53; 95% CI, 0.30–0.96).[7]

References
  1. Simmons B, Saleem J, Hill A, et al.: Risk of Late Relapse or Reinfection With Hepatitis C Virus After Achieving a Sustained Virological Response: A Systematic Review and Meta-analysis. Clin Infect Dis 62 (6): 683-694, 2016. [PUBMED Abstract]
  2. Kanwal F, Kramer J, Asch SM, et al.: Risk of Hepatocellular Cancer in HCV Patients Treated With Direct-Acting Antiviral Agents. Gastroenterology 153 (4): 996-1005.e1, 2017. [PUBMED Abstract]
  3. Buonomo AR, Gentile I, Borgia G: Direct acting antiviral agents and hepatocellular carcinoma development: don’t take it for granted. Transl Gastroenterol Hepatol 2: 101, 2017. [PUBMED Abstract]
  4. Mei Z, Liang M, Li L, et al.: Effects of statins on cancer mortality and progression: A systematic review and meta-analysis of 95 cohorts including 1,111,407 individuals. Int J Cancer 140 (5): 1068-1081, 2017. [PUBMED Abstract]
  5. Singh S, Singh PP, Singh AG, et al.: Statins are associated with a reduced risk of hepatocellular cancer: a systematic review and meta-analysis. Gastroenterology 144 (2): 323-32, 2013. [PUBMED Abstract]
  6. Li X, Sheng L, Liu L, et al.: Statin and the risk of hepatocellular carcinoma in patients with hepatitis B virus or hepatitis C virus infection: a meta-analysis. BMC Gastroenterol 20 (1): 98, 2020. [PUBMED Abstract]
  7. Zamani SA, Graubard BI, Hyer M, et al.: Use of cholesterol-lowering medications in relation to risk of primary liver cancer in the Clinical Practice Research Datalink. Cancer 130 (20): 3506-3518, 2024. [PUBMED Abstract]

Latest Updates to This Summary (12/05/2024)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Incidence, Mortality, and Survival

Revised text to state that in 2021, the hepatocellular cancer (HCC) rate had risen more than threefold to 8.39 per 100,000.

Interventions With Adequate Evidence of Decreased Risk of HCC

The Treatment for Chronic Hepatitis B Virus (HBV) Infection subsection was extensively revised.

Added Potential harms of treatment for chronic HBV infection as a new subsection.

Interventions with Inadequate Evidence of Decreased Risk of HCC

Revised text to state that another meta-analysis indicated that statin use may be associated with a 37% reduced risk of HCC. However, this meta-analysis included a patient population with and without HBV/ hepatitis C virus (HCV) infection, making the results difficult to interpret for HBV- or HCV-infected individuals. Also added text to state that in a U.K. study of 3,719 liver cancer cases and 14,876 controls, the authors observed a 35% lower risk of liver cancer among patients who received one or more statin prescriptions before a liver cancer diagnosis date for cases and corresponding date for matched controls after adjusting for factors including HBV infection, HCV infection, alcohol-related disorders, and diabetes mellitus (cited Zamani et al. as reference 7).

Added Nonstatin Cholesterol-Lowering Medication Use Among Adults as a new subsection.

This summary is written and maintained by the PDQ Screening and Prevention Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about liver (hepatocellular) cancer prevention. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Screening and Prevention Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website’s Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Screening and Prevention Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”

The preferred citation for this PDQ summary is:

PDQ® Screening and Prevention Editorial Board. PDQ Liver (Hepatocellular) Cancer Prevention. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/liver/hp/liver-prevention-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389403]

Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

Disclaimer

The information in these summaries should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

Contact Us

More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website’s Email Us.

Liver (Hepatocellular) Cancer Screening (PDQ®)–Health Professional Version

Liver (Hepatocellular) Cancer Screening (PDQ®)–Health Professional Version

Summary of Evidence

Note: The Summary of Evidence section summarizes the published evidence on this topic. The rest of the summary describes the evidence in more detail.

Other PDQ summaries on Primary Liver Cancer Treatment and Childhood Liver Cancer Treatment are also available.

Benefits

Based on fair evidence, screening of persons at elevated risk does not result in a decrease in mortality from hepatocellular cancer.

Magnitude of Effect: No reduction in mortality.

  • Study Design: Randomized controlled trials.
  • Internal Validity: Fair.
  • Consistency: Multiple studies, large number of participants.
  • External Validity: Fair.

Harms

Based on fair evidence, screening would result in rare but serious side effects associated with needle aspiration cytology such as needle-track seeding, particularly of lesions more than 2 cm in diameter, and hemorrhage, bile peritonitis, and pneumothorax. Transjugular liver biopsy is rarely associated with major complications such as perforation of the hepatic capsule or cholangitis.

Magnitude of Effect: Good evidence for uncommon but serious harms.

  • Study Design: Randomized controlled trials and observational studies.
  • Internal Validity: Fair.
  • Consistency: Multiple studies, large number of participants.
  • External Validity: Good.

Significance

Incidence, Mortality, and Risk Factors

In 2020, liver cancer was the sixth most common cancer and third leading cause of cancer death in the world.[1] In the United States, it is estimated that there will be 41,630 new cases diagnosed in 2024 and 29,840 deaths due to this disease.[2] There is a distinct male preponderance among all ethnic groups in the United States.[3]

Chronic hepatitis B and C are recognized as the major factors worldwide increasing the risk of HCC, with risk being greater in the presence of coinfection with hepatitis B virus and hepatitis C virus.[4–6] The incidence of HCC in individuals with chronic hepatitis is as high as 0.46% per year. In the United States, chronic hepatitis B and C account for about 30% to 40% of HCC. Chronic hepatitis G infection is not associated with HCC in either hepatitis B surface antigen–positive carriers or noncarriers.[7]

Cirrhosis is also a risk factor for HCC, irrespective of the etiology of the cirrhosis. The annual risk of developing HCC among persons with cirrhosis is between 1% and 6%.[5] Other risk factors include alcoholic cirrhosis, hemochromatosis, alpha-l-antitrypsin deficiency, glycogen storage disease, porphyria cutanea tarda, tyrosinemia, and Wilson disease,[8] but rarely biliary cirrhosis.[9] A retrospective case-control study found that features suggestive of nonalcoholic steatohepatitis, including obesity, type 2 diabetes, dyslipidemia, and insulin resistance, were more frequently observed in patients with HCC associated with cryptogenic cirrhosis than in those with HCC of viral or alcohol etiology.[10,11] Aflatoxins, which are mycotoxins formed by certain Aspergillus species, are a frequent contaminant of improperly stored grains and nuts. In parts of Africa, the high incidence of HCC in humans may be related to ingestion of foods contaminated with aflatoxins. This association, however, is blurred by the frequent coexistence of hepatitis B infection in those population groups. The likely etiology of HCC is summarized in the following table.[12]

Likely Etiology of HCC
Causative Agents Dominant Geographical Area
Hepatitis B virus Asia and Africa
Hepatitis C virus Europe, United States, and Japan
Alcohol Europe and United States
Aflatoxins East Asia and Africa
References
  1. Sung H, Ferlay J, Siegel RL, et al.: Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 71 (3): 209-249, 2021. [PUBMED Abstract]
  2. American Cancer Society: Cancer Facts and Figures 2024. American Cancer Society, 2024. Available online. Last accessed December 30, 2024.
  3. Surveillance Research Program, National Cancer Institute: SEER*Explorer: An interactive website for SEER cancer statistics. Bethesda, MD: National Cancer Institute. Available online. Last accessed December 30, 2024.
  4. Benvegnù L, Fattovich G, Noventa F, et al.: Concurrent hepatitis B and C virus infection and risk of hepatocellular carcinoma in cirrhosis. A prospective study. Cancer 74 (9): 2442-8, 1994. [PUBMED Abstract]
  5. Ikeda K, Saitoh S, Koida I, et al.: A multivariate analysis of risk factors for hepatocellular carcinogenesis: a prospective observation of 795 patients with viral and alcoholic cirrhosis. Hepatology 18 (1): 47-53, 1993. [PUBMED Abstract]
  6. Chiaramonte M, Stroffolini T, Vian A, et al.: Rate of incidence of hepatocellular carcinoma in patients with compensated viral cirrhosis. Cancer 85 (10): 2132-7, 1999. [PUBMED Abstract]
  7. Yuan JM, Govindarajan S, Gao YT, et al.: Prospective evaluation of infection with hepatitis G virus in relation to hepatocellular carcinoma in Shanghai, China. J Infect Dis 182 (5): 1300-3, 2000. [PUBMED Abstract]
  8. Di Bisceglie AM, Carithers RL, Gores GJ: Hepatocellular carcinoma. Hepatology 28 (4): 1161-5, 1998. [PUBMED Abstract]
  9. Farinati F, Floreani A, De Maria N, et al.: Hepatocellular carcinoma in primary biliary cirrhosis. J Hepatol 21 (3): 315-6, 1994. [PUBMED Abstract]
  10. Bugianesi E, Leone N, Vanni E, et al.: Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma. Gastroenterology 123 (1): 134-40, 2002. [PUBMED Abstract]
  11. Fattovich G, Stroffolini T, Zagni I, et al.: Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology 127 (5 Suppl 1): S35-50, 2004. [PUBMED Abstract]
  12. Shiratori Y, Yoshida H, Omata M: Management of hepatocellular carcinoma: advances in diagnosis, treatment and prevention. Expert Rev Anticancer Ther 1 (2): 277-90, 2001. [PUBMED Abstract]

Evidence of Benefit

Rationale for Screening

The rationale for screening for hepatocellular carcinoma (HCC) is based on the concept that populations at high risk for HCC, such as those with cirrhosis, can be identified. However, 20% to 50% of patients presenting with HCC have previously undiagnosed cirrhosis.[1,2] These patients would not be recruited into a surveillance program if the presence of cirrhosis is used to define a target population.[3] The modalities potentially available for screening include serum alpha-fetoprotein (AFP) and ultrasonography. Abnormal screening results may lead to liver biopsy for diagnosis. Complications of liver biopsy are reported in 0.06% to 0.32% of patients, and typically occur within the first few hours after the biopsy.

Tumor Markers for the Detection of Hepatocellular Carcinoma

There are four categories of tumor markers that are currently being used or studied for the detection of hepatocellular carcinoma. These include oncofetal antigens and glycoprotein antigens; enzymes and isoenzymes; genes; and cytokines.[4]

Alpha-fetoprotein

Serum AFP, a fetal-specific glycoprotein antigen, is the most widely used tumor marker for detecting patients with HCC. The reported sensitivity of AFP for detecting HCC varies widely in both hepatitis B virus (HBV)-positive and HBV-negative populations, which is attributable to overlap between screening and diagnosis study designs.[3] When AFP is used for screening of high-risk populations, a sensitivity of 39% to 97%, specificity of 76% to 95%, and a positive predictive value (PPV) of 9% to 32% have been reported.[5–9] AFP is not specific for HCC. Titers also rise in acute or chronic hepatitis,[10] in pregnancy, and in the presence of germ cell tumors.

A prospective, 16-year, population-based, observational study of screening for HCC included 1,487 Alaska Native individuals chronically infected with HBV. The study compared survival among screen-detected patients with HCC with a historical comparison group of clinically diagnosed patients with HCC.[8] The screening program’s target was AFP determination every 6 months. It achieved 97% sensitivity and 95% specificity (excluding pregnant women) for HCC. Such high sensitivity and specificity have not been found for other high-risk groups, such as individuals with cirrhosis.[11,12] Whether screening actually improved survival is not clear.

A case-control study conducted within the U.S. Veterans Affairs (VA) health care system assessed whether screening with AFP and/or ultrasound reduced HCC mortality. The cases were 238 patients with cirrhosis who died of HCC from 2013 to 2015 and who had been in VA care with a diagnosis of cirrhosis for 4 years or more before the diagnosis of HCC. The controls, who did not die of HCC and had also been in VA care for 4 years or more, were matched for date of entry (or focal time) and for age, sex, race, model for end-stage liver disease (MELD) score, and etiology of cirrhosis (mainly hepatitis C virus). The study examiners, blinded to outcome status, used chart extraction to assess exposure to ultrasound and AFP screening. The reason for testing (screening vs. other indication) was assessed, also blinded to outcome. The study found that there was no difference between cases and controls regarding the proportion of patients who underwent screening ultrasound (52.9% vs. 54.2%), AFP screening (74.8% vs. 73.5%), or both. The lack of difference persisted for tests within 1, 2, or 3 years of the outcome.[13] Given the paucity of randomized controlled trials and their lack of strength, as noted elsewhere in this section, this case-control study—done with great care to avoid bias—comprised perhaps the strongest evidence about the efficacy of AFP or ultrasound screening; however, it showed no benefit in HCC mortality.

Hepatic Ultrasonography

Limitations in the sensitivity and specificity of AFP in surveillance of high-risk populations led to the use of ultrasonography as an additional method for detection of HCC.[3] Studies in both healthy hepatitis B surface antigen carriers [5] and in patients with cirrhosis [7] have defined the performance characteristics of ultrasound as a screening test for HCC. Sensitivity in the former was 71% and in the latter 78%, with 93% specificity. The PPVs were 14% and 73%, respectively. In a study of patients who were on a waiting list for liver transplant, ultrasonography was found to have a sensitivity of 58%, a specificity of 94%, a negative predictive value of 91%, and a PPV of 68%.[14]

A case-control study conducted in the VA population assessed whether screening with AFP and/or ultrasonography reduced HCC mortality. For more information, see the Alpha-fetoprotein section.

Computed Tomography

Limitations in the sensitivity and specificity of AFP and ultrasonography in surveillance of high-risk populations, such as individuals with cirrhosis, led to the assessment of computed tomography (CT) as an additional method for detection of HCC. Studies in patients with cirrhosis suggest that CT may be a more sensitive test for HCC than ultrasonography or AFP more than 20 μg/L.[11,12]

Efficacy of Screening and Surveillance Programs

A controlled trial of 18,816 individuals aged 35 to 59 years with hepatitis B in Shanghai randomly assigned patients to a screening group using AFP and ultrasonography every 6 months versus a usual-care group. HCC mortality was lower in the screened group (83.2 vs. 131.5 per 100,000; mortality rate ratio of 0.63 [95% confidence interval (CI), 0.41–0.98]). While these results are promising, there were problems, including the following:

  • The results varied in different publications.[15]
  • The comparison group was not actively followed.
  • The CI was near 1.0.
  • Intention-to-treat analysis was not used.
  • Assessment of outcome was not blinded.
  • Generalizability to other populations is uncertain.[16]

A randomized controlled trial studied 5,581 men aged 30 to 69 years who were chronic carriers of HBV between 1989 and 1995 in Qidong County, China. Of these men, 3,712 were randomly assigned to a screening group and 1,869 to a control group. Screening entailed 6-monthly AFP assays, with follow-up of patients having an abnormal (≥20 μg/L) test result. All patients were followed up for liver cancer and/or death. The overall sensitivity and specificity of the program were 55.3% and 86.5%, respectively. In patients who complied with all scheduled screening tests, sensitivity was 80% and specificity was 80.9%. The mortality rate in the screening group (1,138 per 100,000 person-years) was not significantly different from that in the control group (1,114 per 100,000 person-years), although AFP screening resulted in an earlier diagnosis of liver cancer (i.e., percentage of cases in stage I was significantly higher in the screened group [29.0%] than in the control group [6%]).[17] A review concluded that the method of measuring AFP was not sensitive enough to detect HCC, affecting interpretation of the negative result of this trial.[15]

References
  1. Zaman SN, Johnson PJ, Williams R: Silent cirrhosis in patients with hepatocellular carcinoma. Implications for screening in high-incidence and low-incidence areas. Cancer 65 (7): 1607-10, 1990. [PUBMED Abstract]
  2. Primary liver cancer in Japan. Clinicopathologic features and results of surgical treatment. Liver Cancer Study Group of Japan. Ann Surg 211 (3): 277-87, 1990. [PUBMED Abstract]
  3. Collier J, Sherman M: Screening for hepatocellular carcinoma. Hepatology 27 (1): 273-8, 1998. [PUBMED Abstract]
  4. Zhou L, Liu J, Luo F: Serum tumor markers for detection of hepatocellular carcinoma. World J Gastroenterol 12 (8): 1175-81, 2006. [PUBMED Abstract]
  5. Sherman M, Peltekian KM, Lee C: Screening for hepatocellular carcinoma in chronic carriers of hepatitis B virus: incidence and prevalence of hepatocellular carcinoma in a North American urban population. Hepatology 22 (2): 432-8, 1995. [PUBMED Abstract]
  6. Oka H, Tamori A, Kuroki T, et al.: Prospective study of alpha-fetoprotein in cirrhotic patients monitored for development of hepatocellular carcinoma. Hepatology 19 (1): 61-6, 1994. [PUBMED Abstract]
  7. Pateron D, Ganne N, Trinchet JC, et al.: Prospective study of screening for hepatocellular carcinoma in Caucasian patients with cirrhosis. J Hepatol 20 (1): 65-71, 1994. [PUBMED Abstract]
  8. McMahon BJ, Bulkow L, Harpster A, et al.: Screening for hepatocellular carcinoma in Alaska natives infected with chronic hepatitis B: a 16-year population-based study. Hepatology 32 (4 Pt 1): 842-6, 2000. [PUBMED Abstract]
  9. Soresi M, Magliarisi C, Campagna P, et al.: Usefulness of alpha-fetoprotein in the diagnosis of hepatocellular carcinoma. Anticancer Res 23 (2C): 1747-53, 2003 Mar-Apr. [PUBMED Abstract]
  10. Di Bisceglie AM, Hoofnagle JH: Elevations in serum alpha-fetoprotein levels in patients with chronic hepatitis B. Cancer 64 (10): 2117-20, 1989. [PUBMED Abstract]
  11. Chalasani N, Horlander JC, Said A, et al.: Screening for hepatocellular carcinoma in patients with advanced cirrhosis. Am J Gastroenterol 94 (10): 2988-93, 1999. [PUBMED Abstract]
  12. Peterson MS, Baron RL, Marsh JW, et al.: Pretransplantation surveillance for possible hepatocellular carcinoma in patients with cirrhosis: epidemiology and CT-based tumor detection rate in 430 cases with surgical pathologic correlation. Radiology 217 (3): 743-9, 2000. [PUBMED Abstract]
  13. Moon AM, Weiss NS, Beste LA, et al.: No Association Between Screening for Hepatocellular Carcinoma and Reduced Cancer-Related Mortality in Patients With Cirrhosis. Gastroenterology 155 (4): 1128-1139.e6, 2018. [PUBMED Abstract]
  14. Dodd GD, Miller WJ, Baron RL, et al.: Detection of malignant tumors in end-stage cirrhotic livers: efficacy of sonography as a screening technique. AJR Am J Roentgenol 159 (4): 727-33, 1992. [PUBMED Abstract]
  15. Aghoram R, Cai P, Dickinson JA: Alpha-foetoprotein and/or liver ultrasonography for screening of hepatocellular carcinoma in patients with chronic hepatitis B. Cochrane Database Syst Rev 9: CD002799, 2012. [PUBMED Abstract]
  16. Zhang BH, Yang BH, Tang ZY: Randomized controlled trial of screening for hepatocellular carcinoma. J Cancer Res Clin Oncol 130 (7): 417-22, 2004. [PUBMED Abstract]
  17. Chen JG, Parkin DM, Chen QG, et al.: Screening for liver cancer: results of a randomised controlled trial in Qidong, China. J Med Screen 10 (4): 204-9, 2003. [PUBMED Abstract]

Evidence of Harms

Two kinds of harms or complications may result from screening. Direct harms may result from complications of liver biopsy done as part of the diagnostic workup. Such complications are reported in 0.06% to 0.32% of patients, and typically occur within the first few hours after the biopsy. Complications include hemorrhage, bile peritonitis, penetration of viscera, and pneumothorax. Rarely, death occurs as a direct result of liver biopsy (0.009%–0.12%). About one third of patients experience pain at the site of entry, in the right upper quadrant, or in the right shoulder.[1] Needle aspiration cytology and liver biopsy are rarely associated with needle-track implantation of malignant cells. Lead-time bias (earlier diagnosis in the natural history of hepatocellular carcinoma [HCC] rather than improved survival from earlier diagnosis and treatment), length bias (earlier detection of slower-growing and less aggressive tumors through screening), and/or overdiagnosis of HCC (detection of tumors that will not affect morbidity or mortality) may wholly or partially account for the improved 5-year and 10-year survival rates reported.

References
  1. Tobkes AI, Nord HJ: Liver biopsy: review of methodology and complications. Dig Dis 13 (5): 267-74, 1995 Sep-Oct. [PUBMED Abstract]

Latest Updates to This Summary (03/06/2024)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Significance

Updated statistics with estimated new cases and deaths for 2024 (cited American Cancer Society as reference 2).

This summary is written and maintained by the PDQ Screening and Prevention Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about liver (hepatocellular) cancer screening. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Screening and Prevention Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website’s Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Screening and Prevention Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”

The preferred citation for this PDQ summary is:

PDQ® Screening and Prevention Editorial Board. PDQ Liver (Hepatocellular) Cancer Screening. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/liver/hp/liver-screening-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389228]

Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

Disclaimer

The information in these summaries should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

Contact Us

More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website’s Email Us.

Primary Liver Cancer Treatment (PDQ®)–Health Professional Version

Primary Liver Cancer Treatment (PDQ®)–Health Professional Version

General Information About Primary Liver Cancer

Liver cancer includes two major types: hepatocellular carcinoma (HCC) and intrahepatic bile duct cancer. For information about bile duct cancer, see Bile Duct Cancer (Cholangiocarcinoma) Treatment. For more information about other, less common types of liver cancer, see the Cellular Classification of Primary Liver Cancer section.

Incidence and Mortality

Estimated new cases and deaths from liver and intrahepatic bile duct cancer in the United States in 2025:[1]

  • New cases: 42,240.
  • Deaths: 30,090.

HCC is relatively uncommon in the United States, although its incidence is rising, principally in relation to the spread of hepatitis C virus infection.[2] Worldwide, HCC is the sixth most prevalent cancer and the third leading cause of cancer-related deaths.[3]

Anatomy

EnlargeAnatomy of the liver; drawing shows the right and left lobes of the liver. Also shown are the bile ducts, gallbladder, stomach, spleen, pancreas, small intestine, and colon.
Anatomy of the liver. The liver is in the upper abdomen near the stomach, intestines, gallbladder, and pancreas. The liver has a right lobe and a left lobe. Each lobe is divided into two sections (not shown).

Risk Factors

Increasing age is the most important risk factor for most cancers. Other risk factors for liver (hepatocellular) cancer include:

  • Chronic and/or persistent infection with hepatitis B and/or hepatitis C.[4–7]
  • Cirrhosis.[5,7,8]
  • Heavy alcohol use.[6,8,9]
  • Ingestion of foods contaminated with aflatoxin B1.[10–13]
  • Nonalcoholic steatohepatitis (NASH).[14–17]
  • Tobacco use.[18–20]
  • Certain inherited or rare disorders that include:
    • Hereditary hemochromatosis.[7,10]
    • Alpha-1 antitrypsin deficiency.[21]
    • Glycogen storage disease.[10]
    • Porphyria cutanea tarda.[10]
    • Wilson disease.[10,22,23]

For more information, see Liver (Hepatocellular) Cancer Prevention.

Screening

For more information, see Liver (Hepatocellular) Cancer Screening.

Diagnostic Factors

Lesions smaller than 1 cm that are detected during screening in patients at high risk of HCC do not require further diagnostic evaluation. Most of these lesions will be cirrhotic lesions rather than HCC.[24][Level of evidence C1] Close follow-up at 3-month intervals is a common surveillance strategy, using the same technique that first documented the presence of the lesions.

For patients with liver lesions larger than 1 cm who are at risk of HCC, a diagnosis can be considered. The tests required to diagnose HCC may include imaging, biopsy, or both.

Diagnostic imaging

In patients with cirrhosis, liver disease, or other risk factors for HCC, and with lesions greater than 1 cm, triple-phase, contrast-enhanced studies (dynamic computed tomography [CT] or magnetic resonance imaging [MRI]) can be used to diagnose HCC.[25]

A triple-phase CT or MRI assesses the entire liver in distinct phases of perfusion. Following the controlled administration of intravenous contrast media, the arterial and venous phases of perfusion are imaged.

During the arterial phase of the study, HCC enhances more intensely than the surrounding liver because the arterial blood in the liver is diluted by venous blood that does not contain contrast, whereas the HCC contains only arterial blood. In the venous phase, the HCC enhances less than the surrounding liver (which is referred to as the venous washout of HCC), because the arterial blood flowing through the lesion no longer contains contrast; however, the portal blood in the liver now contains contrast.

The presence of arterial uptake followed by washout in a single dynamic study is highly specific (95%–100%) for HCC of 1 to 3 cm in diameter and virtually diagnostic of HCC.[26–28][Level of evidence C1] In these cases, the diagnosis of HCC may be established without a second imaging modality, even in the absence of a biopsy confirmation.[28–30][Level of evidence C1]

However, if a first imaging modality, such as a contrast-enhanced CT or MRI, is not conclusive, sequential imaging with a different modality can improve sensitivity for HCC detection (from 33% to 41% for either CT or MRI to 76% for both studies when performed sequentially) without a decrease in specificity.[27]

If, despite the use of two imaging modalities, a lesion larger than 1 cm remains uncharacterized in a patient at high risk of HCC (i.e., with no or only one classic enhancement pattern), a liver biopsy can be considered.[28,29]

Liver biopsy

A liver biopsy may be performed when a diagnosis of HCC is not established by a dynamic imaging modality (three-phase CT or MRI) for liver lesions 1 cm or larger in high-risk patients.

Alpha-fetoprotein (AFP) levels

AFP is insufficiently sensitive or specific for use as a diagnostic assay. AFP can be elevated in intrahepatic cholangiocarcinoma and in some cases in which there are metastases from colon cancer. Finding a mass in the liver of a patient with an elevated AFP does not automatically indicate HCC. However, if the AFP level is high, it can be used to monitor for recurrence.

Prognosis

The natural course of early tumors is poorly understood because most HCC patients receive treatment. However, older reports have described 3-year survival rates of 13% to 21% in patients who do not receive any specific treatment.[31,32] At present, only 10% to 23% of patients with HCC may be surgical candidates for curative-intent treatment.[33,34] The 5-year overall survival (OS) rate for patients with early HCC who undergo liver transplant is 44% to 78%. For patients who undergo a liver resection, the OS rate is 27% to 70%.[35]

Liver transplant, surgical resection, and ablation offer high rates of complete responses and a potential for cure in patients with early HCC.[29]

The natural course of advanced-stage HCC is better known. Untreated patients with advanced disease usually survive less than 6 months.[36] The survival rate of untreated patients in 25 randomized clinical trials ranged from 10% to 72% at 1 year and 8% to 50% at 2 years.[37]

Unlike most patients with solid tumors, the prognosis of patients with HCC is affected by the tumor stage at presentation and by the underlying liver function. The following prognostic factors guide the selection of treatment:

  • Anatomical extension of the tumor (i.e., tumor size, number of lesions, presence of vascular invasion, and extrahepatic spread).
  • Performance status.
  • Functional hepatic reserve based on the Child-Pugh score.[36,38,39]
References
  1. American Cancer Society: Cancer Facts and Figures 2025. American Cancer Society, 2025. Available online. Last accessed January 16, 2025.
  2. Altekruse SF, McGlynn KA, Reichman ME: Hepatocellular carcinoma incidence, mortality, and survival trends in the United States from 1975 to 2005. J Clin Oncol 27 (9): 1485-91, 2009. [PUBMED Abstract]
  3. Forner A, Llovet JM, Bruix J: Hepatocellular carcinoma. Lancet 379 (9822): 1245-55, 2012. [PUBMED Abstract]
  4. Bosetti C, Turati F, La Vecchia C: Hepatocellular carcinoma epidemiology. Best Pract Res Clin Gastroenterol 28 (5): 753-70, 2014. [PUBMED Abstract]
  5. El-Serag HB: Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology 142 (6): 1264-1273.e1, 2012. [PUBMED Abstract]
  6. El-Serag HB, Kanwal F: Epidemiology of hepatocellular carcinoma in the United States: where are we? Where do we go? Hepatology 60 (5): 1767-75, 2014. [PUBMED Abstract]
  7. Lafaro KJ, Demirjian AN, Pawlik TM: Epidemiology of hepatocellular carcinoma. Surg Oncol Clin N Am 24 (1): 1-17, 2015. [PUBMED Abstract]
  8. Fattovich G, Stroffolini T, Zagni I, et al.: Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology 127 (5 Suppl 1): S35-50, 2004. [PUBMED Abstract]
  9. Grewal P, Viswanathen VA: Liver cancer and alcohol. Clin Liver Dis 16 (4): 839-50, 2012. [PUBMED Abstract]
  10. London WT, McGlynn K: Liver cancer. In: Schottenfeld D, Fraumeni JF Jr, eds.: Cancer Epidemiology and Prevention. 3rd ed. Oxford University Press, 2006, pp 763-86.
  11. McGlynn KA, Petrick JL, London WT: Global epidemiology of hepatocellular carcinoma: an emphasis on demographic and regional variability. Clin Liver Dis 19 (2): 223-38, 2015. [PUBMED Abstract]
  12. Liu Y, Wu F: Global burden of aflatoxin-induced hepatocellular carcinoma: a risk assessment. Environ Health Perspect 118 (6): 818-24, 2010. [PUBMED Abstract]
  13. Chen JG, Egner PA, Ng D, et al.: Reduced aflatoxin exposure presages decline in liver cancer mortality in an endemic region of China. Cancer Prev Res (Phila) 6 (10): 1038-45, 2013. [PUBMED Abstract]
  14. Baffy G, Brunt EM, Caldwell SH: Hepatocellular carcinoma in non-alcoholic fatty liver disease: an emerging menace. J Hepatol 56 (6): 1384-91, 2012. [PUBMED Abstract]
  15. Diehl AM, Day C: Cause, Pathogenesis, and Treatment of Nonalcoholic Steatohepatitis. N Engl J Med 377 (21): 2063-2072, 2017. [PUBMED Abstract]
  16. White DL, Kanwal F, El-Serag HB: Association between nonalcoholic fatty liver disease and risk for hepatocellular cancer, based on systematic review. Clin Gastroenterol Hepatol 10 (12): 1342-1359.e2, 2012. [PUBMED Abstract]
  17. Ascha MS, Hanouneh IA, Lopez R, et al.: The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. Hepatology 51 (6): 1972-8, 2010. [PUBMED Abstract]
  18. Chuang SC, Lee YC, Hashibe M, et al.: Interaction between cigarette smoking and hepatitis B and C virus infection on the risk of liver cancer: a meta-analysis. Cancer Epidemiol Biomarkers Prev 19 (5): 1261-8, 2010. [PUBMED Abstract]
  19. Lee YC, Cohet C, Yang YC, et al.: Meta-analysis of epidemiologic studies on cigarette smoking and liver cancer. Int J Epidemiol 38 (6): 1497-511, 2009. [PUBMED Abstract]
  20. Koh WP, Robien K, Wang R, et al.: Smoking as an independent risk factor for hepatocellular carcinoma: the Singapore Chinese Health Study. Br J Cancer 105 (9): 1430-5, 2011. [PUBMED Abstract]
  21. Lomas DA, Evans DL, Finch JT, et al.: The mechanism of Z alpha 1-antitrypsin accumulation in the liver. Nature 357 (6379): 605-7, 1992. [PUBMED Abstract]
  22. Huster D: Wilson disease. Best Pract Res Clin Gastroenterol 24 (5): 531-9, 2010. [PUBMED Abstract]
  23. Pfeiffenberger J, Mogler C, Gotthardt DN, et al.: Hepatobiliary malignancies in Wilson disease. Liver Int 35 (5): 1615-22, 2015. [PUBMED Abstract]
  24. Furuya K, Nakamura M, Yamamoto Y, et al.: Macroregenerative nodule of the liver. A clinicopathologic study of 345 autopsy cases of chronic liver disease. Cancer 61 (1): 99-105, 1988. [PUBMED Abstract]
  25. Brunello F, Cantamessa A, Gaia S, et al.: Radiofrequency ablation: technical and clinical long-term outcomes for single hepatocellular carcinoma up to 30 mm. Eur J Gastroenterol Hepatol 25 (7): 842-9, 2013. [PUBMED Abstract]
  26. Leoni S, Piscaglia F, Golfieri R, et al.: The impact of vascular and nonvascular findings on the noninvasive diagnosis of small hepatocellular carcinoma based on the EASL and AASLD criteria. Am J Gastroenterol 105 (3): 599-609, 2010. [PUBMED Abstract]
  27. Khalili K, Kim TK, Jang HJ, et al.: Optimization of imaging diagnosis of 1-2 cm hepatocellular carcinoma: an analysis of diagnostic performance and resource utilization. J Hepatol 54 (4): 723-8, 2011. [PUBMED Abstract]
  28. Sangiovanni A, Manini MA, Iavarone M, et al.: The diagnostic and economic impact of contrast imaging techniques in the diagnosis of small hepatocellular carcinoma in cirrhosis. Gut 59 (5): 638-44, 2010. [PUBMED Abstract]
  29. Bruix J, Sherman M; American Association for the Study of Liver Diseases: Management of hepatocellular carcinoma: an update. Hepatology 53 (3): 1020-2, 2011. [PUBMED Abstract]
  30. Khalili K, Kim TK, Jang HJ, et al.: Implementation of AASLD hepatocellular carcinoma practice guidelines in North America: two years of experience. [Abstract] Hepatology 48 (Suppl 1): A-128, 362A, 2008.
  31. Barbara L, Benzi G, Gaiani S, et al.: Natural history of small untreated hepatocellular carcinoma in cirrhosis: a multivariate analysis of prognostic factors of tumor growth rate and patient survival. Hepatology 16 (1): 132-7, 1992. [PUBMED Abstract]
  32. Ebara M, Ohto M, Shinagawa T, et al.: Natural history of minute hepatocellular carcinoma smaller than three centimeters complicating cirrhosis. A study in 22 patients. Gastroenterology 90 (2): 289-98, 1986. [PUBMED Abstract]
  33. Shah SA, Smith JK, Li Y, et al.: Underutilization of therapy for hepatocellular carcinoma in the medicare population. Cancer 117 (5): 1019-26, 2011. [PUBMED Abstract]
  34. Sonnenday CJ, Dimick JB, Schulick RD, et al.: Racial and geographic disparities in the utilization of surgical therapy for hepatocellular carcinoma. J Gastrointest Surg 11 (12): 1636-46; discussion 1646, 2007. [PUBMED Abstract]
  35. Dhir M, Lyden ER, Smith LM, et al.: Comparison of outcomes of transplantation and resection in patients with early hepatocellular carcinoma: a meta-analysis. HPB (Oxford) 14 (9): 635-45, 2012. [PUBMED Abstract]
  36. Okuda K, Ohtsuki T, Obata H, et al.: Natural history of hepatocellular carcinoma and prognosis in relation to treatment. Study of 850 patients. Cancer 56 (4): 918-28, 1985. [PUBMED Abstract]
  37. Llovet JM, Bruix J: Systematic review of randomized trials for unresectable hepatocellular carcinoma: Chemoembolization improves survival. Hepatology 37 (2): 429-42, 2003. [PUBMED Abstract]
  38. Llovet JM, Brú C, Bruix J: Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin Liver Dis 19 (3): 329-38, 1999. [PUBMED Abstract]
  39. A new prognostic system for hepatocellular carcinoma: a retrospective study of 435 patients: the Cancer of the Liver Italian Program (CLIP) investigators. Hepatology 28 (3): 751-5, 1998. [PUBMED Abstract]

Cellular Classification of Primary Liver Cancer

Malignant primary tumors of the liver consist of two major cell types, hepatocellular (90% of cases) and cholangiocarcinoma.[1]

Histological classification is as follows:

  • Hepatocellular carcinoma (HCC; liver cell carcinoma).
  • Fibrolamellar variant of HCC.

    It is important to distinguish between the fibrolamellar variant of HCC and HCC itself because an increased proportion of patients with the fibrolamellar variant may be cured if the tumor can be resected. Found more frequently in young women, this variant generally exhibits a slower clinical course than the more common HCC.[2]

  • Cholangiocarcinoma (intrahepatic bile duct carcinoma).
  • Mixed hepatocellular cholangiocarcinoma.
  • Undifferentiated.
  • Hepatoblastoma. This occurs more often in children than in adults. For more information, see Childhood Liver Cancer Treatment.
References
  1. Llovet JM, Burroughs A, Bruix J: Hepatocellular carcinoma. Lancet 362 (9399): 1907-17, 2003. [PUBMED Abstract]
  2. Mavros MN, Mayo SC, Hyder O, et al.: A systematic review: treatment and prognosis of patients with fibrolamellar hepatocellular carcinoma. J Am Coll Surg 215 (6): 820-30, 2012. [PUBMED Abstract]

Stage Information for Primary Liver Cancer

Prognostic modeling in hepatocellular carcinoma (HCC) is complex because cirrhosis is involved in as many as 80% of cases. Tumor features and the factors related to functional hepatic reserve must be considered. The key prognostic factors are only partially known and vary at different stages of the disease.

More than ten classifications are used throughout the world, but no system is accepted worldwide. New classifications have been proposed to overcome the difficulties of having several staging systems.

This summary discusses the following three staging systems:

Barcelona Clinic Liver Cancer (BCLC) Staging System

Currently, the BCLC staging classification is the most accepted staging system for HCC and is useful in the staging of early tumors. Evidence from an American cohort has shown that BCLC staging offers better prognostic stratification power than other staging systems.[1]

The BCLC staging system attempts to overcome the limitations of previous staging systems by including variables related to the following:[2]

  • Tumor stage.
  • Functional status of the liver.
  • Physical status.
  • Cancer-related symptoms.

Five stages (0 and A through D) are identified based on the variables mentioned above. The BCLC staging system links each HCC stage to appropriate treatment modalities as follows:

  • Patients with early-stage HCC may benefit from curative therapies (i.e., liver transplant, surgical resection, and radiofrequency ablation).
  • Patients with intermediate-stage or advanced-stage disease may benefit from palliative treatments (i.e., transcatheter arterial chemoembolization and sorafenib).
  • Patients with end-stage disease who have a very poor life expectancy are offered supportive care and palliation.

Okuda Staging System

The Okuda staging system has been extensively used in the past and includes variables related to tumor burden and liver function, such as bilirubin, albumin, and ascites. However, many significant prognostic tumor factors confirmed in both surgical and nonsurgical series (e.g., unifocal or multifocal, vascular invasion, portal venous thrombosis, or locoregional lymph node involvement) are not included.[3,4] As a result, Okuda staging is unable to stratify prognosis for early-stage cancers and mostly serves to recognize end-stage disease.

AJCC Staging System and TNM Definitions

The TNM (tumor, node, metastasis) classification for staging, proposed by the AJCC, is not widely used for liver cancer. Clinical use of TNM staging is limited because liver function is not considered. It is also difficult to use this system to select treatment options because TNM staging relies on detailed histopathological examination available only after tumor excision. TNM may be useful in prognostic prediction after liver resection.[5]

Table 1. Definitions of TNM Stages IA and IBa
Stage TNM Description
Tumor = primary tumor; N = regional lymph nodes; M = distant metastasis.
aReprinted with permission from AJCC: Liver. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 287–93.
IA T1a, N0, M0 T1a = Solitary tumor ≤2 cm.
N0 = No regional lymph node metastasis.
M0 = No distant metastasis.
IB T1b, N0, M0 T1b = Solitary tumor >2 cm without vascular invasion.
N0 = No regional lymph node metastasis.
M0 = No distant metastasis.
Table 2. Definitions of TNM Stage IIa
Stage TNM Description
T = primary tumor; N = regional lymph nodes; M = distant metastasis.
aReprinted with permission from AJCC: Liver. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 287–93.
II T2, N0, M0 T2 = Solitary tumor >2 cm with vascular invasion, or multiple tumors, none >5 cm.
N0 = No regional lymph node metastasis.
M0 = No distant metastasis.
Table 3. Definitions of TNM Stages IIIA and IIIBa
Stage TNM Description
T = primary tumor; N = regional lymph nodes; M = distant metastasis.
aReprinted with permission from AJCC: Liver. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 287–93.
IIIA T3, N0, M0 T3 = Multiple tumors, at least one of which is >5 cm.
N0 = No regional lymph node metastasis.
M0 = No distant metastasis.
IIIB T4, N0, M0 T4 = Single tumor or multiple tumors of any size involving a major branch of the portal vein or hepatic vein, or tumor(s) with direct invasion of adjacent organs other than the gallbladder or with perforation of visceral peritoneum.
N0 = No regional lymph node metastasis.
M0 = No distant metastasis.
Table 4. Definitions of TNM Stages IVA and IVBa
Stage TNM Description
T = primary tumor; N = regional lymph nodes; M = distant metastasis.
aReprinted with permission from AJCC: Liver. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 287–93.
IVA Any T, N1, M0 TX = Primary tumor cannot be assessed.
T0 = No evidence of primary tumor.
T1 = Solitary tumor ≤2 cm, or >2 cm without vascular invasion.
–T1a = Solitary tumor ≤2 cm.
–T1b = Solitary tumor >2 cm without vascular invasion.
T2 = Solitary tumor >2 cm with vascular invasion, or multiple tumors, none >5 cm.
T3 = Multiple tumors, at least one of which is >5 cm.
T4 = Single tumor or multiple tumors of any size involving a major branch of the portal vein or hepatic vein, or tumor(s) with direct invasion of adjacent organs other than the gallbladder or with perforation of visceral peritoneum.
N1 = Regional lymph node metastasis.
M0 = No distant metastasis.
IVB Any T, Any N, M1 Any T = See descriptions above in this table, stage IVA, Any T, N1, M0.
NX = Regional lymph nodes cannot be assessed.
N0 = No regional lymph node metastasis.
N1 = Regional lymph node metastasis.
M1 = Distant metastasis.
References
  1. Marrero JA, Fontana RJ, Barrat A, et al.: Prognosis of hepatocellular carcinoma: comparison of 7 staging systems in an American cohort. Hepatology 41 (4): 707-16, 2005. [PUBMED Abstract]
  2. Llovet JM, Brú C, Bruix J: Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin Liver Dis 19 (3): 329-38, 1999. [PUBMED Abstract]
  3. Poon RT, Ng IO, Fan ST, et al.: Clinicopathologic features of long-term survivors and disease-free survivors after resection of hepatocellular carcinoma: a study of a prospective cohort. J Clin Oncol 19 (12): 3037-44, 2001. [PUBMED Abstract]
  4. Pompili M, Rapaccini GL, Covino M, et al.: Prognostic factors for survival in patients with compensated cirrhosis and small hepatocellular carcinoma after percutaneous ethanol injection therapy. Cancer 92 (1): 126-35, 2001. [PUBMED Abstract]
  5. Liver. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. Springer; 2017, pp. 287–93.

Treatment Option Overview for Primary Liver Cancer

There is no agreement on a single treatment strategy for patients with hepatocellular carcinoma (HCC). Selection of treatment is complex due to several factors, including:

  • Underlying liver function.
  • Extent and location of the tumor.
  • General condition of the patient.

Several treatments for HCC are associated with long-term survival, including surgical resection, liver transplant, and ablation. There are no large, robust, randomized studies that compare treatments considered effective for early-stage disease, nor are there studies comparing these treatments with best supportive care. Often, patients with HCC are evaluated by a multidisciplinary team that includes hepatologists, radiologists, interventional radiologists, radiation oncologists, transplant surgeons, surgical oncologists, pathologists, and medical oncologists.

Best survivals are achieved when the HCC can be removed either by surgical resection or liver transplant. Surgical resection is usually performed in patients with localized HCC and enough functional hepatic reserve.

For patients with decompensated cirrhosis and a solitary lesion (<5 cm) or early multifocal disease (≤3 lesions, ≤3 cm in diameter), the best option is liver transplant.[1] However, the limited availability of liver donors restricts the use of this approach.

Transarterial chemoembolization, multikinase inhibitors, and immunotherapy are noncurative treatments for HCC that improve survival.[2–4]

Table 5 shows the standard treatment options for HCC.

Table 5. Treatment Options for HCC
Stage Treatment Options
Localized Surveillance
Surgical resection
Liver transplant
Ablation
Radiation therapy
Locally advanced or metastatic Transarterial embolization and transcatheter arterial chemoembolization in patients with nonmetastatic disease
First-line systemic therapy
Second-line systemic therapy
Radiation therapy
Recurrent (liver-limited disease without vascular involvement) Liver transplant
Surgical resection
Ablation
Radiation therapy
Recurrent (extrahepatic disease or vascular involvement) Palliative therapy
References
  1. Bruix J, Sherman M; American Association for the Study of Liver Diseases: Management of hepatocellular carcinoma: an update. Hepatology 53 (3): 1020-2, 2011. [PUBMED Abstract]
  2. Llovet JM, Ricci S, Mazzaferro V, et al.: Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359 (4): 378-90, 2008. [PUBMED Abstract]
  3. Llovet JM, Bruix J: Systematic review of randomized trials for unresectable hepatocellular carcinoma: Chemoembolization improves survival. Hepatology 37 (2): 429-42, 2003. [PUBMED Abstract]
  4. Cammà C, Schepis F, Orlando A, et al.: Transarterial chemoembolization for unresectable hepatocellular carcinoma: meta-analysis of randomized controlled trials. Radiology 224 (1): 47-54, 2002. [PUBMED Abstract]

Treatment of Localized Primary Liver Cancer

About 30% of hepatocellular carcinoma (HCC) cases present as localized disease, with a solitary mass in part of the liver or as a limited number of tumors (≤3 lesions, ≤3 cm in diameter) without major vascular invasion.

Treatment Options for Localized Primary Liver Cancer

Treatment options for localized primary liver cancer include:

  1. Surveillance.
  2. Surgical resection.
  3. Liver transplant.
  4. Ablation.
  5. Radiation therapy.

Resection and transplant achieve the best outcomes in well-selected candidates, and are usually considered the first option for curative intent.

Surveillance

Surveillance is an option for patients at high risk of HCC with lesions smaller than 1 cm detected during screening.[1][Level of evidence C1] Close follow-up at 3-month intervals is a common surveillance strategy, using the same technique that first documented the presence of the lesions.

Surgical resection

Surgery is the mainstay of HCC treatment.

Preoperative assessment includes three-phase helical computed tomography, magnetic resonance imaging, or both to determine the presence of an extension of a tumor across interlobar planes and potential involvement of the hepatic hilus, hepatic veins, and inferior vena cava. Tumors can be resected only if enough liver parenchyma can be spared with adequate vascular and biliary inflow and outflow. Patients with well-compensated cirrhosis can generally tolerate resection of up to 50% of their liver parenchyma.

Surgical resection can be considered for patients who meet the following criteria:

  • A solitary mass.
  • Good performance status.
  • Normal or minimally abnormal liver function tests.
  • No evidence of portal hypertension.
  • No evidence of cirrhosis beyond Child-Pugh class A.

After considering the location and number of tumors and the patient’s hepatic function, only 5% to 10% of patients with liver cancer will prove to have localized disease amenable to resection.[2–6]

The principles of surgical resection involve obtaining a clear margin around the tumor, which may require any of the following procedures:

  • Segmental resection.
  • Hormone-lymphatic lobectomy.
  • Extended lobectomy.

The 5-year overall survival (OS) rate after curative resection ranges between 27% and 70% and depends on tumor stage and underlying liver function.[2–6]

In patients with limited multifocal disease, hepatic resection is controversial.

Liver transplant

Liver transplant is a potentially curative therapy for HCC and has the benefit of treating the underlying cirrhosis, but the scarcity of organ donors limits the availability of this treatment modality.[2]

According to the Milan criteria, patients with a single HCC lesion smaller than 5 cm, or 2 to 3 lesions smaller than 3 cm are eligible for liver transplant. Expansion of the accepted transplant criteria for HCC is not supported by consistent data. Liver transplant is considered if resection is precluded because of multiple small tumor lesions (≤3 lesions, each ≤3 cm), or impaired liver function (Child-Pugh class B and class C). In patients who meet the criteria, transplant is associated with a 5-year OS rate of approximately 70%.[7][Level of evidence C1]

Ablation

When tumor excision, either by transplant or resection, is not feasible or advisable, ablation may be used if the tumor can be accessed percutaneously or, if necessary, through minimally invasive or open surgery. Ablation may be particularly useful for patients with early-stage HCC that is centrally located in the liver and cannot be surgically removed without excessive sacrifice of functional parenchyma.

Ablation can be achieved in the following ways:

  • Change in temperature (e.g., radiofrequency ablation [RFA], microwave, or cryoablation).
  • Exposure to a chemical substance (e.g., percutaneous ethanol injection [PEI]).
  • Direct damage of the cellular membrane (definitive electroporation).

With ablation, a margin of normal liver around the tumor can be considered. Ablation is relatively contraindicated for lesions near bile ducts, the diaphragm, or other intra-abdominal organs that might be injured during the procedure. Furthermore, when tumors are located adjacent to major vessels, the blood flow in the vessels may keep thermal ablation techniques, such as RFA, from reaching optimal temperatures. This is known as the heat-sink effect, which may preclude complete tumor necrosis.

RFA achieves best results in patients with tumors smaller than 3 cm. In this subpopulation, 5-year OS rates may be as high as 59%, and the recurrence-free survival rates may not differ significantly from treatment with hepatic resection.[8,9] Local control success progressively diminishes as the tumor size increases beyond 3 cm.

PEI yields good results in patients with Child-Pugh class A cirrhosis and a single tumor smaller than 3 cm in diameter. In those cases, the 5-year OS rate can be as high as 40% to 59%.[10,11][Level of evidence C2]

In the few randomized controlled trials that included patients with Child-Pugh class A cirrhosis, RFA proved superior to PEI in rates of complete response and local recurrences. Some of those studies have also shown improved OS with RFA. Furthermore, RFA requires fewer treatment sessions than PEI to achieve comparable outcomes.[12–15]

Of note, RFA may have higher complication rates than PEI,[13] but both techniques are associated with lower complication rates than excision procedures. RFA is a well-established technique in the treatment of HCC.

Radiation therapy

Radiation therapy can be delivered with curative or palliative intent for patients with primary liver cancer. One form of radiation, stereotactic body radiation therapy (SBRT), treats patients with a small number of fractions of precise, image-guided radiation therapy at a high biologically equivalent dose. Numerous retrospective studies have shown excellent local control for patients with HCC who receive SBRT (local control rates ranging from 70%–95% at 2 years for smaller HCCs).

Evidence (curative radiation therapy):

  1. The phase III NRG/RTOG 1112 study (NCT01730937) evaluated sorafenib alone or SBRT followed by sorafenib in patients with HCC. Patients were included if they had Child-Pugh class A, Barcelona Clinic Liver Cancer stage B or C, new or recurrent HCC. Patients also had five or fewer lesions, a tumor sum measuring 20 cm or less, and distant metastases measuring 3 cm or less. A total of 177 patients were randomly assigned (92 to sorafenib alone, 85 to SBRT followed by sorafenib). The primary end point was OS.[16][Level of evidence B1]
    • The median OS was 12.3 months for the sorafenib-alone group and 15.8 months for the SBRT-plus-sorafenib group (hazard ratio [HR], 0.77; one-sided P = .0554). This was not statistically significant.
    • Grade 3 or higher adverse events were not significantly different between the two groups: 42% for the sorafenib-alone group and 47% for the SBRT-plus-sorafenib group (P = .52).
    • There were three grade 5 adverse events: one hepatic failure and one death not otherwise specified in the sorafenib-alone group and one grade 5 lung infection in the SBRT-plus-sorafenib group.

Based on these results, SBRT is a standard of care treatment with curative intent for HCC. It can also be used to provide local control before liver transplant.

Evidence (radiation therapy for palliation):

  1. The Canadian Cancer Trials Group HE.1 trial (NCT02511522), a phase III study published in abstract form, included 66 patients with HCC. Patients were randomly assigned to receive either best supportive care alone or palliative radiation therapy to the liver (8 Gy in one fraction). Patients had end-stage disease unsuitable for local, regional, or systemic therapies. Patients also had to be more than 4 weeks from receiving chemotherapy or transcatheter arterial chemoembolization, more than 2 weeks from receiving targeted therapy or immunotherapy, and not planning any systemic therapy. The primary outcome of the study was the proportion of patients who reported an improvement of at least two points from baseline on the Brief Pain Inventory when asked to rate their liver cancer pain “intensity at worst.” A secondary end point included 3-month OS.[17][Level of evidence B3]
    • A significant improvement in the “worst” pain score from baseline to 1 month was seen in 67% of patients who received radiation therapy and 22% of patients who received best supportive care.
    • Although radiation therapy has not been historically used in this patient population, this study showed no decrease in OS for patients who received radiation. The 3-month OS rate was 51% for patients who received radiation therapy and 33% for patients who received best supportive care alone (P = .07), despite the study including patients with Child-Pugh class A, B, and C cirrhosis.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References
  1. Furuya K, Nakamura M, Yamamoto Y, et al.: Macroregenerative nodule of the liver. A clinicopathologic study of 345 autopsy cases of chronic liver disease. Cancer 61 (1): 99-105, 1988. [PUBMED Abstract]
  2. Llovet JM, Fuster J, Bruix J: Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: resection versus transplantation. Hepatology 30 (6): 1434-40, 1999. [PUBMED Abstract]
  3. Chok KS, Ng KK, Poon RT, et al.: Impact of postoperative complications on long-term outcome of curative resection for hepatocellular carcinoma. Br J Surg 96 (1): 81-7, 2009. [PUBMED Abstract]
  4. Kianmanesh R, Regimbeau JM, Belghiti J: Selective approach to major hepatic resection for hepatocellular carcinoma in chronic liver disease. Surg Oncol Clin N Am 12 (1): 51-63, 2003. [PUBMED Abstract]
  5. Poon RT, Fan ST, Lo CM, et al.: Long-term survival and pattern of recurrence after resection of small hepatocellular carcinoma in patients with preserved liver function: implications for a strategy of salvage transplantation. Ann Surg 235 (3): 373-82, 2002. [PUBMED Abstract]
  6. Dhir M, Lyden ER, Smith LM, et al.: Comparison of outcomes of transplantation and resection in patients with early hepatocellular carcinoma: a meta-analysis. HPB (Oxford) 14 (9): 635-45, 2012. [PUBMED Abstract]
  7. Hemming AW, Cattral MS, Reed AI, et al.: Liver transplantation for hepatocellular carcinoma. Ann Surg 233 (5): 652-9, 2001. [PUBMED Abstract]
  8. Huang J, Hernandez-Alejandro R, Croome KP, et al.: Radiofrequency ablation versus surgical resection for hepatocellular carcinoma in Childs A cirrhotics-a retrospective study of 1,061 cases. J Gastrointest Surg 15 (2): 311-20, 2011. [PUBMED Abstract]
  9. Zhou YM, Shao WY, Zhao YF, et al.: Meta-analysis of laparoscopic versus open resection for hepatocellular carcinoma. Dig Dis Sci 56 (7): 1937-43, 2011. [PUBMED Abstract]
  10. Huang GT, Lee PH, Tsang YM, et al.: Percutaneous ethanol injection versus surgical resection for the treatment of small hepatocellular carcinoma: a prospective study. Ann Surg 242 (1): 36-42, 2005. [PUBMED Abstract]
  11. Yamamoto J, Okada S, Shimada K, et al.: Treatment strategy for small hepatocellular carcinoma: comparison of long-term results after percutaneous ethanol injection therapy and surgical resection. Hepatology 34 (4 Pt 1): 707-13, 2001. [PUBMED Abstract]
  12. Lencioni RA, Allgaier HP, Cioni D, et al.: Small hepatocellular carcinoma in cirrhosis: randomized comparison of radio-frequency thermal ablation versus percutaneous ethanol injection. Radiology 228 (1): 235-40, 2003. [PUBMED Abstract]
  13. Lin SM, Lin CJ, Lin CC, et al.: Randomised controlled trial comparing percutaneous radiofrequency thermal ablation, percutaneous ethanol injection, and percutaneous acetic acid injection to treat hepatocellular carcinoma of 3 cm or less. Gut 54 (8): 1151-6, 2005. [PUBMED Abstract]
  14. Brunello F, Veltri A, Carucci P, et al.: Radiofrequency ablation versus ethanol injection for early hepatocellular carcinoma: A randomized controlled trial. Scand J Gastroenterol 43 (6): 727-35, 2008. [PUBMED Abstract]
  15. Shiina S, Teratani T, Obi S, et al.: A randomized controlled trial of radiofrequency ablation with ethanol injection for small hepatocellular carcinoma. Gastroenterology 129 (1): 122-30, 2005. [PUBMED Abstract]
  16. Dawson LA, Winter KA, Knox JJ, et al.: Stereotactic Body Radiotherapy vs Sorafenib Alone in Hepatocellular Carcinoma: The NRG Oncology/RTOG 1112 Phase 3 Randomized Clinical Trial. JAMA Oncol 11 (2): 136-144, 2025. [PUBMED Abstract]
  17. Dawson LA, Fairchild AM, Dennis K, et al.: Canadian Cancer Trials Group HE.1: A phase III study of palliative radiotherapy for symptomatic hepatocellular carcinoma and liver metastases. [Abstract] J Clin Oncol 41 (Suppl 4): A-LBA492, 2023.

Treatment of Locally Advanced or Metastatic Primary Liver Cancer

Treatment Options for Locally Advanced or Metastatic Primary Liver Cancer

Treatment options for locally advanced or metastatic primary liver cancer not amenable to surgical or locoregional interventions include:

  1. Transarterial embolization (TAE) and transcatheter arterial chemoembolization (TACE) in patients with nonmetastatic disease.
  2. First-line systemic therapy. 
    1. Combination immunotherapy and targeted therapy.
    2. Combination immunotherapy alone.
    3. Targeted therapy (multikinase inhibitors).
  3. Second-line systemic therapy.
    1. Targeted therapy (multikinase inhibitors).
    2. Combination immunotherapy and immunotherapy alone.
  4. Radiation therapy.

Transarterial embolization (TAE) and transcatheter arterial chemoembolization (TACE) in patients with nonmetastatic disease

TAE is the most widely used primary treatment for hepatocellular carcinoma (HCC) not amenable to curative treatment by excision or ablation. Most of the blood supply to the normal liver parenchyma comes from the portal vein, whereas blood flow to the tumor comes mainly from the hepatic artery. Furthermore, HCC tumors are generally hypervascular compared with the surrounding normal parenchyma. The obstruction of the arterial branch(es) feeding the tumor may reduce the blood flow to the tumor and result in tumor ischemia and necrosis.

Embolization agents, such as microspheres and particles, may also be administered along with concentrated doses of chemotherapeutic agents (generally doxorubicin or cisplatin) mixed with lipiodol or other emulsifying agents during chemoembolization, arterial chemoembolization (usually via percutaneous access), and TACE. TAE-TACE is considered for patients with HCC not amenable to surgery or percutaneous ablation in the absence of extrahepatic disease.

In patients with cirrhosis, any interference with arterial blood supply may be associated with significant morbidity and is relatively contraindicated in the presence of portal hypertension, portal vein thrombosis, or clinical jaundice. In patients with liver decompensation, TAE-TACE could increase the risk of liver failure.

A number of randomized controlled trials have compared TAE and TACE with supportive care.[1] Those trials have been heterogeneous in terms of patient baseline demographics and treatment. The survival advantage of TAE-TACE over supportive care has been demonstrated by two trials.[2,3] No standardized approach for TAE has been determined (e.g., embolizing agent, chemotherapy agent and dose, and treatment schedule). However, a meta-analysis has shown that TAE-TACE improves survival more than supportive treatment.[1]

The use of drug-eluting beads (DEB) for TACE may reduce the systemic side effects of chemotherapy and may increase objective tumor response.[4–7] Only one study suggested that DEB-TACE may offer an advantage in overall survival (OS).[8]

First-line systemic therapy

Historically, sorafenib (a multikinase inhibitor) has been the standard of care for patients with advanced HCC and intact liver function (Child-Pugh class A) who were not candidates for locoregional therapy. This standard was based on the results of the SHARP trial, which showed improved OS for patients who received sorafenib compared with placebo (10.7 vs. 7.9 months; hazard ratio [HR], 0.69; P < .001). However, treatment-related adverse events may make adherence to sorafenib regimens difficult, especially in a population with concurrent liver disease. Since 2018, additional drugs and drug combinations, including atezolizumab-bevacizumab and durvalumab-tremelimumab, have resulted in improved OS when compared with sorafenib, resulting in U.S. Food and Drug Administration (FDA) approval. Other regimens have demonstrated noninferiority when compared with sorafenib, including lenvatinib (a multikinase inhibitor) and immunotherapy monotherapy. In choosing first-line therapy, survival data, response rates, bleeding risk (i.e., active varices), and the likelihood of tolerating individual therapies should be considered.

Combination immunotherapy and targeted therapy

The combination of atezolizumab (an anti–PD-L1 inhibitor) and bevacizumab (a VEGF inhibitor) has produced improved OS compared with sorafenib. The FDA approved this combination for patients with advanced HCC and Child-Pugh class A liver function. Additional combination therapies are being evaluated.

Atezolizumab and bevacizumab

Evidence (atezolizumab and bevacizumab):

  1. The global, open-label, phase III Imbrave150 trial (NCT03434379) included 501 patients with unresectable HCC who had not received prior systemic therapy. Patients were randomly assigned in a 2:1 ratio to receive either atezolizumab (1,200 mg intravenously [IV]) and bevacizumab (15mg/kg IV) every 3 weeks (n = 336) or sorafenib (400 mg PO bid) (n = 165). Eligibility criteria included intact liver function (Child-Pugh class A), and the study excluded patients with untreated or incompletely treated esophageal or gastric varices.[9]
    • The OS was 19.2 months (95% confidence interval [CI], 17.0–23.7) in the atezolizumab-bevacizumab arm and 13.4 months (95% CI, 11.4–16.9) in the sorafenib arm (HR, 0.66; 95% CI, 0.52–0.85; P < .001).[9][Level of evidence A1]
    • The objective response rates were 30% (95% CI, 25%–35%) in the atezolizumab-bevacizumab arm and 11% (95% CI, 7%–17%) in the sorafenib arm.
    • In subgroup-analyses, the OS benefit was generally consistent, but with less effect in those with a nonviral etiology of HCC.
    • Grade 3 or higher treatment-related adverse events occurred in 63% of patients in the atezolizumab-bevacizumab arm and 57% of patients in the sorafenib arm.[10]
Atezolizumab and cabozantinib

Evidence (atezolizumab and cabozantinib):

  1. The global, open-label, phase III COSMIC-312 trial (NCT03755791) included 837 patients with unresectable HCC who had not received prior systemic therapy. Patients were randomly assigned in a 2:1:1 ratio to receive either cabozantinib (40 mg PO daily) with atezolizumab (1,200 mg IV every 3 weeks), sorafenib (400 mg PO bid), or cabozantinib (60 mg daily). Eligibility criteria included intact liver function (Child-Pugh class A), and the study excluded patients with gastric or esophageal varices with active bleeding in the 6 months before enrollment.[11]
    • The first primary end point explored median progression-free survival (PFS) in the first 372 patients randomly assigned to combination therapy or sorafenib. Among those patients, the median PFS was 6.8 months (99% CI, 5.6–8.3) in the cabozantinib-atezolizumab arm and 4.2 months (95% CI, 2.8–7.0) in the sorafenib arm (HR, 0.63; 99% CI, 0.44–0.91; P = .0012).[11][Level of evidence B1]
    • However, at interim analysis, the OS was similar, at 15.4 months (96% CI, 13.7–17.7) for patients in the cabozantinib-atezolizumab combination arm (n = 432) and 15.5 months (12.1–not estimable) for patients in the sorafenib arm (n = 217) (HR, 0.90; 96% CI, 0.69–1.18; P = .44).
    • At interim analysis, the PFS was 5.8 months (99% CI, 5.4–8.2) in the cabozantinib arm and 4.3 months (99% CI, 2.9–6.1) in the sorafenib arm (HR, 0.71; 99% CI, 0.51–1.01; P = .011).
    • Objective response rates were 11% (8.1%–14.2%) in the cabozantinib-atezolizumab arm, 4% (1.6%–7.1%) in the sorafenib arm, and 6% (3.3%–10.9%) in the cabozantinib arm.
    • Grade 3 or higher treatment-related adverse events occurred in 76% of patients in the cabozantinib-atezolizumab arm, 57% of patients in the sorafenib arm, and 76% of patients in the cabozantinib arm.
Combination immunotherapy alone

While single-agent immune checkpoint inhibitors have not demonstrated improved survival benefit over tyrosine kinase inhibitors (TKIs), dual immune checkpoint inhibitors have shown improved objective response rates and OS, but with increased autoimmune side effects. Optimal dosing of combination therapies is being evaluated. In 2022, based on the data below, the FDA approved the combination of a single priming dose of tremelimumab with durvalumab every 4 weeks.

Doublet immune checkpoint inhibitors

Evidence (doublet immune checkpoint inhibitors):

  1. The global, open-label, phase III HIMALAYA trial (NCT03298451) included 1,171 patients with unresectable HCC and Child-Pugh class A liver disease who had not received prior systemic treatment. Patients were randomly assigned in a 1:1:1 ratio to receive STRIDE (a single dose of tremelimumab 300 mg IV) with durvalumab (1,500 mg IV) every 4 weeks, durvalumab monotherapy (1,500 mg IV every 4 weeks), or sorafenib (500 mg PO bid).[12]
    • The median OS was 16.43 months (95% CI, 14.16–19.58) in the combination tremelimumab-durvalumab arm and 13.77 months (95% CI, 12.25–16.13) in the sorafenib arm (HR, 0.78; 96.02% CI, 0.65–0.93; P = .0035).[12][Level of evidence A1]
    • The objective response rate was 20.1% for patients who received STRIDE and 5.1% for patients who received sorafenib.
    • Grade 3 or higher treatment-related adverse events occurred in 50.5% of patients who received combination tremelimumab and durvalumab and 52.4% of patients who received sorafenib.
Single-agent immune checkpoint inhibitors

Evidence (single-agent immune checkpoint inhibitors):

  1. The HIMALAYA trial discussed above analyzed end points for patients randomly assigned to the durvalumab monotherapy arm (n = 389) or the sorafenib monotherapy arm (n = 389).[12]
    • The median OS for patients who received durvalumab monotherapy (16.56 months; 95% CI, 14.06–19.12) was noninferior to the median OS for patients who received sorafenib monotherapy (13.77 months; 95% CI, 12.25–16.13) (HR, 0.86; 95.67% CI, 0.73–1.03; noninferiority margin, 1.08).[12][Level of evidence B3]
    • The objective response rate was 8.2% in the durvalumab arm and 4.9% in the sorafenib arm.
    • Grade 3 or higher treatment-related adverse events occurred in 37.1% of patients who received durvalumab.
  2. The randomized, open-label, phase III CheckMate 459 trial (NCT02576509) included 743 patients with Child-Pugh class A liver disease and unresectable HCC who were naïve to systemic treatment. Patients were randomly assigned in a 1:1 ratio to receive either nivolumab (n = 371) or sorafenib (n = 372).[13]
    • The median OS was 16.4 months (95% CI, 13.9–18.4) in the nivolumab arm and 14.7 months (95% CI, 11.9–17.2) in the sorafenib arm (HR, 0.85; 95% CI, 0.72–1.02; P = .075).[13][Level of evidence B3]
    • The objective response rate was 15% (95% CI, 12%–19%) in the nivolumab arm and 7% (95% CI, 5%–10%) in the sorafenib arm.
    • Grade 3 or higher treatment-related adverse events occurred in 23% of patients who received nivolumab and 49% of patients who received sorafenib.
Targeted therapy (multikinase inhibitors)

The FDA has approved two oral multikinase inhibitors, lenvatinib and sorafenib, for first-line treatment of patients with advanced HCC with well-compensated liver function who are not amenable to local therapies.

There are limited data on treatment options for patients with decompensated liver function.

Lenvatinib

Evidence (lenvatinib):

  1. An international, open-label, phase III, noninferiority trial (E7080-G000-304 [NCT01761266]) that included patients from 20 countries in Asia, Europe, and North America enrolled 954 patients with advanced HCC and Child-Pugh class A disease. Patients were randomly assigned in a 1:1 ratio to receive either lenvatinib (12 mg qd for body weight >60 kg or 8 mg for body weight <60 kg) or sorafenib (400 mg bid in 28-day cycles).[14] Patients with more than 50% liver involvement and portal vein invasion were excluded.
    1. The median OS was 13.6 months, which reached noninferiority, for patients who received lenvatinib and 12.3 months for patients who received sorafenib (HR, 0.92; 95% CI, 0.79–1.06).[14][Level of evidence B1]
    2. The median PFS was 7.4 months for patients who received lenvatinib and 3.7 months for patients who received sorafenib (HR, 0.66; 95% CI, 0.57–0.77).
    3. Treatment-related adverse events were similar between the lenvatinib arm and the sorafenib arm.
      • In the lenvatinib arm, the most common side effects were hypertension (any grade, 42%), diarrhea (39%), decreased appetite (34%), and decreased weight (31%), with 11 treatment-related deaths (hepatic failure, hemorrhage, and respiratory failure).
      • In the sorafenib arm, the most common side effects were palmar-plantar erythrodysesthesia (any grade, 52%), diarrhea (46%), hypertension (30%), and decreased appetite (27%), with four treatment-related deaths (hemorrhage, stroke, respiratory failure, and sudden death).
Sorafenib

Evidence (sorafenib):

  1. The SHARP trial (NCT00105443) randomly assigned 602 patients with advanced HCC to receive either sorafenib 400 mg twice daily or a placebo. All but 20 of the patients had a Child-Pugh class A liver disease score; 13% were women.[15]
    • The study was stopped at the second planned interim analysis, after 321 deaths. The median survival was significantly longer in the sorafenib group than the placebo group (10.7 months vs. 7.9 months; HR favoring sorafenib, 0.69; 95% CI, 0.55–0.87; P < .001).
  2. A subsequent, similar trial was conducted in 23 centers in China, South Korea, and Taiwan. The study included 226 patients (97% with Child-Pugh class A liver function), and twice as many patients were randomly assigned to sorafenib than to placebo.[16]
    • The median OS was 6.5 months for the sorafenib group versus 4.2 months for the placebo group (HR, 0.68; 95% CI, 0.50–0.93; P = .014).

Adverse events attributed to sorafenib in both of these trials included hand-foot skin reaction and diarrhea.[15,16]

Studies are also ongoing to evaluate the role of sorafenib after TACE, with chemotherapy, or in the presence of more-advanced liver disease.

Second-line systemic therapy

TKIs (regorafenib, cabozantinib, and ramucirumab) and immune checkpoint inhibitors (pembrolizumab and combination nivolumab with ipilimumab) are approved for the second-line treatment of patients with advanced HCC who have progressed while receiving sorafenib. However, the most effective second-line treatment after first-line combination atezolizumab and bevacizumab has not been determined. Physicians may consider other therapies approved in the first line (e.g., lenvatinib after atezolizumab and bevacizumab or immune checkpoint inhibitors).

Targeted therapy (multikinase inhibitors)
Regorafenib

Evidence (regorafenib):

  1. An international, double-blind, placebo-controlled, phase III trial (RESORCE [NCT01774344]) included patients from 21 countries in Asia, Europe, North America, South America, and Australia. The trial enrolled 573 patients with advanced HCC and Child-Pugh class A disease who had tolerated sorafenib but had disease progression. Patients were randomly assigned in a 2:1 ratio to receive either regorafenib (160 mg/day on days 1–21 of a 28-day cycle) or placebo.[17]
    • The median OS was 10.6 months for patients who received regorafenib and 7.8 months for patients who received a placebo (HR, 0.63; 95% CI, 0.50–0.79).[17][Level of evidence A1]
    • The median PFS was 3.1 months for patients who received regorafenib and 1.5 months for patients who received placebo.
    • The most common grade 3 and 4 regorafenib-related side effects were hypertension (15%), hand-foot syndrome (13%), fatigue (9%), and diarrhea (3%).
Cabozantinib

Evidence (cabozantinib):

  1. An international, double-blind, placebo-controlled, phase III trial (CELESTIAL [NCT01908426]) that enrolled patients from 19 countries in Asia, Europe, North America, Australia, and New Zealand included 707 patients with advanced HCC and Child-Pugh class A disease. Patients had previously received sorafenib and progressed on at least one previous systemic therapy. Patients were randomly assigned in a 2:1 ratio to receive either cabozantinib (60 mg/day) or matching placebo. The primary end point was median OS.[18]
    • The median OS was 10.2 months for patients who received cabozantinib and 8.0 months for patients who received placebo (HR, 0.76; 95% CI, 0.63–0.92, P = .005).[18][Level of evidence A1]
    • The median PFS was 1.9 months for patients who received placebo and 5.2 months for patients who received cabozantinib (HR, 0.44; 95% CI, 0.36–0.52, P < .001).
    • Grade 3 or 4 side effects occurred in 68% of patients who received cabozantinib compared with 37% who received placebo. Common grade 3 or 4 side effects of cabozantinib included hand-foot syndrome (17%), hypertension (16%), abnormal aspartate aminotransferase level (12%), diarrhea (11%), and fatigue (10%).

While these findings are statistically significant for OS and PFS, the absolute improvement to OS was small, toxicity (including financial toxicity) was high, and the quality-of-life data are lacking to help guide selection of regimen and who should receive treatment. These factors should all be considered and individualized for each patient.

Ramucirumab

Ramucirumab is only used in patients with alpha-fetoprotein (AFP) levels of 400 ng/mL or higher.

Evidence (ramucirumab):

  1. The REACH trial (NCT01140347) randomly assigned 565 patients with advanced HCC to receive either ramucirumab or placebo after first-line sorafenib. The primary end point was OS.[19][Level of evidence A1]
    • The OS benefit was not statistically significant (9.2 months [95% CI, 8.0–10.6] in the ramucirumab arm and 7.6 months [95% CI, 6.0–9.3] in the placebo arm).
    • An unplanned subgroup analysis showed that patients with an AFP response had improved survival compared with patients who did not.
  2. The REACH-2 trial (NCT02435433) included 292 patients with an Eastern Cooperative Oncology Group performance status of 0 or 1, an AFP level of at least 400 ng/mL, and Child-Pugh class A liver disease who had previously received sorafenib. Patients were randomly assigned to receive either ramucirumab or placebo.[20,21][Level of evidence A1]
    • OS and PFS were improved in patients who received ramucirumab. The median OS was 8.5 months (95% CI, 7.0–10.6) for patients who received ramucirumab and 7.3 months (95% CI, 5.4–9.1) for patients who received placebo (HR, 0.710; 95% CI, 0.531–0.949; P = .0199).
  3. A pooled analysis of the patients in the REACH trial with an AFP greater than 400 ng/mL and the patients in REACH-2 showed improved survival regardless of Barcelona Clinic Liver Cancer (BCLC) stage.[22][Level of evidence C1]
    • Among patients with BCLC stage B disease, the median OS was 13.7 months for the ramucirumab group and 8.2 months for the placebo group (HR, 0.43; 95% CI, 0.23–0.83). Among patients with BCLC stage C disease, the median OS was 7.7 months for the ramucirumab group and 4.8 months for the placebo group (HR, 0.72; 95% CI, 0.59–0.89).
Combination immunotherapy and immunotherapy alone
Pembrolizumab

Evidence (pembrolizumab):

  1. In an international, phase II, open-label, single-arm study (KEYNOTE-224 [NCT02702414]), 104 patients with BCLC stage B or C disease were enrolled across Europe, North America, and Japan. Patients had advanced HCC refractory to, or intolerant of, sorafenib and received pembrolizumab (200 mg IV every 3 weeks).[23]
    • The objective response rate was 18.3% (95% CI, 11.4%–27.1%), and the median duration of response was 21.0 months (range, 3.1–39.5+).[23,24]
    • The median OS was 13.2 months (95% CI, 9.7–15.3).
  2. The phase III KEYNOTE-394 study (NCT03062358) included 453 patients in Asia with advanced HCC previously treated with sorafenib or oxaliplatin-based chemotherapy. Patients were randomly assigned in a 2:1 ratio to receive either pembrolizumab (200 mg IV) or placebo every 3 weeks for up to 35 cycles.[25]
    • The OS was 14.6 months (95% CI, 12.6–18.0) in the pembrolizumab arm and 13.0 months (95% CI, 10.5–15.1) in the placebo arm (HR, 0.79; 95% CI, 0.63–0.99; P = .0180). Notably, the 24-month OS rate was 34.3% in the pembrolizumab arm and 24.9% in the placebo arm.[25][Level of evidence A1]
    • Grade 3 or higher treatment-related adverse events occurred in 14.4% of patients in the pembrolizumab arm and 5.9% of patients in the placebo arm.

Based on these data, the FDA granted accelerated approval for pembrolizumab in patients with advanced HCC previously treated with sorafenib.

Nivolumab and ipilimumab

Evidence (nivolumab and ipilimumab):

  1. Cohort 4 of CheckMate 040 (NCT01658878), a multicenter, open-label, phase I/II study, enrolled 148 patients with advanced HCC and Child-Pugh class A liver function previously treated with sorafenib. Patients were randomly assigned in a 1:1:1 ratio to one of the following three dosages:[26]
    1. Arm A: Nivolumab 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks for 4 doses, followed by maintenance nivolumab 240 mg every 2 weeks.
    2. Arm B: Nivolumab 3 mg/kg with ipilimumab 1 mg/kg every 3 weeks for 4 doses, followed by maintenance nivolumab 240 mg every 2 weeks.
    3. Arm C: Nivolumab 3 mg/kg every 2 weeks with ipilimumab 1 mg/kg every 6 weeks.
    • The median OS was 22.8 months (95% CI, 9.4–not reached) in arm A, 12.5 months (95% CI, 7.6–16.4) in arm B, and 12.7 months (95% CI, 7.4–33.0) in arm C.[26][Level of evidence A1]
    • The objective response rates were 32% (95% CI, 20%–47%) in arm A, 27% (95% CI, 15%–41%) in arm B, and 29% (95% CI, 17%–43%) in arm C.
    • Grade 3 or higher treatment-related adverse events occurred in 76% of patients in arm A, 65% of patients in arm B, and 69% of patients in arm C.

Based on these data, the FDA granted accelerated approval for nivolumab (1 mg/kg IV) with ipilimumab (3 mg/kg IV every 3 weeks for 4 doses), followed by nivolumab (240 mg IV every 2 weeks) for patients with advanced HCC previously treated with sorafenib.[27]

Nivolumab

Evidence (nivolumab):

  1. A phase I/II, open-label, single-arm, dose-escalation and dose-expansion trial (CheckMate 040 [NCT01658878]) included 262 patients with advanced HCC and well-compensated liver function. Of those patients, 48 were enrolled in the dose-escalation phase and 214 patients were enrolled in the dose-expansion phase with nivolumab 3 mg/kg. Patients were treated with nivolumab every 2 weeks.[28] Cohorts included patients with active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, uninfected patients with sorafenib-naïve disease, and uninfected patients with sorafenib-refractory disease.
    • The total overall objective response rate in the dose-expansion phase was 20% (95% CI, 15%–26%) with three complete responses. Results were similar in untreated, refractory, and HBV/HCV-infected patients.[28][Level of evidence B4]

However, based on postmarketing requirements showing lack of confirmatory benefit, the indication for nivolumab monotherapy in the second-line setting was withdrawn in 2021.

Radiation therapy

Several phase II studies have suggested a benefit of radiation therapy in local control and OS compared with historical controls for patients with locally advanced HCC unsuitable for standard locoregional therapies.[29,30][Level of evidence C2]

Curative-intent stereotactic body radiation therapy (SBRT) improved OS in a group of patients with HCC in the NRG/RTOG 1112 study (NCT01730937), which has been presented in abstract form. Most studies have included patients with Child-Pugh class A cirrhosis. Patients with Child-Pugh class B and C cirrhosis can also be treated with liver radiation, although with a higher risk of toxicity.[31][Level of evidence B1]

Many centers deliver photon-based SBRT, while others also offer proton-based (or other heavy-ion based) radiation therapy to the liver. Based on retrospective data, proton-based radiation therapy has the potential to offer a lower dose to the normal liver and dose-escalation to the liver tumor.[32,33] Clinical trials, including NRG-GI003 (NCT03186898), are evaluating whether photon or proton therapy is superior for patients with HCC.

Palliative radiation therapy improved pain response in a randomized trial presented in abstract form. Doses commonly used included 30 Gy in ten fractions and 8 Gy in one fraction. For more information, see the Radiation therapy section in Treatment of Localized Primary Liver Cancer.[34][Level of evidence B3]

Systemic chemotherapy

There is no evidence supporting a survival benefit for patients with advanced HCC receiving systemic cytotoxic chemotherapy when compared with no treatment or best supportive care.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References
  1. Llovet JM, Bruix J: Systematic review of randomized trials for unresectable hepatocellular carcinoma: Chemoembolization improves survival. Hepatology 37 (2): 429-42, 2003. [PUBMED Abstract]
  2. Llovet JM, Real MI, Montaña X, et al.: Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet 359 (9319): 1734-9, 2002. [PUBMED Abstract]
  3. Lo CM, Ngan H, Tso WK, et al.: Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology 35 (5): 1164-71, 2002. [PUBMED Abstract]
  4. Malagari K, Pomoni M, Kelekis A, et al.: Prospective randomized comparison of chemoembolization with doxorubicin-eluting beads and bland embolization with BeadBlock for hepatocellular carcinoma. Cardiovasc Intervent Radiol 33 (3): 541-51, 2010. [PUBMED Abstract]
  5. Varela M, Real MI, Burrel M, et al.: Chemoembolization of hepatocellular carcinoma with drug eluting beads: efficacy and doxorubicin pharmacokinetics. J Hepatol 46 (3): 474-81, 2007. [PUBMED Abstract]
  6. Poon RT, Tso WK, Pang RW, et al.: A phase I/II trial of chemoembolization for hepatocellular carcinoma using a novel intra-arterial drug-eluting bead. Clin Gastroenterol Hepatol 5 (9): 1100-8, 2007. [PUBMED Abstract]
  7. Lammer J, Malagari K, Vogl T, et al.: Prospective randomized study of doxorubicin-eluting-bead embolization in the treatment of hepatocellular carcinoma: results of the PRECISION V study. Cardiovasc Intervent Radiol 33 (1): 41-52, 2010. [PUBMED Abstract]
  8. Dhanasekaran R, Kooby DA, Staley CA, et al.: Comparison of conventional transarterial chemoembolization (TACE) and chemoembolization with doxorubicin drug eluting beads (DEB) for unresectable hepatocelluar carcinoma (HCC). J Surg Oncol 101 (6): 476-80, 2010. [PUBMED Abstract]
  9. Finn RS, Qin S, Ikeda M, et al.: Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N Engl J Med 382 (20): 1894-1905, 2020. [PUBMED Abstract]
  10. Cheng AL, Qin S, Ikeda M, et al.: Updated efficacy and safety data from IMbrave150: Atezolizumab plus bevacizumab vs. sorafenib for unresectable hepatocellular carcinoma. J Hepatol 76 (4): 862-873, 2022. [PUBMED Abstract]
  11. Kelley RK, Rimassa L, Cheng AL, et al.: Cabozantinib plus atezolizumab versus sorafenib for advanced hepatocellular carcinoma (COSMIC-312): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol 23 (8): 995-1008, 2022. [PUBMED Abstract]
  12. Abou-Alfa GK, Lau G, Kudo M, et al.: Tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. NEJM Evid 1 (8): 2022. Available online. Last accessed March 26, 2025.
  13. Yau T, Park JW, Finn RS, et al.: Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol 23 (1): 77-90, 2022. [PUBMED Abstract]
  14. Kudo M, Finn RS, Qin S, et al.: Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet 391 (10126): 1163-1173, 2018. [PUBMED Abstract]
  15. Llovet JM, Ricci S, Mazzaferro V, et al.: Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359 (4): 378-90, 2008. [PUBMED Abstract]
  16. Cheng AL, Kang YK, Chen Z, et al.: Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol 10 (1): 25-34, 2009. [PUBMED Abstract]
  17. Bruix J, Qin S, Merle P, et al.: Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 389 (10064): 56-66, 2017. [PUBMED Abstract]
  18. Abou-Alfa GK, Meyer T, Cheng AL, et al.: Cabozantinib in Patients with Advanced and Progressing Hepatocellular Carcinoma. N Engl J Med 379 (1): 54-63, 2018. [PUBMED Abstract]
  19. Zhu AX, Park JO, Ryoo BY, et al.: Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol 16 (7): 859-70, 2015. [PUBMED Abstract]
  20. Chau I, Park JO, Ryoo BY, et al.: Alpha-fetoprotein kinetics in patients with hepatocellular carcinoma receiving ramucirumab or placebo: an analysis of the phase 3 REACH study. Br J Cancer 119 (1): 19-26, 2018. [PUBMED Abstract]
  21. Zhu AX, Kang YK, Yen CJ, et al.: Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 20 (2): 282-296, 2019. [PUBMED Abstract]
  22. Kudo M, Finn RS, Morimoto M, et al.: Ramucirumab for Patients with Intermediate-Stage Hepatocellular Carcinoma and Elevated Alpha-Fetoprotein: Pooled Results from Two Phase 3 Studies (REACH and REACH-2). Liver Cancer 10 (5): 451-460, 2021. [PUBMED Abstract]
  23. Zhu AX, Finn RS, Edeline J, et al.: Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol 19 (7): 940-952, 2018. [PUBMED Abstract]
  24. Kudo M, Finn RS, Edeline J, et al.: Updated efficacy and safety of KEYNOTE-224: a phase II study of pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib. Eur J Cancer 167: 1-12, 2022. [PUBMED Abstract]
  25. Qin S, Chen Z, Fang W, et al.: Pembrolizumab Versus Placebo as Second-Line Therapy in Patients From Asia With Advanced Hepatocellular Carcinoma: A Randomized, Double-Blind, Phase III Trial. J Clin Oncol 41 (7): 1434-1443, 2023. [PUBMED Abstract]
  26. Yau T, Kang YK, Kim TY, et al.: Efficacy and Safety of Nivolumab Plus Ipilimumab in Patients With Advanced Hepatocellular Carcinoma Previously Treated With Sorafenib: The CheckMate 040 Randomized Clinical Trial. JAMA Oncol 6 (11): e204564, 2020. [PUBMED Abstract]
  27. Saung MT, Pelosof L, Casak S, et al.: FDA Approval Summary: Nivolumab Plus Ipilimumab for the Treatment of Patients with Hepatocellular Carcinoma Previously Treated with Sorafenib. Oncologist 26 (9): 797-806, 2021. [PUBMED Abstract]
  28. El-Khoueiry AB, Sangro B, Yau T, et al.: Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet 389 (10088): 2492-2502, 2017. [PUBMED Abstract]
  29. Bujold A, Massey CA, Kim JJ, et al.: Sequential phase I and II trials of stereotactic body radiotherapy for locally advanced hepatocellular carcinoma. J Clin Oncol 31 (13): 1631-9, 2013. [PUBMED Abstract]
  30. Kawashima M, Furuse J, Nishio T, et al.: Phase II study of radiotherapy employing proton beam for hepatocellular carcinoma. J Clin Oncol 23 (9): 1839-46, 2005. [PUBMED Abstract]
  31. Dawson LA, Winter KA, Knox JJ, et al.: NRG/RTOG 1112: Randomized phase III study of sorafenib vs. stereotactic body radiation therapy (SBRT) followed by sorafenib in hepatocellular carcinoma (HCC). [Abstract] J Clin Oncol 41 (Suppl 4): A-489, 2023.
  32. Sugahara S, Oshiro Y, Nakayama H, et al.: Proton beam therapy for large hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 76 (2): 460-6, 2010. [PUBMED Abstract]
  33. Hong TS, Wo JY, Yeap BY, et al.: Multi-Institutional Phase II Study of High-Dose Hypofractionated Proton Beam Therapy in Patients With Localized, Unresectable Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma. J Clin Oncol 34 (5): 460-8, 2016. [PUBMED Abstract]
  34. Dawson LA, Fairchild AM, Dennis K, et al.: Canadian Cancer Trials Group HE.1: A phase III study of palliative radiotherapy for symptomatic hepatocellular carcinoma and liver metastases. [Abstract] J Clin Oncol 41 (Suppl 4): A-LBA492, 2023.

Treatment of Recurrent Primary Liver Cancer

Treatment Options for Recurrent Primary Liver Cancer

Intrahepatic recurrence is the most common pattern of failure after curative treatment.[1] Intrahepatic recurrence of hepatocellular carcinoma (HCC) may be the result of either intrahepatic metastasis or metachronous de novo tumor. Theoretically, intrahepatic metastasis may be associated with less favorable outcomes because it is most likely the result of concurrent hematogenous metastases. However, in clinical practice, the two causes of recurrence cannot be differentiated.

Treatment options for patients with recurrent primary liver cancer with liver-limited disease without vascular involvement include:

  1. Liver transplant.
  2. Surgical resection.
  3. Ablation.
  4. Radiation therapy.

Evidence (curative radiation therapy):

  1. A randomized controlled trial (NCT04047173) included 166 patients with recurrent HCC (after prior resection or ablation). Patients had a Karnofsky performance status score of at least 90, Child-Pugh class A cirrhosis, and a single HCC (measuring ≤5 cm). Patients were randomly assigned to receive either stereotactic body radiation therapy (SBRT) or radiofrequency ablation (RFA). The primary end point was local progression-free survival (PFS).[2]
    • The local PFS rate was better with SBRT than RFA (hazard ratio [HR], 0.45, 95% confidence interval [CI], 0.24–0.87; P = .04). The 2-year local PFS rates were 92.7% (95% CI, 87.3%–98.5%) with SBRT and 75.8% (95% CI, 67.2%–85.7%) with RFA.[2][Level of evidence B1]
    • There was no statistically significant difference in the 2-year OS rate between the two groups, at 97.6% (95% CI, 94.3%–100.0%) for SBRT and 93.9% (95% CI, 88.9%–99.2%) for RFA (HR, 0.91; 95% CI, 0.37–2.22; P = .830).
    • The rate of adverse events was not different between the two groups.

Treatment options for patients with recurrent primary liver cancer with extrahepatic disease or vascular involvement include:

  1. Palliative therapy (transcatheter arterial chemoembolization [TACE] and systemic therapy).

Regarding primary HCC, the treatment strategy for recurrent intrahepatic HCC is determined by the function of the liver and the macroscopic tumor features (e.g., number of lesions, site of recurrence, and invasion of major vessels). Using the same selection criteria that are used for primary HCC, either curative (i.e., salvage liver transplant, surgical resection, and ablation) or palliative treatments (e.g., TACE and sorafenib) can be offered for recurrent HCC.

Evidence (salvage liver transplant, resection, and ablation):

  1. In a retrospective study of 183 patients with intrahepatic recurrence, only 87 of the patients could be treated with curative intent (transplant, resection, and ablation).[3][Level of evidence A2]
    • The 5-year tumor-free survival rate was 57.9% for liver transplant, 49.3% for resection, and 10.6% for radiofrequency ablation. Subgroup analysis showed that transplant and resection led to comparable survival and that both treatments led to significantly better outcomes than did ablation (P < .001). However, selection bias was a major pitfall of this retrospective study.
    • Other than the use of ablation for secondary treatment, risk factors for shorter disease-free survival were identified as alpha-fetoprotein blood levels above 400 ng/mL and recurrence within 1 year of treatment (47.5% vs. 6.7% at 5 years, P < .001).

Other studies have also suggested that most of the recurrences that appear early during follow-up are caused by tumor dissemination and have a more aggressive biological pattern than primary tumors.[4,5]

Clinical trials are appropriate and can be offered to patients with recurrent HCC whenever possible.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References
  1. Fan ST, Poon RT, Yeung C, et al.: Outcome after partial hepatectomy for hepatocellular cancer within the Milan criteria. Br J Surg 98 (9): 1292-300, 2011. [PUBMED Abstract]
  2. Xi M, Yang Z, Hu L, et al.: Radiofrequency Ablation Versus Stereotactic Body Radiotherapy for Recurrent Small Hepatocellular Carcinoma: A Randomized, Open-Label, Controlled Trial. J Clin Oncol 43 (9): 1073-1082, 2025. [PUBMED Abstract]
  3. Chan AC, Chan SC, Chok KS, et al.: Treatment strategy for recurrent hepatocellular carcinoma: salvage transplantation, repeated resection, or radiofrequency ablation? Liver Transpl 19 (4): 411-9, 2013. [PUBMED Abstract]
  4. Minagawa M, Makuuchi M, Takayama T, et al.: Selection criteria for repeat hepatectomy in patients with recurrent hepatocellular carcinoma. Ann Surg 238 (5): 703-10, 2003. [PUBMED Abstract]
  5. Chen YJ, Yeh SH, Chen JT, et al.: Chromosomal changes and clonality relationship between primary and recurrent hepatocellular carcinoma. Gastroenterology 119 (2): 431-40, 2000. [PUBMED Abstract]

Latest Updates to This Summary (04/17/2025)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Treatment Option Overview for Primary Liver Cancer

Revised Table 5 to include radiation therapy as a treatment option for patients with recurrent primary liver cancer with liver-limited disease without vascular involvement.

Treatment of Localized Primary Liver Cancer

Revised text about a phase III study that evaluated sorafenib alone or stereotactic body radiation therapy (SBRT) followed by sorafenib in patients with hepatocellular carcinoma (HCC) to state that the median overall survival results were not statistically significant (cited Dawson et al. as reference 16).

Treatment of Recurrent Primary Liver Cancer

Added radiation therapy as a treatment option for patients with recurrent primary liver cancer with liver-limited disease without vascular involvement.

Added text about a randomized controlled trial that included 166 patients with recurrent HCC. Patients had a Karnofsky performance status score of at least 90, Child-Pugh class A cirrhosis, and a single HCC. Patients were randomly assigned to receive either SBRT or radiofrequency ablation. The primary end point was local progression-free survival (cited Xi et al. as reference 2 and level of evidence B1).

This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of adult primary liver cancer. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Primary Liver Cancer Treatment are:

  • Amit Chowdhry, MD, PhD (University of Rochester Medical Center)
  • Leon Pappas, MD, PhD (Massachusetts General Hospital)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website’s Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”

The preferred citation for this PDQ summary is:

PDQ® Adult Treatment Editorial Board. PDQ Primary Liver Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/liver/hp/adult-liver-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389465]

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Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

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Bile Duct Cancer (Cholangiocarcinoma) Treatment (PDQ®)–Health Professional Version

Bile Duct Cancer (Cholangiocarcinoma) Treatment (PDQ®)–Health Professional Version

General Information About Bile Duct Cancer

Cancer of the bile duct (also called cholangiocarcinoma) is extremely rare. The true incidence of bile duct cancer is unknown because establishing an accurate diagnosis is difficult.

Traditionally, bile duct tumors located within the liver were classified with hepatocellular carcinoma as primary liver tumors.[1] In contrast, bile duct tumors located outside of the liver were classified with gallbladder cancer as extrahepatic biliary tract tumors.[1] The classification of bile duct tumors has changed to include intrahepatic tumors of the bile ducts and extrahepatic tumors (perihilar and distal) of the bile ducts.

Approximately 50% of cholangiocarcinomas arise in the bile ducts of the perihilar region, 40% in the distal region, and 10% in the intrahepatic region.

Many bile duct cancers are multifocal. In most patients, the tumor cannot be completely removed by surgery and is incurable. Palliative measures such as resection, radiation therapy (e.g., brachytherapy or external-beam radiation therapy), or stenting procedures may maintain adequate biliary drainage and allow for improved quality of life.

Anatomy

The biliary system consists of a network of ducts that carry bile from the liver to the small bowel and is classified by its anatomical location (Figure 1). Bile is produced by the liver and is important for fat digestion.

Intrahepatic bile duct

The bile ducts located within the liver are called intrahepatic bile ducts. Tumors of the intrahepatic bile ducts originate in small intrahepatic ductules or large intrahepatic ducts that are proximal to the bifurcation of the right and left hepatic ducts. These tumors are also known as intrahepatic cholangiocarcinomas.

EnlargeAnatomy of the intrahepatic bile ducts; drawing shows the liver and the intrahepatic bile ducts, which include the right and left hepatic ducts. Also shown is the common hepatic duct, gallbladder, cystic duct, common bile duct, pancreas, ampulla of Vater, and small intestine. An inset shows a cross section of a liver lobule with a network of bile ductules leading into a bile duct.
Figure 1. Anatomy of the intrahepatic bile duct.

Extrahepatic bile duct

The bile ducts located outside of the liver are called extrahepatic bile ducts. They include part of the right and left hepatic ducts that are outside of the liver, the common hepatic duct, and the common bile duct. The extrahepatic bile ducts can be further divided into the perihilar (hilum) region and distal region.

EnlargeAnatomy of the extrahepatic bile ducts; drawing shows the extrahepatic bile ducts, including the common hepatic duct (perihilar region) and the common bile duct (distal region). Also shown are the liver, right and left hepatic ducts, gallbladder, cystic duct, pancreas, ampulla of Vater, and small intestine.
Figure 2. Anatomy of the extrahepatic bile duct.
  • Perihilar (hilum) region. The hilum is the region where the right and left hepatic ducts exit the liver and join to form the common hepatic duct that is proximal to the origin of the cystic duct. Tumors of this region are also known as perihilar cholangiocarcinomas or Klatskin tumors.
  • Distal region. This region includes the common bile duct and inserts into the small intestine. Tumors of this region are also known as extrahepatic cholangiocarcinomas (Figure 2).

Risk Factors

Bile duct cancer may occur more frequently in patients with a history of primary sclerosing cholangitis, chronic ulcerative colitis, choledochal cysts, or infections with the liver fluke Clonorchis sinensis.[2]

Clinical Features

Distal and perihilar bile duct cancers frequently cause biliary tract obstruction, leading to the following symptoms:

  • Jaundice.
  • Weight loss.
  • Abdominal pain.
  • Fever.
  • Pruritus.

Intrahepatic bile duct cancer may be relatively indolent and difficult to differentiate clinically from metastatic adenocarcinoma deposits in the liver.

Diagnostic and Staging Evaluation

Clinical evaluation is dependent on laboratory and radiographic imaging tests that include:

  • Liver function tests and other laboratory studies.
  • Abdominal ultrasonography.
  • Computed tomography.
  • Magnetic resonance imaging.
  • Magnetic resonance cholangiopancreatography.

These tests demonstrate the extent of the primary tumor and help determine the presence or absence of distant metastases.

If a patient is medically fit for surgery and the tumor is amenable to surgical resection, surgical exploration is performed. Pathological examination of the resected specimen is done to establish definitive pathological staging.

Prognosis

Prognosis depends in part on the tumor’s anatomical location, which affects resectability. Because of proximity to major blood vessels and diffuse extension within the liver, a bile duct tumor can be difficult to resect. Total resection is possible in 25% to 30% of lesions that originate in the distal bile duct; the resectability rate is lower for lesions that occur in more proximal sites.[3]

Complete resection with negative surgical margins offers the only chance of cure for bile duct cancer. For localized, resectable extrahepatic and intrahepatic tumors, the presence of involved lymph nodes and perineural invasion are significant adverse prognostic factors.[4–6]

Additionally, among patients with intrahepatic cholangiocarcinomas, the following prognostic factors have been associated with worse outcomes:[7–9]

  • A personal history of primary sclerosing cholangitis.
  • Elevated cancer antigen 19-9 level.
  • Periductal infiltrating tumor growth pattern.
  • Presence of hepatic venous invasion.
References
  1. Siegel R, Ma J, Zou Z, et al.: Cancer statistics, 2014. CA Cancer J Clin 64 (1): 9-29, 2014 Jan-Feb. [PUBMED Abstract]
  2. de Groen PC, Gores GJ, LaRusso NF, et al.: Biliary tract cancers. N Engl J Med 341 (18): 1368-78, 1999. [PUBMED Abstract]
  3. Stain SC, Baer HU, Dennison AR, et al.: Current management of hilar cholangiocarcinoma. Surg Gynecol Obstet 175 (6): 579-88, 1992. [PUBMED Abstract]
  4. Wakai T, Shirai Y, Moroda T, et al.: Impact of ductal resection margin status on long-term survival in patients undergoing resection for extrahepatic cholangiocarcinoma. Cancer 103 (6): 1210-6, 2005. [PUBMED Abstract]
  5. Klempnauer J, Ridder GJ, von Wasielewski R, et al.: Resectional surgery of hilar cholangiocarcinoma: a multivariate analysis of prognostic factors. J Clin Oncol 15 (3): 947-54, 1997. [PUBMED Abstract]
  6. Bhuiya MR, Nimura Y, Kamiya J, et al.: Clinicopathologic studies on perineural invasion of bile duct carcinoma. Ann Surg 215 (4): 344-9, 1992. [PUBMED Abstract]
  7. Rosen CB, Nagorney DM, Wiesner RH, et al.: Cholangiocarcinoma complicating primary sclerosing cholangitis. Ann Surg 213 (1): 21-5, 1991. [PUBMED Abstract]
  8. Shirabe K, Mano Y, Taketomi A, et al.: Clinicopathological prognostic factors after hepatectomy for patients with mass-forming type intrahepatic cholangiocarcinoma: relevance of the lymphatic invasion index. Ann Surg Oncol 17 (7): 1816-22, 2010. [PUBMED Abstract]
  9. Isa T, Kusano T, Shimoji H, et al.: Predictive factors for long-term survival in patients with intrahepatic cholangiocarcinoma. Am J Surg 181 (6): 507-11, 2001. [PUBMED Abstract]

Cellular Classification of Bile Duct Cancer

Intrahepatic Bile Duct Cancer

The most common histopathological types of intrahepatic bile duct tumor include:[1]

  • Intrahepatic cholangiocarcinoma.
  • Biliary intraepithelial neoplasia, grade 3 (high-grade dysplasia).
  • Combined hepatocellular-cholangiocarcinoma.
  • Carcinosarcoma.
  • Intraductal papillary neoplasm with an associated invasive carcinoma.
  • Mucinous cystic neoplasm with an associated invasive carcinoma.
  • Neuroendocrine carcinoma.
  • Large cell neuroendocrine carcinoma.
  • Small cell neuroendocrine carcinoma.
  • Intraductal papillary neoplasm with high-grade dysplasia.

Perihilar Bile Duct Cancer

Adenocarcinomas are the most common type of perihilar bile duct tumor. The histological types of perihilar bile duct cancer include:[2]

  • Carcinoma in situ.
  • Biliary intraepithelial neoplasia, high grade.
  • Intraductal papillary neoplasm with high-grade dysplasia.
  • Mucinous cystic neoplasm with high-grade intraepithelial neoplasia.
  • Adenocarcinoma.
  • Adenocarcinoma, biliary type.
  • Adenocarcinoma, gastric foveolar type.
  • Adenocarcinoma, intestinal type.
  • Clear cell adenocarcinoma.
  • Mucinous carcinoma.
  • Signet-ring cell carcinoma.
  • Squamous cell carcinoma.
  • Adenosquamous carcinoma.
  • Undifferentiated carcinoma.
  • High-grade neuroendocrine carcinoma.
  • Small cell neuroendocrine carcinoma.
  • Intraductal papillary neoplasm with an associated invasive carcinoma.
  • Mucinous cystic neoplasm with an associated invasive carcinoma.

Distal Bile Duct Cancer

Adenocarcinomas are the most common type of distal bile duct tumor. The histological types of distal bile duct cancer include:[3]

  • Carcinoma in situ.
  • Biliary intraepithelial neoplasia, high grade.
  • Intraductal papillary neoplasm with high-grade intraepithelial neoplasia.
  • Mucinous cystic neoplasm with high-grade intraepithelial neoplasia.
  • Adenocarcinoma.
  • Adenocarcinoma, biliary type.
  • Adenocarcinoma, intestinal type.
  • Adenocarcinoma, gastric foveolar type.
  • Mucinous adenocarcinoma.
  • Clear cell adenocarcinoma.
  • Signet-ring cell carcinoma.
  • Squamous cell carcinoma.
  • Adenosquamous carcinoma.
  • Undifferentiated carcinoma.
  • High-grade neuroendocrine carcinoma.
  • Small cell neuroendocrine carcinoma.
  • Mixed adenoneuroendocrine carcinoma.
  • Intraductal papillary neoplasm with an associated invasive carcinoma.
  • Mucinous cystic neoplasm with an associated invasive carcinoma.
References
  1. Intrahepatic Bile Ducts. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. Springer; 2017, pp. 295–302.
  2. Perihilar bile ducts. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. Springer; 2017, pp. 311–16.
  3. Distal bile duct. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. Springer; 2017, pp. 317–25.

Stage Information for Bile Duct Cancer

Staging for Bile Duct Cancer

Bile duct cancer is classified as resectable (localized) or unresectable, with obvious prognostic importance. The TNM (tumor, node, metastasis) staging system is used for staging bile duct cancer, commonly after surgery and pathological examination of the resected specimen. Evaluation of the extent of disease at laparotomy is an important component of staging.

AJCC Staging System for Bile Duct Cancer

AJCC staging system for intrahepatic bile duct cancer

The AJCC has designated staging by TNM classification to define intrahepatic bile duct cancer.[1]

Tables 1, 2, 3, 4, and 5 pertain to the intrahepatic bile duct cancer stages.

Table 1. Definitions of TNM Stage 0 Intrahepatic Bile Duct Cancera
Stage TNM Description
T = primary tumor; N = regional lymph node; M = distant metastasis.
aReprinted with permission from AJCC: Intrahepatic Bile Duct. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 295–302.
0 Tis, N0, M0 Tis = Carcinoma in situ (intraductal tumor).
N0 = No regional lymph node metastasis.
M0 = No distant metastasis.
Table 2. Definitions of TNM Stage I Intrahepatic Bile Duct Cancera
Stage TNM Description
T = primary tumor; N = regional lymph node; M = distant metastasis.
aReprinted with permission from AJCC: Intrahepatic Bile Duct. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 295–302.
I IA T1a, N0, M0 T1a = Solitary tumor ≤5 cm without vascular invasion.
N0 = No regional lymph node metastasis.
M0 = No distant metastasis.
IB T1b, N0, M0 T1b = Solitary tumor >5 cm without vascular invasion.
N0 = No regional lymph node metastasis.
M0 = No distant metastasis.
Table 3. Definitions of TNM Stage II Intrahepatic Bile Duct Cancera
Stage TNM Description
T = primary tumor; N = regional lymph node; M = distant metastasis.
aReprinted with permission from AJCC: Intrahepatic Bile Duct. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 295–302.
II T2, N0, M0 T2 = Solitary tumor with intrahepatic vascular invasion or multiple tumors, with or without vascular invasion.
N0 = No regional lymph node metastasis.
M0 = No distant metastasis.
Table 4. Definitions of TNM Stage III Intrahepatic Bile Duct Cancera
Stage TNM Description
T = primary tumor; N = regional lymph node; M = distant metastasis.
aReprinted with permission from AJCC: Intrahepatic Bile Duct. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 295–302.
III IIIA T3, N0, M0 T3 =Tumor perforating the visceral peritoneum.
N0 = No regional lymph node metastasis.
M0 = No distant metastasis.
IIIB T4, N0, M0 T4 = Tumor involving local extrahepatic structures by direct invasion.
N0 = No regional lymph node metastasis.
M0 = No distant metastasis.
Any T, N1, M0 TX = Primary tumor cannot be assessed.
T0 = No evidence of primary tumor.
Tis = Carcinoma in situ (intraductal tumor).
T1 = Solitary tumor without vascular invasion, ≤5 cm or >5 cm.
–T1a = Solitary tumor ≤5 cm without vascular invasion.
–T1b = Solitary tumor >5 cm without vascular invasion.
T2 = Solitary tumor with intrahepatic vascular invasion or multiple tumors, with or without vascular invasion.
T3 = Tumor perforating the visceral peritoneum.
T4 = Tumor involving local extrahepatic structures by direct invasion.
N1 = Regional lymph node metastasis present.
M0 = No distant metastasis.
Table 5. Definitions of TNM Stage IV Intrahepatic Bile Duct Cancera
Stage TNM Description
T = primary tumor; N = regional lymph node; M = distant metastasis.
aReprinted with permission from AJCC: Intrahepatic Bile Duct. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 295–302.
IV Any T, Any N, M1 TX = Primary tumor cannot be assessed.
T0 = No evidence of primary tumor.
Tis = Carcinoma in situ (intraductal tumor).
T1 = Solitary tumor without vascular invasion, ≤5 cm or >5 cm.
–T1a = Solitary tumor ≤5 cm without vascular invasion.
–T1b = Solitary tumor >5 cm without vascular invasion.
T2 = Solitary tumor with intrahepatic vascular invasion or multiple tumors, with or without vascular invasion.
T3 = Tumor perforating the visceral peritoneum.
T4 = Tumor involving local extrahepatic structures by direct invasion.
NX = Regional lymph nodes cannot be assessed.
N0 = No regional lymph node metastasis.
N1 = Regional lymph node metastasis present.
M1 = Distant metastasis present.

AJCC staging system for perihilar bile duct cancer

The AJCC has designated staging by TNM classification to define perihilar bile duct cancer.[2]

Tables 6, 7, 8, 9, and 10 pertain to the perihilar bile duct cancer stages.

Table 6. Definitions of TNM Stage 0 Perihilar Bile Duct Cancera
Stage TNM Description
T = primary tumor; N = regional lymph node; M = distant metastasis.
aReprinted with permission from AJCC: Perihilar Bile Ducts. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 311–6.
0 Tis, N0, M0 Tis = Carcinoma in situ/high-grade dysplasia.
N0 = No regional lymph node metastasis.
M0 = No distant metastasis.
Table 7. Definitions of TNM Stage I Perihilar Bile Duct Cancera
Stage TNM Description
T = primary tumor; N = regional lymph node; M = distant metastasis.
aReprinted with permission from AJCC: Perihilar Bile Ducts. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 311–6.
I T1, N0, M0 T1 = Tumor confined to the bile duct, with extension up to the muscle layer or fibrous tissue.
N0 = No regional lymph node metastasis.
M0 = No distant metastasis.
Table 8. Definitions of TNM Stage II Perihilar Bile Duct Cancera
Stage TNM Description
T = primary tumor; N = regional lymph node; M = distant metastasis.
aReprinted with permission from AJCC: Perihilar Bile Ducts. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 311–6.
II T2a–b, N0, M0 T2 = Tumor invades beyond the wall of the bile duct to surrounding adipose tissue, or tumor invades adjacent hepatic parenchyma.
–T2a = Tumor invades beyond the wall of the bile duct to surrounding adipose tissue.
–T2b = Tumor invades adjacent hepatic parenchyma.
N0 = No regional lymph node metastasis.
M0 = No distant metastasis.
Table 9. Definitions of TNM Stage III Perihilar Bile Duct Cancera
Stage TNM Description
T = primary tumor; N = regional lymph node; M = distant metastasis.
aReprinted with permission from AJCC: Perihilar Bile Ducts. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 311–6.
III IIIA T3, N0, M0 T3 = Tumor invades unilateral branches of the portal vein or hepatic artery.
N0 = No regional lymph node metastasis.
M0 = No distant metastasis.
IIIB T4, N0, M0 T4 = Tumor invades the main portal vein or its branches bilaterally, or the common hepatic artery; or unilateral second-order biliary radicals with contralateral portal vein or hepatic artery involvement.
N0 = No regional lymph node metastasis.
M0 = No distant metastasis.
IIIC Any T, N1, M0 TX = Primary tumor cannot be assessed.
T0 = No evidence of primary tumor.
Tis = Carcinoma in situ/high-grade dysplasia.
T1 = Tumor confined to the bile duct, with extension up to the muscle layer or fibrous tissue.
T2 = Tumor invades beyond the wall of the bile duct to surrounding adipose tissue, or tumor invades adjacent hepatic parenchyma.
–T2a = Tumor invades beyond the wall of the bile duct to surrounding adipose tissue.
–T2b = Tumor invades adjacent hepatic parenchyma.
T3 = Tumor invades unilateral branches of the portal vein or hepatic artery.
T4 = Tumor invades the main portal vein or its branches bilaterally, or the common hepatic artery; or unilateral second-order biliary radicals with contralateral portal vein or hepatic artery involvement.
N1 = One to three positive lymph nodes typically involving the hilar, cystic duct, common bile duct, hepatic artery, posterior pancreatoduodenal, and portal vein lymph nodes.
M0 = No distant metastasis.
Table 10. Definitions of TNM Stage IV Perihilar Bile Duct Cancera
Stage TNM Description
T = primary tumor; N = regional lymph node; M = distant metastasis.
aReprinted with permission from AJCC: Perihilar Bile Ducts. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 311–6.
IV IVA Any T, N2, M0 TX = Primary tumor cannot be assessed.
T0 = No evidence of primary tumor.
Tis = Carcinoma in situ/high-grade dysplasia.
T1 = Tumor confined to the bile duct, with extension up to the muscle layer or fibrous tissue.
T2 = Tumor invades beyond the wall of the bile duct to surrounding adipose tissue, or tumor invades adjacent hepatic parenchyma.
–T2a = Tumor invades beyond the wall of the bile duct to surround adipose tissue.
–T2b = Tumor invades adjacent hepatic parenchyma.
T3 = Tumor invades unilateral branches of the portal vein or hepatic artery.
T4 = Tumor invades the main portal vein or its branches bilaterally, or the common hepatic artery; or unilateral second-order biliary radicals with contralateral portal vein or hepatic artery involvement.
N2 = Four or more positive lymph nodes from the sites described for N1.
M0 = No distant metastasis.
IVB Any T, Any N, M1 TX = Primary tumor cannot be assessed.
T0 = No evidence of primary tumor.
Tis = Carcinoma in situ/high-grade dysplasia.
T1 = Tumor confined to the bile duct, with extension up to the muscle layer or fibrous tissue.
T2 = Tumor invades beyond the wall of the bile duct to surrounding adipose tissue, or tumor invades adjacent hepatic parenchyma.
–T2a = Tumor invades beyond the wall of the bile duct to surround adipose tissue.
–T2b = Tumor invades adjacent hepatic parenchyma.
T3 = Tumor invades unilateral branches of the portal vein or hepatic artery.
T4 = Tumor invades the main portal vein or its branches bilaterally, or the common hepatic artery; or unilateral second-order biliary radicals with contralateral portal vein or hepatic artery involvement.
NX = Regional lymph nodes cannot be assessed.
N0 = No regional lymph node metastasis.
N1 = One to three positive lymph nodes typically involving the hilar, cystic duct, common bile duct, hepatic artery, posterior pancreatoduodenal, and portal vein lymph nodes.
N2 = Four or more positive lymph nodes from the sites described for N1.
M1 = Distant metastasis.

AJCC staging system for distal bile duct cancer

The AJCC has designated staging by TNM classification to define distal bile duct cancer.[3] Stages defined by TNM classification apply to all primary carcinomas arising in the distal bile duct or in the cystic duct; these stages do not apply to perihilar or intrahepatic cholangiocarcinomas, sarcomas, or carcinoid tumors.

Tables 11, 12, 13, 14, and 15 pertain to the distal bile duct cancer stages.

Table 11. Definitions of TNM Stage 0 Distal Bile Duct Cancera
Stage TNM Definition
T = primary tumor; N = regional lymph node; M = distant metastasis.
aReprinted with permission from AJCC: Distal Bile Duct. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 317–325.
0 Tis, N0, M0 Tis = Carcinoma in situ/high-grade dysplasia.
N0 = No regional lymph node metastasis.
M0 = No distant metastasis.
Table 12. Definitions of TNM Stage I Distal Bile Duct Cancera
Stage TNM Definition
T = primary tumor; N = regional lymph node; M = distant metastasis.
aReprinted with permission from AJCC: Distal Bile Duct. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 317–325.
I T1, N0, M0 T1 = Tumor invades the bile duct wall with a depth <5 mm.
N0 = No regional lymph node metastasis.
M0 = No distant metastasis.
Table 13. Definitions of TNM II Distal Bile Duct Cancera
Stage TNM Definition
T = primary tumor; N = regional lymph node; M = distant metastasis.
aReprinted with permission from AJCC: Distal Bile Duct. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 317–325.
II IIA T1, N1, M0 T1 = Tumor invades the bile duct wall with a depth <5 mm.
N1 = Metastasis in one to three regional lymph nodes.
M0 = No distant metastasis.
T2, N0, M0 Tumor invades the bile duct wall with a depth of 5–12 mm.
N0 = No regional lymph node metastasis.
M0 = No distant metastasis.
IIB T2, N1, M0 T2 = Tumor invades the bile duct wall with a depth of 5–12 mm.
N1 = Metastasis in one to three regional lymph nodes.
M0 = No distant metastasis.
T3, N0, M0 T3 = Tumor invades the bile duct wall with a depth >12 mm.
N0 = No regional lymph node metastasis.
M0 = No distant metastasis.
T3, N1, M0 T3 = Tumor invades the bile duct wall with a depth >12 mm.
N1 = Metastasis in one to three regional lymph nodes.
M0 = No distant metastasis.
Table 14. Definitions of TNM Stage III Distal Bile Duct Cancer
Stage TNM Definition
T = primary tumor; N = regional lymph node; M = distant metastasis.
aReprinted with permission from AJCC: Distal Bile Duct. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 317–325.
III IIIA T1, N2, M0 T1 = Tumor invades the bile duct wall with a depth <5 mm.
N2 = Metastasis in four or more regional lymph nodes.
M0 = No distant metastasis.
T2, N2, M0 T2 = Tumor invades the bile duct wall with a depth of 5–12 mm.
N2 = Metastasis in four or more regional lymph nodes.
M0 = No distant metastasis.
T3, N2, M0 T3 = Tumor invades the bile duct wall with a depth >12 mm.
N2 = Metastasis in four or more regional lymph nodes.
M0 = No distant metastasis.
IIIB T4, N0, M0 T4 = Tumor involves the celiac axis, superior mesenteric artery, and/or common hepatic artery.
N0 = No regional lymph node metastasis.
M0 = No distant metastasis.
T4, N1, M0 T4 = Tumor involves the celiac axis, superior mesenteric artery, and/or common hepatic artery.
N1 = Metastasis in one to three regional lymph nodes.
M0 = No distant metastasis.
T4, N2, M0 T4 = Tumor involves the celiac axis, superior mesenteric artery, and/or common hepatic artery.
N2 = Metastasis in four or more regional lymph nodes.
M0 = No distant metastasis.
Table 15. Definitions of TNM Stage IV Distal Bile Duct Cancera
Stage TNM Definition
T = primary tumor; N = regional lymph node; M = distant metastasis.
aReprinted with permission from AJCC: Distal Bile Duct. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 317–325.
IV Any T, Any N, M1 TX = Primary tumor cannot be assessed.
TIS = Carcinoma in situ/high-grade dysplasia.
T1 = Tumor invades the bile duct wall with a depth <5 mm.
T2 = Tumor invades the bile duct wall with a depth of 5–12 mm.
T3 = Tumor invades the bile duct wall with a depth >12 mm.
T4 = Tumor involves the celiac axis, superior mesenteric artery, and/or common hepatic artery.
NX = Regional lymph nodes cannot be assessed.
N0 = No regional lymph node metastasis.
N1 = Metastasis in one to three regional lymph nodes.
N2 = Metastasis in four or more regional lymph nodes.
M1 = Distant metastasis.
References
  1. Intrahepatic Bile Ducts. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. Springer; 2017, pp. 295–302.
  2. Perihilar Bile Ducts. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. Springer; 2017, pp. 311–6.
  3. Distal bile duct. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. Springer; 2017, pp. 317–25.

Treatment Option Overview for Bile Duct Cancer

The treatment of bile duct cancer depends primarily on whether the cancer can be completely removed by surgery.

Resectable (Localized) Bile Duct Cancer

Localized intrahepatic and extrahepatic bile duct cancer may be completely removed by surgery. These tumors represent a very small number of cases and are usually in the distal common bile duct. Among patients treated with surgical resection, long-term prognosis varies depending on primary tumor extent, margin status, lymph node involvement, and additional pathological features.[1,2]

Extended resections of hepatic duct bifurcation tumors (Klatskin tumors, also known as hilar tumors) to include adjacent liver, either by lobectomy or removal of portions of segments 4 and 5 of the liver, may be performed. If major hepatic resection is necessary to achieve a complete resection, postoperative hepatic reserve should be evaluated. For patients with underlying cirrhosis, the Child-Pugh class and the Model for End-Stage Liver Disease score are determined.

Unresectable (Including Metastatic and Recurrent) Bile Duct Cancer

Most cases of intrahepatic, distal, and perihilar bile duct cancer are unresectable and cannot be completely removed. Often the cancer directly invades the portal vein, the adjacent liver, along the common bile duct, and the adjacent lymph nodes. Portal hypertension may result from invasion of the portal vein. Spread to distant parts of the body is uncommon, but intra-abdominal metastases, particularly peritoneal metastases, do occur. Transperitoneal and hematogenous hepatic metastases also occur with bile duct cancer of all sites. Moreover, most patients who undergo resection will develop recurrent disease within the hepatobiliary system or, less frequently, at distant sites.

In locally advanced disease, phase II trials have evaluated chemoradiotherapy with the goal of improved local control and potential downstaging for surgical resection.[3,4] These approaches have not been compared with standard therapy, and the curative potential is unknown.

For patients with unresectable bile duct cancer, management is directed at palliation.

Treatment options for bile duct cancer are described in Table 16.

Table 16. Treatment Options for Bile Duct Cancer
Staging Criteria Treatment Options
Resectable (Localized) Bile Duct Cancer Surgery
Adjuvant therapy
Unresectable (Including Metastatic and Recurrent) Bile Duct Cancer Palliative therapy
Chemotherapy
Immunotherapy
Targeted therapy

Capecitabine and Fluorouracil Dosing

The DPYD gene encodes an enzyme that catabolizes pyrimidines and fluoropyrimidines, like capecitabine and fluorouracil. An estimated 1% to 2% of the population has germline pathogenic variants in DPYD, which lead to reduced DPD protein function and an accumulation of pyrimidines and fluoropyrimidines in the body.[5,6] Patients with the DPYD*2A variant who receive fluoropyrimidines may experience severe, life-threatening toxicities that are sometimes fatal. Many other DPYD variants have been identified, with a range of clinical effects.[5–7] Fluoropyrimidine avoidance or a dose reduction of 50% may be recommended based on the patient’s DPYD genotype and number of functioning DPYD alleles.[8–10] DPYD genetic testing costs less than $200, but insurance coverage varies due to a lack of national guidelines.[11] In addition, testing may delay therapy by 2 weeks, which would not be advisable in urgent situations. This controversial issue requires further evaluation.[12]

References
  1. Nagorney DM, Donohue JH, Farnell MB, et al.: Outcomes after curative resections of cholangiocarcinoma. Arch Surg 128 (8): 871-7; discussion 877-9, 1993. [PUBMED Abstract]
  2. Washburn WK, Lewis WD, Jenkins RL: Aggressive surgical resection for cholangiocarcinoma. Arch Surg 130 (3): 270-6, 1995. [PUBMED Abstract]
  3. Edeline J, Touchefeu Y, Guiu B, et al.: Radioembolization Plus Chemotherapy for First-line Treatment of Locally Advanced Intrahepatic Cholangiocarcinoma: A Phase 2 Clinical Trial. JAMA Oncol 6 (1): 51-59, 2020. [PUBMED Abstract]
  4. Cercek A, Boerner T, Tan BR, et al.: Assessment of Hepatic Arterial Infusion of Floxuridine in Combination With Systemic Gemcitabine and Oxaliplatin in Patients With Unresectable Intrahepatic Cholangiocarcinoma: A Phase 2 Clinical Trial. JAMA Oncol 6 (1): 60-67, 2020. [PUBMED Abstract]
  5. Sharma BB, Rai K, Blunt H, et al.: Pathogenic DPYD Variants and Treatment-Related Mortality in Patients Receiving Fluoropyrimidine Chemotherapy: A Systematic Review and Meta-Analysis. Oncologist 26 (12): 1008-1016, 2021. [PUBMED Abstract]
  6. Lam SW, Guchelaar HJ, Boven E: The role of pharmacogenetics in capecitabine efficacy and toxicity. Cancer Treat Rev 50: 9-22, 2016. [PUBMED Abstract]
  7. Shakeel F, Fang F, Kwon JW, et al.: Patients carrying DPYD variant alleles have increased risk of severe toxicity and related treatment modifications during fluoropyrimidine chemotherapy. Pharmacogenomics 22 (3): 145-155, 2021. [PUBMED Abstract]
  8. Amstutz U, Henricks LM, Offer SM, et al.: Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Dihydropyrimidine Dehydrogenase Genotype and Fluoropyrimidine Dosing: 2017 Update. Clin Pharmacol Ther 103 (2): 210-216, 2018. [PUBMED Abstract]
  9. Henricks LM, Lunenburg CATC, de Man FM, et al.: DPYD genotype-guided dose individualisation of fluoropyrimidine therapy in patients with cancer: a prospective safety analysis. Lancet Oncol 19 (11): 1459-1467, 2018. [PUBMED Abstract]
  10. Lau-Min KS, Varughese LA, Nelson MN, et al.: Preemptive pharmacogenetic testing to guide chemotherapy dosing in patients with gastrointestinal malignancies: a qualitative study of barriers to implementation. BMC Cancer 22 (1): 47, 2022. [PUBMED Abstract]
  11. Brooks GA, Tapp S, Daly AT, et al.: Cost-effectiveness of DPYD Genotyping Prior to Fluoropyrimidine-based Adjuvant Chemotherapy for Colon Cancer. Clin Colorectal Cancer 21 (3): e189-e195, 2022. [PUBMED Abstract]
  12. Baker SD, Bates SE, Brooks GA, et al.: DPYD Testing: Time to Put Patient Safety First. J Clin Oncol 41 (15): 2701-2705, 2023. [PUBMED Abstract]

Treatment of Resectable (Localized) Bile Duct Cancer

Treatment Options for Resectable (Localized) Bile Duct Cancer

Treatment options for resectable (localized) bile duct cancer include:

  1. Surgery.
  2. Adjuvant therapy.

Surgery

Intrahepatic bile duct cancer

For intrahepatic bile duct cancers, hepatic resection to achieve negative margins is potentially curative. If a major liver resection is necessary to achieve negative surgical margins, preoperative portal vein embolization may be considered to optimize the volume of the remnant liver.

Partial liver resection or partial hepatectomy to achieve negative margins is a procedure with curative intent for patients with intrahepatic cholangiocarcinoma.[1] The extent of liver resection necessary depends on the extent of hepatic parenchymal involvement and the proximity of the tumor to major blood vessels in this region.

The role of routine portal lymphadenectomy has not been well established because of the risk of common bile duct devascularization.

Perihilar bile duct cancer

For perihilar cholangiocarcinomas (Klatskin tumors), bile duct resection alone leads to high local recurrence rates resulting from the early confluence of the hepatic ducts and the caudate lobe. The addition of partial hepatectomy that includes the caudate lobe has improved long-term outcomes, but it may be associated with increased postoperative complications.[2] With this aggressive surgical approach, 5-year survival rates of 20% to 50% have been reported.[3] An understanding of both the normal and varied vascular and ductal anatomy of the porta hepatis has increased the number of hepatic duct bifurcation tumors that can be resected.

The primary site of relapse after surgical resection is local, but distant recurrence is also frequently reported.[4]

The optimal surgical procedure for carcinoma of the perihilar bile duct varies according to the location of the tumor along the biliary tree, the extent of hepatic parenchymal involvement, and the proximity of the tumor to major blood vessels in this region. The state of the regional lymph nodes is assessed at the time of surgery because of their prognostic significance. Operations for bile duct cancer are usually extensive. A historical cohort reported an operative mortality rate of approximately 10%, along with a roughly 40% risk of disease recurrence.[5]

In jaundiced patients, the role of percutaneous transhepatic catheter drainage or endoscopic placement of a stent for relief of biliary obstruction is controversial because of inconsistent findings of significant clinical benefit and concerns of increased risk of postoperative complications.[6] However, percutaneous transhepatic catheter drainage or endoscopic placement of a stent for relief of biliary obstruction may be considered before surgery, particularly if jaundice is severe or an element of azotemia is present.[7,8]

Distal bile duct cancer

Complete surgical resection with negative surgical margins offers the only chance of cure for distal bile duct cancers. Bile duct tumors can be difficult to resect because of their proximity to major blood vessels and diffuse infiltration of adjacent bile ducts. Total resection is possible in 25% to 30% of lesions that originate in the distal bile duct. The resectability rate is lower for lesions that occur in more proximal sites.[9]

The optimum surgical procedure for carcinoma of the distal bile duct will vary according to the location of the tumor along the biliary tree, the extent of hepatic parenchymal involvement, and the proximity of the tumor to major blood vessels in this region. The regional lymph nodes are assessed at the time of surgery because they have prognostic significance. Patients with cancer of the lower end of the duct and regional lymph node involvement may warrant an extensive resection (Whipple procedure). The 5-year survival outcomes range between 20% and 50%.[10,11] Bypass operations or endoluminal stents are alternatives if intraoperatively the tumor is found to be unresectable.[10,11]

In jaundiced patients, the role of percutaneous transhepatic catheter drainage or endoscopic placement of a stent for relief of biliary obstruction is controversial, but these options may be considered before surgery, particularly if jaundice is severe or an element of azotemia is present.[7,8]

Adjuvant therapy

Chemotherapy

Numerous retrospective series have suggested that adjuvant chemotherapy after complete surgical resection may be beneficial.[12,13][Level of evidence C2] However, prospective randomized trials have failed to consistently show a significant benefit in overall survival (OS).

Evidence (chemotherapy):

  1. A multicenter phase III study in the United Kingdom (BILCAP) included 447 patients with cholangiocarcinoma or muscle-invasive gallbladder cancer who underwent a macroscopically complete resection with curative intent. Patients were randomly assigned to receive eight cycles of capecitabine (1,250 mg/m2 twice a day on days 1−14 of a 21-day cycle) or observation.[13][Level of evidence B1] At a median follow-up of 106 months, the following results were observed:
    • There was no statistically significant difference in OS in the intention-to-treat analysis (median OS, 49.6 months in the capecitabine group vs. 36.1 months in the observation group; adjusted hazard ratio [HR], 0.84; 95% confidence interval [CI], 0.67−1.06; P > .05).
    • In the intention-to-treat analysis, the median recurrence-free survival (RFS) was 24.3 months (95% CI, 18.6–34.6) in the capecitabine group and 17.4 months (95% CI, 11.8–23) in the observation group. An adjusted Cox proportional hazards model suggested potential improvement in RFS in the first 24 months from randomization (HR, 0.74; 95% CI, 0.57–0.96), but with no significant difference in the period after 24 months (HR, 1.57; 95% CI, 0.90–2.74).
  2. The open-label, randomized, phase II STAMP study (NCT03079427), presented in abstract form, included 101 patients with perihilar or distal bile duct cancer, at least one regional lymph node metastasis (N1 or greater), and complete macroscopic (R0 or R1) resection within 12 weeks. Patients were assigned to receive either eight cycles of capecitabine (1,250 mg/m2) twice a day on days 1–14 of a 21-day cycle (based on the BILCAP trial) or eight cycles of cisplatin (25 mg/m2) and gemcitabine (1,000 mg/m2) on days 1 and 8 of a 21-day cycle. The primary end point was disease-free survival (DFS).[14][Level of evidence B1] At a median follow-up of 28.7 months, the following results were observed:
    • The median DFS was 14.3 months (1-sided 90% CI, 10.7–16.5) in the cisplatin-and-gemcitabine group and 11.1 months in the capecitabine group (1-sided 90% CI, 8.4–12.7).
    • The median OS was 35.7 months (1-sided 90% CI, 29.5–not estimated) in the cisplatin-and-gemcitabine group and 35.7 months (1-sided 90% CI, 30.9–not estimated) in the capecitabine group.
    • The gemcitabine-and-cisplatin group had increased rates of toxicity. Grade 3 to 4 adverse events occurred in 84% of patients who received gemcitabine and cisplatin (most commonly neutropenia) and in 16% of patients who received capecitabine (most commonly hand-foot syndrome).
    • Given the lack of significant difference in DFS and OS and the higher toxicity rate in the cisplatin-and-gemcitabine group, capecitabine remains the reference standard for adjuvant therapy.
  3. A French multicenter phase III study (PRODIGE 12-ACCORD 18-UNICANCER GI) randomly assigned 196 patients with R0 or R1 resection of localized biliary tract cancer to 12 cycles of adjuvant gemcitabine plus oxaliplatin (GEMOX) or surveillance. The primary end point was RFS, and the secondary end point was OS.[15][Level of evidence B1] After a median follow-up of 46.5 months the following results were observed:
    • There was no statistically significant difference in RFS (median, 30.4 months with GEMOX vs. 18.5 months with observation; HR, 0.88; 95% CI, 0.62–1.25, P = .48).
    • There was also no statistically significant difference in OS (75.8 months with GEMOX vs. 50.8 months with observation; HR, 1.08; 95% CI, 0.7–1.66; P = .74).
  4. The Bile Duct Cancer Adjuvant Trial (BCAT), a Japanese, multicenter, phase III study, included 225 patients with resected bile duct cancer. Patients were randomly assigned to six cycles of adjuvant gemcitabine or observation. The primary end point was OS, and the secondary end point was RFS.[16][Level of evidence B1]
    • There was no significant difference in OS (median, 62.3 months with gemcitabine vs. 63.8 months with observation; HR, 1.01; 95% CI, 0.7–1.45; P = .964).
    • No OS differences were observed, even in subgroups stratified by lymph node status and surgical margin status.
    • There was also no significant difference in RFS (median, 36 months with gemcitabine vs. 39.9 months with observation; HR, 0.93; P = .693).
  5. The European Study Group for Pancreatic Cancer (ESPAC-3 trial [NCT00058201]) enrolled 428 patients with periampullary cancer, which included 96 patients with bile duct cancers. Patients were randomly assigned to observation, 6 months of fluorouracil (5-FU)/leucovorin, or 6 months of gemcitabine.[17][Level of evidence B1]
    • Among all patients, adjuvant chemotherapy was not associated with significant OS benefit when compared with observation. However, after adjusting for prognostic variables by multivariable analysis, a statistically significant OS benefit was associated with adjuvant chemotherapy (HR, 0.75; 95% CI, 0.57–0.98; P = .03).
    • In a preplanned subgroup analysis of the 96 patients with bile duct cancer, no benefit was seen among patients treated with chemotherapy. Limitations of this subgroup analysis include limited statistical power and difficulty in differentiating ampullary versus distal common bile duct tumors as the pathological site of origin.
    • The median survival was 27 months for the observation-alone group, 18 months for the 5-FU-leucovorin group, and 20 months for the gemcitabine-alone group.[17]
  6. A multi-institutional Japanese study compared surgery alone with mitomycin and infusional 5-FU followed by 5-FU until disease progression.[18][Level of evidence B1]
    • Among the subset of patients with bile duct cancer (n = 139), no survival benefit was seen.

For a list of chemotherapy regimens with potential activity, see the Treatment of Unresectable (Including Metastatic and Recurrent) Bile Duct Cancer section.

External-beam radiation therapy (EBRT)

Numerous retrospective studies have suggested that adding EBRT after complete surgical resection may be beneficial.[19,20][Level of evidence A1] However, no prospective randomized trials have demonstrated an OS benefit.

Evidence (EBRT):

  1. One small randomized trial of 207 patients with pancreatic and periampullary cancers demonstrated no survival benefit of adding chemoradiation therapy after surgery. This study had limitations: only a few patients had a diagnosis of bile duct cancer, and 20% of the patients randomly assigned to receive chemoradiation therapy did not receive treatment.[21][Level of evidence C3]
  2. A phase II cooperative group trial, SWOG S0809 (NCT00789958), evaluated adjuvant capecitabine and gemcitabine followed by chemoradiation therapy for resected extrahepatic cholangiocarcinoma and gallbladder cancer. In total, 79 eligible patients with pT2 to pT4 disease, node-positive disease, or positive-margin resection were enrolled (extrahepatic bile duct cancer, n = 54; gallbladder cancer, n = 25).[22][Level of evidence C2]
    • The 2-year survival rate of 65% was significantly higher than expected, based on historical controls.[22][Level of evidence C2]
    • Grade 3 toxicity was observed in 52% of patients, and grade 4 toxicity was observed in 11% of patients.
    • Based on these results, this regimen was observed to be well tolerated, but it needs to be tested in a randomized controlled trial.

All patients are encouraged to enroll in clinical trials for adjuvant therapies. Information about ongoing clinical trials is available from the NCI website.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References
  1. Dodson RM, Weiss MJ, Cosgrove D, et al.: Intrahepatic cholangiocarcinoma: management options and emerging therapies. J Am Coll Surg 217 (4): 736-750.e4, 2013. [PUBMED Abstract]
  2. Burke EC, Jarnagin WR, Hochwald SN, et al.: Hilar Cholangiocarcinoma: patterns of spread, the importance of hepatic resection for curative operation, and a presurgical clinical staging system. Ann Surg 228 (3): 385-94, 1998. [PUBMED Abstract]
  3. Nakeeb A, Tran KQ, Black MJ, et al.: Improved survival in resected biliary malignancies. Surgery 132 (4): 555-63; discussion 563-4, 2002. [PUBMED Abstract]
  4. Hasegawa S, Ikai I, Fujii H, et al.: Surgical resection of hilar cholangiocarcinoma: analysis of survival and postoperative complications. World J Surg 31 (6): 1256-63, 2007. [PUBMED Abstract]
  5. Loehrer AP, House MG, Nakeeb A, et al.: Cholangiocarcinoma: are North American surgical outcomes optimal? J Am Coll Surg 216 (2): 192-200, 2013. [PUBMED Abstract]
  6. Liu F, Li Y, Wei Y, et al.: Preoperative biliary drainage before resection for hilar cholangiocarcinoma: whether or not? A systematic review. Dig Dis Sci 56 (3): 663-72, 2011. [PUBMED Abstract]
  7. Nimura Y: Preoperative biliary drainage before resection for cholangiocarcinoma (Pro). HPB (Oxford) 10 (2): 130-3, 2008. [PUBMED Abstract]
  8. Laurent A, Tayar C, Cherqui D: Cholangiocarcinoma: preoperative biliary drainage (Con). HPB (Oxford) 10 (2): 126-9, 2008. [PUBMED Abstract]
  9. Stain SC, Baer HU, Dennison AR, et al.: Current management of hilar cholangiocarcinoma. Surg Gynecol Obstet 175 (6): 579-88, 1992. [PUBMED Abstract]
  10. Fong Y, Blumgart LH, Lin E, et al.: Outcome of treatment for distal bile duct cancer. Br J Surg 83 (12): 1712-5, 1996. [PUBMED Abstract]
  11. Bortolasi L, Burgart LJ, Tsiotos GG, et al.: Adenocarcinoma of the distal bile duct. A clinicopathologic outcome analysis after curative resection. Dig Surg 17 (1): 36-41, 2000. [PUBMED Abstract]
  12. Murakami Y, Uemura K, Sudo T, et al.: Adjuvant gemcitabine plus S-1 chemotherapy improves survival after aggressive surgical resection for advanced biliary carcinoma. Ann Surg 250 (6): 950-6, 2009. [PUBMED Abstract]
  13. Bridgewater J, Fletcher P, Palmer DH, et al.: Long-Term Outcomes and Exploratory Analyses of the Randomized Phase III BILCAP Study. J Clin Oncol 40 (18): 2048-2057, 2022. [PUBMED Abstract]
  14. Yoo C, Jeong H, Kim K, et al.: Adjuvant gemcitabine plus cisplatin (GemCis) versus capecitabine (CAP) in patients (pts) with resected lymph node (LN)-positive extrahepatic cholangiocarcinoma (CCA): A multicenter, open-label, randomized, phase 2 study (STAMP). [Abstract] J Clin Oncol 40 (Suppl 16): A-4019, 2022.
  15. Edeline J, Benabdelghani M, Bertaut A, et al.: Gemcitabine and Oxaliplatin Chemotherapy or Surveillance in Resected Biliary Tract Cancer (PRODIGE 12-ACCORD 18-UNICANCER GI): A Randomized Phase III Study. J Clin Oncol 37 (8): 658-667, 2019. [PUBMED Abstract]
  16. Ebata T, Hirano S, Konishi M, et al.: Randomized clinical trial of adjuvant gemcitabine chemotherapy versus observation in resected bile duct cancer. Br J Surg 105 (3): 192-202, 2018. [PUBMED Abstract]
  17. Neoptolemos JP, Moore MJ, Cox TF, et al.: Effect of adjuvant chemotherapy with fluorouracil plus folinic acid or gemcitabine vs observation on survival in patients with resected periampullary adenocarcinoma: the ESPAC-3 periampullary cancer randomized trial. JAMA 308 (2): 147-56, 2012. [PUBMED Abstract]
  18. Takada T, Amano H, Yasuda H, et al.: Is postoperative adjuvant chemotherapy useful for gallbladder carcinoma? A phase III multicenter prospective randomized controlled trial in patients with resected pancreaticobiliary carcinoma. Cancer 95 (8): 1685-95, 2002. [PUBMED Abstract]
  19. Kim TH, Han SS, Park SJ, et al.: Role of adjuvant chemoradiotherapy for resected extrahepatic biliary tract cancer. Int J Radiat Oncol Biol Phys 81 (5): e853-9, 2011. [PUBMED Abstract]
  20. Hughes MA, Frassica DA, Yeo CJ, et al.: Adjuvant concurrent chemoradiation for adenocarcinoma of the distal common bile duct. Int J Radiat Oncol Biol Phys 68 (1): 178-82, 2007. [PUBMED Abstract]
  21. Klinkenbijl JH, Jeekel J, Sahmoud T, et al.: Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary region: phase III trial of the EORTC gastrointestinal tract cancer cooperative group. Ann Surg 230 (6): 776-82; discussion 782-4, 1999. [PUBMED Abstract]
  22. Ben-Josef E, Guthrie KA, El-Khoueiry AB, et al.: SWOG S0809: A Phase II Intergroup Trial of Adjuvant Capecitabine and Gemcitabine Followed by Radiotherapy and Concurrent Capecitabine in Extrahepatic Cholangiocarcinoma and Gallbladder Carcinoma. J Clin Oncol 33 (24): 2617-22, 2015. [PUBMED Abstract]

Treatment of Unresectable (Including Metastatic and Recurrent) Bile Duct Cancer

Treatment Options for Unresectable (Including Metastatic and Recurrent) Bile Duct Cancer

Treatment options for unresectable (including metastatic and recurrent) bile duct cancer include:

  1. Palliative therapy.
  2. Chemotherapy.
  3. Immunotherapy.
  4. Targeted therapy.

Palliative therapy

Relief of biliary obstruction is warranted when symptoms such as pruritus and hepatic dysfunction outweigh other symptoms of the cancer. When possible, such palliation can be achieved with the placement of bile duct stents by operative, endoscopic, or percutaneous techniques.[1,2]

Palliative radiation therapy may be beneficial, and patients may be candidates for stereotactic body radiation therapy [3] and intra-arterial embolization.[4]

Chemotherapy

Systemic chemotherapy is appropriate for selected patients with adequate performance status and intact organ function.

Evidence (chemotherapy):

  1. The phase III ABC-02 study (NCT00262769) randomly assigned 410 patients with unresectable, recurrent, or metastatic biliary tract carcinoma to receive either cisplatin plus gemcitabine or gemcitabine alone for up to 6 months.[5][Level of evidence A1]
    • The median overall survival (OS) was prolonged in the cisplatin-gemcitabine group (11.7 months) compared with the gemcitabine-alone group (8.1 months) (hazard ratio [HR], 0.64; 95% confidence interval [CI], 0.52−0.80; P < .001).[5]
    • A similar median OS benefit was demonstrated in all subgroups, including 73 patients with extrahepatic bile duct cancer and 57 patients with hilar tumors.
    • Grades 3 and 4 toxicities occurred with similar frequencies in both study groups, with the exception of increased hematologic toxicity in the cisplatin-gemcitabine group and increased hepatic toxicity in the gemcitabine-alone group.
  2. A phase II study (NCT03044587) included 91 patients with advanced cholangiocarcinoma. Patients were randomly assigned to receive the combination of liposomal irinotecan, 5-fluorouracil (5-FU), and leucovorin (arm A) or the ABC-02 study regimen of cisplatin plus gemcitabine (arm B). The primary end point was a prespecified benchmark of a 4-month progression-free survival (PFS) rate of 40%.[6][Level of evidence B3]
    • The 4-month PFS rate was 51% in arm A. The median PFS was 6 months (95% CI, 2.4–9.6) in arm A and 6.9 months (95% CI, 2.5–7.9) in arm B.
    • The median OS was 15.9 months (95% CI, 10.6–20.3) in arm A and 13.6 months (95% CI, 6.5–17.7) in arm B.
  3. A phase III noninferiority study (NCT01470443) enrolled 114 patients with metastatic biliary tract cancers, including 30 (26%) with primary gallbladder cancer. Patients were randomly assigned to receive capecitabine plus oxaliplatin (XELOX) or gemcitabine plus oxaliplatin (GEMOX). The primary end point was 6-month PFS.[7][Level of evidence B1]
    • OS was not significantly different between treatment groups. It was 10.4 months (95% CI, 8.0−12.6) in the GEMOX group and 10.6 months (95% CI, 7.3−15.5) in the XELOX group (P = .131).
    • The PFS rate was 44.6% in the GEMOX group and 46.7% in the XELOX group (95% CI of difference in 6-month PFS rate, -12% to 16%, meeting criteria for noninferiority).
    • A predefined subgroup analysis based on primary site of disease did not reveal a difference in objective response rate between the two arms in patients with gallbladder cancer (P = .598).

Pending further clinical trials, cisplatin plus gemcitabine is considered the reference standard first-line chemotherapy backbone for patients with unresectable, metastatic, or recurrent bile duct cancer. Following the results of the TOPAZ-1 and KEYNOTE-966 trials, addition of a checkpoint inhibitor (either durvalumab or pembrolizumab) to front-line therapy has become the standard of care (for more information, see the Immunotherapy section). Potential alternatives include 5-FU plus liposomal irinotecan, gemcitabine plus capecitabine, GEMOX, and XELOX. All patients should consider clinical trials.

There is limited high-quality evidence to guide selection of a second-line regimen in refractory disease:

  1. A multicenter phase III trial in the United Kingdom (ABC-06 [NCT01926236]) included 162 patients with locally advanced or metastatic biliary tract cancer and documented radiological disease progression on first-line cisplatin and gemcitabine. Patients were randomly assigned to receive either FOLFOX (folinic acid, 5-FU, and oxaliplatin) with active symptom control (ASC) or ASC alone. The following results were observed after a median follow-up of 21.7 months:[8][Level of evidence A1]
    • The median OS was significantly longer in the FOLFOX group (6.2 months) than in the ASC-alone group (5.3 months) (adjusted HR, 0.69; 95% CI, 0.50−0.97; P = .031). In the FOLFOX group, the OS rate was 50.6% at 6 months and 25.9% at 12 months, compared with 35.5% at 6 months and 11.4% at 12 months in the ASC-alone group.
    • Grade 3 to 5 adverse events were reported in 56 patients (69%) in the FOLFOX group, compared with 42 patients (52%) in the ASC-alone group. The most frequently reported grade 3 to 5 FOLFOX-related adverse events were neutropenia (12%), fatigue/lethargy (11%), and infection (10%). There were three chemotherapy-related deaths, one each due to infection, acute kidney injury, and febrile neutropenia.

    Two phase II trials have evaluated 5-FU and leucovorin with or without liposomal irinotecan, but results differed.

  2. A multicenter phase IIb trial in South Korea (NIFTY [NCT03524508]) randomly assigned 174 patients with metastatic biliary tract cancer that had progressed during first-line cisplatin and gemcitabine to receive 5-FU and leucovorin with or without liposomal irinotecan. The following was observed after a median follow-up of 6.1 months:[9][Level of evidence A1]
    • The primary end point of median PFS was significantly longer in the group who received liposomal irinotecan (3.9 months) compared with the group who received 5-FU plus leucovorin alone (1.6 months) (HR, 0.38; 95% CI, not reported; P = .0001). A secondary end point of median OS was also significantly longer in the group who received liposomal irinotecan (8.6 months) compared with the group who received 5-FU plus leucovorin alone (5.3 months) (HR, 0.68; 95% CI, not reported; P = .024).
  3. The German multicenter phase II NALIRICC trial (NCT03043547) included 100 patients with metastatic biliary tract cancer that progressed during gemcitabine-based therapy. Patients were randomly assigned to receive 5-FU plus leucovorin with or without liposomal irinotecan.[10][Level of evidence A1]
    • The median PFS in the liposomal irinotecan group was 2.6 months, compared with 2.3 months in the 5-FU–leucovorin-alone group (HR, 0.87; 95% CI, 0.56–1.35; P not reported). The median OS was 6.9 months in the liposomal irinotecan group and 8.2 months in the 5-FU–leucovorin-alone group (HR, 1.08; 95% CI, 0.68–1.72; P not reported).
    • Toxicity was significantly higher in the liposomal irinotecan group, with treatment-related serious adverse events occurring in 16 patients (33%), compared with one patient (2%) in the 5-FU–leucovorin-alone group. The most common grade 3 or higher adverse events in the liposomal irinotecan group were neutropenia (17%), diarrhea (15%), and nausea (8%).

Immunotherapy

Based on results from the TOPAZ-1 and KEYNOTE-966 trials, all patients with unresectable, metastatic, or recurrent disease should consider treatment with a checkpoint inhibitor (either durvalumab or pembrolizumab) with cisplatin and gemcitabine (the previous standard-of-care doublet) in the first-line setting.[11–13]

Evidence (immunotherapy):

  1. An international, multicenter, phase III study (TOPAZ-1 [NCT03875235]) included 685 patients with locally advanced, recurrent, or metastatic biliary tract cancer that was unresectable and previously untreated. Patients were randomly assigned to receive either durvalumab or placebo with cisplatin plus gemcitabine for up to eight cycles, followed by durvalumab or placebo maintenance until disease progression or unacceptable toxicity occurred. The primary end point was OS. After a median follow-up of 23.4 months for patients in the durvalumab arm, the following results were observed:[12,13]
    • The median OS was significantly improved in the durvalumab group (12.9 months) compared with the placebo group (11.3 months) (HR, 0.76; 95% CI, 0.64–0.91). In the durvalumab group, the 18-month OS rate was 35.1% and the 24-month OS rate was 24.9%. In the placebo group, the 18-month OS rate was 25.5% and the 24-month OS rate was 10.4%.[12,13][Level of evidence A1]
    • There was no significant difference between groups in the number of grade 3 or 4 treatment-related adverse events or the number of events leading to discontinuation of a study medication.
  2. An international, multicenter, phase III study (KEYNOTE-966 [NCT04003636]) enrolled 1,069 patients with previously untreated, unresectable, locally advanced or metastatic biliary tract cancer. Patients were randomly assigned to receive either pembrolizumab or placebo for up to 35 cycles. This was combined with gemcitabine (with no maximum duration) and cisplatin for up to 8 cycles. After a median follow-up of 25.6 months, the following results were observed:[11][Level of evidence A1]
    • The median OS was 12.7 months in the pembrolizumab group and 10.9 months in the placebo group (HR, 0.83; 95% CI, 0.72–0.95; one-sided P = .0034).
    • There was no difference in the total frequency of treatment-related adverse events between treatment groups, including grade 3 or grade 4 events. Death due to treatment-related adverse events was seen in a total of eight patients (2%) in the pembrolizumab arm and three patients (1%) in the placebo arm.

All patients with unresectable, metastatic, or recurrent disease who have not already received a checkpoint inhibitor should have molecular testing for deficient mismatch repair (dMMR) or microsatellite instability-high (MSI-H) tumors. Extrapolating from a subgroup of patients with gastrointestinal and hepatopancreatobiliary tumors in the I-PREDICT (NCT02534675) and KEYNOTE-158 (NCT02628067) studies, patients with either dMMR or MSI-H tumors can consider pembrolizumab treatment.[14,15][Level of evidence C3]

Targeted therapy

Patients with targetable pathogenic variants can consider clinical trials of investigational therapies. Currently, targeted therapies have only been approved for patients whose disease has progressed or who are ineligible for first-line therapies.

IDH1 inhibitors

Up to 15% of bile duct cancers have IDH1 variants.

Evidence (IDH1 inhibitors):

  1. The phase III ClarIDHy trial (NCT02989857) included 187 patients with cholangiocarcinoma and IDH1 variants. Patients had disease that had progressed during previous systemic therapy. Patients were randomly assigned to receive either the IDH1 inhibitor ivosidenib or placebo. The primary end point was PFS.[16,17][Level of evidence B1]
    • The median PFS was improved among patients treated with ivosidenib (2.7 months) compared with placebo (1.4 months) (HR, 0.37; 95% CI, 0.25−0.54; P < .001). PFS rates at 6 months and 12 months were 32% and 21.9%, respectively, in the ivosidenib arm. No patients in the placebo group were progression free at 6 months.
    • In the intention-to-treat analysis, median OS was 10.3 months in the ivosidenib group compared with 7.5 months for the placebo group (HR, 0.79; one-sided P = .09), despite crossover of 57% of placebo patients to ivosidenib. When adjusted for crossover, median OS for the placebo group was 5.1 months.
    • Grades 3 and 4 toxicities occurred in 46% of patients in the ivosidenib group and 36% of patients in the placebo group.
FGFR inhibitors

FGFR2 gene fusions are present in approximately 15% of intrahepatic cholangiocarcinomas. Multiple phase II trials, some reported in abstract form, have suggested activity of FGFR inhibitors in patients with cholangiocarcinoma and FGFR2 fusions whose disease progressed after or who were ineligible for first-line chemotherapy.[18,19]

Evidence (FGFR inhibitors):

  1. The multicenter, open-label, single-arm phase II FIGHT-202 trial (NCT02924376) enrolled 147 patients with disease progression during or after at least one previous therapy. A total of 108 patients had FGFR2 rearrangements or fusions. All patients received 13.5 mg of pemigatinib orally once daily for 14 consecutive days, followed by 7 days off therapy. At a median follow-up of 45.4 months, the following results were observed:[20][Level of evidence C3]
    • The overall response rate in the cohort of patients with FGFR2 rearrangements/fusions was 37% (95% CI, 27.9%−46.9%), including three complete responses. Among the 40 patients who achieved an objective response, the median duration of response was 9.1 months (95% CI, 6.0–14.5).
    • The median PFS in patients with FGFR2 rearrangements or fusions was 7.0 months (95% CI, 6.1–10.5), and the median OS was 17.5 months (95% CI, 14.4–22.9). Given the single-arm study design, the relative effect of pemigatinib on PFS and OS was not established. However, in the cohort of study patients whose tumors did not harbor FGFR rearrangements, the median PFS was only 1.5 months and the median OS was only 4.0 months.
    • The most common adverse effect was hyperphosphatemia, occurring in 58.5% of patients, although no adverse effect was grade 3 or higher. Adverse events led to treatment discontinuation in 10.2% of patients, dose reduction in 13.64% of patients, and dose interruptions in 42.2% of patients.

    In 2020, the FDA granted accelerated approval of pemigatinib for the treatment of adults with previously treated unresectable or metastatic cholangiocarcinoma with an FGFR2 fusion or other rearrangement.

  2. Futibatinib is an irreversible noncompetitive inhibitor of FGFR1–4. Preclinical in vitro studies showed that futibatinib was less susceptible to on-target resistance variants than pemigatinib. However, there are no head-to-head clinical trial data comparing outcomes for the various FGFR inhibitors. The multinational, open-label, single-group, phase II FOENIX-CCA2 trial (NCT02052778) evaluated futibatinib in patients with previously treated intrahepatic cholangiocarcinoma and FGFR2 fusions or rearrangements. The study enrolled 103 patients with disease progression after at least one previous line of systemic therapy. All patients received futibatinib at a continuous dose of 20 mg once daily.[21][Level of evidence C3]
    • The overall response rate was 42% (95% CI, 31.1%–50.4%), including one complete response. Of the patients who had a response, the median duration of response was 9.7 months.
    • The median PFS was 9 months (95% CI, 6.9–13.1), and the median OS was 21.7 months (95% CI 14.5–NR). Given the single-arm study design, the relative effect of futibatinib on PFS and OS has not yet been established.
    • The most common adverse effect of any grade was hyperphosphatemia, which occurred in 85% of patients and was grade 3 in 30% of patients. Other common adverse effects included alopecia (33%), dry mouth (30%), dry skin (27%), and fatigue (25%). Other notable grade 3 toxicities included aspartate aminotransferase elevation (7%) and stomatitis (6%). Treatment-related adverse events led to dose interruptions in 50% of patients, dose reductions in 54% of patients, and permanent drug discontinuation in 2% of patients.

Patients with FGFR2 fusion−positive disease should be encouraged to enroll in a clinical trial.

HER2-targeted therapy
  1. The international, multicenter, single-arm, phase IIb HERIZON-BTC-01 trial (NCT04466891) enrolled 87 patients with HER2-amplified (by fluorescence in situ hybridization), unresectable, locally advanced or metastatic biliary tract cancer whose disease progressed on prior gemcitabine-based therapy. Cohort 1 included 80 patients with HER2 2+ or 3+ expression by immunohistochemistry (IHC), while cohort 2 included seven patients with HER2 0+ or 1+ expression by IHC. All patients received zanidatamab, a bispecific antibody targeting two distinct HER2 epitopes, at a dose of 20 mg/kg intravenously every 2 weeks. At a median follow-up of 12.4 months, the following results were observed:[22][Level of evidence C3]
    • In cohort 1, the objective response rate was 41.3% (95% CI, 30.4%–52.8%). The median duration of response was 12.9 months (95% CI, 6.0–not reached).
    • The median PFS was 5.5 months in cohort 1 (95% CI, 3.7–7.2) and 1.9 months (95% CI, 1.2–not estimable) in cohort 2.
    • Serious treatment-related adverse events occurred in 8% of patients. Zanidatamab was discontinued in two patients: one due to reduced ejection fraction and one due to pneumonitis. Diarrhea (37%) and infusion reactions with the first cycle (33%) were relatively common, but mostly low-grade.
    • The FDA has granted breakthrough therapy designation for zanidatamab in this setting, but it is not yet FDA approved.

Although not FDA approved specifically for biliary tract cancer, a growing body of evidence demonstrated activity of the antibody-drug conjugate trastuzumab deruxtecan in patients with HER2-expressing solid tumors.

  1. The DESTINY-PanTumor02 trial (NCT04482309), reported in abstract form, was tumor-agnostic (enrolled patients with HER2-positive tumors from any site) but included a subset of 41 patients with biliary tract cancer.[23][Level of evidence C3]
    • The overall response rate was 22% in this subset of patients.
  2. The phase II HERB trial (NCT04482309) enrolled 32 patients (24 with HER2-positive disease, 8 with HER2-low disease) with biliary tract cancers refractory to, or intolerant of, a gemcitabine-containing regimen. All patients received trastuzumab deruxtecan.[24][Level of evidence C3]
    • Among the patients with HER2-positive disease, the overall response rate was 36.4%. The median PFS was 5.1 months (95% CI, 3.0–7.3), and the median OS was 7.1 months (95% CI, 4.7–14.6).
    • Among the small sample of eight patients with HER2-low disease, the overall response rate was 12.5%. The median PFS was 3.5 months (95% CI, 1.2–5.5), and the median OS was 8.9 months (95% CI, 3.0–12.8).

Similarly, the combination of tucatinib and trastuzumab—which the FDA has not approved for the treatment of biliary tract cancer but has approved for breast and colorectal cancer indications—was shown to have potential activity in previously treated patients.

  1. The tumor-agnostic phase II SGNTUC-019 study (NCT04579380) evaluated the combination of tucatinib and trastuzumab. The trial included a cohort of 30 patients with previously treated HER2-overexpressing or HER2-amplified biliary tract cancer.[25][Level of evidence C3]
    • At a median follow-up of 10.8 months, the objective response rate was 46.7% (90% CI, 30.8%–63.0%), with a disease control rate of 76.7% (90% CI, 60.6%–88.5%).
    • The median PFS was 5.5 months (90% CI, 3.9–8.2).
    • The most common treatment-related adverse events were pyrexia (43.3%) and diarrhea (40%). Adverse events caused no deaths but led one patient to discontinue treatment.

Patients with HER2-amplified disease are candidates for clinical trials.

All patients are encouraged to enroll in clinical trials for adjuvant therapies. Information about ongoing clinical trials is available from the NCI website.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References
  1. Nordback IH, Pitt HA, Coleman J, et al.: Unresectable hilar cholangiocarcinoma: percutaneous versus operative palliation. Surgery 115 (5): 597-603, 1994. [PUBMED Abstract]
  2. Levy MJ, Baron TH, Gostout CJ, et al.: Palliation of malignant extrahepatic biliary obstruction with plastic versus expandable metal stents: An evidence-based approach. Clin Gastroenterol Hepatol 2 (4): 273-85, 2004. [PUBMED Abstract]
  3. Barney BM, Olivier KR, Miller RC, et al.: Clinical outcomes and toxicity using stereotactic body radiotherapy (SBRT) for advanced cholangiocarcinoma. Radiat Oncol 7: 67, 2012. [PUBMED Abstract]
  4. Hyder O, Marsh JW, Salem R, et al.: Intra-arterial therapy for advanced intrahepatic cholangiocarcinoma: a multi-institutional analysis. Ann Surg Oncol 20 (12): 3779-86, 2013. [PUBMED Abstract]
  5. Valle J, Wasan H, Palmer DH, et al.: Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med 362 (14): 1273-81, 2010. [PUBMED Abstract]
  6. Ettrich TJ, Modest DP, Sinn M, et al.: Nanoliposomal Irinotecan With Fluorouracil and Leucovorin or Gemcitabine Plus Cisplatin in Advanced Cholangiocarcinoma: A Phase II Study of the AIO Hepatobiliary-YMO Cancer Groups (NIFE-AIO-YMO HEP-0315). J Clin Oncol 42 (26): 3094-3104, 2024. [PUBMED Abstract]
  7. Kim ST, Kang JH, Lee J, et al.: Capecitabine plus oxaliplatin versus gemcitabine plus oxaliplatin as first-line therapy for advanced biliary tract cancers: a multicenter, open-label, randomized, phase III, noninferiority trial. Ann Oncol 30 (5): 788-795, 2019. [PUBMED Abstract]
  8. Lamarca A, Palmer DH, Wasan HS, et al.: Second-line FOLFOX chemotherapy versus active symptom control for advanced biliary tract cancer (ABC-06): a phase 3, open-label, randomised, controlled trial. Lancet Oncol 22 (5): 690-701, 2021. [PUBMED Abstract]
  9. Yoo C, Kim KP, Kim I, et al.: Final results from the NIFTY trial, a phase IIb, randomized, open-label study of liposomal Irinotecan (nal-IRI) plus fluorouracil (5-FU)/leucovorin (LV) in patients (pts) with previously treated metastatic biliary tract cancer (BTC). Ann Oncol 33 (Suppl 7): S565, 2022.
  10. Vogel A, Saborowski A, Wenzel P, et al.: Nanoliposomal irinotecan and fluorouracil plus leucovorin versus fluorouracil plus leucovorin in patients with cholangiocarcinoma and gallbladder carcinoma previously treated with gemcitabine-based therapies (AIO NALIRICC): a multicentre, open-label, randomised, phase 2 trial. Lancet Gastroenterol Hepatol 9 (8): 734-744, 2024. [PUBMED Abstract]
  11. Kelley RK, Ueno M, Yoo C, et al.: Pembrolizumab in combination with gemcitabine and cisplatin compared with gemcitabine and cisplatin alone for patients with advanced biliary tract cancer (KEYNOTE-966): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 401 (10391): 1853-1865, 2023. [PUBMED Abstract]
  12. Oh DY, He AR, Qin S, et al.: Updated overall survival (OS) from the phase III TOPAZ-1 study of durvalumab (D) or placebo (PBO) plus gemcitabine and cisplatin (+ GC) in patients (pts) with advanced biliary tract cancer (BTC). Ann Oncol 33 (Suppl 7): S565-S566, 2022.
  13. Oh DY, He AR, Bouattour M, et al.: Durvalumab or placebo plus gemcitabine and cisplatin in participants with advanced biliary tract cancer (TOPAZ-1): updated overall survival from a randomised phase 3 study. Lancet Gastroenterol Hepatol 9 (8): 694-704, 2024. [PUBMED Abstract]
  14. Sicklick JK, Kato S, Okamura R, et al.: Molecular profiling of cancer patients enables personalized combination therapy: the I-PREDICT study. Nat Med 25 (5): 744-750, 2019. [PUBMED Abstract]
  15. Marabelle A, Le DT, Ascierto PA, et al.: Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer: Results From the Phase II KEYNOTE-158 Study. J Clin Oncol 38 (1): 1-10, 2020. [PUBMED Abstract]
  16. Abou-Alfa GK, Macarulla T, Javle MM, et al.: Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol 21 (6): 796-807, 2020. [PUBMED Abstract]
  17. Zhu AX, Macarulla T, Javle MM, et al.: Final Overall Survival Efficacy Results of Ivosidenib for Patients With Advanced Cholangiocarcinoma With IDH1 Mutation: The Phase 3 Randomized Clinical ClarIDHy Trial. JAMA Oncol 7 (11): 1669-1677, 2021. [PUBMED Abstract]
  18. Mazzaferro V, El-Rayes BF, Droz Dit Busset M, et al.: Derazantinib (ARQ 087) in advanced or inoperable FGFR2 gene fusion-positive intrahepatic cholangiocarcinoma. Br J Cancer 120 (2): 165-171, 2019. [PUBMED Abstract]
  19. Droz Dit Busset M, Braun S, El-Rayes B, et al.: Efficacy of derazantinib (DZB) in patients (pts) with intrahepatic cholangiocarcinoma (ICCA) expressing FGFR2-fusion or FGFR2 mutations/amplifications. [Abstract] Ann Oncol 30 (Suppl 5): A-721P, 2019.
  20. Vogel A, Sahai V, Hollebecque A, et al.: An open-label study of pemigatinib in cholangiocarcinoma: final results from FIGHT-202. ESMO Open 9 (6): 103488, 2024. [PUBMED Abstract]
  21. Goyal L, Meric-Bernstam F, Hollebecque A, et al.: Futibatinib for FGFR2-Rearranged Intrahepatic Cholangiocarcinoma. N Engl J Med 388 (3): 228-239, 2023. [PUBMED Abstract]
  22. Harding JJ, Fan J, Oh DY, et al.: Zanidatamab for HER2-amplified, unresectable, locally advanced or metastatic biliary tract cancer (HERIZON-BTC-01): a multicentre, single-arm, phase 2b study. Lancet Oncol 24 (7): 772-782, 2023. [PUBMED Abstract]
  23. Meric-Bernstam F, Makker V, Oaknin A, et al.: Efficacy and safety of trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2-expressing solid tumors: DESTINY-PanTumor02 (DP-02) interim results. [Abstract] J Clin Oncol 41 (Suppl 17): A-LBA3000, 2023.
  24. Ohba A, Morizane C, Kawamoto Y, et al.: Trastuzumab Deruxtecan in Human Epidermal Growth Factor Receptor 2-Expressing Biliary Tract Cancer (HERB; NCCH1805): A Multicenter, Single-Arm, Phase II Trial. J Clin Oncol 42 (27): 3207-3217, 2024. [PUBMED Abstract]
  25. Nakamura Y, Mizuno N, Sunakawa Y, et al.: Tucatinib and Trastuzumab for Previously Treated Human Epidermal Growth Factor Receptor 2-Positive Metastatic Biliary Tract Cancer (SGNTUC-019): A Phase II Basket Study. J Clin Oncol 41 (36): 5569-5578, 2023. [PUBMED Abstract]

Latest Updates to This Summary (03/28/2025)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Treatment of Unresectable (Including Metastatic and Recurrent) Bile Duct Cancer

Added text about the results of a phase II study that randomly assigned 91 patients with advanced cholangiocarcinoma to receive the combination of liposomal irinotecan, 5-fluorouracil (5-FU), and leucovorin or the ABC-02 study regimen of cisplatin plus gemcitabine (cited Ettrich et al. as reference 6 and level of evidence B3).

Added text to state that two phase II trials have evaluated 5-FU and leucovorin with or without liposomal irinotecan, but results differed. Also added text about a phase II trial that included 100 patients with metastatic biliary tract cancer that progressed during gemcitabine-based therapy. Patients were randomly assigned to receive 5-FU plus leucovorin with or without liposomal irinotecan (cited Vogel [Lancet Gastroenterol Hepatol 2024] et al. as reference 10 and level of evidence A1).

Revised text about the results of a multicenter, open-label, single-arm phase II trial of pemigatinib that included 147 patients with disease progression during or after at least one previous therapy (cited Vogel [ESMO Open 2024] et al. as reference 20).

Revised text about the results of a phase II trial of trastuzumab deruxtecan in 32 patients with biliary tract cancers refractory to, or intolerant of, a gemcitabine-containing regimen (cited Ohba et al. as reference 24).

This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of bile duct cancer. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Bile Duct Cancer (Cholangiocarcinoma) Treatment are:

  • Amit Chowdhry, MD, PhD (University of Rochester Medical Center)
  • Leon Pappas, MD, PhD (Massachusetts General Hospital)
  • Ari Seifter, MD (Advocate Health Care)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website’s Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

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PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”

The preferred citation for this PDQ summary is:

PDQ® Adult Treatment Editorial Board. PDQ Bile Duct Cancer (Cholangiocarcinoma) Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/liver/hp/bile-duct-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389308]

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Childhood Rhabdomyosarcoma Treatment (PDQ®)–Health Professional Version

Childhood Rhabdomyosarcoma Treatment (PDQ®)–Health Professional Version

General Information About Childhood Rhabdomyosarcoma

Go to Patient Version

Continual improvements in survival have been achieved for children and adolescents with cancer.[1] Between 1975 and 2020, childhood cancer mortality decreased by more than 50%.[1–3] Between 1975 and 2017, the 5-year relative survival rate for patients with rhabdomyosarcoma increased from 53% to 71% for children younger than 15 years and from 30% to 52% for adolescents aged 15 to 19 years.[1,2] In more recent years, improvements in outcome have plateaued.

Childhood and adolescent cancer survivors require close monitoring because side effects of cancer and its therapy may persist or develop months to years later. For specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors, see Late Effects of Treatment for Childhood Cancer.

Incidence

Childhood rhabdomyosarcoma is a soft tissue malignant tumor of mesenchymal origin. It accounts for approximately 2.7% of cancer cases among children aged 0 to 14 years and 1.4% of the cases among adolescents and young adults aged 15 to 19 years.[2] The incidence is 4.6 cases per 1 million children younger than 20 years, which translates into about 350 new cases per year. Fifty percent of these cases are seen in the first decade of life.[2,4]

The 2020 World Health Organization classification distinguishes four histological subtypes of rhabdomyosarcoma, including embryonal, alveolar, spindle cell/sclerosing, and pleomorphic.[5] While these subtypes classify rhabdomyosarcoma into prognostically useful histological categories, FOXO1 gene fusions uniquely occur in alveolar histology tumors; however, not all tumors that have been classified as alveolar histology have a FOXO1 fusion. Molecular characterization has replaced histopathological assessment for treatment risk assignment. Male patients have a higher incidence of embryonal tumors, and Black patients have a slightly higher incidence of alveolar tumors.[4] For more information, see the sections on Cellular Classification for Childhood Rhabdomyosarcoma and Molecular Characteristics of Rhabdomyosarcoma.

Incidence may depend on the histological subtype of rhabdomyosarcoma, as follows:

  • Embryonal: Patients with embryonal rhabdomyosarcoma are predominantly male (male-to-female ratio, 1.5). The peak incidence is in children between the ages of 0 and 4 years, with approximately 4 cases per 1 million children. The incidence rate is lower in adolescents, with approximately 1.5 cases per 1 million adolescents. This subtype constitutes 57% of patients in the Surveillance, Epidemiology, and End Results (SEER) Program database.[4]
  • Alveolar: The incidence of alveolar rhabdomyosarcoma does not vary by sex and is constant from ages 0 to 19 years, with approximately 1 case per 1 million children and adolescents. This subtype constitutes 23% of patients in the SEER database.[4]
  • Spindle cell/sclerosing: Spindle cell and sclerosing rhabdomyosarcoma are considered in the same diagnostic category. This uncommon variant accounts for 3% to 10% of all cases.[5]
  • Pleomorphic: Pleomorphic rhabdomyosarcoma is a high-grade pleomorphic sarcoma seen in adults. Childhood cases are considered to be rhabdomyosarcoma with diffuse anaplasia.[5]

Rhabdomyosarcoma may occur anywhere in the body. The most common primary sites include the following:[6,7]

  • Head and neck region (parameningeal) (approximately 25%).
  • Genitourinary tract (approximately 31%).
  • Extremities (approximately 13%). Within extremity tumors, tumors of the hand and foot occur more often in older patients and usually have an alveolar histology.[8]

Other less common primary sites include the trunk, chest wall, perineal/anal region, and abdomen, including the retroperitoneum and biliary tract.[7]

Risk Factors

Most cases of rhabdomyosarcoma occur sporadically, with no recognized predisposing risk factor.

Predisposition factors reported for rhabdomyosarcoma include the following:

  • Genetic factors:
    • Li-Fraumeni cancer susceptibility syndrome (with germline TP53 pathogenic variants).[9–11]
    • DICER1 syndrome.[12,13]
    • Neurofibromatosis type I (NF1).[14,15]
    • Costello syndrome (with germline HRAS pathogenic variants).[16–19]
    • Beckwith-Wiedemann syndrome (more commonly associated with Wilms tumor and hepatoblastoma).[20,21]
    • Noonan syndrome.[19,22,23]
  • High birth weight and large size for gestational age are associated with an increased incidence of embryonal rhabdomyosarcoma.[24]

The Children’s Oncology Group (COG) performed retrospective exome sequencing on germline DNA to determine the prevalence of 63 autosomal dominant cancer-predisposing genes in 615 patients with newly diagnosed rhabdomyosarcoma.[25] They identified germline cancer-predisposition (pathogenic or likely pathogenic) variants in 45 patients with rhabdomyosarcoma (7.3%; all FOXO1 fusion negative) across 15 autosomal dominant genes. Specifically, 73.3% of the predisposition variants were found in predisposition syndrome genes previously associated with pediatric rhabdomyosarcoma risk, such as Li-Fraumeni syndrome (TP53, n = 11) and NF1 (NF1, n = 9). Notably, five patients had well-described oncogenic missense variants in HRAS (p.G12V and p.G12S) associated with Costello syndrome, and two patients each had variants in DICER1 and CBL, respectively. Germline pathogenic or likely pathogenic variants were more frequent in patients with embryonal rhabdomyosarcoma than in those with alveolar rhabdomyosarcoma (10% vs. 3%, P = .02), but all of the patients with alveolar rhabdomyosarcoma were FOXO1 negative, and no germline variants were identified in patients with FOXO1 translocations. Although patients with a cancer-predisposition variant tended to be younger at diagnosis (P = .00099), 40% of germline variants were identified in patients older than 3 years.

The COG reviewed the impact of germline pathogenic or likely pathogenic variants in cancer predisposition genes on patient outcomes.[26] In this study of 580 individuals with rhabdomyosarcoma, the median age was 5.9 years (range, 0.01–23.23 years), and the male-to-female ratio was 1.5:1 (351 [60.5%] male). For patients with congenital variants in rhabdomyosarcoma-associated cancer-predisposition genes, the event-free survival (EFS) rate was 48.4%, compared with 57.8% for patients without congenital predisposition variants (P = .10). The overall survival (OS) rate was 53.7% for patients with congenital predisposition variants, compared with 65.3% for patients without these variants (P = .06). Analyses were stratified by tumor histology and PAX3::FOXO1 or PAX7::FOXO1 gene fusion status. After adjustment, patients with congenital predisposition variants had significantly worse OS (adjusted hazard ratio [HR], 2.49; 95% confidence interval [CI], 1.39–4.45; P = .002), and patients with embryonal histology did not have better outcomes (EFS: adjusted HR, 2.25; 95% CI, 1.25–4.06; P = .007 and OS: adjusted HR, 2.83; 95% CI, 1.47–5.43; P = .002). These associations were not due to the development of a second malignant neoplasm. In addition, patients with fusion-negative rhabdomyosarcoma who harbored congenital predisposition variants had similarly inferior outcomes as patients with fusion-positive rhabdomyosarcoma who did not have congenital predisposition variants (EFS: adjusted HR, 1.35; 95% CI, 0.71–2.59; P = .37 and OS: adjusted HR, 1.71; 95% CI, 0.84–3.47; P = .14).

The COG reviewed the correlation between anaplastic histology and germline TP53 pathogenic variants in 239 patients with rhabdomyosarcoma. Among the 46 patients with anaplastic rhabdomyosarcoma, 11% (n = 5) carried a germline TP53 pathogenic variant, compared with 1% (n = 2) of the patients without anaplasia (P = .003). The rates of TP53 pathogenic variants in those with diffuse anaplasia and focal anaplasia were 9% (n = 3) and 17% (n = 2), respectively. Among the seven patients with TP53 pathogenic variants, 71% (5 of 7) had tumors with anaplastic histology.[27]

Prognostic Factors

Rhabdomyosarcoma is usually curable in children with localized disease who receive combined-modality therapy, with more than 70% of patients surviving 5 years after diagnosis.[6,7,28] Relapses are uncommon in patients who were alive and event free at 5 years, with a 10-year late-event rate of 9%. Relapses are more common in patients who have unresectable disease, tumor in an unfavorable site at diagnosis, or metastatic disease at diagnosis.[29]

The prognosis for children or adolescents with rhabdomyosarcoma is related to many clinical and biological factors, including the following:

Because treatment and prognosis partly depend on the histology and molecular characterization of the tumor, it is necessary that the tumor tissue be reviewed by expert pathologists with experience in the evaluation and diagnosis of tumors in children. Typically, accurate diagnosis requires additional molecular characterization. The diversity of primary sites, the distinctive surgical and radiation therapy treatments for each primary site, and the subsequent site-specific rehabilitation underscore the importance of treating children with rhabdomyosarcoma in medical centers with appropriate experience in all therapeutic modalities.

Age

Children aged 1 to 9 years have the best prognosis, while those younger than 1 year and older than 10 years fare less well. In Intergroup Rhabdomyosarcoma Study Group (IRSG) and COG trials, the 5-year failure-free survival (FFS) rate was 57% for patients younger than 1 year, 81% for patients aged 1 to 9 years, and 68% for patients older than 10 years. The 5-year OS rates were 76% for patients younger than 1 year, 87% for patients aged 1 to 9 years, and 76% for patients older than 10 years.[30] Historical data show that adults have fared less well than children (5-year OS rates, 27% ± 1.4% vs. 61% ± 1.4%; P < .0001).[31–34]

  • Young age: Infants tend to do poorly, often because of treatment modifications to reduce toxicity. Typically, chemotherapy doses are reduced by 50% on the basis of reports that infants have higher death rates related to chemotherapy toxicity when compared with older patients; therefore, young patients may be underdosed.[35] In addition, infants younger than 1 year are less likely to receive radiation therapy for local control because of the high incidence of late effects in this age group.[28,36,37]

    The 5-year FFS rate was 67% for infants, compared with 81% in a matched group of older patients treated by the COG.[30,38] This inferior FFS rate was largely the result of a relatively high rate of local failure.

    In another retrospective study of 126 patients (aged ≤24 months) who were enrolled on the ARST0331 (NCT00075582) and ARST0531 (NCT00354835) trials, the 5-year local failure rate was 24%, the 5-year EFS rate was 68.3%, and the OS rate was 81.9%. Forty-three percent of the patients had an individualized local therapy plan that more frequently omitted radiation therapy. These patients had inferior local control and EFS rates.[38]

    Members of the Cooperative Weichteilsarkom Studiengruppe (CWS) reviewed 155 patients with rhabdomyosarcoma presenting from birth to age 12 months; 144 patients had localized disease; 11 patients had metastases; and 32 patients presented with alveolar rhabdomyosarcoma pathology. The following results were reported:[39][Level of evidence C1]

    • Of the 144 patients with localized disease, 129 had a complete response.
    • Fifty-one infants had a recurrence of their disease; 63% of patients with alveolar rhabdomyosarcoma had a relapse, and 28% of patients with embryonal rhabdomyosarcoma had a relapse.
    • The 5-year OS rates were 69% for patients with localized disease, 14% for patients with metastatic disease, and 41% for patients with relapsed disease.

    A retrospective analysis of five consecutive studies from the CWS group examined infants and older children with localized rhabdomyosarcoma of the female genitourinary tract.[40] Among 67 patients treated from 1981 to 2019, age of 12 months or younger at diagnosis was the only significant negative prognostic factor that influenced EFS.

    The European Paediatric Soft Tissue Sarcoma Study Group (EpSSG) enrolled 490 children younger than 36 months in their prospective RMS2005 study. The study included 110 patients younger than 12 months and 380 patients aged 12 to 36 months. Chemotherapy was given according to the risk group. Radiation therapy (22% received brachytherapy) was administered to 33.6% of the infants and 63.5% of the children aged 12 to 36 months. The 5-year OS rate was 88.4% for the infants, which was significantly better than the 72.5% rate observed in children aged 12 to 36 months. The treatment protocol in this trial, which used an increased application of adequate local therapy, may have contributed to these improved outcomes.[41][Level of evidence B4]

    The EpSSG analyzed neonates with congenital rhabdomyosarcoma, which they defined as infants younger than 2 months at diagnosis who were enrolled in EpSSG trials.[42] Twenty-four patients with congenital rhabdomyosarcoma were registered. All patients had favorable histology and localized disease, except for one patient with PAX3::FOXO1 fusion–positive metastatic rhabdomyosarcoma. Three patients had VGLL2::CITED2 or VGLL2::NCOA2 fusions. Complete tumor resection was achieved in ten patients. No radiation therapy was given. Chemotherapy doses were adjusted to age and weight. Only two patients required further dose reduction for toxicity. The 5-year EFS rate was 75.0% (95% CI, 52.6%–87.9%), and the OS rate was 87.3% (95% CI, 65.6%–95.7%).

    An international consortium identified 40 infants with spindle cell rhabdomyosarcoma.[43] The 5-year EFS rate for these infants with localized disease was 86% (± 11%; 95% CI), and the OS rate was 91% (± 9%; 95% CI). These outcomes compare favorably with those of all infants with localized rhabdomyosarcoma, for whom the 5-year failure-free survival rates range from 42% to 72% and the 5-year OS rates range from 61% to 88%. This finding suggests that infants with congenital spindle cell rhabdomyosarcoma have a favorable outcome compared with infants with other subtypes of rhabdomyosarcoma.

  • Older children: In older children, the upper dosage limits of vincristine and dactinomycin are based on body surface area (BSA), and these patients may require reduced vincristine doses because of neurotoxicity.[37,44]
  • Adolescents: A report from the Associazione Italiana Ematologia Oncologia Pediatrica Soft Tissue Sarcoma Committee suggests that adolescents may have more frequent unfavorable tumor characteristics, including alveolar histology, regional lymph node involvement, and metastatic disease at diagnosis, accounting for their poor prognosis. This study also found that 5-year OS and progression-free survival (PFS) rates were somewhat lower in adolescents than in children, but the differences among age groups younger than 1 year and aged 10 to 19 years at diagnosis were significantly worse than those in the group aged 1 to 9 years.[45]

    Two reports from the COG have documented inferior 5-year EFS rates in patients older than 10 years.[37,44] When compared with younger patients, this group of older patients was more likely to present with advanced-stage, large, and invasive alveolar tumors, with nodal involvement arising in the extremity and paratesticular sites. Older patients experienced less myelosuppression and more peripheral nervous system toxicity, suggesting that dose modifications during therapy cannot account for the age-related differences in EFS.

    Adolescent and young adult (AYA) patients were more likely to have worse survival outcomes than children.[46]

    • AYA patients were more likely to have metastatic tumors (61 of 257 [23.7%] vs. 197 of 1,720 [11.5%]; P < .0001), unfavorable histological subtypes (119 [46.3%] vs. 451 [26.2%]; P < .0001), tumors larger than 5 cm (177 [68.9%] vs. 891 [51.8%]; P < .0001), and regional lymph node involvement (109 [42.4%] vs. 339 [19.7%]; P < .0001) than children.
    • AYA patients had lower 5-year EFS rates (52.6% [95% CI, 46.3%–58.6%] vs. 67.8% [95% CI, 65.5%–70.0%]; P < .0001) and OS rates (57.1% [95% CI, 50.4%–63.1%] vs. 77.9% [95% CI, 75.8%–79.8%]; P < .0001) than children.
    • The multivariable analysis confirmed the inferior prognosis of patients aged 15 to 21 years (HR, 1.48 [95% CI, 1.20–1.83; P = .0002] for poorer EFS; HR, 1.73 [95% CI, 1.37–2.19; P < .0001] for poorer OS).
  • Adults: Adult patients with rhabdomyosarcoma have a higher incidence of pleomorphic histology (19%) than do children (<2%). Adults also have a higher incidence of tumors in unfavorable sites than do children.[31]

Site of origin

Prognosis for childhood rhabdomyosarcoma varies according to the primary tumor site (see Table 1).

Table 1. 5-Year Survival by Primary Site of Disease
Primary Site Number of Patients Survival at 5 Years (%)
aPatients treated on the ARST0331 study.[47]
bPatients treated on Intergroup Rhabdomyosarcoma Studies III–IV.[48]
cPooled analysis of European and North American groups.[49]
dCombined result from the Children’s Oncology Group, German Cooperative Soft Tissue Sarcoma Study, Italian Cooperative Group, and International Society of Pediatric Oncology groups.[50]
ePooled analysis of European and North American groups.[51]
fPatients treated on Intergroup Rhabdomyosarcoma Study III.[6]
gPatients treated on Intergroup Rhabdomyosarcoma Studies I–IV.[52]
hPatients treated on the D9602 and ARST0331 trials.[53]
Orbita 82 97
Head and neck (nonparameningeal)b 164 83
Cranial parameningealc 204 69.5
Genitourinary (excluding bladder/prostate)b 158 89
Localized bladder/prostated 322 84
Localized extremitye 643 67
Trunk, abdomen, perineum, etc.f 147 67
Biliaryg,h 25 76.5–78

Tumor size

Children with tumors 5 cm or smaller have improved survival, compared with children with tumors larger than 5 cm.[6] Both tumor volume and maximum tumor diameter are associated with outcome.[54][Level of evidence C1]

A retrospective review of soft tissue sarcomas in children and adolescents suggests that the 5-cm cutoff used for adults with soft tissue sarcoma may not be ideal for smaller children, especially infants. The review identified an interaction between tumor diameter and BSA.[55] This was not confirmed by a COG study of patients with intermediate-risk rhabdomyosarcoma.[56] This relationship requires prospective study to determine the therapeutic implications of the observation.

Resectability

The extent of disease after the primary surgical procedure (i.e., the Surgical-pathologic Group, also called the Clinical Group) is correlated with outcome.[6] In the IRS-III study, patients with localized, gross residual disease after initial surgery (Surgical-pathologic Group III) had a 5-year survival rate of approximately 70%, compared with a rate of more than 90% for patients without residual tumor after surgery (Group I) and a rate of approximately 80% for patients with microscopic residual tumor after surgery (Group II).[6,57] Groups I and II represent a minority of patients; approximately 50% of patients have unresectable Group III disease at time of diagnosis.[6]

Resectability without functional impairment is related to the tumor’s initial size and site and does not account for the biology of the disease. Outcome is optimized with the use of multimodality therapy. All patients require chemotherapy, and at least 85% of patients also benefit from radiation therapy, with favorable outcomes even for patients with nonresectable disease. In the IRS-IV study, the Group III patients with localized unresectable disease who were treated with chemotherapy and radiation therapy had a 5-year FFS rate of about 75% and a local control rate of 87%.[58] Two intermediate-risk COG rhabdomyosarcoma studies (D9803 and ARST0531 [NCT00354835]) were pooled to assess the benefit of delayed primary excision. In the D9803 study, local control with radiation therapy after either a partial or complete excision was completed at week 12. In the ARST0531 study, radiation was administered upfront at week 4. Patients with bladder or prostate rhabdomyosarcoma who received a delayed primary excision had no difference in survival, whereas patients with extremity rhabdomyosarcoma or nonbladder/nonprostate nonextremity rhabdomyosarcoma had an improved OS with delayed primary excision. Delayed primary excision strategy with a reduction in radiation dose resulted in superior OS for those sites.[59,60]

Histopathological subtype

The alveolar subtype of childhood rhabdomyosarcoma is more prevalent among patients with less favorable clinical features (e.g., younger than 1 year or older than 10 years, extremity and truncal primary tumors, and metastatic disease at diagnosis). It is generally associated with a worse outcome than in similar patients with embryonal rhabdomyosarcoma.

  • In the IRS-I and IRS-II studies, the alveolar subtype was associated with a less favorable outcome, even in patients whose primary tumor was completely resected (Group I).[61]
  • A statistically significant difference in 5-year survival by histopathological subtype (82% for embryonal rhabdomyosarcoma vs. 65% for alveolar rhabdomyosarcoma) was noted when 1,258 IRS-III and IRS-IV patients with rhabdomyosarcoma were analyzed.[62]
  • In the IRS-III study, the outcome for patients with Group I alveolar subtype tumors was similar to that for other patients with Group I tumors, but the alveolar patients received more intensive therapy.[6]
  • Patients with alveolar rhabdomyosarcoma who have regional lymph node involvement have significantly worse outcomes than patients who do not have regional lymph node involvement (5-year FFS rates, 43% vs. 73%).[63]
  • Local-control rates after radiation therapy are similar among patients with alveolar and embryonal tumors. However, patients who present with tumors 5 cm or larger have a significantly higher local failure rate.[64]

Anaplasia has been observed in 13% of embryonal rhabdomyosarcoma cases, with some studies suggesting the presence of anaplasia adversely influenced clinical outcome in patients with intermediate-risk disease. However, anaplasia has not been shown to be an independent prognostic variable.[65,66]

PAX3::FOXO1 or PAX7::FOXO1 gene fusion status

Approximately 80% of rhabdomyosarcoma cases morphologically defined as alveolar rhabdomyosarcoma express a FOXO1 fusion. FOXO1 gene fusions occur only in alveolar histology tumors.[67] Several retrospective studies found that fusion status is an independent prognostic factor. Patients with translocation-negative alveolar rhabdomyosarcoma have tumors with genetic and molecular profiles and outcomes similar to patients with embryonal rhabdomyosarcoma, and they fare better than patients with fusion-positive alveolar rhabdomyosarcoma.[68,69] Early retrospective studies relied on convenience samples of available tumor tissue.[68,69] A subsequent prospective study from the Soft Tissue Sarcoma Committee of the COG that examined 434 cases of intermediate-risk rhabdomyosarcoma treated on a single intermediate protocol (D9803) confirmed these observations.[70] Analysis of 38 patients enrolled in the COG D9802 (NCT00003955) low-risk study determined that fusion-positive, low-risk patients should be treated as intermediate risk.[71]

The specific fusion partner may have prognostic impact. In a COG study, fusion-positive patients with Stage 2 or 3, Group III, and PAX3-positive tumors had a lower EFS rate (54%) than those with PAX7-positive tumors (65%). Both fusion-positive groups did worse than those with embryonal rhabdomyosarcoma (EFS rate, 77%; P < .001). Patients with alveolar rhabdomyosarcoma and PAX3 fusions had a poorer OS rate (64%) than patients with alveolar rhabdomyosarcoma and PAX7 fusions (87%), patients with alveolar rhabdomyosarcoma who were fusion negative (89%), and patients with embryonal rhabdomyosarcoma (82%; P = .006).[70] Comparable results were observed in the U.K. study; patients with PAX7-positive tumors and patients with fusion-negative tumors had similar outcomes.[72]

Using data from six consecutive COG studies, a retrospective analysis of 1,727 patients with rhabdomyosarcoma refined the risk stratification for childhood rhabdomyosarcoma. The study reported that after metastatic status, FOXO1 status was the most important prognostic factor and improved the risk stratification of patients with localized rhabdomyosarcoma.[69]

The COG performed a retrospective analysis of 269 patients with confirmed FOXO1 fusion–positive rhabdomyosarcoma who were enrolled in three completed clinical trials for localized rhabdomyosarcoma.[73] The estimated 4-year EFS rate was 53% (95% CI, 47%–59%), and the OS rate was 69% (95% CI, 63%–74%). Multivariate analysis identified older age (≥10 years) and larger tumor size (>5 cm) as independent, adverse prognostic factors for EFS within this population. Patients who had both of these adverse features experienced substantially inferior outcomes.

An EpSSG study evaluated the role of clinical factors together with FOXO1 fusion status in patients with nonmetastatic rhabdomyosarcoma, using data from the EpSSG RMS2005 study. The multivariable analysis of 1,661 evaluable patients retained five prognostic variables: age at diagnosis, tumor size, primary site, IRS Group, and FOXO1 status. A nomogram was created, stratifying patients into four risk groups. The 5-year EFS rates were 94.1% for patients in the low-risk group, 78.4% for patients in the intermediate-risk group, 65.2% for patients in the high-risk group, and 52.1% for patients in the very high-risk group.[74]

These studies demonstrated that fusion status was a better predictor of outcome than histology. Similar conclusions were reached in a retrospective study of three consecutive trials in the United Kingdom. Fusion status has now been incorporated into the risk stratification of patients in the current COG ARST1431 (NCT02567435) study for patients with intermediate-risk rhabdomyosarcoma, in subsequent COG trials, and in the new international EpSSG trial.[74] The authors underscored the probable value of treating fusion-negative patients whose tumors have alveolar histology with therapy that is stage appropriate for embryonal histology tumors.[75][Level of evidence C1]

Metastases at diagnosis

Children with metastatic disease at diagnosis have the worst prognosis.

The prognostic significance of metastatic disease is modified by the following:

  • Tumor histology (embryonal rhabdomyosarcoma is more favorable than alveolar). Patients with localized alveolar histology and regional node disease have a similar prognosis as patients with a single site of metastatic disease, provided that the regional disease is treated with radiation therapy.[63]
  • Age at diagnosis (<10 years for children with embryonal rhabdomyosarcoma).
  • The site of primary disease. Patients with metastatic genitourinary (nonbladder, nonprostate) primary tumors have a more favorable outcome than patients with metastatic disease from other primary sites.[76]
  • The number of metastatic sites.[77–80]

The COG performed a retrospective analysis of 179 patients who were diagnosed with rhabdomyosarcoma that was metastatic to the bone marrow. These patients were enrolled in one of four COG rhabdomyosarcoma clinical trials (D9802, D9803, ARST0431, and ARST08P1) between 1997 and 2013.[81] Patients were a median age of 14.8 years and 58% were male. Alveolar histology was the predominant type (76%), the extremity was the most common primary site (32%), and most patients had metastatic disease to additional sites (87%). The 3-year EFS rate was 9.4%, and the 5-year EFS rate was 8.2%. The 3-year OS rate was 26.1%, and the 5-year OS rate was 12.6%.

The COG performed a retrospective review of patients enrolled in high-risk protocols for rhabdomyosarcoma. FOXO1 fusion status correlated with clinical characteristics at diagnosis, including age, stage, histology, and extent of metastatic disease (Oberlin status). Among patients with metastatic disease, PAX::FOXO1 fusion status was not an independent predictor of outcome.[82][Level of evidence B1]

Lymph node involvement at diagnosis

Lymph node involvement at diagnosis is seen in about 23% of patients with rhabdomyosarcoma and is associated with an inferior prognosis.[62,83] Clinical and/or imaging evaluation is performed before treatment and preoperatively. These findings are incorporated into the initial staging and grouping of a patient with rhabdomyosarcoma. The updated TNM staging defines clinical node involvement as larger than 1 cm.[84]

Pathological assessment of nodal disease is determined by biopsy and incorporated in the Surgical/Pathologic Clinical Group classification. Core-needle or open biopsy of clinically enlarged nodes is appropriate to confirm the presence of disease. Approximately 25% of enlarged nodes will be pathologically negative. Suspicious nodes are sampled surgically with open biopsy, preferred to needle aspiration, although needle aspiration may occasionally be appropriate. Pathological evaluation of clinically uninvolved nodes is site specific. In COG studies, it is required for extremity sites and for boys older than 10 years with paratesticular primary tumors.[85] Given the poorer outcomes, pathological node evaluation is required for patients with fusion-positive disease in current European and North American clinical trials.

Data on the frequency of lymph node involvement in various sites are useful for making clinical decisions. For example, up to 40% of patients with rhabdomyosarcoma in genitourinary sites have lymph node involvement, while patients with certain head and neck sites have a much lower likelihood (<10%). Patients with nongenitourinary pelvic sites (e.g., anus/perineum) have an intermediate frequency of lymph node involvement.[86]

In the extremities and select truncal sites, sentinel lymph node evaluation is a more accurate form of diagnosis than random regional lymph node sampling. In clinically negative lymph nodes of the extremity or trunk, sentinel lymph node biopsy is the preferred form of node sampling by the COG. Technical considerations are obtained from surgical experts. Needle or open biopsy of clinically enlarged nodes is appropriate.[87–90] Lymph node removal does not improve outcome, and it is useful for staging but not treatment.

The EpSSG performed a retrospective analysis of 109 patients with rhabdomyosarcoma with extremity primary tumors distal to the elbow or knee who were treated in the EpSSG RMS-2005 (NCT00379457) trial (2005–2016).[91] Thirty-seven of 109 patients (34%) had lymph node metastases at diagnosis. Of the 37 patients, 19 (51%) had in-transit metastases (ITM), especially in lower extremity rhabdomyosarcoma. The 5-year EFS rates were 88.9% for patients with ITM, 21.4% for patients with proximal lymph node involvement, and 20% for combined proximal lymph node involvement and ITM (P = .01). The 5-year OS rates were 100% for patients with ITM, 25.2% for patients with proximal lymph node involvement, and 15% for patients with combined proximal lymph node involvement and ITM (P =. 003). The authors concluded that popliteal and epitrochlear nodes should be considered as true (distal) regional nodes, instead of ITM. The authors recommended biopsy of these nodes, especially for distal extremity rhabdomyosarcoma of the lower limb.

The EpSSG reported a retrospective analysis of 1,294 children with embryonal rhabdomyosarcoma enrolled in the RMS-2005 protocol.[92] Of these patients, 143 had nodal involvement (N1). Patients with N1 disease were older and presented with tumors of unfavorable size, invasiveness, site, and resectability. Unlike alveolar rhabdomyosarcoma, nodal involvement was more frequent in the head and neck area and rare in extremity sites. The 5-year EFS rate was 75.5%, and the OS rate was 86.3% for patients with N0 disease. The 5-year EFS rate was 65.2%, and the OS rate was 70.7% for patients with N1 disease. Nodal involvement and the result of surgery at diagnosis (Intergroup Rhabdomyosarcoma Study group) were independent prognostic factors on multivariate analysis. Investigators concluded that regional nodal involvement is an independent prognostic factor in patients with embryonal rhabdomyosarcoma; therefore, it is appropriate to include this population in the high-risk category.

Bone marrow involvement

The COG performed a retrospective analysis of patients with rhabdomyosarcoma who had bone marrow metastasis at initial presentation and were treated in COG protocols.[93] Rhabdomyosarcoma metastatic to bone was identified in 154 patients (median age at diagnosis, 14.9 years). Fifty-eight percent of patients were male, 90% of patients had metastases at additional sites, 74% of patients had alveolar histology, and extremities were the most common primary site (31%). The 3-year EFS rate was 15.4%, and the 5-year EFS rate was 14.5%. The 3-year OS rate was 30.4%, and the 5-year OS rate was 18.0%. Alveolar histology, presence of FOXO1 gene fusions, unfavorable primary tumor location, higher Oberlin score, and lack of radiation therapy were poor prognostic characteristics for both EFS and OS in univariate analysis.

Biological characteristics

For more information, see the Molecular Characteristics of Rhabdomyosarcoma section.

Response to therapy

It is unlikely that response to induction chemotherapy or best tumor response during therapy, assessed by anatomic imaging, correlates with the likelihood of survival in patients with rhabdomyosarcoma. This finding was based on the IRSG, COG, and International Society of Pediatric Oncology (SIOP) studies that found no association.[94,95]; [96][Level of evidence C2]; [97][Level of evidence C1] However, an Italian study did find that patient response correlated with likelihood of survival.[54][Level of evidence C1] In patients with embryonal rhabdomyosarcoma who had metastases only in the lungs, the CWS assessed the relationship between complete response of the lung metastases at weeks 7 to 10 after chemotherapy and outcome in 53 patients.[98][Level of evidence C1] The 5-year survival rate was 68% for 26 complete responders at weeks 7 to 10 versus 36% for 27 patients who achieved complete responses at later time points (P = .004).

Other studies have investigated response to induction therapy, showing benefit to response. These data are somewhat flawed because therapy is usually tailored on the basis of response. Thus the situation is not as clear as the COG data suggest.[99–104]

Response as judged by sequential functional imaging studies with fluorine F 18-fludeoxyglucose positron emission tomography (18F-FDG PET) may be an early indicator of outcome [105] and is under investigation by several pediatric cooperative groups. A retrospective analysis of 107 patients from a single institution examined PET scans performed at baseline, after induction chemotherapy, and after local therapy.[105] Standardized uptake value measured at baseline predicted PFS and OS, but not local control. A negative scan after induction chemotherapy correlated with statistically significantly better PFS. A positive scan after local therapy predicted worse PFS, OS, and local control. The COG evaluated the relationship between complete metabolic response, as assessed by 18F-FDG PET imaging, and EFS in patients with intermediate- or high-risk rhabdomyosarcoma.[106][Level of evidence B4] The maximum standard uptake values (SUVmax) at study entry did not correlate with EFS for intermediate-risk (P = .32) or high-risk (P = .86) patients. Compared with patients who did not achieve a complete metabolic response, EFS was not superior for intermediate-risk patients who achieved a complete metabolic response at weeks 4 (P = .66) or 15 (P = .46), or for high-risk patients who achieved a complete metabolic response at weeks 6 (P = .75) or 19 (P = .28). Change in SUVmax at weeks 4 (P = .21) or 15 (P = .91) for intermediate-risk patients and at weeks 6 (P = .75) or 19 (P = .61) for high-risk patients did not correlate with EFS.

PET scans have been shown to be useful in understanding patterns of spread, particularly in patients with extremity disease.[107][Level of evidence C2]

Circulating tumor DNA (ctDNA) and RNA

A retrospective study of 99 children with rhabdomyosarcoma used reverse transcription–polymerase chain reaction to analyze an 11-gene panel in peripheral blood and bone marrow samples at the time of initial diagnosis.[108] The 5-year EFS rate was 35.5% (95% CI, 17.5%–53.5%) for the 33 patients who were RNA positive, compared with 88.0% (95% CI, 78.9%–97.2%) for the 66 patients who were RNA negative (P < .0001). The predictive power of the assay was maintained in a multivariate analysis, which included the usual clinical characteristics that correlate with prognosis such as the presence of metastatic disease. These investigators also studied the diagnostic potential of ctDNA in 57 patients enrolled in the EpSSG RMS-2005 (NCT00379457) study. ctDNA was detected using both shallow whole-genome sequencing (WGS) and cell-free reduced representation bisulfite sequencing (cfRRBS). Of the 25 samples tested, 21 were correctly classified as embryonal histology by cfRRBS. The presence of methylated RASSF1A correlated with a poor outcome.[109]

The COG analyzed ctDNA in 124 patients with newly diagnosed, intermediate-risk rhabdomyosarcoma from the COG biorepository, which included 75 patients with fusion-negative rhabdomyosarcoma and 49 patients with fusion-positive rhabdomyosarcoma.[110] Ultralow passage WGS was used to detect copy number alterations. Rhabdo-Seq, a new custom sequencing assay, was used to detect rearrangements and single-nucleotide variants (SNVs).

  • The authors reported that ultralow passage WGS was a method that could detect ctDNA in all patients with fusion-negative rhabdomyosarcoma. ctDNA was detected in 13 of 75 serum samples (17%).
  • However, the use of Rhabdo-Seq in fusion-negative rhabdomyosarcoma samples also identified SNVs, such as the L122R variant in the MYOD1 gene. This variant was previously associated with a poor prognosis.
  • Identification of pathognomonic translocations between PAX3 or PAX7 and FOXO1 by Rhabdo-Seq was the best method for measuring ctDNA in fusion-positive rhabdomyosarcoma tumors. It detected ctDNA in 27 of 49 cases (55%).
  • Patients with fusion-negative rhabdomyosarcoma with detectable ctDNA at diagnosis had significantly worse outcomes than patients without detectable ctDNA (EFS rates, 33.3% vs. 68.9%; P = .0028; OS rates, 33.3% vs. 83.2%; P < .0001).
  • Patients with fusion-positive rhabdomyosarcoma with detectable ctDNA at diagnosis had significantly worse outcomes than patients without detectable ctDNA (EFS rates, 37% vs. 70%; P = .045; OS rates, 39.2% vs. 75%; P = .023).
  • In a multivariate analysis, ctDNA was independently associated with poor prognoses in patients with fusion-negative rhabdomyosarcoma but not in the smaller cohort of patients with fusion-positive rhabdomyosarcoma.
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  78. Bisogno G, Ferrari A, Prete A, et al.: Sequential high-dose chemotherapy for children with metastatic rhabdomyosarcoma. Eur J Cancer 45 (17): 3035-41, 2009. [PUBMED Abstract]
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  85. Walterhouse DO, Barkauskas DA, Hall D, et al.: Demographic and Treatment Variables Influencing Outcome for Localized Paratesticular Rhabdomyosarcoma: Results From a Pooled Analysis of North American and European Cooperative Groups. J Clin Oncol : JCO2018789388, 2018. [PUBMED Abstract]
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  91. Terwisscha van Scheltinga CEJ, Wijnen MHWA, Martelli H, et al.: In transit metastases in children, adolescents and young adults with localized rhabdomyosarcoma of the distal extremities: Analysis of the EpSSG RMS 2005 study. Eur J Surg Oncol 48 (7): 1536-1542, 2022. [PUBMED Abstract]
  92. Ben-Arush M, Minard-Colin V, Scarzello G, et al.: Therapy and prognostic significance of regional lymph node involvement in embryonal rhabdomyosarcoma: a report from the European paediatric Soft tissue sarcoma Study Group. Eur J Cancer 172: 119-129, 2022. [PUBMED Abstract]
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  94. Burke M, Anderson JR, Kao SC, et al.: Assessment of response to induction therapy and its influence on 5-year failure-free survival in group III rhabdomyosarcoma: the Intergroup Rhabdomyosarcoma Study-IV experience–a report from the Soft Tissue Sarcoma Committee of the Children’s Oncology Group. J Clin Oncol 25 (31): 4909-13, 2007. [PUBMED Abstract]
  95. Lautz TB, Chi YY, Tian J, et al.: Relationship between tumor response at therapy completion and prognosis in patients with Group III rhabdomyosarcoma: A report from the Children’s Oncology Group. Int J Cancer 147 (5): 1419-1426, 2020. [PUBMED Abstract]
  96. Rosenberg AR, Anderson JR, Lyden E, et al.: Early response as assessed by anatomic imaging does not predict failure-free survival among patients with Group III rhabdomyosarcoma: a report from the Children’s Oncology Group. Eur J Cancer 50 (4): 816-23, 2014. [PUBMED Abstract]
  97. Vaarwerk B, van der Lee JH, Breunis WB, et al.: Prognostic relevance of early radiologic response to induction chemotherapy in pediatric rhabdomyosarcoma: A report from the International Society of Pediatric Oncology Malignant Mesenchymal Tumor 95 study. Cancer 124 (5): 1016-1024, 2018. [PUBMED Abstract]
  98. Sparber-Sauer M, von Kalle T, Seitz G, et al.: The prognostic value of early radiographic response in children and adolescents with embryonal rhabdomyosarcoma stage IV, metastases confined to the lungs: A report from the Cooperative Weichteilsarkom Studiengruppe (CWS). Pediatr Blood Cancer 64 (10): , 2017. [PUBMED Abstract]
  99. Koscielniak E, Harms D, Henze G, et al.: Results of treatment for soft tissue sarcoma in childhood and adolescence: a final report of the German Cooperative Soft Tissue Sarcoma Study CWS-86. J Clin Oncol 17 (12): 3706-19, 1999. [PUBMED Abstract]
  100. Koscielniak E, Jürgens H, Winkler K, et al.: Treatment of soft tissue sarcoma in childhood and adolescence. A report of the German Cooperative Soft Tissue Sarcoma Study. Cancer 70 (10): 2557-67, 1992. [PUBMED Abstract]
  101. Dantonello TM, Int-Veen C, Harms D, et al.: Cooperative trial CWS-91 for localized soft tissue sarcoma in children, adolescents, and young adults. J Clin Oncol 27 (9): 1446-55, 2009. [PUBMED Abstract]
  102. Oberlin O, Rey A, Sanchez de Toledo J, et al.: Randomized comparison of intensified six-drug versus standard three-drug chemotherapy for high-risk nonmetastatic rhabdomyosarcoma and other chemotherapy-sensitive childhood soft tissue sarcomas: long-term results from the International Society of Pediatric Oncology MMT95 study. J Clin Oncol 30 (20): 2457-65, 2012. [PUBMED Abstract]
  103. Stevens MC, Rey A, Bouvet N, et al.: Treatment of nonmetastatic rhabdomyosarcoma in childhood and adolescence: third study of the International Society of Paediatric Oncology–SIOP Malignant Mesenchymal Tumor 89. J Clin Oncol 23 (12): 2618-28, 2005. [PUBMED Abstract]
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  105. Casey DL, Wexler LH, Fox JJ, et al.: Predicting outcome in patients with rhabdomyosarcoma: role of [(18)f]fluorodeoxyglucose positron emission tomography. Int J Radiat Oncol Biol Phys 90 (5): 1136-42, 2014. [PUBMED Abstract]
  106. Harrison DJ, Chi YY, Tian J, et al.: Metabolic response as assessed by 18 F-fluorodeoxyglucose positron emission tomography-computed tomography does not predict outcome in patients with intermediate- or high-risk rhabdomyosarcoma: A report from the Children’s Oncology Group Soft Tissue Sarcoma Committee. Cancer Med 10 (3): 857-866, 2021. [PUBMED Abstract]
  107. La TH, Wolden SL, Rodeberg DA, et al.: Regional nodal involvement and patterns of spread along in-transit pathways in children with rhabdomyosarcoma of the extremity: a report from the Children’s Oncology Group. Int J Radiat Oncol Biol Phys 80 (4): 1151-7, 2011. [PUBMED Abstract]
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Cellular Classification for Childhood Rhabdomyosarcoma

Histological Subtypes

The 5th edition of the World Health Organization (WHO) Classification of Tumors of Soft Tissue and Bone recognizes the following four categories of rhabdomyosarcoma:[1]

Embryonal rhabdomyosarcoma

The embryonal subtype, which includes classic, dense, and botryoid variants, is the most frequently observed subtype in children, accounting for 70% to 75% of childhood rhabdomyosarcomas.[1,2] Tumors with embryonal histology typically arise in the head and neck region or in the genitourinary tract, although they may occur at any primary site.

Anaplasia has been observed in 13% of embryonal rhabdomyosarcoma cases, with some studies suggesting the presence of anaplasia adversely influenced clinical outcome in patients with intermediate-risk disease. However, anaplasia has not been shown to be an independent prognostic variable.[3,4]

Botryoid tumors, which represent about 10% of all rhabdomyosarcoma cases, are embryonal tumors that arise under the mucosal surface of body orifices such as the vagina, bladder, nasopharynx, and biliary tract. The WHO Classification of Tumors of Soft Tissue and Bone (4th and 5th editions) and the Children’s Oncology Group (COG) eliminated botryoid rhabdomyosarcoma as a separate entity, with these cases classified as typical embryonal rhabdomyosarcoma.[1,5]

A COG study of 2,192 children with embryonal rhabdomyosarcoma (including botryoid and spindle cell variants) enrolled in clinical trials showed improved event-free survival (EFS) rates for patients with botryoid tumors (80%; 95% confidence interval [CI], 74%–84%), compared with typical embryonal rhabdomyosarcoma (73%; 95% CI, 71%–75%).[6] However, after adjusting for primary site, resection, and metastatic status, there was no difference in EFS by histological subtype. In this COG report, botryoid tumors accounted for 14% of intermediate-risk patients and 15% of low-risk patients. The botryoid histology retained prognostic significance in only a small proportion of patients with low-risk head and neck tumors, who are known to have excellent outcomes. For these reasons, the COG concluded that the addition of this histological classification of rhabdomyosarcoma has limited clinical utility and endorsed the recommendations of the WHO to remove this subtype from the current COG pathology classification.

One study analyzed the clinical and variant spectrum of 24 pediatric fusion-negative rhabdomyosarcoma tumors with high levels of myogenic differentiation. The analysis revealed that most tumors arose in the head and neck or genitourinary region. The overall survival rate was 100% for these patients (median follow-up, 4.6 years).[7]

Alveolar rhabdomyosarcoma

Approximately 20% to 25% of children with rhabdomyosarcoma have the alveolar subtype, when histology alone is used to determine subtype.[1] An increased frequency of this subtype is noted in adolescents and in patients with primary sites involving the extremities, trunk, and perineum/perianal region.[2] Eighty percent of patients with alveolar histology tumors will have one of two gene fusions, PAX3 on chromosome 2 or PAX7 on chromosome 1, with the FOXO1 gene on chromosome 13.[8–10] Patients without a fusion have outcomes that are similar to those for patients with embryonal rhabdomyosarcoma.[11–13]

The current trial for intermediate-risk patients from the Soft Tissue Sarcoma Committee of the COG (ARST1431 [NCT02567435]) and all future trials will use fusion status rather than histology to determine eligibility. Fusion-negative patients with alveolar histology will undergo the same treatments as patients with embryonal histology.

Spindle cell/sclerosing rhabdomyosarcoma

The 4th edition of the WHO Classification of Tumors of Soft Tissue and Bone added spindle cell/sclerosing rhabdomyosarcoma as a separate subtype of rhabdomyosarcoma.[5] The 5th edition of the WHO Classification of Tumors of Soft Tissue and Bone continues to identify this separate subtype.[1] The spindle cell variant of embryonal rhabdomyosarcoma is most frequently observed at the paratesticular site.[6,14]

A COG study of 2,192 children with embryonal rhabdomyosarcoma (including botryoid and spindle cell variants) and enrolled in clinical trials showed improved EFS rates for patients with spindle cell rhabdomyosarcoma (83%; 95% CI, 77%–87%) compared with typical embryonal rhabdomyosarcoma (73%; 95% CI, 71%–75%).[6] Patients with spindle cell rhabdomyosarcoma with parameningeal primary tumors (n = 18) were the exception to the overall favorable prognosis for this subtype, with a 5-year EFS rate of 28% (compared with >70% for parameningeal nonspindle cell embryonal rhabdomyosarcoma).

In the WHO classification, sclerosing rhabdomyosarcoma is considered a variant pattern of spindle cell rhabdomyosarcoma, as descriptions note increasing degrees of hyalinization and matrix formation in spindle cell tumors. There are at least two distinct molecular subtypes of spindle cell/sclerosing rhabdomyosarcoma in children:

  • One subtype affects patients in their first year of life, with a median age at presentation of 3 months. The tumors usually arise in the trunk and morphologically resemble infantile fibrosarcoma. This variant is characterized by fusions involving the VGLL2 gene with the CITED2 or NCOA2 genes. In a series of six patients with long-term follow-up data, two patients developed a local recurrence, but all were alive at a median of 7 years.[15,16] For more information on spindle cell/sclerosing histology, see the Molecular Characteristics of Rhabdomyosarcoma section.
  • Another subtype is characterized by MYOD1 (p.L122R) variants, and about one-third of this subset have coexistent PIK3CA variants.[17] These tumors can affect children, adolescents, and adults. They more frequently arise in the head and neck region and are characterized by an aggressive clinical course. In one series, 10 of 12 pediatric patients with follow-up data died of disease.[17]

Pleomorphic rhabdomyosarcoma

Pleomorphic rhabdomyosarcoma occurs in adults in their sixth and seventh decades, most commonly involves the extremities, and is associated with a poor prognosis. This histological variant is extremely rare and not well characterized in the pediatric population.[18,19] In children, tumors with extensive pleomorphism are considered anaplastic embryonal rhabdomyosarcoma.[1]

Machine learning of rhabdomyosarcoma histopathology can potentially provide predictive models for identifying the histological subtypes of rhabdomyosarcoma.[20,21] Digital whole-slide hematoxylin and eosin (H&E) images were collected from a cohort of 321 patients with rhabdomyosarcoma enrolled in COG trials from 1998 to 2017. These images were fed into deep learning convolutional neural networks (CNNs) to learn features associated with driver variants and patient outcomes.[22]

  • The trained CNNs accurately classified alveolar rhabdomyosarcoma (subtype associated with PAX3 or PAX7 fused with FOXO1) with a receiver operating characteristic (ROC) curve of 0.85.
  • CNN models identified tumors with RAS pathway variants with an ROC of 0.67. These models also identified high-risk variants in MYOD1 or TP53 with an ROC of 0.97 and 0.63, respectively.
  • CNN models were superior at predicting EFS and OS when compared with current molecular–clinical risk stratification models.

Molecular Characteristics of Rhabdomyosarcoma

Genomics of rhabdomyosarcoma

The four histological categories recognized in the 5th edition of the World Health Organization (WHO) Classification of Tumors of Soft Tissue and Bone have distinctive genomic alterations and are briefly summarized below.[1,2,23]

  • Embryonal rhabdosarcoma: Characterized by loss of heterozygosity at 11p15 and by a high frequency of variants in genes in the RAS pathway. For the purposes of this section, patients with embryonal rhabdomyosarcoma are considered negative for PAX3::FOXO1 and PAX7::FOXO1 gene fusions (i.e., fusion-negative rhabdomyosarcoma).
  • Alveolar rhabdomyosarcoma: Characterized by gene fusions involving FOXO1 with either PAX3 or PAX7 (i.e., FOXO1 fusion–positive rhabdomyosarcoma). Cases with alveolar rhabdomyosarcoma histology without FOXO1 gene fusions have clinical behavior, gene alteration patterns, and transcriptomic profiles like cases with embryonal rhabdomyosarcoma. Therefore, the discussion below focuses only on alveolar rhabdomyosarcoma with FOXO1 gene fusions.[12,13,24–26]
  • Spindle cell/sclerosing rhabdomyosarcoma: Characterized by variants of MYOD1 in older patients and by VGLL2 and NCOA2 gene rearrangements in young children.
  • Pleomorphic rhabdomyosarcoma: Characterized by complex karyotypes with numerical and unbalanced structural changes that are indistinguishable from those of undifferentiated pleomorphic sarcomas.

The distribution of gene variants and gene amplifications (for CDK4 and MYCN) differs between patients with embryonal histology lacking a PAX::FOXO1 gene fusion (fusion-negative rhabdomyosarcoma) and patients with PAX::FOXO1 gene fusions (fusion-positive rhabdomyosarcoma). See Table 2 below and the text that follows. These frequencies are derived from a combined cohort of the Children’s Oncology Group (COG) and United Kingdom rhabdomyosarcoma patients (n = 641).[27]

Table 2. Frequency of Gene Alterations in Patients With Fusion-Negative (FN) and Fusion-Positive (FP) Rhabdomyosarcomaa
Gene % FN Cases With Gene Alteration % FP Cases With Gene Alteration
aAdapted from Shern et al.[27]
NRAS 17% 1%
KRAS 9% 1%
HRAS 8% 2%
FGFR4 13% 0%
NF1 15% 4%
BCOR 15% 6%
TP53 13% 4%
CTNNB1 6% 0%
CDK4 0% 13%
MYCN 0% 10%

Details of the genomic alterations that predominate within each of the WHO histological categories are as follows.

  1. Fusion-negative rhabdomyosarcoma (embryonal histology): Embryonal rhabdomyosarcoma tumors often show loss of heterozygosity at 11p15 and gains on chromosome 8.[9,28–30] Embryonal tumors have a higher background variant rate and a higher single-nucleotide variant rate than do alveolar rhabdomyosarcoma tumors, and the number of somatic variants increases with older age at diagnosis.[30,31] The most common recurring variants include those in the RAS pathway (e.g., NRAS, KRAS, HRAS, and NF1), which together are observed in approximately one-half of cases.[27] Variants in NRAS are the most frequent RAS pathway gene variants beyond infancy, while variants in HRAS predominate during infancy.[27] The presence of a RAS variant does not confer prognostic significance.

    Among the RAS pathway genes, germline pathogenic variants in NF1 and HRAS predispose to rhabdomyosarcoma. In a study of 615 children with rhabdomyosarcoma, 347 had tumors with embryonal histology. Of these, nine patients had NF1 germline pathogenic variants, and five patients had HRAS germline pathogenic variants, representing 2.6% and 1.4% of embryonal histology cases, respectively.[32]

    Other genes with recurring variants in fusion-negative rhabdomyosarcoma tumors include FGFR4, PIK3CA, CTNNB1, FBXW7, and BCOR, all of which are present in fewer than 15% of cases.[27,30,31]

    TP53 variants: TP53 variants are observed in 10% to 15% of patients with fusion-negative rhabdomyosarcoma and occur less commonly (about 4%) in patients with alveolar rhabdomyosarcoma.[27] In other childhood cancers (e.g., Wilms tumor), TP53 variants are associated with anaplastic histology,[33] and the same is true for embryonal rhabdomyosarcoma. In a study of 146 rhabdomyosarcoma patients with known TP53 status, approximately two-thirds of tumors with TP53 variants showed anaplasia (69%), but only one-quarter of tumors with anaplasia had TP53 variants.[4]

    The presence of TP53 variants was associated with reduced EFS in both nonrisk-stratified and risk-stratified analyses for both a COG and a U.K. rhabdomyosarcoma cohort.[27] The poor prognosis associated with TP53 variants was observed for both embryonal and alveolar patients. Based on these results, the COG plans to consider TP53 variant as a high-risk defining characteristic in its upcoming trials.[34]

    Rhabdomyosarcoma is one of the childhood cancers associated with Li-Fraumeni syndrome. In a study of 614 pediatric patients with rhabdomyosarcoma, 11 patients (1.7%) had TP53 germline pathogenic variants. Variants were less common in patients with alveolar histology (0.6%), compared with patients with nonalveolar histologies (2.2%).[32] Rhabdomyosarcoma with nonalveolar anaplastic morphology may be a presenting feature for children with Li-Fraumeni syndrome and germline TP53 variants.[35]

    • Among eight consecutively presenting children with rhabdomyosarcoma and TP53 germline pathogenic variants, all showed anaplastic morphology. Among an additional seven children with anaplastic rhabdomyosarcoma and unknown TP53 germline variant status, three of the seven children had functionally relevant TP53 germline pathogenic variants. The median age at diagnosis of the 11 children with TP53 germline pathogenic variant status was 40 months (range, 19–67 months).[35]
    • In another series, 26 of 31 patients with germline TP53 pathogenic variants had tumors with embryonal histology. Of the 16 tumors that were submitted for central pathology review, 12 had focal or diffuse anaplasia. The median age of patients in this group was 2.3 years.[36]

    DICER1 variants in embryonal rhabdomyosarcoma: DICER1 variants are observed in a small subset of patients with embryonal rhabdomyosarcoma, most commonly arising in tumors of the female genitourinary tract.[27] More specifically, most cases of cervical embryonal rhabdomyosarcoma,[37–39] which most commonly occurs in adolescents and young adults,[40,41] have DICER1 variants. In contrast, DICER1 variants are rarely observed in patients with vaginal primary sites, an entity occurring primarily in girls younger than 2 or 3 years.[38,40] DICER1 variants are also common in embryonal rhabdomyosarcoma arising in the uterine corpus, but this presentation is primarily observed in adults.[38,42] Cervical rhabdomyosarcoma generally shows a sarcoma botryoides histological pattern, and many cases show areas of cartilaginous differentiation, a feature also observed in other tumor types with DICER1 variants.[40,41,43] In support of the distinctive biology of embryonal rhabdomyosarcoma with DICER1 variants, these cases have a DNA methylation pattern that is distinctive from that of other embryonal rhabdomyosarcoma cases.[39] A diagnosis of cervical rhabdomyosarcoma is an indication for genetic testing for DICER1 syndrome.[38,44]

  2. Fusion-positive rhabdomyosarcoma (alveolar histology): About 70% to 80% of alveolar tumors are characterized by translocations between the FOXO1 gene on chromosome 13 and either the PAX3 gene on chromosome 2 (t(2;13)(q35;q14)) or the PAX7 gene on chromosome 1 (t(1;13)(p36;q14)).[8–10] Other rare fusions include PAX3::NCOA1 and PAX3::INO80D.[30] Translocations involving the PAX3 gene occur in approximately 60% of alveolar rhabdomyosarcoma cases, while the PAX7 gene appears to be involved in about 20% of cases.[8] Patients with solid-variant alveolar histology have a lower incidence of PAX::FOXO1 gene fusions than do patients showing classical alveolar histology.[45] The alveolar histology that is associated with the PAX7 gene in patients with or without metastatic disease appears to occur at a younger age and may be associated with longer EFS rates than those associated with PAX3 gene rearrangements.[46–51] Patients with alveolar histology and the PAX3 gene are older and have a higher incidence of invasive tumor (T2). Around 20% of cases showing alveolar histology have no detectable PAX gene translocation.[25,45] These patients have clinical behaviors, gene alteration patterns, and transcriptomic profiles that align with patients who have embryonal rhabdomyosarcoma and are now classified together with embryonal rhabdomyosarcoma, as fusion-negative rhabdomyosarcoma.[12,13,24–26]

    For the diagnosis of alveolar rhabdomyosarcoma, a FOXO1 gene rearrangement may be detected with good sensitivity and specificity using either fluorescence in situ hybridization or reverse transcription–polymerase chain reaction.[52]

    In addition to FOXO1 rearrangements, alveolar tumors are characterized by a lower mutational burden than are fusion-negative tumors, with fewer genes having recurring mutations.[30,31] The most frequently observed alterations in fusion-positive tumors are focal amplification of CDK4 (13%) or MYCN (10%), with small numbers of patients having recurring mutations in other genes (e.g., BCOR, 6%; NF1, 4%; TP53, 4%; and PIK3CA, 2%).[27] TP53 mutations in alveolar rhabdomyosarcoma appear to connote a high risk of treatment failure.[27]

  3. Spindle cell/sclerosing histology: Spindle cell/sclerosing rhabdomyosarcoma has been proposed as a separate entity in the WHO Classification of Tumors of Soft Tissue and Bone.[53] Within the spindle cell/sclerosing rhabdomyosarcoma category, several entities have distinctive molecular and clinical characteristics, described below.

    Congenital/infantile spindle cell rhabdomyosarcoma: Several reports have described cases of congenital or infantile spindle cell rhabdomyosarcoma with gene fusions involving VGLL2 and NCOA2 (e.g., VGLL2::CITED2, TEAD1::NCOA2, VGLL2::NCOA2, SRF::NCOA2).[15,54]

    • For congenital/infantile spindle cell rhabdomyosarcoma, a study reported that 10 of 11 patients showed recurrent fusion genes. Most of these patients had truncal primary tumors, and there were no paratesticular tumors. Novel VGLL2 rearrangements were observed in seven patients (63%), including the VGLL2::CITED2 fusion in four patients and the VGLL2::NCOA2 fusion in two patients.[15] Three patients (27%) harbored different NCOA2 gene fusions, including TEAD1::NCOA2 in two patients and SRF::NCOA2 in one patient. In this report, all fusion-positive congenital/infantile spindle cell rhabdomyosarcoma patients with long-term follow-up data were alive and well, and no patients developed distant metastases.[15]
    • While most studies of congenital/infantile spindle cell rhabdomyosarcoma have shown favorable outcomes, it was reported that four patients developed metastatic disease and two patients had fatal outcomes. Disease progression occurred a median of 3.5 years from diagnosis (range, 1–8 years).[55] All four patients had unresectable tumors and were treated with chemotherapy. However, most literature reported cases in which surgical resection was achieved. At disease progression, a tumor from one patient had a TP53 variant, and a tumor from another patient showed a homozygous CDKN2A and CDKN2B deletion.
    • A study of 40 patients with congenital/infantile spindle cell rhabdomyosarcoma (defined by diagnosis at age ≤12 months) found that almost all patients had localized disease (n = 39) and that one-half of patients who underwent molecular testing (13 of 26) had rearrangements of NCOA2 and/or VGLL2.[16] Because testing was limited to NCOA2 and VGLL2, it is possible that more comprehensive genomic analysis would identify a higher proportion of patients with relevant gene fusions. The 5-year EFS rate for the 13 patients with either a VGLL2 and/or a NCOA2 fusion was 90% (95% CI, ±19%), and the overall survival (OS) rate was 100% (95% CI, ±9%).
    • Further study is needed to better define the prevalence and prognostic significance of gene rearrangements in VGLL2, NCOA2, and other relevant genes in young children with congenital/infantile spindle cell rhabdomyosarcoma.

    MYOD1-altered spindle cell/sclerosing rhabdomyosarcoma: In older children and adults with spindle cell/sclerosing rhabdomyosarcoma, a specific MYOD1 variant (p.L122R) has been observed in a large proportion of patients.[15,56–58] In the combined cohort of COG and U.K. rhabdomyosarcoma patients (n = 641), variants in MYOD1 were found in 3% (17 of 515) of all fusion-negative rhabdomyosarcoma cases and in no fusion-positive cases. The presenting age of patients with MYOD1 variants was 10.8 years.[27] Most cases in this cohort showed spindle or sclerosing features, but cases with densely packed cells that mimicked the dense pattern of embryonal rhabdomyosarcoma were also observed. Most cases in this cohort (15 of 17, 88%) had either head and neck or parameningeal region primary sites. Activating PIK3CA variants are seen in about one-half of cases with MYOD1 variants.[17,27] The presence of the MYOD1 variant is associated with a markedly increased risk of local and distant failure.[15,27,56,57]

    Intraosseous spindle cell rhabdomyosarcoma: Primary intraosseous rhabdomyosarcoma is a very uncommon presentation for rhabdomyosarcoma. Most cases present with gene rearrangements involving TFCP2, with either FUS or EWSR1.[59–63] Rhabdomyosarcoma with a FUS::TFCP2 or EWSR1::TFCP2 gene fusion most commonly presents in young adults, although cases in older children and adolescents have been reported.[59,62,63] Craniofacial bones are the most common primary tumor location, and positivity for ALK and cytokeratins by immunohistochemistry is commonly observed. Other characteristics of this entity include a complex genomic profile, with most cases showing deletion of the CDKN2A tumor suppressor gene.[62] Intraosseous spindle cell rhabdomyosarcoma with a FUS::TFCP2 or EWSR1::TFCP2 gene fusion shows an aggressive clinical course. In one study, the median OS was only 8 months.[62]

Recurrent and refractory rhabdomyosarcomas from pediatric (n = 105) and young-adult patients (n = 15) underwent tumor sequencing in the National Cancer Institute–Children’s Oncology Group (NCI-COG) Pediatric MATCH trial. Actionable genomic alterations were found in 53 of 120 tumors (44.2%), and patients with these alterations qualified for treatment on MATCH study arms.[64] Variants of MAPK pathway genes (HRAS, KRAS, NRAS, NF1) were most frequent and were reported in 32 of 120 tumors (26.7%). Amplifications of cyclin-dependent kinase genes (CDK4, CDK6) were detected in 15 of 120 tumors (12.5%).

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  34. Haduong JH, Heske CM, Allen-Rhoades W, et al.: An update on rhabdomyosarcoma risk stratification and the rationale for current and future Children’s Oncology Group clinical trials. Pediatr Blood Cancer 69 (4): e29511, 2022. [PUBMED Abstract]
  35. Hettmer S, Archer NM, Somers GR, et al.: Anaplastic rhabdomyosarcoma in TP53 germline mutation carriers. Cancer 120 (7): 1068-75, 2014. [PUBMED Abstract]
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  37. de Kock L, Yoon JY, Apellaniz-Ruiz M, et al.: Significantly greater prevalence of DICER1 alterations in uterine embryonal rhabdomyosarcoma compared to adenosarcoma. Mod Pathol 33 (6): 1207-1219, 2020. [PUBMED Abstract]
  38. Apellaniz-Ruiz M, McCluggage WG, Foulkes WD: DICER1-associated embryonal rhabdomyosarcoma and adenosarcoma of the gynecologic tract: Pathology, molecular genetics, and indications for molecular testing. Genes Chromosomes Cancer 60 (3): 217-233, 2021. [PUBMED Abstract]
  39. Kommoss FKF, Stichel D, Mora J, et al.: Clinicopathologic and molecular analysis of embryonal rhabdomyosarcoma of the genitourinary tract: evidence for a distinct DICER1-associated subgroup. Mod Pathol 34 (8): 1558-1569, 2021. [PUBMED Abstract]
  40. Dehner LP, Jarzembowski JA, Hill DA: Embryonal rhabdomyosarcoma of the uterine cervix: a report of 14 cases and a discussion of its unusual clinicopathological associations. Mod Pathol 25 (4): 602-14, 2012. [PUBMED Abstract]
  41. Daya DA, Scully RE: Sarcoma botryoides of the uterine cervix in young women: a clinicopathological study of 13 cases. Gynecol Oncol 29 (3): 290-304, 1988. [PUBMED Abstract]
  42. Bennett JA, Ordulu Z, Young RH, et al.: Embryonal rhabdomyosarcoma of the uterine corpus: a clinicopathological and molecular analysis of 21 cases highlighting a frequent association with DICER1 mutations. Mod Pathol 34 (9): 1750-1762, 2021. [PUBMED Abstract]
  43. McCluggage WG, Foulkes WD: DICER1-associated sarcomas: towards a unified nomenclature. Mod Pathol 34 (6): 1226-1228, 2021. [PUBMED Abstract]
  44. Schultz KAP, Williams GM, Kamihara J, et al.: DICER1 and Associated Conditions: Identification of At-risk Individuals and Recommended Surveillance Strategies. Clin Cancer Res 24 (10): 2251-2261, 2018. [PUBMED Abstract]
  45. Parham DM, Qualman SJ, Teot L, et al.: Correlation between histology and PAX/FKHR fusion status in alveolar rhabdomyosarcoma: a report from the Children’s Oncology Group. Am J Surg Pathol 31 (6): 895-901, 2007. [PUBMED Abstract]
  46. Sorensen PH, Lynch JC, Qualman SJ, et al.: PAX3-FKHR and PAX7-FKHR gene fusions are prognostic indicators in alveolar rhabdomyosarcoma: a report from the children’s oncology group. J Clin Oncol 20 (11): 2672-9, 2002. [PUBMED Abstract]
  47. Krsková L, Mrhalová M, Sumerauer D, et al.: Rhabdomyosarcoma: molecular diagnostics of patients classified by morphology and immunohistochemistry with emphasis on bone marrow and purged peripheral blood progenitor cells involvement. Virchows Arch 448 (4): 449-58, 2006. [PUBMED Abstract]
  48. Kelly KM, Womer RB, Sorensen PH, et al.: Common and variant gene fusions predict distinct clinical phenotypes in rhabdomyosarcoma. J Clin Oncol 15 (5): 1831-6, 1997. [PUBMED Abstract]
  49. Barr FG, Qualman SJ, Macris MH, et al.: Genetic heterogeneity in the alveolar rhabdomyosarcoma subset without typical gene fusions. Cancer Res 62 (16): 4704-10, 2002. [PUBMED Abstract]
  50. Missiaglia E, Williamson D, Chisholm J, et al.: PAX3/FOXO1 fusion gene status is the key prognostic molecular marker in rhabdomyosarcoma and significantly improves current risk stratification. J Clin Oncol 30 (14): 1670-7, 2012. [PUBMED Abstract]
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  52. Thway K, Wang J, Wren D, et al.: The comparative utility of fluorescence in situ hybridization and reverse transcription-polymerase chain reaction in the diagnosis of alveolar rhabdomyosarcoma. Virchows Arch 467 (2): 217-24, 2015. [PUBMED Abstract]
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  55. Cyrta J, Gauthier A, Karanian M, et al.: Infantile Rhabdomyosarcomas With VGLL2 Rearrangement Are Not Always an Indolent Disease: A Study of 4 Aggressive Cases With Clinical, Pathologic, Molecular, and Radiologic Findings. Am J Surg Pathol 45 (6): 854-867, 2021. [PUBMED Abstract]
  56. Kohsaka S, Shukla N, Ameur N, et al.: A recurrent neomorphic mutation in MYOD1 defines a clinically aggressive subset of embryonal rhabdomyosarcoma associated with PI3K-AKT pathway mutations. Nat Genet 46 (6): 595-600, 2014. [PUBMED Abstract]
  57. Agaram NP, Chen CL, Zhang L, et al.: Recurrent MYOD1 mutations in pediatric and adult sclerosing and spindle cell rhabdomyosarcomas: evidence for a common pathogenesis. Genes Chromosomes Cancer 53 (9): 779-87, 2014. [PUBMED Abstract]
  58. Szuhai K, de Jong D, Leung WY, et al.: Transactivating mutation of the MYOD1 gene is a frequent event in adult spindle cell rhabdomyosarcoma. J Pathol 232 (3): 300-7, 2014. [PUBMED Abstract]
  59. Watson S, Perrin V, Guillemot D, et al.: Transcriptomic definition of molecular subgroups of small round cell sarcomas. J Pathol 245 (1): 29-40, 2018. [PUBMED Abstract]
  60. Dashti NK, Wehrs RN, Thomas BC, et al.: Spindle cell rhabdomyosarcoma of bone with FUS-TFCP2 fusion: confirmation of a very recently described rhabdomyosarcoma subtype. Histopathology 73 (3): 514-520, 2018. [PUBMED Abstract]
  61. Agaram NP, Zhang L, Sung YS, et al.: Expanding the Spectrum of Intraosseous Rhabdomyosarcoma: Correlation Between 2 Distinct Gene Fusions and Phenotype. Am J Surg Pathol 43 (5): 695-702, 2019. [PUBMED Abstract]
  62. Le Loarer F, Cleven AHG, Bouvier C, et al.: A subset of epithelioid and spindle cell rhabdomyosarcomas is associated with TFCP2 fusions and common ALK upregulation. Mod Pathol 33 (3): 404-419, 2020. [PUBMED Abstract]
  63. Xu B, Suurmeijer AJH, Agaram NP, et al.: Head and neck rhabdomyosarcoma with TFCP2 fusions and ALK overexpression: a clinicopathological and molecular analysis of 11 cases. Histopathology 79 (3): 347-357, 2021. [PUBMED Abstract]
  64. Parsons DW, Janeway KA, Patton DR, et al.: Actionable Tumor Alterations and Treatment Protocol Enrollment of Pediatric and Young Adult Patients With Refractory Cancers in the National Cancer Institute-Children’s Oncology Group Pediatric MATCH Trial. J Clin Oncol 40 (20): 2224-2234, 2022. [PUBMED Abstract]

Stage Information for Childhood Rhabdomyosarcoma

Staging Evaluation

Before a suspected tumor mass is biopsied, imaging studies of the mass and baseline laboratory studies should be obtained. After the patient is diagnosed with rhabdomyosarcoma, an extensive evaluation to determine the extent of the disease should be performed before instituting therapy. This evaluation typically includes the following:

  1. Chest x-ray.
  2. Computed tomography (CT) scan of the chest.

    The European Paediatric Soft Tissue Sarcoma Study Group reviewed 367 patients enrolled in the CCLG-EPSSG-RMS-2005 (NCT00379457) study.[1][Level of evidence B4] By prospective study design, patients with indeterminate pulmonary nodules identified on baseline CT scan of the chest (defined as ≤4 pulmonary nodules measuring <5 mm or 1 nodule measuring ≥5 mm and <10 mm) received the same treatment as did patients with no pulmonary nodules identified on baseline CT of the chest. Rates of event-free survival and overall survival for both groups were the same. The authors concluded that indeterminate pulmonary nodules at diagnosis, as defined in this summary, do not affect outcome in patients with localized rhabdomyosarcoma.

  3. CT scan of the abdomen and pelvis (for lower extremity or genitourinary primary tumors).
  4. Magnetic resonance imaging (MRI) of the base of the skull and brain (for parameningeal primary tumors) and of the primary site of other nonparameningeal primary tumors, as appropriate.
  5. Regional lymph node evaluation.
    • CT or MRI: Cross-sectional imaging (CT or MRI scan) of regional lymph nodes should be obtained.
    • Lymph node evaluation: Clearly enlarged lymph nodes should be biopsied when possible. Sentinel lymph node biopsy is more accurate than random lymph node sampling and is preferred in patients with extremity and trunk rhabdomyosarcoma, in which enlarged lymph nodes are not revealed on imaging or by physical examination.[2] Many studies have demonstrated that sentinel lymph node biopsies can be safely performed in children with rhabdomyosarcoma, and tumor-positive biopsies alter the treatment plan.[2–7]

      Pathological evaluation of normal-appearing regional nodes is currently required for all Soft Tissue Sarcoma Committee of the Children’s Oncology Group (COG-STS) study participants with extremity and trunk primary rhabdomyosarcoma. In boys aged 10 years and older with paratesticular rhabdomyosarcoma, retroperitoneal node sampling (ipsilateral nerve sparing) is currently required for normal-appearing lymph nodes because microscopic tumor is often documented, even when the nodes are not enlarged.[8] The International Society of Paediatric Oncology Malignant Mesenchymal Tumour Group has confirmed this is a necessary approach.[9] For more information, see the Regional and in-transit lymph nodes for extremity tumors section.

    • Positron emission tomography (PET): PET with fluorine F 18-fludeoxyglucose scans can identify areas of possible metastatic disease not seen by other imaging modalities.[10–12]

    The efficacy of these imaging studies for identifying involved lymph nodes or other sites of disease is important for staging, and PET imaging is recommended on current COG-STS treatment protocols.

  6. Bilateral bone marrow aspirates and biopsies for selected patients.
  7. Bone scan for selected patients.

A retrospective study of 1,687 children with rhabdomyosarcoma enrolled in Intergroup Rhabdomyosarcoma Study Group (IRSG) and COG studies from 1991 to 2004 suggests those with localized negative regional lymph nodes, noninvasive embryonal tumors, and Group I alveolar tumors (about one-third of patients) can have limited staging procedures that eliminate bone marrow and bone scan examinations at diagnosis.[13]

Assessment of Extent of Disease

Assessing extent of disease of rhabdomyosarcoma is complex. The process includes the following steps:

  1. Assignment of Stage: Stage is a clinical assessment determined by primary site, tumor size (longest diameter), and clinical (imaging) presence or absence of regional lymph node and/or distant metastases (TNM criteria).
  2. Assignment of Group: Group is determined by status of the initial surgical procedure (resection/biopsy), with pathological assessment of the tumor margin and of lymph node involvement, before the initiation of therapy.
  3. Assignment of Risk Group: Determined by Stage, Group, and fusion status.

Prognosis for children with rhabdomyosarcoma depends predominantly on the primary tumor site, tumor size, surgical-pathological Group, presence or absence of nodal disease and distant metastasis, and fusion status. Favorable prognostic groups were identified in previous IRSG studies, and treatment plans were designed on the basis of patient assignment to different treatment protocols according to prognosis.

Assignment of clinical Stage

Current COG-STS protocols for rhabdomyosarcoma use the TNM-based pretreatment staging system that incorporates the primary tumor site, presence or absence of tumor invasion of surrounding tissues, tumor size, clinical (imaging) assessment of regional lymph node status, and the presence or absence of metastases. This staging system is described in Table 4 below.[14–16]

Terms defining the TNM criteria are described in Table 3.

Table 3. Definition of Termsa
Term Definition
CSF = cerebrospinal fluid; CT = computed tomography; MRI = magnetic resonance imaging.
aAdapted from Crane et al.[16]
Favorable site Orbit; head and neck (excluding parameningeal); genitourinary tract (nonbladder/nonprostate).
Unfavorable site Any site other than a favorable site.
T1 Tumor confined to anatomical site of origin.
T2 Extension and/or fixative to surrounding tissue.
a Tumor ≤5 cm in longest diameter.
b Tumor >5 cm in longest diameter.
N0 Regional nodes not clinically involved.
N1 Regional nodes clinically involved as defined as >1 cm measured in short axis on CT or MRI.
NX Clinical status of regional nodes unknown (especially sites that preclude lymph node evaluation).
M0 No distant metastases.
M1 Distant metastases present (Note: the presence of positive cytology in pleural fluid, abdominal fluid, or CSF and the presence of pleural or peritoneal implants are considered evidence of metastases).
Table 4. Soft Tissue Sarcoma Committee of the Children’s Oncology Group: Pretreatment Staging System
Stage Sites of Primary Tumor Tumor Sizec Regional Lymph Nodesd Distant Metastasisd
cTumor size: (a) <5 cm in longest diameter; (b) >5 cm in longest diameter.
dFor definitions of the TNM criteria, see Table 3.
1 Favorable sites a or b N0 or N1 or NX M0
2 Unfavorable sites a N0 or NX M0
3 Unfavorable sites a N1 M0
b N0 or N1 or NX
4 Any site a or b N0 or N1 or NX M1

Assignment of Group

The IRS-I, IRS-II, IRS-III, and IRS-IV studies prescribed treatment plans on the basis of the surgical-pathological Group system. In this system, Groups are defined by the extent of disease and by the completeness or extent of initial surgical resection after pathological review of the tumor specimen(s). The definitions for these Groups are shown in Table 5 below.[16–19]

Table 5. Soft Tissue Sarcoma Committee of the Children’s Oncology Group: Surgical-Pathological Group Systema
Group Incidence Definition
CSF = cerebrospinal fluid.
aAdapted from Crane et al.[16]
I Approximately 15% Localized disease, completely resected (regional lymph nodes not involved).
II Approximately 16% Localized disease, grossly resected with microscopic residual disease or regional disease, grossly resected with or without microscopic residual disease. (a) Localized disease, grossly resected tumor with microscopic residual disease, regional nodes not involved. (b) Regional disease with involved nodes, completely resected with no microscopic residual disease (including most distal node is histologically negative). (c) Regional disease with involved nodes, grossly resected with evidence of microscopic residual and/or histological involvement of the most distal regional node in the dissection.
III Approximately 50% Localized or regional disease, biopsy only or incomplete resection with gross residual disease.
IV Approximately 20% Distant metastatic disease present at onset. Although not limited to these, the following are considered evidence of metastatic disease: (a) presence of positive cytology in CSF, (b) positive cytology in pleural or abdominal fluids, (c) presence of implants on pleural or peritoneal surfaces. (Note: Regional lymph node involvement and adjacent organ infiltration are not considered metastatic disease. Presence of a pleural effusion or ascites, without positive cytological evaluation, is not considered evidence of metastatic disease.)

Assignment of Risk Group

After patients are categorized by Stage and surgical-pathological Group, a Risk Group is assigned on the basis of the Stage, Group, and FOXO1 fusion status. The planned COG low-risk study will also use TP53 and MYOD1 variant status to assign risk group. Patients are classified for protocol purposes as having a low risk, intermediate risk, or high risk of disease recurrence.[20–22] Treatment assignment is based on Risk Group, as shown in Table 6.

Table 6. Soft Tissue Sarcoma Committee of the Children’s Oncology Group: Rhabdomyosarcoma Risk Group Classificationa
Risk Group Fusion Status/Molecular Profile Stage Group
Very low risk Fusion negative: MYOD1 wild-type, TP53 wild-type 1 I
Low risk Fusion negative: MYOD1 wild-type, TP53 wild-type 1 II, III (orbit only)
2 I, II
Intermediate risk Fusion negative 1 III (nonorbit)
2, 3 III
3 I, II
4 IV (age <10 years)
Fusion positive 1, 2, 3 I, II, III
High risk Fusion positive 4 IV
Fusion negative 4 IV (age ≥10 years)
aAdapted from Crane et al.[16]

The most recent COG protocols use fusion status and molecular findings, as opposed to histology, to define Risk Groups.

References
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  9. Rogers T, Minard-Colin V, Cozic N, et al.: Paratesticular rhabdomyosarcoma in children and adolescents-Outcome and patterns of relapse when utilizing a nonsurgical strategy for lymph node staging: Report from the International Society of Paediatric Oncology (SIOP) Malignant Mesenchymal Tumour 89 and 95 studies. Pediatr Blood Cancer 64 (9): , 2017. [PUBMED Abstract]
  10. Völker T, Denecke T, Steffen I, et al.: Positron emission tomography for staging of pediatric sarcoma patients: results of a prospective multicenter trial. J Clin Oncol 25 (34): 5435-41, 2007. [PUBMED Abstract]
  11. Tateishi U, Hosono A, Makimoto A, et al.: Comparative study of FDG PET/CT and conventional imaging in the staging of rhabdomyosarcoma. Ann Nucl Med 23 (2): 155-61, 2009. [PUBMED Abstract]
  12. Federico SM, Spunt SL, Krasin MJ, et al.: Comparison of PET-CT and conventional imaging in staging pediatric rhabdomyosarcoma. Pediatr Blood Cancer 60 (7): 1128-34, 2013. [PUBMED Abstract]
  13. Weiss AR, Lyden ER, Anderson JR, et al.: Histologic and clinical characteristics can guide staging evaluations for children and adolescents with rhabdomyosarcoma: a report from the Children’s Oncology Group Soft Tissue Sarcoma Committee. J Clin Oncol 31 (26): 3226-32, 2013. [PUBMED Abstract]
  14. Lawrence W, Gehan EA, Hays DM, et al.: Prognostic significance of staging factors of the UICC staging system in childhood rhabdomyosarcoma: a report from the Intergroup Rhabdomyosarcoma Study (IRS-II). J Clin Oncol 5 (1): 46-54, 1987. [PUBMED Abstract]
  15. Lawrence W, Anderson JR, Gehan EA, et al.: Pretreatment TNM staging of childhood rhabdomyosarcoma: a report of the Intergroup Rhabdomyosarcoma Study Group. Children’s Cancer Study Group. Pediatric Oncology Group. Cancer 80 (6): 1165-70, 1997. [PUBMED Abstract]
  16. Crane JN, Xue W, Qumseya A, et al.: Clinical group and modified TNM stage for rhabdomyosarcoma: A review from the Children’s Oncology Group. Pediatr Blood Cancer 69 (6): e29644, 2022. [PUBMED Abstract]
  17. Crist WM, Garnsey L, Beltangady MS, et al.: Prognosis in children with rhabdomyosarcoma: a report of the intergroup rhabdomyosarcoma studies I and II. Intergroup Rhabdomyosarcoma Committee. J Clin Oncol 8 (3): 443-52, 1990. [PUBMED Abstract]
  18. Crist W, Gehan EA, Ragab AH, et al.: The Third Intergroup Rhabdomyosarcoma Study. J Clin Oncol 13 (3): 610-30, 1995. [PUBMED Abstract]
  19. Crist WM, Anderson JR, Meza JL, et al.: Intergroup rhabdomyosarcoma study-IV: results for patients with nonmetastatic disease. J Clin Oncol 19 (12): 3091-102, 2001. [PUBMED Abstract]
  20. Raney RB, Anderson JR, Barr FG, et al.: Rhabdomyosarcoma and undifferentiated sarcoma in the first two decades of life: a selective review of intergroup rhabdomyosarcoma study group experience and rationale for Intergroup Rhabdomyosarcoma Study V. J Pediatr Hematol Oncol 23 (4): 215-20, 2001. [PUBMED Abstract]
  21. Breneman JC, Lyden E, Pappo AS, et al.: Prognostic factors and clinical outcomes in children and adolescents with metastatic rhabdomyosarcoma–a report from the Intergroup Rhabdomyosarcoma Study IV. J Clin Oncol 21 (1): 78-84, 2003. [PUBMED Abstract]
  22. HaDuong JH, Martin AA, Skapek SX, et al.: Sarcomas. Pediatr Clin North Am 62 (1): 179-200, 2015. [PUBMED Abstract]

Treatment Option Overview for Childhood Rhabdomyosarcoma

Multimodality Therapy

All children with rhabdomyosarcoma require multimodality therapy with systemic chemotherapy, in conjunction with either surgery, radiation therapy (RT), or both modalities to maximize local tumor control.[1–3] Surgical resection is performed before chemotherapy if it will not result in disfigurement, functional compromise, or organ dysfunction. If this is not possible, only an initial biopsy is performed.

Low-risk Group I (complete tumor resection, about 15% of patients) patients are treated with multiagent chemotherapy after surgical resection. Group II patients typically require chemotherapy and local tumor bed irradiation (about 20% of patients). Most patients (about 50%) have Group III (gross residual) disease.[4] After initial chemotherapy, Group III patients receive definitive RT for local control of the primary tumor. Some patients with initially unresected tumors may undergo delayed primary excision after induction chemotherapy to remove residual tumor before the initiation of RT. This is appropriate only if the delayed excision is deemed feasible with acceptable functional and cosmetic outcome and if a grossly complete resection is anticipated. If a delayed primary excision results in complete resection or microscopic residual disease, a modest (15%–30%) reduction in RT could be utilized.[5] Patients with Group IV disease (about 15%) receive chemotherapy and RT to the primary tumor and metastatic disease sites when feasible.

RT is given to clinically suspicious lymph nodes (detected by palpation or imaging) unless the suspicious lymph nodes are biopsied and shown to be free of rhabdomyosarcoma. RT is also administered to lymph node basins where a sentinel lymph node biopsy has identified microscopic disease.[5]

The discussion of treatment options for children with rhabdomyosarcoma is divided into the following sections:

Rhabdomyosarcoma treatment options used by the Children’s Oncology Group (COG) and by groups in Europe (as exemplified by trials from the Soft Tissue Sarcoma Committee of the COG [COG-STS], the Intergroup Rhabdomyosarcoma Study Group [IRSG], the International Society of Pediatric Oncology Malignant Mesenchymal Tumor [MMT] Group, and the European Paediatric Soft Tissue Sarcoma Study Group [EpSSG]) differ in management and overall treatment philosophy, as noted below:[2]

  • The primary objective of the COG-STS, after the initial surgical resection or biopsy and induction chemotherapy, has been to use additional local control therapy, predominantly with RT or surgical resection when appropriate. Event-free survival is the target end point, attempting to avoid relapse and subsequent salvage therapy.[3]
  • In the MMT trials, the main objective has been to reduce the use of local therapies using initial front-line chemotherapy, followed by second-line therapy in the presence of poor response. Subsequent surgical resection is preferred over RT, which is used only after incomplete resection, documented regional lymph node involvement, or a poor clinical response to initial chemotherapy. This approach is designed to avoid major surgical procedures and long-term damaging effects from RT. Some patients have been spared aggressive local therapy, which may reduce the potential for morbidities associated with such therapy.[1–3]

    The MMT Group approach led to an overall survival (OS) rate of 71% in the European MMT89 study, compared with an OS rate of 84% in the IRS-IV study. Similarly, EFS rates at 5 years were 57% in the MMT89 study versus 78% in the IRS-IV study. Differences in outcomes were most striking for patients with extremity and head and neck nonparameningeal tumors. Failure-free survival was lower for patients with bladder/prostate primary tumors who did not receive RT as part of their initial treatment, but there was no difference in OS between the two strategies for these patients.[6] The overall impression is that survival for most patient subsets is superior with the use of early local therapy, including RT.[1–3]

  • The EpSSG RMS-2005 (NCT00379457) study reported comprehensive outcome data for 1,733 children and adolescents with nonmetastatic rhabdomyosarcoma. These patients were enrolled in two phase III randomized trials for high-risk patients and observational trials for low-risk, standard-risk, and very-high risk patients. Eighty percent of children with localized rhabdomyosarcoma were long-term survivors. This study established the standard of care across EpSSG countries, including the following:[7]
    • A 22-week vincristine/dactinomycin regimen for patients with low-risk rhabdomyosarcoma.
    • The reduction of the cumulative ifosfamide dose for patients with standard-risk disease.
    • The omission of doxorubicin and the addition of maintenance chemotherapy for patients with high-risk disease.
References
  1. Donaldson SS, Meza J, Breneman JC, et al.: Results from the IRS-IV randomized trial of hyperfractionated radiotherapy in children with rhabdomyosarcoma–a report from the IRSG. Int J Radiat Oncol Biol Phys 51 (3): 718-28, 2001. [PUBMED Abstract]
  2. Stevens MC, Rey A, Bouvet N, et al.: Treatment of nonmetastatic rhabdomyosarcoma in childhood and adolescence: third study of the International Society of Paediatric Oncology–SIOP Malignant Mesenchymal Tumor 89. J Clin Oncol 23 (12): 2618-28, 2005. [PUBMED Abstract]
  3. Donaldson SS, Anderson JR: Rhabdomyosarcoma: many similarities, a few philosophical differences. J Clin Oncol 23 (12): 2586-7, 2005. [PUBMED Abstract]
  4. Wexler LH, Skapek SX, Helman LJ: Rhabdomyosarcoma. In: Pizzo PA, Poplack DG, eds.: Principles and Practice of Pediatric Oncology. 7th ed. Lippincott Williams and Wilkins, 2015, pp 798-826.
  5. Wolden SL, Lyden ER, Arndt CA, et al.: Local Control for Intermediate-Risk Rhabdomyosarcoma: Results From D9803 According to Histology, Group, Site, and Size: A Report From the Children’s Oncology Group. Int J Radiat Oncol Biol Phys 93 (5): 1071-6, 2015. [PUBMED Abstract]
  6. Rodeberg DA, Anderson JR, Arndt CA, et al.: Comparison of outcomes based on treatment algorithms for rhabdomyosarcoma of the bladder/prostate: combined results from the Children’s Oncology Group, German Cooperative Soft Tissue Sarcoma Study, Italian Cooperative Group, and International Society of Pediatric Oncology Malignant Mesenchymal Tumors Committee. Int J Cancer 128 (5): 1232-9, 2011. [PUBMED Abstract]
  7. Bisogno G, Minard-Colin V, Zanetti I, et al.: Nonmetastatic Rhabdomyosarcoma in Children and Adolescents: Overall Results of the European Pediatric Soft Tissue Sarcoma Study Group RMS2005 Study. J Clin Oncol 41 (13): 2342-2349, 2023. [PUBMED Abstract]

Special Considerations for the Treatment of Children With Cancer

Cancer in children and adolescents is rare, although the overall incidence has slowly increased since 1975.[1] Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the following pediatric specialists and others to ensure that children receive treatment, supportive care, and rehabilitation to achieve optimal survival and quality of life:

  • Primary care physicians.
  • Pediatric surgeons.
  • Transplant surgeons.
  • Pathologists.
  • Pediatric radiation oncologists.
  • Pediatric medical oncologists and hematologists.
  • Ophthalmologists.
  • Rehabilitation specialists.
  • Pediatric oncology nurses.
  • Social workers.
  • Child-life professionals.
  • Psychologists.
  • Nutritionists.

For specific information about supportive care for children and adolescents with cancer, see the summaries on Supportive and Palliative Care.

The American Academy of Pediatrics has outlined guidelines for pediatric cancer centers and their role in the treatment of children and adolescents with cancer.[2] At these centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate is offered to most patients and their families. Clinical trials for children and adolescents diagnosed with cancer are generally designed to compare potentially better therapy with current standard therapy. Other types of clinical trials test novel therapies when there is no standard therapy for a cancer diagnosis. Most of the progress in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI website.

References
  1. Smith MA, Seibel NL, Altekruse SF, et al.: Outcomes for children and adolescents with cancer: challenges for the twenty-first century. J Clin Oncol 28 (15): 2625-34, 2010. [PUBMED Abstract]
  2. American Academy of Pediatrics: Standards for pediatric cancer centers. Pediatrics 134 (2): 410-4, 2014. Also available online. Last accessed February 25, 2025.

Treatment of Childhood Rhabdomyosarcoma

Optimizing care for patients with rhabdomyosarcoma requires a multidisciplinary team approach. All patients require chemotherapy and effective local tumor control. Because rhabdomyosarcoma can arise from multiple sites, surgical care decisions and radiotherapeutic options must be tailored to the specific aspects of each site and should be discussed with a multidisciplinary team, including representatives of those specialties and pediatric oncologists. These multidisciplinary discussions ideally occur at the time of diagnosis, either before or after the diagnostic biopsy and before the initiation of therapy.

Local control remains a significant problem in children with rhabdomyosarcoma. The predominant site of treatment failure in patients with initially localized rhabdomyosarcoma has been local recurrence. In the Intergroup Rhabdomyosarcoma Study Group (IRS)-II trial, of patients who achieved a complete remission with chemotherapy and surgery, almost 20% of patients with Groups I to III disease relapsed locally or regionally, and 30% of patients with Group IV disease relapsed locally or regionally. Local or regional relapses accounted for 70% to 80% of all relapses in children with Groups I to III disease and 46% of all relapses in patients with Group IV disease.[1]

Both surgery and radiation therapy (RT) are procedures primarily focused on local tumor control, but each treatment has risks and benefits.

For more information about surgical and radiotherapeutic management of the more common primary sites, see the Surgery and RT by Primary Site of Disease (Local Control Management) section.

Treatment options for childhood rhabdomyosarcoma include the following:

  1. Surgery (local control management).
  2. RT (local control management).
  3. Surgery and RT by primary site of disease (local control management).
  4. Chemotherapy.

Surgery (Local Control Management)

Surgical removal of the entire tumor should be considered initially, but only if functional and cosmetic impairment will not result.[2] With that stipulation, complete gross resection of the primary tumor, with a surrounding margin of normal tissue, and biopsy are recommended by the authors of one study. For some tumor sites, sampling of regional draining lymph nodes is necessary. Children’s Oncology Group (COG) protocols require regional draining node sampling in extremity tumors and paratesticular tumors in patients older than 10 years. Important exceptions to achieving an R0 resection (negative margins) are in tumors of the orbit and the genitourinary region.[3,4] Additionally, the principle of wide and complete resection of the primary tumor is less applicable for patients known to have metastatic disease at the initial operation, but it is an appropriate approach if easily accomplished without loss of form (cosmesis) and function.

Patients with microscopic residual tumor after their initial surgery appear to have improved prognoses if a second operation (primary re-excision) to resect the primary tumor bed before beginning chemotherapy can completely remove the tumor without loss of form and function.[5]

There is no evidence that debulking surgery (i.e., surgery that is expected to leave macroscopic residual tumor) improves outcomes, compared with biopsy alone; therefore, debulking surgery is not recommended for patients with rhabdomyosarcoma.[6][Level of evidence B4] Rather than debulking a tumor at the time of initial biopsy, it is preferable to delay definitive surgery until after induction chemotherapy (delayed primary excision). In a retrospective study of 73 selected patients, delayed primary excision allowed for the identification of viable tumor that remained after initial chemotherapy. Of the 73 patients, 65 also received RT. Patients with viable tumor had shorter event-free survival (EFS) rates than did patients without viable tumor, but there was no effect on overall survival (OS).[7] There is also no evidence that performing surgical resection on residual masses detected by imaging at completion of all planned therapy improves outcomes.[8] Thus, residual masses can be monitored without therapeutic intervention.

For children with low-risk rhabdomyosarcoma, local control was not diminished with reduced doses of RT after surgical resection.[9] Subsequently, delayed primary excision was evaluated by the Soft Tissue Sarcoma Committee of the COG (COG-STS) in the D9602 and D9803 studies.[8] Delayed primary excision at week 12 after induction chemotherapy was completed in 45% to 54% of patients with Group III rhabdomyosarcoma tumors when appropriate (anticipated complete resection with no loss of form or function at select sites such as bladder, prostrate, extremity, trunk, retroperitoneum, intrathoracic, perineum, or perianal). Of these patients, 81% to 84% were eligible for modest RT dose reduction. Approximately 50% of these patients had an R0 resection (negative margins) and received a reduced RT dose of 36 Gy, and 30% of patients had an R1 resection (margins were microscopically involved) and received a reduced RT dose of 41.4 Gy (from the standard 50.4-Gy dose). Local control and survival outcomes were similar to those of patients who received full-dose RT alone in the IRS-IV study.[7]

A retrospective analysis compared patients with clinical Group III rhabdomyosarcoma treated on consecutive COG protocols D9803 (encouraged delayed primary excision) and ARST0531 (NCT00354835) (discouraged delayed primary excision).[10] Among 369 patients in an adjusted-regression analysis, the risk of death (hazard ratio [HR], 0.71; 95% confidence interval [CI], 0.43–1.16) was similar for patients who did or did not undergo delayed primary excision. A subset of patients who had tumors of the trunk and retroperitoneum did have a reduced risk of death with delayed primary excision (HR, 0.44; 95% CI, 0.20–0.97).

RT (Local Control Management)

RT is an effective method for achieving local control of the tumor for patients with microscopic or gross residual disease after biopsy, initial surgical resection, or chemotherapy.

  • Group I: Patients with completely resected embryonal rhabdomyosarcoma at diagnosis before initiation of chemotherapy do well without RT. However, because approximately 75% of embryonal rhabdomyosarcoma patients are Groups II to IV, RT is used in most patients.[11]

    A study of Group I patients with alveolar rhabdomyosarcoma and undifferentiated soft tissue sarcoma found that omission of RT was followed by decreased local control.[12] A subsequent review of patients with only alveolar rhabdomyosarcoma found that the improvement in outcome with RT did not reach statistical significance for patients with Stage 1 and Stage 2 tumors. There were very few patients (n = 4) with large tumors (Stage 3, >5 cm) who did not receive RT, but their outcome was poor.[13][Level of evidence C2] COG recommends the use of RT for all patients with FOXO1 fusion–positive disease (previously called alveolar rhabdomyosarcoma).

  • Group II: In more than 50% of Group II rhabdomyosarcoma patients, local recurrence was the result of noncompliance with guidelines or omission of RT.[14]

    The German Cooperative Weichteilsarkom Studiengruppe (CWS) conducted a review of European trials between 1981 and 1998, in which RT was omitted for some Group II patients. This review demonstrated a benefit to using RT as a component of local tumor control for all Group II patient subsets, as defined by tumor histology, tumor size, and tumor site.[15]

  • Group III: The predominant type of relapse for patients with Group III disease is local failure. Approximately 35% of patients with Group III disease either fail to achieve a complete remission or relapse locally. Patients with tumor-involved regional lymph nodes at diagnosis also have a higher risk of local and distant failure than do patients whose lymph nodes are uninvolved.[16]

The CWS performed a retrospective analysis of 395 children with parameningeal rhabdomyosarcoma. Patients had IRS Groups II (n = 15) and III (n = 380) disease. Delayed resection was performed in 88 of 395 patients (22%), and RT was also given to 79 of the 88 patients (90%) who underwent resections. RT was the predominant local treatment for 355 of 395 patients (90%), which included hyperfractionated accelerated photon RT (HART) (n = 77), conventionally fractionated photon RT (n = 91) or proton-beam RT (n = 126), brachytherapy (n = 4), and heavy ions (n = 1). Details of the RT received were not available for 56 patients.[17]

  • In the subgroup of patients who received RT as the only local treatment (n = 278), significant positive prognostic factors included no intracranial tumor extension and complete remission at the end of treatment.
  • No significant differences in tumor outcomes were seen between the different RT concepts.

Investigators performed a retrospective analysis of 1,470 patients (aged 21 years or younger) with localized rhabdomyosarcoma. These patients were enrolled in the CWS-96, CWS-2002P, and Soft Tissue Sarcoma Registry (SoTiSaR) trials. The study analyzed and compared the indications, doses, and application methods of RT and their influence on prognosis.[18] The authors concluded the following:

  • RT can be omitted in patients with IRS Group I embryonal rhabdomyosarcoma (fusion-negative rhabdomyosarcoma).
  • RT improves EFS and local control survival (LCS) in patients with IRS Groups II and III disease.
  • Patients with tumors in the head and neck region (orbital, parameningeal, and nonparameningeal) and in other sites who received proton RT had EFS and LCS that were comparable with those of patients who received photon RT. Patients with parameningeal tumors had an improved OS with proton RT.
  • The efficacy of low RT doses of 32 Gy (HART) and 36 Gy to 41.4 Gy (conventional fractionated RT [CFRT]) in the favorable-risk groups of patients and higher doses of 44.8 Gy (HART) and 50.4 Gy to 55.4 Gy (CFRT) in the unfavorable-risk group of patients was comparable.

External-beam RT (EBRT)

As with the surgical management of patients with rhabdomyosarcoma, recommendations for RT depend on the following:

  • Site of primary tumor.
  • Histological subtype/fusion status.
  • Postsurgical amount of residual disease (none vs. microscopic vs. macroscopic), if surgery was performed.
  • Presence of involved lymph nodes.

For optimal care of pediatric patients undergoing radiation treatments, it is imperative that radiation oncologists, radiation therapists, and nurses who are experienced in treating children are available. An anesthesiologist may be necessary to sedate young patients. Computerized treatment planning with a 3-dimensional planning system is essential. Techniques to deliver radiation specifically to the tumor while sparing normal tissue (e.g., conformal radiation therapy, intensity-modulated radiation therapy [IMRT], volumetrical modulated arc therapy, proton-beam therapy [charged-particle radiation therapy], or brachytherapy) are appropriate.[19–24]

Dosimetric comparison of proton-beam RT and photon IMRT treatment plans has shown that proton-beam treatment plans may spare more normal tissue adjacent to the targeted volume than IMRT plans, but with no difference in local control using photon RT. Late effects data are lacking.[25,26]

Evidence (radiation delivery techniques):

  1. A prospective, phase II trial compared proton-beam therapy with IMRT in pediatric rhabdomyosarcoma.[27]
    • Target coverage was comparable between proton-beam therapy and IMRT plans. However, the mean integral dose for IMRT was 1.8 to 3.5 times higher than with proton therapy, depending on the site. Proton radiation may lower the radiation dose in the uninvolved tissue surrounding the tumor and, thus, improves normal tissue sparing when compared with IMRT.
    • Follow-up of treated patients remains short, and there are no data available to determine whether the reduction in dose to adjacent tissue will result in improved functional outcomes or reduce the risk of secondary malignancy or other toxicities.
  2. A retrospective review of patients with intermediate-risk rhabdomyosarcoma compared 3-dimensional conformal RT with IMRT.[28][Level of evidence B4]
    • IMRT improved the target coverage but did not show a difference in local failure rate or EFS.
  3. In a study on the patterns of failure in 11 of 66 children with nonmetastatic rhabdomyosarcoma who were treated with proton RT, the following results were observed:[29]
    • The 2-year local control rate was 88%.
    • All 11 children with local recurrences were Group III (gross residual disease) and experienced relapse in the radiation field, suggesting that the conformality of the proton field did not lead to out-of-field failures. The radiation dose was 41.4 Gy (relative biological effectiveness [RBE]) to the prechemotherapy tumor volume and 50.4 Gy (RBE) to the visible disease at the time of RT.
    • Eight patients with local recurrences had tumors larger than 5 cm at diagnosis. The COG ARST1431 (NCT02567435) protocol is testing escalated doses to 59.4 Gy for these patients.
    • This study did not delineate whether the recurrence was in the 41.4 Gy or 50.4 Gy irradiated volumes.
  4. In the COG ARST0531 (NCT00354835) trial, local failure rates were similar among patients who were treated with proton and photon radiation therapy.[30]

The radiation doses according to Group, histology, and disease site for children with rhabdomyosarcoma are described in Table 7:

Table 7. Radiation Therapy (RT) Dose According to Rhabdomyosarcoma Group, Histology, and Site of Disease (Children’s Oncology Group [COG])
Group Treatment
N = regional lymph node.
Group I  
Fusion negative (embryonal) No RT required.
FOXO1 fusion positive 36 Gy to involved (prechemotherapy) site.
Group II  
N0 (microscopic residual disease after surgery) 36 Gy to involved (prechemotherapy) site.
N1 (resected regional lymph node involvement) 36 Gy to involved (prechemotherapy) site and 41.4 Gy to nodes.
Group III  
Orbital and nonorbital tumors 45 Gy for orbital tumors with complete response to chemotherapy. For other sites and orbital tumors in partial remission, 50.4 Gy with volume reduction after 36 Gy if excellent response to chemotherapy (or complete remission after delayed re-excision) and noninvasive pushing tumors; no volume reduction for invasive tumors. 59.4 Gy boost to residual disease at 9 weeks for tumors >5 cm at diagnosis (if enrolled on the COG ARST1431 [NCT02567435]) protocol.
N1 with gross residual disease after surgery/chemotherapy 50.4 Gy
Group IV  
  As for other Groups and including all metastatic sites, if safe and possible. Exception: lung (pulmonary metastases) treated with 12 Gy to 15 Gy depending on age.

In the COG ARST1431 (NCT02567435) study, risk group is in part determined by fusion status. The recommended dose of RT depends on the amount of residual disease, if any, after the initial primary surgical procedure and fusion status. For patients with fusion-positive rhabdomyosarcoma who have had an initial complete resection (Group I), radiation therapy with 36 Gy is recommended.

  • Group II. In general, patients with microscopic residual disease (Group II) receive 36 Gy of RT if they do not have involved lymph nodes and 41.4 Gy in the presence of involved nodes.[12,31] Low-risk patients (embryonal histology and favorable sites with microscopic residual disease) treated in a COG study had excellent local control with 36 Gy, which was comparable to historical controls who received 41.4 Gy.[9] For Group II patients, 36 Gy of RT is recommended to the prechemotherapy involved site, and 41.4 Gy to involved nodes.
  • Group III. IRS-II patients with gross residual disease (Group III) who received 40 Gy to more than 50 Gy had locoregional relapse rates greater than 30%, but higher doses of radiation (>60 Gy) were associated with unacceptable long-term toxic effects.[32,33] Group III patients on the standard treatment arm of the IRS-IV study received 50.4 Gy to 59.4 Gy, with 5-year progression-free survival (PFS) rates of 55% to 75% and local control rates of 85% to 88%.[34]

    Select COG subgroups with Group III disease received somewhat reduced radiation doses of 36 Gy after delayed gross-total resection with negative margins (R0 resection), and 41.4 Gy if the margins were microscopically involved (R1 resection) or the nodes were positive. In the COG-D9602 study, a limited number of low-risk patients had a greater than 85% likelihood of local control with 36 Gy.[9] Similarly, the intermediate-risk studies for patients with Group III disease investigated the paradigm of delayed resection in amenable patients (anticipated complete resection with no loss of form or function at select sites such as bladder, prostate, extremity, trunk, peritoneum, intrathoracic, perineum, and perianal), with a subsequent reduced dose of RT (36 Gy for R0 resections or 41.4 Gy for R1 resections). The study demonstrated that patients who received reduced doses of RT had outcomes equivalent to patients who were treated with full-dose RT of 50.4 Gy.[8,10]

  • Group IV. Radiation therapy is appropriate treatment for sites of metastatic disease (technique, timing, and volume discussed below). The European Paediatric Soft Tissue Sarcoma Study Group (EpSSG) examined 102 patients with metastatic rhabdomyosarcoma (97 analyzed). Patients received radical RT (all metastatic sites except those completely resected), partial RT, or no RT. The OS was superior in patients treated with radical RT than partial RT (HR, 0.245; P = .039); however, it should be noted that some component of the difference in survival likely relates to the patients selected to receive radical versus partial RT rather than the type of RT administered. The 3-year OS rate was 84% for patients who received radical RT, 54% for patients who received partial RT, and 23% for patients who received no RT.[35]

    Patients with lung metastases who were enrolled in four COG studies (D9802, D9803, ARST08P1, and ARST0431) were retrospectively analyzed. All four protocols required whole-lung irradiation therapy for patients with rhabdomyosarcoma and lung metastases. In 143 patients, 65 (45.5%) received whole-lung irradiation and 78 (54.5%) did not receive whole-lung irradiation, despite protocol mandates.[36] In this retrospective study, there was no statistically significant differences in known prognostic factors between those who did and did not receive whole-lung irradiation. The prognostic factors included patient age, tumor histology, FOXO1 gene fusion status, primary tumor site, tumor size, lymph node status, number of metastatic sites, and Oberlin score. The 5-year EFS rate was 38.3% (95% CI, 24.8%–51.8%) for patients who received whole-lung irradiation and 25.2% (95% CI, 13.8%–36.6%) for patients who did not receive whole-lung irradiation (P = .0496). The 5-year OS rate was 45.5% (95% CI, 31.8%–59.3%) for patients who received whole-lung irradiation and 32.4% (95% CI, 20.4%–44.4%) for patients who did not receive whole-lung irradiation (P = .08). These results highlight the potential importance of whole-lung irradiation.

In the D9803 study of patients with intermediate-risk rhabdomyosarcoma, local control was 90% in 41 patients with Groups I and II alveolar rhabdomyosarcoma but lower in 280 patients with Group III embryonal (80%) and alveolar (83%) rhabdomyosarcoma. Histology, regional lymph node status, and primary site were not related to the likelihood of local failure; however, the local failure rate for 47 patients with retroperitoneal tumors was 33% (probably caused by tumors ≥5 cm in diameter), compared with 14% to 19% for patients with bladder/prostate, extremity, and parameningeal tumors. Tumor size was the strongest predictor of local failure (10% for patients with primary tumors <5 cm vs. 25% for larger tumors; P = .0004).[37][Level of evidence C2]

Treatment volume

The treated radiation volume should be determined by the extent of tumor at diagnosis before surgical resection and before chemotherapy, including clinically involved regional lymph nodes. With conformal plans and image-guided RT, a margin of 1 cm to 1.3 cm to a clinical target volume or planning target volume may be used.[12] This clinical tumor volume can be modified on the basis of anatomical constraints, especially in situations where the tumor was pushing, rather than invading, the adjacent normal tissues, or when adjacent normal tissues are functionally critical (e.g., head and neck rhabdomyosarcoma). Thus, while the volume irradiated may be modified because of considerations for normal tissue tolerance, gross residual disease at the time of RT should receive full-dose RT. A reduction in volume after 36 Gy is appropriate in chemoresponsive disease for patients with noninvasive displacement (T1) that has regressed in size, but not for invasive tumors (T2). Gross residual disease still receives the full RT dose (50.4–59.4 Gy, the higher dose if >5 cm at diagnosis).

For involved nodal sites, the treated volume is defined as the extent of nodal involvement at diagnosis, factoring in changes in anatomy, plus a 3-cm margin superiorly and inferiorly in the direction of lymphatic drainage, or inclusion of the entire nodal chain where there is uncertainty.

For metastatic disease, the treated volume is the extent of metastases at diagnosis, with the exception of the lung or extensive brain metastases where the whole organ is irradiated, or diffuse peritoneal metastases where the entire peritoneal cavity is included. The use of novel techniques, such as stereotactic body RT to appropriate sites (e.g., bone or small volume soft tissue metastases), can be considered.

Timing of RT

The timing of RT generally allows for chemotherapy to be given for up to 3 months before RT is initiated. RT is usually administered over 5 to 6 weeks (e.g., 1.8 Gy once per day, 5 days per week), during which time chemotherapy is usually modified to avoid the radiosensitizing agents dactinomycin, doxorubicin, and temsirolimus. Another consideration is the administration of RT before a planned second surgical excision that will be R0 or R1, particularly if RT might facilitate surgical resection to decrease the chances of loss of form or function. This approach is protocol dependent.

  • The randomized IRS-IV trial reported that the administration of RT twice a day, using 6-hour interfractional intervals at 1.1 Gy per fraction (hyperfractionated schedule), 5 days per week, was feasible, did not improve local control, and was associated with increased acute toxicity.[38] The 5-year local control rate was 87% for all patients on this study.

For metastatic sites, RT is usually given after 16 to 20 weeks of chemotherapy or, rarely, as consolidation at the completion of planned chemotherapy.

Thus, conventional RT remains the standard for treating patients who have rhabdomyosarcoma with gross residual disease.[39]

Brachytherapy

Brachytherapy, using either intracavitary or interstitial implants, is another method of local control that has been used in selected situations for children with rhabdomyosarcoma, especially for patients with primary tumors at a vaginal site [40–45] and selected bladder/prostate sites.[46][Level of evidence C1] This technique requires specialized technical skill and expertise and is limited to only a few institutions. In small series from one or two institutions, this treatment approach was associated with a high survival rate and retention of a functional organ or tissue in most patients.[41,47]; [48][Level of evidence C2] Other sites, especially head and neck, have also been treated with brachytherapy.[49]

Intraoperative RT (IORT)

Local control for pediatric solid tumors, such as rhabdomyosarcoma, often requires high doses of EBRT, which can cause unwanted damage to the normal tissues surrounding the tumor. After maximal tumor resection, delivering some or all of the radiation dose to the sites of highest recurrence risk intraoperatively could mitigate this issue, especially in relapsed patients who have received previous EBRT or very young children. This procedure is called intraoperative radiation therapy (IORT), and it can be used in challenging cases where standard full-dose EBRT is contraindicated. During IORT, a single large dose of radiation is administered during surgical exploration with direct visualization of the tumor bed and radiation field. IORT has been deemed safe to use for malignancies in pediatric patients, with minimal long-term toxicities.[50]

A single-institution retrospective study examined IORT (108 applications) in 96 pediatric patients with solid tumors (42 with rhabdomyosarcoma) who were treated from 1995 to 2022. The median age at time of IORT was 8 years (range, 0.8–20.9 years). The median follow-up was 16 months for all patients and 3 years for surviving patients. About one-half of patients (54%) were treated with upfront IORT to the primary tumor because of difficult circumstances, such as very young age or challenging anatomy. The median IORT dose was 12 Gy (range, 4–18 Gy). The cumulative incidence rate of local failure was 17% at 2 years and 23% at 5 years. A total of 15 patients (16%) experienced postoperative complications likely related to IORT.[51]

While IORT may be advantageous in the treatment of certain high-risk patients, there are important disadvantages. IORT is only available at certain institutions. In addition, while IORT minimizes the radiation dose to surrounding tissues by delivering one large fraction, any healthy tissue that is exposed is at risk of long-term treatment effects later in life.[51]

Local control treatment of children aged 3 years and younger

Very young children (aged ≤36 months) diagnosed with rhabdomyosarcoma pose a therapeutic challenge because of their increased risk of treatment-related morbidity.[9] Reduced radiation doses have been used when delayed surgery can provide negative margins. However, for most patients and those in whom surgical resection is not appropriate, higher doses of RT are given.[52] Radiation techniques are designed to maximize normal tissue sparing and should include conformal approaches, often with intensity-modulation or protons. When radiation is omitted, even in those with Stage 1 disease, there is a high risk of recurrence, with local recurrence being the most common, confirming the need for RT.[53–55]

Delayed primary excision may allow for a radiation dose reduction and has been studied in select patients.[8] However, the youngest patients frequently do not get appropriate RT because of concerns about normal tissue toxicity, and these are the best patients for whom surgical resection by delayed primary excision is a particularly important consideration. Local control can be achieved by both RT and surgery. Both treatments are optimal, but at least one approach is necessary in addition to chemotherapy. Local control rates from delayed primary excision and reduced-dose RT are equivalent to that from RT alone.[8]

In studies of infants younger than 1 or 2 years, 77 patients with nonmetastatic rhabdomyosarcoma were included. These studies showed 5-year failure-free survival (FFS) rates of 57% to 68% and OS rates of 76% to 82%.[56] Most failures were local, often because RT was withheld in violation of protocol guidelines. In contrast, for infants treated according to guidelines, both FFS and OS were clearly superior.[57] This experience has been confirmed for children up to age 2 years.[56] Consequently, the COG recommends treating children aged 2 years or younger with the same guidelines as recommended for children older than 2 years.

Surgery and RT by Primary Site of Disease (Local Control Management)

Local control of primary disease in rhabdomyosarcoma has evolved with the use of more effective chemotherapy protocols, improved surgical approaches and techniques, and improvements in RT, including better definition of therapy fields, tailored dosing, and new techniques such as IMRT, brachytherapy, and proton therapy. Data are predominantly derived from retrospective reviews of primary tumor sites from cooperative group studies, including the IRSG, COG, EpSSG, CWS, Gesellschaft für Pädiatrische Onkologie und Hämatologie, International Society for Pediatric Oncology (SIOP) Malignant Mesenchymal Tumour (MMT), and the Associazione Italiana di Ematologia e Oncologia Pediatrica Soft Tissue Sarcoma Committee. These groups created the International Soft Tissue Sarcoma Consortium (INSTRuCT) and agreed to form a single data commons by merging multiple cooperative group databases. Leaders of INSTRuCT have initiated efforts to define international consensus statements for approaches to several primary tumor sites, predominantly through their expert review of published data, sometimes enhanced with new analyses of merged data.

Head and neck sites

Primary sites for childhood rhabdomyosarcoma within the head and neck include the orbit; nonorbital head and neck and cranial parameningeal; and nonparameningeal, nonorbital head and neck. Specific considerations for the surgical and radiotherapeutic management of tumors arising at each of these sites are discussed below.

For patients with head and neck primary tumors that are considered unresectable, chemotherapy and RT with organ preservation are the mainstay of primary management.[58–63] Several studies have reported excellent local control in patients with rhabdomyosarcoma of the head and neck treated with IMRT, fractionated stereotactic radiation therapy, or proton RT, and chemotherapy. Further study is needed, but the use of IMRT and chemotherapy in patients with head and neck rhabdomyosarcoma may result in less-severe late effects.[64–66]; [67][Level of evidence C1]

  1. Orbit.

    Rhabdomyosarcomas of the orbit should not undergo exenteration, but biopsy is needed for diagnosis.[68,69] Biopsy is followed by chemotherapy and RT, with orbital exenteration reserved for the small number of patients with locally persistent or recurrent disease.[60,70] RT and chemotherapy are the standard of care, with survival rates exceeding 90% to 95%. When RT is omitted, there is risk of local relapse. For patients with orbital tumors, precaution should be taken to limit the RT dose to the lens, conjunctiva, and cornea.

    The COG investigators have shown that patients with embryonal rhabdomyosarcoma of the orbit who achieve a complete response to induction chemotherapy have improved local control after radiation therapy of 45 Gy, compared with patients who fail to achieve a complete response.[71][Level of evidence B4] For patients in whom a complete response has not been achieved with induction chemotherapy, 50.4 Gy of RT is recommended by the investigators.

    The COG studied a lower dose of cyclophosphamide to reduce the risk of infertility. In the COG ARST0331 (NCT00075582) trial, only four cycles of therapy contained cyclophosphamide, for a total cyclophosphamide exposure of 4.8 g/m2. Sixty-two patients with Group III orbital embryonal rhabdomyosarcoma were treated. None of the 15 patients with radiographic complete response (CR) had local recurrences, compared with 6 of the 38 patients who had less than a CR after 12 weeks of vincristine, dactinomycin, and cyclophosphamide (VAC) chemotherapy (P = .11). The authors concluded that for patients with Group III orbital embryonal rhabdomyosarcoma achieving a CR after VAC chemotherapy that includes modest-dose cyclophosphamide, 45 Gy of RT may be sufficient for durable FFS. However, for patients with less than a CR who were treated with the ARST0331 systemic therapy, a radiation dose of 50.4 Gy or a higher dose of cyclophosphamide may be needed to achieve the control rate reported in the IRS-IV trial.[71][Level of evidence B4]

    Long-term outcomes were evaluated in 218 patients with orbital rhabdomyosarcoma enrolled in COG clinical trials between 1997 and 2013. The 192 patients with low-risk orbital rhabdomyosarcoma (clinical groups I–III with mostly embryonal histology treated on the low-risk D9602 and ARST0331 studies) had 10-year EFS and OS rates of 85.5% (95% CI, 77.0%–94.0%) and 95.6% (95% CI, 90.8%–100.0%), respectively. The 26 patients with non–low-risk orbital rhabdomyosarcoma (mostly tumors with alveolar histology that were treated with more intensive intermediate-risk protocols [D9802, D9803 and ARST0531]), had 5-year EFS and OS rates of 88.5% (95% CI, 75.6%–100.0%) and 95.8% (95% CI, 87.7%–100.0%), respectively. Twenty-eight patients experienced a recurrence, including 25 who were treated in low-risk trials (6 patients did not receive radiation therapy during initial therapy). Twenty-seven recurrences were local. One metastatic recurrence occurred in a patient with Group III, PAX3::FOXO1 fusion–positive alveolar rhabdomyosarcoma. Patients with recurrent orbital rhabdomyosarcoma had a 10-year OS rate of 69.4% (95% CI, 50.0%–88.8%) from time of recurrence, showing that a significant number of patients with recurrent orbital rhabdomyosarcoma may achieve long-term survival.[72]

  2. Nonorbital and cranial parameningeal.

    If the tumors are nonorbital and cranial parameningeal (arising in the middle ear/mastoid, nasopharynx/nasal cavity, paranasal sinus, parapharyngeal region, or pterygopalatine/infratemporal fossa), a magnetic resonance imaging (MRI) scan with contrast of the primary site and brain should be obtained to check for presence of base-of-skull erosion and possible extension onto or through the dura.[61,73,74] If skull erosion and/or transdural extension is equivocal, a computed tomography (CT) scan with contrast of the same regions is indicated. Also, if there is any suspicion of extension down the spinal cord, an MRI scan with contrast of the entire cord should be obtained. The cerebrospinal fluid (CSF) should be examined for malignant cells in patients with high-risk parameningeal tumors. Because complete removal of these tumors is not feasible, owing to their location, the initial surgical procedure for these patients is usually only a biopsy for diagnosis.

    Nonorbital head and neck rhabdomyosarcomas, including cranial parameningeal tumors, are optimally managed by conformal RT and chemotherapy. Patients with parameningeal disease with intracranial extension bordering the primary tumor and/or signs of meningeal impingement (i.e., cranial base bone erosion and/or cranial nerve palsy) do not require whole-brain irradiation or intrathecal therapy, unless tumor cells are present in the CSF at diagnosis.[73] Patients should receive RT to the site of primary tumor with a 1.5-cm margin to include the meninges adjacent to the primary tumor and the region of intracranial extension, if present, with a 1.5-cm margin.[74]

    Evidence (timing of RT for nonorbital and cranial parameningeal tumors):

    1. In a retrospective trial, starting RT within 2 weeks of diagnosis for patients with signs of meningeal impingement was associated with lower rates of local failure but was of borderline significance.[74]
      • When no signs of meningeal impingement were present, delay of RT for more than 10 weeks did not impact local failure rates.
    2. A comparison of local control, FFS, and OS rates showed no statistical difference between early irradiation (day 0) for Group III patients in the IRS-IV study with cranial nerve palsy and/or cranial base erosion versus later initiation of RT (week 12) for Group III patients in the D9803 study who had similar evidence of meningeal involvement. This suggested that early RT for this group of patients is not necessary.[75][Level of evidence B4]
    3. A retrospective analysis of 47 patients with parameningeal primary sites suggested that the subgroup of adolescent patients with alveolar rhabdomyosarcoma (n = 13) might benefit from the addition of prophylactic irradiation (36 Gy) to bilateral cervical nodes.[76][Level of evidence C2]
    4. A single-institution retrospective review identified 14 patients with head and neck alveolar rhabdomyosarcoma. All patients were treated with multiagent chemotherapy and RT to the primary site and clinically involved nodes.[77][Level of evidence C2]
      • There were ten relapses in the cohort: seven regional nodal, one combination local and regional nodal, and two leptomeningeal.
      • In six of eight patients (75%) with no nodal disease at diagnosis, isolated regional nodal relapse developed.
      • The authors recommended elective nodal irradiation to treat at-risk draining lymph node stations relative to the primary tumor site for patients who present with head and neck alveolar rhabdomyosarcoma.
    5. An analysis of 1,105 patients with localized parameningeal rhabdomyosarcoma treated from 1984 to 2004 in North America and Europe found that several prognostic factors could be used to define subgroups of patients with significantly different survival rates.[78][Level of evidence C1]
      • The OS rate at 10 years for the entire cohort was 66%.
      • Patients with zero or one adverse factor (age <3 or >10 years at diagnosis, presence of meningeal involvement, tumor diameter >5 cm, unfavorable primary parameningeal site) had a 10-year OS rate of 80.7%.
      • Patients with two adverse factors had a 10-year OS rate of 68.4%.
      • Patients with three or four adverse factors had a 10-year OS rate of 52.2%.
      • Patients who did not receive RT as a component of their initial therapy had a poor prognosis, and their tumors were not salvaged with introduction of RT after relapse. This finding establishes RT as a necessary component of initial treatment.
    6. A single-institution prospective registry identified 25 patients with head and neck parameningeal rhabdomyosarcoma who were treated with proton-beam RT.[79]
      • Of 25 total patients, 11 had intracranial extension at baseline, 6 of whom experienced a local recurrence.
      • This recurrence rate is similar to the rate reported in the IRS-IV and D9803 trials for patients with high-risk parameningeal rhabdomyosarcoma.[75]
    7. A study included 15 children and adolescents with intermediate- and high-risk parameningeal rhabdomyosarcoma who were treated with proton RT during cycle 1 or 2 of chemotherapy.[80]
      • At 3 weeks from RT simulation, most patients demonstrated a significant reduction in initial tumor volume.
      • This finding suggests that for patients who receive early RT after the initiation of chemotherapy, on-treatment imaging should be performed approximately 4 weeks from the initiation of chemotherapy.

    Children who present with tumor cells in the CSF (Stage 4) may or may not have other evidence of diffuse meningeal disease and/or distant metastases. In a review of experience from IRSG protocols II though IV, eight patients had tumor cells in the CSF at diagnosis. Three of four patients without other distant metastases were alive at 6 to 16 years after diagnosis, as was one of the four patients who had concomitant metastases elsewhere.[81]

    Patients may also have multiple intraparenchymal brain metastases from a distant primary tumor. They may be treated with central nervous system–directed RT in addition to treatment with chemotherapy and RT for the primary tumor. Craniospinal axis RT may also be indicated.[82,83]

  3. Nonparameningeal, nonorbital head and neck.

    For nonparameningeal, nonorbital head and neck tumors, wide excision of the primary tumor (when feasible without functional impairment) and ipsilateral neck lymph node sampling of clinically involved nodes may be appropriate but requires postoperative RT if margins or nodes are positive.[84]; [85][Level of evidence C1] Narrow resection margins (<1 mm) are acceptable because of anatomical restrictions. Cosmetic and functional factors should always be considered, but with modern techniques, complete resection in patients with superficial tumors is consistent with good cosmetic and functional results.

    The EpSSG RMS-2005 (NCT00379457) study prospectively enrolled 165 patients with localized head and neck, nonparameningeal rhabdomyosarcoma. Local therapy included surgery (58%) and/or RT (72%). Chemotherapy was given according to the patient’s risk group. Low-risk patients received vincristine and dactinomycin (VA) therapy. High-risk patients were randomly assigned to receive either neoadjuvant therapy with ifosfamide, vincristine, and dactinomycin (IVA) or IVA and doxorubicin for four courses followed by five courses of IVA. The 5-year EFS rate was 75% (95% CI, 67.3%–81.2%), and the OS rate was 84.9% (95% CI, 77.5%–89.7%). Favorable histology was associated with a better EFS rate (82.3% vs. 64.6%, P = .02), and nodal spread was associated with a worse OS rate (88.6% vs. 76.1%, P = .04). Locoregional relapse/progression was the main tumor failure event (84% of events).[86][Level of evidence B4]

    Specialized, multidisciplinary surgical teams also have performed resections of anterior skull-based tumors in areas previously considered inaccessible to definitive surgical management, including the nasal areas, paranasal sinuses, and temporal fossa. However, these procedures should be considered only in children with recurrent locoregional disease or residual disease after chemotherapy and RT.

Extremity sites

A pooled analysis of 642 patients from four international cooperative groups in Europe and North America was performed to identify prognostic factors in patients with localized extremity rhabdomyosarcoma. Regional lymph node involvement was approximately 2.5 times higher with alveolar rhabdomyosarcoma than with embryonal rhabdomyosarcoma. The 5-year OS rate was 67%. Multivariate analysis showed that decreased OS was correlated with age older than 3 years, T2 invasive disease and N1 nodal status, incomplete initial surgery, treatment before 1995, and treatment by European groups. This analysis also suggested that duration of chemotherapy might have an impact on outcome in these patients.[87]

Primary re-excision before initiation of chemotherapy (i.e., not delayed) may be appropriate in patients whose initial surgical procedure leaves microscopic residual disease that is deemed resectable by a second procedure without loss of cosmesis or function.[5] Chemotherapy or delayed primary excision does not improve outcome over chemotherapy and RT.[8]

Delayed primary excision has been studied in patients with extremity tumors enrolled in the COG intermediate-risk rhabdomyosarcoma trials. Two COG studies (D9803 and ARST0531 [NCT00354835]) were pooled to assess the benefit of delayed primary excision. In the D9803 study, local control with RT after a partial or complete excision was completed at week 12. In the ARST0531 study, RT was done upfront at week 4. Patients with bladder or prostate rhabdomyosarcoma who received a delayed primary excision had no difference in survival, whereas patients with extremity rhabdomyosarcoma had an improved OS with delayed primary excision. The delayed primary excision strategy with a reduction in RT dose resulted in superior OS for those sites.[8,10] Delayed primary excision may be most appropriate for infants because the late effects of RT are more severe than in older patients; thus, even a moderate reduction in radiation dose is desirable. For more information, see the Surgery (Local Control Management) section.

IMRT can be used to spare the bone yet provide optimal soft tissue coverage in extremity rhabdomyosarcoma. Complete primary tumor removal from the hand or foot is not feasible in most cases because of functional impairment.[88][Level of evidence C1] For children presenting with a primary tumor of the hands or feet, COG studies have shown a 10-year local control rate of 100% using RT along with chemotherapy, avoiding amputation in these children.[89][Level of evidence C1] Definitive RT and chemotherapy for Group III tumors resulted in a local control rate of 90% to 95% in the IRS-IV trial.[38]

Regional and in-transit lymph nodes for extremity tumors

Because of the significant incidence of regional nodal spread in patients with extremity primary tumors (often without clinical evidence of involvement) and because of the prognostic and therapeutic implications of nodal involvement, extensive pretreatment assessment of regional and in-transit nodes is warranted.[90–94]; [95][Level of evidence C2] In-transit nodes are defined as epitrochlear and brachial for upper-extremity tumors and popliteal for lower-extremity tumors. Regional lymph nodes are defined as axillary/infraclavicular nodes for upper-extremity tumors and inguinal/femoral nodes for lower-extremity tumors.

  • In a review of 226 patients with primary extremity rhabdomyosarcoma, 5% had tumor-involved in-transit nodes. Over 5 years, the rate of in-transit node recurrence was 12%. Very few patients (n = 11) underwent in-transit node examination at diagnosis, but five of them, all with alveolar rhabdomyosarcoma, had tumor-involved nodes. However, the EFS rates were not significantly different among those evaluated initially and those not evaluated initially for in-transit nodal disease.[95]

Positron emission tomography (PET) scanning is recommended for evaluation and staging of extremity primary tumors before initiation of therapy [95] and is useful in RT treatment planning.[96]

For patients enrolled in clinical trials, the COG-STS recommends biopsy of all enlarged or clinically suspicious lymph nodes, if possible, without delay in therapy or adverse functional outcome. If biopsy is not feasible, clinically abnormal nodes need to be included in the RT treatment plan.

In the trunk and extremity, if no enlarged lymph nodes are identified in the draining nodal basin, a sentinel lymph node biopsy is recommended. This type of biopsy is a more accurate way of assessing regional lymph nodes than random lymph node sampling. Techniques for sentinel lymph node biopsy are standardized and should be completed by an experienced surgeon.[93,97–103]

In a single-institution study of 28 patients aged 6 months to 32 years with soft tissue sarcomas, but not confined to rhabdomyosarcoma, sentinel lymph node biopsy was prospectively compared with PET-CT scan for detection of lymph node metastases. Forty-three percent of patients (3 of 7) with proven malignant sentinel lymph nodes had negative cross-sectional and functional imaging (PET-CT). Also, PET-CT suggested nodal involvement in 14 patients, whereas only 4 of those were proven to have metastatic disease. The study does not address relapse rate or follow-up in these patients. Therefore, the use of PET-CT staging to diagnose lymph node disease in soft tissue sarcomas is of uncertain utility.[104]

Truncal sites

Primary sites for childhood rhabdomyosarcoma within the trunk include the chest wall or abdominal wall, intrathoracic or intra-abdominal area, biliary tree, and perineum or anus. Specific considerations for the surgical and radiotherapeutic management of tumors arising at each of these sites are discussed below.

  1. Chest wall or abdominal wall.

    The surgical management of patients with lesions of the chest wall or abdominal wall follows the same guidelines as those used for lesions of the extremities (i.e., wide local excision and an attempt to achieve negative microscopic margins if cosmetic and functional outcomes are acceptable).[105] These resections may require use of prosthetic materials for subsequent reconstruction.

    Initial primary resection is performed if there is a realistic expectation of achieving negative margins (R0 resection). However, most patients who present with large tumors in these sites have localized disease that is unresectable at diagnosis but may become amenable to resection with negative margins after preoperative chemoradiation therapy. These patients may have excellent long-term survival.[105–108]

    Chest wall rhabdomyosarcoma, which is usually Group III, does not require R0 resection (no microresidual disease) at delayed primary resection. The COG data show equivalent survival for R0 and R1 (microresidual disease at the margin) resections in chest wall rhabdomyosarcoma, likely because of the addition of postoperative RT.[108] Aggressive resections at diagnosis before chemotherapy are not necessary because rhabdomyosarcoma is chemosensitive and radiosensitive.

  2. Intrathoracic or intra-abdominal sarcomas.

    Intrathoracic or intra-abdominal sarcomas may not be resectable at diagnosis because of the massive size of the tumor and extension into vital organs or vessels.[109]

    For patients with initially unresectable retroperitoneal/pelvic tumors, complete surgical removal after induction chemotherapy, with or without RT, offers a significant survival advantage (73% vs. 34%–44% without removal).[109]

    Evidence (chemotherapy with or without RT followed by surgery):

    1. The SIOP-MMT Group found that RT improved local control in patients with localized pelvic rhabdomyosarcoma whose initial surgical procedure was biopsy only, leaving macroscopic residual tumor.[110][Level of evidence B4]
      • Age older than 10 years and lymph node involvement were unfavorable prognostic factors.
    2. A German study reported on 100 patients with intra-abdominal nonmetastatic embryonal rhabdomyosarcoma larger than 5 cm in dimension; 61% had tumors larger than 10 cm and 88% were T2. Eighty-one patients were treated with chemotherapy and delayed primary excision, while 19 patients with emergency presentations (tumor rupture, ileus, hydronephrosis, oliguria, and venous congestion) underwent initial debulking surgery.[111][Level of evidence C1]
      • The EFS rate was 52% (± 10%), and the OS rate was 65% (± 9%).
      • Unfavorable factors were initial diagnosis at age older than 10 years, lack of complete remission, and inadequate local control (incomplete secondary resection or no RT).
    3. A small series of seven patients with rhabdomyosarcoma who had peritoneal dissemination and/or malignant ascites achieved good outcomes with whole-abdomen irradiation using IMRT with dose painting.[112][Level of evidence C1] This technique involves simultaneously irradiating the whole abdomen with a lower dose than that used for the primary tumor (or resection-bed). The larger volume receives a lower (fractional) daily dose than the high-dose target receives.
  3. Biliary tree.

    With rhabdomyosarcoma of the biliary tree, total resection at diagnosis is rarely feasible. The standard treatment includes chemotherapy and RT. Outcomes for patients with this primary tumor site were considered favorable despite residual disease after surgery;[113] however, an analysis of COG low-risk studies found that patients with this site had suboptimal outcomes.[114] The CWS also reported poorer outcomes,[115] confirmed by a systematic review and meta-analysis.[116] The COG now recommends that this site be classified as unfavorable. External biliary drains significantly increase the risk of postoperative infectious complications. Thus, external biliary drainage is not warranted.[113]

    Evidence (chemotherapy, surgery, and RT):

    1. A retrospective review by the CWS identified 17 patients with rhabdomyosarcoma of the biliary tree.[115]
      • The 5-year OS rate was 58% (45%–71%), and the EFS rate was 47% (34%–50%).
      • Patients older than 10 years and those with alveolar histology had the worst prognosis (OS rate, 0%).
      • Patients with botryoid histology had an excellent survival (OS rate, 100%) compared with those with nonbotryoid histology (OS rate, 38%; 22%–54%; P = .047).
      • Microscopic complete tumor resection was achieved in five of six patients who received initial tumor biopsy followed by chemotherapy and delayed surgery.
    2. A COG analysis of 17 patients enrolled in two consecutive low-risk studies (D9602 and ARST0331) reported the following results:[114]
      • The 5-year EFS rate was 76.5% (95% CI, 54.6%–98.4%), and the OS rate was 70.6% (95% CI, 46.9%–94.3%).
      • Most patients (80%) who received RT did not have disease recurrence.
      • Of 14 patients with Group III disease, 5 underwent delayed primary excision, 2 of whom had local relapses.
      • Of the nine patients without delayed primary excision, two developed local relapses.
  4. Perineum or anus.

    Patients with rhabdomyosarcoma arising from tissue around the perineum or anus often present with advanced disease. These patients have a high likelihood of regional lymph node involvement, and about half of the tumors have alveolar histology.[117] The high frequency of nodal involvement and the prognostic association between nodal involvement and poorer outcome support the recommendation to sample the regional lymph nodes.[118] When feasible and without unacceptable morbidity, removing all gross tumor before chemotherapy may improve the likelihood of cure; however, chemotherapy and RT remain the standard of care. With the goal of organ preservation, patients with tumors of the perineum or anus are preferentially managed with chemotherapy and RT without aggressive surgery, as aggressive surgery may result in the loss of sphincter control. Very aggressive surgery is not indicated because of multiple critical structures that limit the ability to achieve negative margins near the anus and urethra.[118]

    • In IRSG protocols I through IV, the OS rate after aggressive therapy for 71 patients with tumors in this location was 49%, best for patients with Stage 2 disease (small tumors, negative regional nodes), intermediate for those with Stage 3 disease, and worst for those with Stage 4 disease at diagnosis.[118]
    • In a subsequent report from the German CWS trials, 32 patients had an EFS and OS rate of 47% at 5 years. In addition, patients with embryonal histology fared significantly better than did patients with alveolar histology.[119][Level of evidence C1]
    • A retrospective review examined 50 patients with nonmetastatic perianal/perineal rhabdomyosarcoma treated in the SIOP-MMT-95 (NCT00002898), Italian RMS-96, and EpSSG RMS-2005 trials. The study found a 5-year EFS rate of 47.8% and an OS rate of 52.6%. Eighty-seven percent of patients with relapse or disease progression died. Older patients and those with large tumors had the worst outcomes.[120][Level of evidence C1]

Genitourinary system sites

Primary sites for childhood rhabdomyosarcoma within the genitourinary system include the paratesticular area, bladder, prostate, kidney, vulva, vagina, and uterus. Specific considerations for the surgical and radiotherapeutic management of tumors arising at each of these sites are discussed below.[121]

  1. Testis or spermatic cord (paratesticular).

    Recommendations for paratesticular primary tumors are primarily based on the results from cooperative group trials and a recent INSTRuCT consensus opinion.[122]

    Lesions occurring adjacent to the testis or spermatic cord and up to the internal inguinal ring should be removed by orchiectomy with resection of the spermatic cord, using an inguinal incision with proximal vascular control (i.e., radical orchiectomy).[123] Resection of hemiscrotal skin is required when there is tumor fixation or invasion.

    Hemiscrotectomy had been recommended by the COG, German groups, and Italian groups when a previous transscrotal biopsy had been performed. A retrospective German CWS study of 28 patients with embryonal rhabdomyosarcoma found a 5-year EFS rate of 91.7% in 12 patients with an initial transscrotal excision followed by hemiscrotectomy, while the 5-year EFS rate was 93.8% in 16 patients without subsequent hemiscrotectomy. All of these patients also received chemotherapy with vincristine, dactinomycin, an alkylating agent, and other agents.[124][Level of evidence C2]

    A retrospective study examined 842 patients with localized paratesticular rhabdomyosarcoma who were enrolled in COG, CWS, EpSSG, Italian Cooperative Group, and MMT studies from 1988 to 2013. Of all patients, 7.7% had a transscrotal resection; however, this surgical factor did not contribute to an inferior EFS in stratified univariable and multivariable analysis.[125] A COG study evaluated 279 patients with paratesticular rhabdomyosarcoma. The study also found that hemiscrotectomy did not improve outcome after transscrotal violation.[126][Level of evidence C1] These findings support the consensus statement from INSTRuCT that hemiscrotectomy is no longer recommended for scrotal violation.[122]

    The EpSSG RMS-2005 (NCT00379457) study enrolled 237 patients with paratesticular tumors. Seventy-five patients (32%) had an inappropriate first surgery, defined as tumorectomy without orchidectomy, transscrotal orchidectomy without an inguinal approach, or biopsy in a resectable tumor. These patients required intensified therapy to maintain excellent OS and EFS. Ten patients required additional local surgery and intensified chemotherapy.[127]

    For patients with incompletely removed paratesticular tumors that require RT, temporarily repositioning the contralateral testicle into the adjacent thigh before scrotal radiation may preserve hormone production; however, more data are needed.[128][Level of evidence C1] A retrospective review of 49 patients with paratestis rhabdomyosarcoma referred to Memorial Sloan Kettering Cancer Center found that 20 patients had scrotal violation as a part of their original surgery. Fifteen of these patients underwent salvage surgery or RT. Eleven of these patients had continuous PFS, whereas four of the five patients who were treated without a salvage procedure developed recurrent disease.[129][Level of evidence C2]

    Paratesticular tumors have a relatively high incidence of lymphatic spread (26% in IRS-I and IRS-II).[90] All patients with paratesticular primary tumors should have thin-cut abdominal and pelvic CT scans with intravenous contrast to evaluate nodal involvement. For patients who have Group I disease, are younger than 10 years, and in whom CT scans show no evidence of lymph node enlargement, retroperitoneal node biopsy/sampling is unnecessary, but a repeat CT scan every 3 months is recommended.[130,131] For patients with suggestive or positive CT scans, retroperitoneal, ipsilateral, infra-renal vein lymph node sampling of 10 to 12 nodes (but not formal node dissection) is recommended, and treatment is based on the findings of this procedure.[4,39,132] Patients with suspicious or documented retroperitoneal/pelvic lymph nodes require nodal RT.

    In patients aged 10 years and older, only 9% will have clinical or radiological evidence of retroperitoneal node enlargement. However, pathological evaluation has shown that imaging alone will miss 50% of nodal disease. Therefore, patients aged 10 years and older should have an ipsilateral, nerve-sparing retroperitoneal node dissection, regardless of imaging findings.[133] Staging ipsilateral retroperitoneal lymph node sampling is currently required for all children aged 10 years and older with paratesticular rhabdomyosarcoma on COG-STS studies.

    Many European investigators relied on radiographic, rather than surgical-pathological assessment, for retroperitoneal lymph node involvement.[123,130] European studies, as well as an international pooled data analysis, demonstrated worse outcomes in this patient population when surgical lymph node evaluation was not performed.[125,127,134] On the basis of these results and with the high relapse rate and worse EFS in Stage N0 patients, investigators from SIOP, EpSSG, and COG recommended surgical resection, in the form of ipsilateral retroperitoneal lymph node sampling of clinically normal nodes (not enlarged by CT or MRI), in patients aged 10 years and older with paratesticular rhabdomyosarcoma.[125] A consensus document regarding paratesticular rhabdomyosarcoma from all North American and European cooperative groups concurred that all patients aged 10 years or older should undergo ipsilateral, infra-renal vein, retroperitoneal surgical lymph node evaluation by sampling 7 to 12 nodes or a nerve-sparing dissection.[122]

    Evidence (lymph node sampling):

    1. In the SIOP-MMT-89 and -95 studies, patients with paratesticular rhabdomyosarcoma were evaluated with imaging but did not undergo routine ipsilateral lymph node sampling.[135][Level of evidence B4]
      • Thirty-one percent of Stage N0 patients aged 10 years and older developed node relapse, compared with 8% of Stage N0 patients younger than 10 years (P = .0005).
      • The SIOP-MMT group subsequently recommended ipsilateral lymph node sampling for all patients aged 10 years and older.
    2. The North American and European cooperative groups performed a pooled analysis of 12 studies from five cooperative groups.[125][Level of evidence C1]
      • For patients with paratesticular rhabdomyosarcoma (N = 842), age 10 years and older at diagnosis and tumor size larger than 5 cm were unfavorable prognostic features.
      • At 7.5 years of median follow-up, the EFS rate was 87.7%, and the OS rate was 94.8% at 5 years.
      • The only treatment variable that was associated with EFS in patients aged 10 years or older was surgical assessment of regional nodes, which may most accurately identify patients who can benefit from RT.
    3. In the EpSSG RMS-2005 (NCT00379457) cooperative group study (n = 237) of patients with paratesticular rhabdomyosarcoma, retroperitoneal lymph node staging was based on conventional imaging with ultrasonography, CT, or MRI, not systematic surgical staging.[127][Level of evidence B4]
      • Twenty-one of 26 recurrences were in patients older than 10 years and were mainly locoregional in 16 of the 26 patients.
      • The 5-year OS and EFS rates were both significantly worse in patients older than 10 years, compared with those younger than 10 years (OS rates, 86.7% vs. 98.1%, respectively; P = .0013; EFS rates, 79.6% vs. 95.8%, respectively; P = .0004).
      • Eight of ten nodal relapses were in patients older than 10 years.
      • The EpSSG group advocates surgical staging for patients aged 10 years and older.
    4. The COG reviewed 279 patients with localized paratesticular rhabdomyosarcoma enrolled in one of four COG studies (D9602, ARST0331, D9803, or ARST0531 [NCT00354835]). Surgical resection of the primary tumor before chemotherapy and RT was encouraged, when possible, with retroperitoneal lymph node dissection (RPLND) recommended for patients aged 10 years and older. Most tumors were resected with negative margins (78.5%), and most patients did not have radiographic enlargement of regional lymph nodes (90.3%). Of 270 analyzed patients, 121 were older than 10 years. Of these patients, 25 (20.9%) underwent template RPLND, 35 (28.9%) had RPLN sampling, and for 12 of the patients (9.9%), the RPLN technique was unknown.[126][Level of evidence B4]
      • In patients older than 10 years, imaging alone will miss over 51.5% of nodal disease.
      • Sampling of ≥7 to 12 nodes appeared optimal.
      • The 5-year EFS rate was 92%.
      • There was a trend toward improved EFS among those who underwent template RPLND (P = .068).
      • Reliance on imaging alone to detect nodal involvement will miss pathological node involvement and may result in undertreatment.

    RT should be considered for patients whose nodes are biopsy positive.

  2. Bladder or prostate.

    Bladder preservation is a major goal of therapy for patients with tumors arising in the bladder and/or prostate. Two reviews provide information about the historical, current, and future treatment approaches for patients with bladder and prostate rhabdomyosarcomas.[136,137]

    The initial surgical procedure in most patients consists of a biopsy, which often can be performed using ultrasound guidance or cystoscopy, or by a direct-vision transanal route.[138]

    In rare cases, the tumor is confined to the dome of the bladder and can be completely resected, leaving a functional bladder intact. Otherwise, to preserve a functional bladder in patients with gross residual disease, chemotherapy and RT have been used in North America and some parts of Europe to reduce tumor bulk.[139,140] This is sometimes followed, when necessary, by a more limited surgical procedure such as partial cystectomy.[141] Early experience with this approach was disappointing, with only 20% to 40% of patients with bladder/prostate tumors alive and with functional bladders 3 years after diagnosis (3-year OS rate was 70% in IRS-II).[141,142] The later experience from the IRS-III and IRS-IV studies, which used more intensive chemotherapy and RT and had a greater emphasis on bladder preservation, showed 55% of patients alive with functional bladders at 3 years postdiagnosis, with 3-year OS rates exceeding 80%.[140,143,144]

    In a prospective registry study of 19 patients (median age, 1.8 years at diagnosis; range, 0.5–5.0 years) who were treated with proton therapy, the 5-year OS and PFS rates were 76%. The 5-year local-control rate was 76%. Tumor size predicted the local-control rate, with 5-year local-control rates of 43% for patients whose tumors were larger than 5 cm versus 100% for patients whose tumors were 5 cm or smaller (P = .006). The four patients who had a relapse all died.[145]

    Patients with a primary tumor of the bladder or prostate who present with a large pelvic mass, resulting from a distended bladder caused by outlet obstruction at diagnosis, receive RT. The RT volume is defined by imaging studies after initial chemotherapy to relieve outlet obstruction. This approach to therapy remains generally accepted, with the belief that more effective chemotherapy and RT will continue to increase the frequency of bladder salvage.

    For patients with biopsy-proven, residual malignant tumor after chemotherapy and RT, appropriate surgical management may include partial cystectomy, prostatectomy, or exenteration (usually approached anteriorly with preservation of the rectum). Very few studies report objective long-term assessment of bladder function. Urodynamic studies can accurately evaluate bladder function.[146]

    An alternative strategy, used in European SIOP protocols, has been to avoid major radical surgery when possible and omit EBRT if complete disappearance of tumor can be achieved by chemotherapy and conservative surgical procedures. The goal is to preserve a functional bladder and prostate without incurring the late effects of RT or having to perform a total cystectomy/prostatectomy. From 1984 to 2003, 172 patients with nonmetastatic bladder and/or bladder/prostate rhabdomyosarcoma were enrolled in a SIOP-MMT study. Of the 119 survivors, 50% had no significant local therapy, and only 26% received RT. The 5-year OS rate was 77%.[147][Level of evidence C1]

    Another alternative strategy in highly selected patients is to perform conservative surgery, followed by brachytherapy at a specialized center.[148]; [149][Level of evidence C2]; [150][Level of evidence C1] A prospective, nonrandomized analysis of this strategy reported the outcomes of 100 children. The 5-year disease-free survival rate was 84%, and the OS rate was 91%. At last follow-up, most survivors presented with only mild-to-moderate genitourinary sequelae and a normal diurnal urinary continence. Five patients required a secondary total cystectomy, three patients for a nonfunctional bladder and two patients for relapse. In another series, bladder-conserving surgery plus brachytherapy for boys with prostate or bladder-neck rhabdomyosarcoma led to excellent survival rates, bladder preservation, and short-term functional results.[46][Level of evidence C1]

    In patients who have been treated with chemotherapy and RT for rhabdomyosarcoma arising in the bladder or prostate region, the presence of well-differentiated rhabdomyoblasts in surgical specimens or biopsies obtained after treatment does not appear to be associated with a high risk of recurrence and is not an indication for a major surgical procedure such as total cystectomy.[143,151,152] One study suggested that in patients with residual bladder tumors with histological evidence of maturation, additional courses of chemotherapy should be given before cystectomy is considered.[143] Surgery should be considered if malignant tumor cells do not disappear over time after initial chemotherapy and RT. Because of limited data, it is unclear whether this situation is analogous for patients with rhabdomyosarcoma arising in other parts of the body.

  3. Kidney.

    The kidney is rarely the primary site for sarcoma. Ten patients were identified among 5,746 eligible patients enrolled in IRSG protocols, including six with embryonal rhabdomyosarcoma and four with undifferentiated sarcoma. The tumors were large (mean widest diameter, 12.7 cm), and anaplasia was present in four (67%) patients. Of the patients with embryonal rhabdomyosarcoma, three Group I and Group II patients survived, one Group III patient died of infection, and two Group IV patients died of recurrent disease; these children were aged 5.8 and 6.1 years at diagnosis. This limited experience concluded that the kidney is an unfavorable site for primary sarcoma.[153]

  4. Vulva, vagina, or uterus.

    For patients with genitourinary primary tumors of the vulva, vagina, or uterus, the initial surgical procedure is usually a vulvar or transvaginal biopsy. Initial radical surgery is not indicated for rhabdomyosarcoma of the vulva, vagina, or uterus.[4] Conservative surgical intervention for vaginal rhabdomyosarcoma, with primary chemotherapy and radiation (external beam or brachytherapy) for Group II or III disease results in excellent 5-year survival rates.[53,154,155][Level of evidence C1]

    In the COG-ARST0331 study, there was an unacceptably high rate of local recurrences in girls with Group III vaginal tumors who did not receive RT.[53][Level of evidence C2] In 21 girls with genitourinary tract disease who were not treated with RT (mostly Group III vaginal primary tumors), the 3-year FFS rate was 57%, compared with 77% in the other 45 patients with non–female genitourinary primary tumors (P = .02).[54][Level of evidence B4] Therefore, the COG-STS recommended that RT be administered to patients with residual viable vaginal tumor, beginning at week 12.[55][Level of evidence C1]

    Because of the small number of patients with uterine rhabdomyosarcoma, it is difficult to make a definitive treatment decision, but chemotherapy with or without RT is effective.[154,156] Twelve of 14 girls with primary cervical embryonal (mainly botryoid) rhabdomyosarcoma were disease-free after VAC chemotherapy and conservative surgery. Of note, two girls also had a pleuropulmonary blastoma and another had a Sertoli-Leydig cell tumor.[157] Exenteration is usually not required for primary tumors at these sites, but may be done if needed, with rectal preservation possible in most cases.

    Four cooperative groups in the United States and Europe evaluated patients with localized vaginal or uterine tumors (N = 427). Some patients received initial RT for local control of residual disease after induction chemotherapy, while others had it later, or not at all if no demonstrable disease was found. The 10-year EFS rate was 74%, and the 10-year OS rate was 92%. Unfavorable factors were positive lymph node disease and uterine corpus primary site. There was no statistical difference in outcomes between patients who received early RT and patients who received later RT. About one-half of these patients were cured without radical surgery or systematic RT.[45][Level of evidence C1]

    A study of five CWS trials (and one registry) included 67 patients with localized vaginal or uterine rhabdomyosarcoma diagnosed at a median age of 2.89 years (0.09–18.08). Multimodality treatment consisted of chemotherapy (n = 66), secondary surgery (n = 32), and RT (n = 11). The study reported the following results:[158][Level of evidence C1]

    • Diagnosis at age 12 months or younger was the only significant negative prognostic factor influencing EFS.
    • The 10-year EFS rate for infants aged 12 months or younger was 50%, and the OS rate was 81%.
    • In contrast, children with local disease older than 1 year to age 10 years had a 10-year EFS rate of 78% and an OS rate of 94% (P = .038). Children older than 10 years had a 10-year EFS rate of 82% and an OS rate of 88% (P = .53).
    • Metastatic disease was observed in four patients, three of whom are alive.
    • Relapsed disease occurred in 5 of 12 infants aged 1 year or younger and 10 of 55 children at a median of 1.38 years (0.53–2.97) after initial diagnosis.
    • Treatment of patients with relapsed disease consisted of multimodality treatment (n = 13) or resection only (n = 2). Nine patients (60%) were alive in clinical remission at a median of 7.02 years (1.23–16.72) after diagnosis of relapsed disease.

    The INSTRuCT group summarized its consensus expert opinion about local treatment of female genital tract tumors as follows:[159]

    • Prognosis for female genital tract tumors is favorable, with an excellent response to chemotherapy.
    • Definitive local control can often be achieved by chemotherapy alone.
    • Adequate biopsy is required and should provide sufficient tissue to establish the diagnosis and for further molecular or genetic analysis.
    • Initial complete surgical resection before chemotherapy can be avoided in most cases:
      • Vaginal: Vaginectomy is unnecessary.
      • Cervix: Up-front vaginectomy/hysterectomy is usually not indicated.
      • Uterus: Up-front hysterectomy is usually not indicated.
    • Primary re-excision to achieve complete resection is usually not indicated.
    • Patients with tumors that are localized to the vagina or cervix and who demonstrate incomplete response after induction chemotherapy receive local RT (brachytherapy).
    • Hysterectomy is indicated for patients with tumors of the corpus uteri who have persistent tumor after definitive initial therapy.
    • Fertility preservation is a consideration for all patients.[159]

    For girls with genitourinary primary tumors who will receive pelvic irradiation, ovarian transposition (oophoropexy) before radiation therapy should be considered unless dose estimations suggest that ovarian function is likely to be preserved.[160] Alternatively, ovarian tissue preservation is under investigation and can be considered.[161]

Unusual primary sites

Rhabdomyosarcoma occasionally arises in sites other than those previously discussed.

  1. Brain.

    Patients with localized primary rhabdomyosarcoma of the brain can occasionally be cured using a combination of tumor excision, RT, and chemotherapy.[162][Level of evidence C2]

  2. Larynx.

    Patients with laryngeal rhabdomyosarcoma will usually be treated with chemotherapy and RT after biopsy in an attempt to preserve the larynx.[163]

  3. Diaphragm.

    Patients with diaphragmatic tumors often have locally advanced disease that is not grossly resectable initially because of fixation to adjacent vital structures such as the lung, great vessels, pericardium, and/or liver. In such circumstances, chemotherapy and RT should be initiated after diagnostic biopsy. Removal of residual tumor at a later date if clinically indicated could be considered.[164]

  4. Ovary.

    Two well-documented cases of primary ovarian rhabdomyosarcoma (one Stage III and one Stage IV) have been reported to supplement the eight previously reported patients. These two patients were alive at 20 and 8 months after diagnosis. Six of the previously reported eight patients had died of their disease.[165][Level of evidence C2] Treatment with combination chemotherapy, followed by removal of the residual mass or masses, can sometimes be successful.[165]

Unknown primary sites

The EpSSG reported a retrospective analysis of ten patients with rhabdomyosarcoma and unknown primary sites, most of whom were adolescents (median age, 15.8 years; range, 4.6–20.4 years).[166] Nine patients had fusion-positive alveolar rhabdomyosarcoma. Seven patients had multiple organ involvement, two patients had only bone marrow disease, and one patient had only leptomeningeal dissemination. All patients received chemotherapy, four received radiation therapy, and none underwent surgery. Three patients underwent allogeneic bone marrow transplant. At the time of this analysis, only two patients were alive in complete remission: one who was treated with radiation therapy, and one who was treated with a bone marrow transplant.

Metastatic disease

Primary resection of metastatic disease at diagnosis (Stage 4, M1, Group IV) is rarely indicated. A site of gross disease is rarely cured with chemotherapy alone; thus, the COG recommends RT to sites of gross disease.

In the COG protocols, resection of the primary tumor in patients with metastatic disease may be considered before initiating chemotherapy if a complete resection is anticipated without the loss of form or function. After induction chemotherapy, delayed resection can be performed, with the same caveat regarding complete resection without loss of form or function, followed by RT of the primary tumor. The paradigm of aggressive local control of primary tumors in patients with metastases is supported by a European evaluation of 101 patients treated from 1998 to 2011 using MMT protocols. OS rates were best when both surgical resection and RT were combined (44%) versus surgical resection alone (19%) or RT alone (16%) (P < .006).[167][Level of evidence C1] Outcome also correlated with completeness of the surgical resection (R0, 41%; R1, 56%; R2, 20%; P < .03). Primary resection of metastatic disease at diagnosis (Stage 4, M1, Group IV) is rarely indicated. Treatment of metastatic disease occurs near the end of therapy using RT and, rarely, resection or other ablative techniques. The primary treatment for bony metastatic disease is RT.

Members of the EpSSG evaluated the role of indeterminate pulmonary nodules at diagnosis in patients with rhabdomyosarcoma. The criteria for indeterminate pulmonary nodules were one to four nodules smaller than 5 mm or one nodule measuring 5 mm to 10 mm. Of 316 patients, 67 patients had nodules and 249 patients did not have nodules. At a median follow-up of 75 months, the 5-year EFS rate was 77% for patients with nodules and 73.2% for patients without nodules (P = .68). The 5-year OS rate was 82% for patients with nodules and 80.8% for patients without nodules (P = .76). The authors concluded that there was no need to perform a biopsy on or upstage the patients with indeterminate pulmonary nodules at diagnosis.[168][Level of evidence C1]

Evidence (treatment of lung-only metastatic disease):

  1. The CWS reviewed four consecutive trials and identified 29 patients with M1 embryonal rhabdomyosarcoma and metastasis limited to the lung at diagnosis.[169][Level of evidence C1]
    • They reported a 5-year EFS rate of approximately 38% for the cohort.
    • The study did not identify any benefit for local control of pulmonary metastasis, whether by lung irradiation (n = 9), pulmonary metastasectomy (n = 3), or no targeted pulmonary therapy (n = 19).
  2. The IRSG reviewed 46 IRS-IV (1991–1997) patients with metastatic disease at diagnosis confined to the lungs. Only 11 patients (24%) had a biopsy of the lung, including six at the time of primary diagnosis. They were compared with 234 patients with single nonlung metastatic sites or multiple other sites of metastases. The lung-only patients were more likely to have embryonal rhabdomyosarcoma and parameningeal primary tumors than the larger group of 234 patients, and they were less likely to have regional lymph node disease at diagnosis.[170][Level of evidence C1]
    • At 4 years, the FFS rate was 35% and the OS rate was 42%, better than for those with two or more sites of metastases (P = .005 and .002, respectively).
    • Age younger than 10 years at diagnosis was also a favorable prognostic factor.
    • Lung irradiation was recommended by the protocols for the lung-only group, but many did not receive it. Patients who received lung irradiation had better FFS and OS at 4 years than those who did not receive lung irradiation (P = .01 and P = .039, respectively).

Chemotherapy

All children with rhabdomyosarcoma should receive chemotherapy. The intensity and duration of the chemotherapy are dependent on the Risk Group assignment.[171] For more information about Risk Groups, see Table 6.

Adolescents treated with chemotherapy for rhabdomyosarcoma experience less hematologic toxicity and more peripheral nerve toxicity than do younger patients.[172]

Low-risk Group

Cooperative group studies have defined low-risk patient populations who have better outcomes. The specific definition of the low-risk group is protocol dependent, and while outcomes have typically been excellent, some subgroups of low-risk patients have received relatively aggressive therapy. In the COG D9602 and ARST0331 studies, low-risk patients had localized (nonmetastatic) embryonal histology tumors in favorable sites that were grossly resected (Groups I and II), embryonal tumors in the orbit that were not completely resected (Group III), and localized tumors in unfavorable sites that were grossly resected (Groups I and II). Approximately 25% of newly diagnosed patients are low risk. For more information, see Table 5 in the Stage Information for Childhood Rhabdomyosarcoma section.

COG and EpSSG studies have evaluated two- and three-drug chemotherapy schedules with varying intensity of alkylator therapy and variations in length of therapy. The goals are to maximize cure rates while attempting to mitigate late effects of chemotherapy. These cooperative groups have evaluated different approaches in different patient subsets.

Evidence (chemotherapy for low-risk Group patients):

  1. The COG-D9602 study stratified 388 patients with low-risk embryonal rhabdomyosarcoma into two groups.[173] Treatment for subgroup A patients (n = 264; Stage 1 Group I/IIA, Stage 2 Group I, and Stage 1 Group III orbit) consisted of VA for 48 weeks with or without RT. Patients with subgroup B disease (n = 78; Stage 1 Group IIB/C, Stage I Group III nonorbit, Stage 2 Group II, and Stage 3 Group I/II disease) received VAC (total cumulative cyclophosphamide dose of 28.6 g/m2). Radiation doses were reduced from 41.4 Gy to 36 Gy for Stage 1 Group IIA patients and from 50 Gy or 59 Gy to 45 Gy for Group III orbit patients.
    • For subgroup A patients, the 5-year overall FFS rate was 89%, and the OS rate was 97%.
    • For subgroup B patients, the 5-year FFS rate was 85%, and the OS rate was 93%.
    Table 8. D9602 Risk Assignment for Low-Risk Patients
    Subset Tumor Site Tumor Size Surgical-Pathological Group Nodes
    N0 = absence of nodal spread; N1 = presence of regional nodal spread beyond the primary site.
    A Favorable Any I, IIA N0
    Orbital Any I, II, III N0
    Unfavorable ≤5 cm I N0
    B Favorable (orbital or nonorbital) Any IIB, IIC, III N0, N1
    Unfavorable <5 cm II N0
    Unfavorable >5 cm I, II N0, N1
  2. The COG-ARST0331 trial evaluated a refinement of therapy for two subsets of low-risk patients.[55] For subset 1 patients, this study reduced the length of therapy by using only four cycles of VAC (cumulative cyclophosphamide dose of 4.8 g/m2) followed by four VA cycles over 22 weeks. Group II and III patients received local RT. For subset 2 patients, the goal of this study was to reduce the total cumulative cyclophosphamide dose, compared with the previous IRS-IV study, without compromising FFS, and to decrease the risk of permanent infertility. Patients received four cycles of VAC (equivalent cyclophosphamide dose as subset 1) followed by VA over 46 weeks.[54][Level of evidence B4]
    1. Subset 1 enrolled 271 newly diagnosed patients with low-risk embryonal rhabdomyosarcoma, defined as patients who presented with Stage 1 or Stage 2 tumors; Group I or Group II tumors; or Stage 1, Group III orbital tumors. This noninferiority trial used a fixed outcome on the basis of expected FFS for similar patients treated in the D9602 trial.[55]
      • There were 35 treatment failures observed (48.8 expected).
      • The 3-year FFS rate was 89%, and the OS rate was 98%. Thus, shorter duration of therapy did not appear to compromise outcome in these patients.
    2. Subset 2 included patients with Stage 1, Group III nonorbital tumors or Stage 3, Group I/II embryonal tumors. Treatment consisted of four cycles of VAC chemotherapy followed by 12 cycles of VA therapy.[53,54]
      • Among 66 eligible patients, there were 20 failures, with an estimated 3-year FFS rate of 70% and an OS rate of 92%.
      • FFS rates at 3 years were even worse (57%) for girls with genital tract tumors.
      • Using reduced total cyclophosphamide, researchers observed suboptimal FFS rates among patients with subset 2 low-risk rhabdomyosarcoma. Eliminating RT for girls with Group III vaginal tumors in combination with reduced total cyclophosphamide appeared to contribute to the suboptimal outcome. However, the OS rate appeared to be similar to the OS rate in previous studies with higher-dose cyclophosphamide. These patients (Stage I, Group III nonorbit and Stage 3, Group I/II) are now being treated in the intermediate-risk ARST1431 (NCT02567435) trial.
    3. For patients with an orbital primary tumor who achieved only a partial response or stability after 12 weeks of induction chemotherapy, the 5-year FFS rate was only 84%, compared with 100% for patients who achieved a CR.[71][Level of evidence C2]
    Table 9. ARST0331 Risk Assignment for Low-Risk Patients
    Subset Tumor Site  Tumor Size  Surgical-Pathological Group  Nodes 
    N0 = absence of nodal spread; N1 = presence of regional nodal spread beyond the primary site.
    1 Favorable  Any  I N0
    II N0, N1
    Orbital  Any  III  N0 
    Unfavorable  <5 cm I, II N0 
    2 Favorable (nonorbital) Any III N0, N1
    Unfavorable >5 cm I, II N0, N1
  3. The EpSSG RMS-2005 study prospectively evaluated the reduction in chemotherapy for patients with low-risk embryonal histology rhabdomyosarcoma. The study enrolled patients from October 2005 to December 2016.
    1. The study enrolled 178 patients with Group 1 N0 disease (subgroups A and B).[174][Level of evidence B4]
      • The 5-year EFS rate was 90.8% (95% CI, 85.0%–94.4%), and the OS rate was 95.7% (95% CI, 90.5%–98.1%).
      • Subgroup A: Patients younger than 10 years with tumors smaller than 5 cm received eight courses of VA therapy for 22 weeks. The EFS rate for this subgroup of 70 patients was 95.5% (95% CI, 86.8%–98.5%), and the OS rate was 100%.
      • Subgroup B: Patients who were older than 10 years or had tumors larger than 5 cm received four courses of IVA (VA plus ifosfamide) and five courses of VA for 25 weeks. The EFS rate for this subgroup was 87.8% (95% CI, 79.3%–93.0%), and the OS rate was 93% (95% CI, 84.8%–96.8%).
      • Treatment with VA for eight courses was effective and well tolerated by subgroup A patients with low-risk embryonal rhabdomyosarcoma. A reduction from nine courses of IVA in previous studies to four courses of IVA plus five courses of VA also produced good results.
    2. The study enrolled 359 patients in subgroup C. Patients in subgroup C had localized, node-negative, IRS Group II/III, nonalveolar rhabdomyosarcoma at favorable sites: orbit (164; 45.7%), head and neck nonparameningeal (77; 21.4%), and genitourinary nonbladder/prostate (118; 32.9%).[175][Level of evidence B4]
      • The 5-year EFS rate was 77.4% (95% CI, 72.5%–81.6%), and the OS rate was 93.5% (95% CI, 90.1%–95.8%).
      • Patients were to receive nine cycles of chemotherapy. Those who were receiving local primary tumor radiation therapy were to receive five cycles of IVA followed by four cycles of VA. For patients who were not receiving radiation therapy, nine cycles of IVA were planned. The actual treatments delivered were:
        • Lower-dose alkylator chemotherapy (n = 7).
        • Lower-dose alkylator chemotherapy and radiation therapy (n = 132).
        • Higher-dose alkylator chemotherapy (n = 113).
        • Higher-dose alkylator chemotherapy and radiation therapy (n = 100).
      • Delayed primary tumor excision was considered for patients with IRS stage III tumors.
      • Lower-dose alkylator chemotherapy and radiation therapy achieved a 5-year OS rate of 93.7%, but the comparison with higher-dose alkylator chemotherapy with or without radiation therapy was not significant (P = .8003). Adjuvant radiation therapy improved the 5-year EFS rate (84.7% vs. 65.2% without radiation therapy; P < .0001), but not OS (P = .9298).
      • Omitting radiation therapy for orbital tumors reduced the 5-year OS rate (87.1% vs. 97.3% for those who received radiation therapy; P = .0257).
      • After an R0 resection (negative margins) (n = 60), radiation therapy did not significantly improve EFS or OS.
  4. The COG and EpSSG studies defined low-risk patient populations, largely based on histology. Genomic classification refined the risk classification for rhabdomyosarcoma and will be used in future COG studies.[176] Tumor samples from patients enrolled in COG trials (1988–2017), U.K. MMT, and RMS-2005 studies (1995–2016) were subjected to custom-capture sequencing. DNA from 641 patients was suitable for analysis. Variants, indels, gene deletions, and amplifications were identified, and survival analysis was performed.
    • A median of one variant per tumor was found.
    • In FOXO1 fusion–negative cases, any variant of RAS pathway members was found in more than 50% of cases. In 21% of cases, no putative driver variant was identified.
    • Variants in BCOR (15%), NF1 (15%), and TP53 (13%) were found at a higher incidence than previously reported.
    • TP53 variants were associated with worse outcomes in both fusion-negative and fusion-positive cases.
    • Variants of MYOD1 were associated with a dismal survival.
  5. The COG and European investigators pooled the results of patients with rhabdomyosarcoma who had definitive surgery of the primary tumor before the initiation of systemic chemotherapy.[177] A total of 113 patients aged 0 to 18 years were identified and enrolled from January 1995 to December 2016 in COG (n = 64) and European protocols. Patients with genitourinary nonbladder and prostate rhabdomyosarcomas were excluded. The recommended chemotherapy in the European protocols was VA for 24 weeks or ifosfamide plus VA. The COG protocols recommended VA for 48 weeks or VA plus cyclophosphamide.
    • With a median follow-up of 97.5 months, the 5-year PFS rate was 80.0% (71.2%–86.4%), and the OS rate was 92.5% (85.6%–96.2%). There were no significant differences in outcomes between the chemotherapy regimens.
    • Tumor size (<5 cm vs. >5 cm) significantly influenced OS (96.2% [88.6%–98.8%] vs. 80.6% [59.5%–91.4%]; P = .01).
    • The authors suggested that to reduce the burden of treatment, VA for 24 weeks may be considered in children with tumors smaller than 5 cm.

Intermediate-risk Group

Approximately 50% of newly diagnosed patients are in the intermediate-risk category. In North America, VAC is the standard multiagent chemotherapy regimen used for intermediate-risk patients. In Europe, ifosfamide is typically used in place of cyclophosphamide. COG studies for intermediate-risk rhabdomyosarcoma use VAC plus vincristine and irinotecan (VI).

Evidence (chemotherapy for intermediate-risk Group patients):

  1. The IRS-IV study randomly assigned intermediate-risk patients to receive either standard VAC therapy or one of two other chemotherapy regimens using ifosfamide as the alkylating agent. This category includes patients with embryonal rhabdomyosarcoma at unfavorable sites (Stages 2 and 3) with gross residual disease (i.e., Group III), and patients with nonmetastatic alveolar rhabdomyosarcoma (Stages 2 and 3) at any site (Groups I, II, and III).[39]
    • At 3 years, intermediate-risk patients had survival rates from 84% to 88%.[39]
    • There was no difference in outcome between these three treatments. The VAC regimen was easier to administer, confirming VAC as the standard chemotherapy combination for children with intermediate-risk rhabdomyosarcoma.[39]
    • Survival in patients with tumors of embryonal histology treated in the IRS-IV trial (who received higher doses of alkylating agents) was compared with similar patients treated in the IRS-III trial (who received lower doses of alkylating agents). A benefit was suggested with the use of higher doses of cyclophosphamide for certain groups of intermediate-risk patients. These included patients with tumors at favorable sites and positive lymph nodes, patients with gross residual disease, or patients with tumors at unfavorable sites who underwent grossly complete resections, but not patients with unresected embryonal rhabdomyosarcoma at unfavorable sites.[178] For other groups of intermediate-risk patients, an intensification of cyclophosphamide was feasible but did not improve outcome.[179] A single-institution retrospective review of patients with head and neck rhabdomyosarcoma identified an increased risk of local failure with the use of reduced-dose cyclophosphamide.[180]
  2. The COG has also evaluated whether the addition of topotecan and cyclophosphamide to standard VAC therapy improved outcome for children with intermediate-risk rhabdomyosarcoma. Topotecan was prioritized for evaluation on the basis of its preclinical activity in rhabdomyosarcoma xenograft models as well as its single-agent activity in previously untreated children with rhabdomyosarcoma, particularly those with alveolar rhabdomyosarcoma.[181,182] Furthermore, the combination of cyclophosphamide and topotecan demonstrated substantial activity, both in patients with recurrent disease and in newly diagnosed patients with metastatic disease.[183,184]
    1. The COG-D9803 clinical trial for newly diagnosed patients with intermediate-risk disease randomly assigned patients to receive either VAC therapy or VAC therapy with additional courses of topotecan and cyclophosphamide.[185][Level of evidence A1]
      • Patients who received topotecan and cyclophosphamide fared no better than those treated with VAC alone. The 4-year FFS rate was 73% with VAC and 68% with VAC plus vincristine, topotecan, and cyclophosphamide.
  3. In a limited-institution pilot study, a combination of vincristine/doxorubicin/cyclophosphamide (VDC) alternating with ifosfamide/etoposide (IE) was used to treat patients with intermediate-risk rhabdomyosarcoma.[186][Level of evidence C1]
    • The relative efficacy of this approach versus the standard approach requires further investigation.
  4. A European trial (SIOP-MMT-95) included 457 patients with incompletely resected embryonal rhabdomyosarcoma, alveolar rhabdomyosarcoma, undifferentiated sarcoma, or soft tissue primitive neuroectodermal tumor. In this study, carboplatin, epirubicin, and etoposide was added to standard IVA therapy.[187]
    • The addition of carboplatin, epirubicin, and etoposide did not improve outcome. The 3-year OS rate was 82% for patients who received IVA and 80% for patients who received IVA plus carboplatin, epirubicin, and etoposide.
    • Toxicity was significantly worse for patients in the six-drug arm.
  5. The COG reported a prospective randomized trial of two treatment strategies for patients with intermediate-risk rhabdomyosarcoma.[188][Level of evidence A1] Patients were randomly assigned to receive treatment with either VAC or VAC with half of the cyclophosphamide cycles replaced with vincristine/irinotecan (VAC/VI). All patients received a lower cumulative dose of cyclophosphamide and earlier introduction of RT than did patients who were treated in previous COG studies. Patients who were treated with VAC/VI received half as much cumulative cyclophosphamide than did patients who were treated with VAC.
    • At a median follow-up of 4.8 years, the 4-year EFS was 63% with VAC and 59% with VAC/VI (P = .51), and the 4-year OS was 73% for VAC and 72% for VAC/VI (P = .80). The COG concluded that the addition of VI to VAC did not improve EFS or OS for patients with intermediate-risk rhabdomyosarcoma.
    • Among patients with Group III embryonal tumors, local failure was higher in the ARST0531 (NCT00354835) trial than in the D9803 (NCT00003958) trial (27.9% vs. 19.4%) and was similar for the VAC and VAC/VI arms.
    • After adjusting for other prognostic factors, OS was inferior in the ARST0531 trial.
    • VAC/VI produced less hematologic toxicity, had a lower cumulative cyclophosphamide dose, and continues to be the backbone for the ARST1431 (NCT02567435) study.
  6. The EpSSG performed a randomized phase III trial to test the addition of vinorelbine and low-dose cyclophosphamide as maintenance chemotherapy in patients with high-risk rhabdomyosarcoma.[189]

    The patients classified as high risk by the EpSSG had:

    • Nonmetastatic incompletely resected embryonal rhabdomyosarcoma at unfavorable sites with unfavorable age (aged 10 years or older) or a tumor larger than 5 cm, or both;
    • Embryonal rhabdomyosarcoma with nodal involvement; or
    • Alveolar rhabdomyosarcoma without nodal involvement.

    These patients would be classified as intermediate risk by the COG.

    Patients received initial treatment with cycles of IVA—ifosfamide (6 g/m2), dactinomycin (1.5 mg/m2), and vincristine (1.5 mg/m2)—for 7 weeks, followed by randomization to continue IVA or IVA with doxorubicin (60 mg/m2). IVA represents a lower alkylating agent dose than the cyclophosphamide dose of 2.2 g/m2 used in COG rhabdomyosarcoma studies. Patients assessed to be in complete remission at the end of initial therapy were randomly assigned to either observation or the addition of six 4-week cycles of maintenance chemotherapy with vinorelbine (25 mg/m2) on days 1, 8, and 15 of each cycle with continuous daily cyclophosphamide (25 mg/m2/day).

    • The 5-year DFS rate was 69.8% for patients in the observation group and 77.6% for patients in the maintenance chemotherapy group (P = .061).
    • The 5-year OS rate was 73.7% for patients in the observation group and 86.5% for patients in the maintenance chemotherapy group (P = .0097).
    • The addition of doxorubicin did not appear to confer any improvement in outcomes.[190]
  7. The CWS conducted a phase III trial (RMS-96) in patients with high-risk nonmetastatic rhabdomyosarcoma and Ewing sarcoma recruited between 1995 to 2004 from the CWS and Italian Soft Tissue Sarcoma Committee institutions.[191] There were 557 evaluable patients with localized rhabdomyosarcoma. Patients were randomly assigned to receive either a four-drug regimen (vincristine, ifosfamide, doxorubicin, dactinomycin; 284 rhabdomyosarcoma patients) or six-drug regimen (carboplatin, epirubicin, vincristine, dactinomycin, ifosfamide, and etoposide; 273 rhabdomyosarcoma patients).
    • The addition of etoposide and carboplatin and increased single-dose ifosfamide did not improve the EFS and overall outcome.
    • Toxicities and secondary malignancies were identical in both treatment arms.
  8. In a randomized, open-label, phase III COG trial (ARST1431), all patients received VAC/VI and a maintenance phase of therapy with vinorelbine and cyclophosphamide.[192] Patients were randomly assigned to receive or not to receive temsirolimus. Among 297 evaluable patients, 148 were assigned to VAC/VI alone and 149 were assigned to VAC/VI with temsirolimus.
    • With a median follow-up of 3.6 years (interquartile range [IQR], 2.8–4.5), the 3-year EFS rate did not differ significantly between the two groups (64.8% [95% CI, 55.5%–74.1%] for the VAC/VI group vs. 66.8% [95% CI, 57.5%–76.2%] for the VAC/VI plus temsirolimus group; HR, 0.86 [95% CI, 0.58–1.26; log-rank P = .44]).

Approximately 20% of Group III patients have a residual mass at the completion of therapy. The presence of a residual mass had no adverse prognostic significance.[185,193] Aggressive alternative therapy is not warranted for patients with rhabdomyosarcoma who have a residual mass at the end of planned therapy unless it has biopsy-proven residual malignant disease. A 2009 analysis by the COG reported that for Group III patients, best response (complete resolution versus partial response or no response) to initial chemotherapy had no impact on overall outcome.[193] In 2020, the COG reported a retrospective analysis of 601 patients with clinical Group III disease. The patients were enrolled in two COG studies (ARST0531 [n = 285] and D9803 [n = 316]) and completed all protocol therapy without developing progressive disease.[194] Response was defined radiographically: 393 patients had complete resolution (65.4%), and 208 patients had partial response/no response (34.6%). The overall 5-year FFS rate was 75% for patients who achieved complete resolution and 66.5% for those who had a partial response/no response (adjusted [adj.] P = .094). Radiographic response was not associated with OS at any site of disease (adj. P = .21). Resection of the end-of-therapy mass did not improve FFS (P = .12) or OS (P = .37). Patients with parameningeal primary sites who achieved complete resolution had significantly improved FFS (adj. P = .037), while those with nonparameningeal primary sites had similar outcomes (adj. P = .47). In conclusion, complete resolution status at the end of protocol therapy in patients with parameningeal clinical Group III rhabdomyosarcoma was associated with improved FFS but not OS.

While induction chemotherapy is commonly administered for 9 to 12 weeks, 2.2% of patients with intermediate-risk rhabdomyosarcoma in the IRS-IV and D9803 studies were found to have early disease progression and did not receive their planned local control therapy.[188][Level of evidence A1]

High-risk Group

High-risk patients have metastatic disease in one or more sites at diagnosis (Stage IV, Group IV). These patients continue to have a relatively poor prognosis with current therapy (5-year survival rate of ≤50%), and new approaches to treatment are needed to improve survival in this group.[170,195,196] Two retrospective studies have examined patients who present with metastases limited to the lungs;[169,170] results are summarized in the Metastatic disease section of this summary.

The standard systemic therapy for children with metastatic rhabdomyosarcoma is the three-drug combination of VAC.

Evidence (chemotherapy for high-risk Group patients):

  1. A multinational pooled analysis included 788 patients with high-risk rhabdomyosarcoma who were treated with multiagent chemotherapy (all regimens used cyclophosphamide or ifosfamide plus dactinomycin and vincristine, with or without other agents), followed by local therapy (surgery with or without RT) within 3 to 5 months after starting chemotherapy.[197][Level of evidence C1]

    The analysis identified several adverse prognostic factors (Oberlin risk factors):

    • Age at diagnosis younger than 1 year or 10 years and older.
    • Unfavorable primary site (all sites that are not orbit, nonparameningeal head and neck, genitourinary tract other than bladder/prostate, and biliary tract).
    • Bone and/or bone marrow involvement.
    • Three or more different metastatic sites or tissues.

    The EFS rate at 3 years depended on the number of adverse prognostic factors:[197][Level of evidence C1]

    • The EFS rate was 50% for patients without any of these adverse prognostic factors.
    • The EFS rates were 42% for patients with one adverse prognostic factor, 18% for patients with two adverse prognostic factors, 12% for patients with three adverse prognostic factors, and 5% for patients with four adverse prognostic factors (P < .0001).

Many clinical trials have tried to improve outcomes by adding additional agents to standard VAC chemotherapy or substituting new agents for one or more components of VAC chemotherapy. To date, no chemotherapy regimens have been shown to be more effective than VAC, including the following:

  1. In the IRS-IV study, three combinations of drug pairs were studied in an up-front window: IE, vincristine/melphalan (VM),[198] and ifosfamide/doxorubicin (ID).[199] These patients received VAC after the up-front window agents were evaluated at weeks 6 and 12.
    • OS rates for patients treated with IE and ID were comparable (31% and 34%, respectively) and better than for those treated with VM (22%).[199]
    • Results with VAC chemotherapy for Stage IV rhabdomyosarcoma in the North American experience are similar.
  2. Results from a phase II window trial of patients with metastatic disease at presentation and treated with topotecan and cyclophosphamide showed activity for this two-drug combination.[183,184]
    • Survival was not different from that seen with previous regimens.
    • An up-front window trial of topotecan in previously untreated children and adolescents with metastatic rhabdomyosarcoma showed similar results.[182]
  3. Irinotecan and the VI combination have also been evaluated as up-front window trials by the COG-STS.[200]
    • The response rates were better when irinotecan was administered with vincristine than without it.
    • Survival in a preliminary analysis was not improved over previous experience.
  4. In a French study, 20 patients with metastatic disease at diagnosis received window therapy with doxorubicin for two courses.[201]
    • Thirteen of 20 patients responded to therapy, and four patients had progressive disease.
  5. A study from the SIOP demonstrated continued poor outcomes for patients with high-risk features such as age 10 years and older or bone/bone marrow involvement. This study compared a standard six-drug combination followed by vincristine/doxorubicin/cyclophosphamide (VDC) maintenance versus an arm that evaluated a window of single-agent doxorubicin or carboplatin followed by sequential high-dose monotherapy courses, including cyclophosphamide, etoposide, and carboplatin followed by maintenance VAC.[202]
    • No benefit was seen for the high-dose therapy arm.
  6. A study of patients with previously untreated metastatic rhabdomyosarcoma from the COG-STS examined outcomes of 109 patients with the disease.[197] Several treatment strategies, all given over 54 planned weeks, were used:
    1. A period of compressed (every 2 weeks) schedule of chemotherapy using VDC alternating with IE.
    2. The addition of VI, including during RT.
    3. A period of VDC therapy.

    The following results were observed:

    • Using Oberlin risk factors (age <1 or >10 years, unfavorable primary site, number of metastatic sites, and presence or absence of bone/bone marrow involvement), the strategy improved outcome compared with historical controls for patients with lower-risk disease. The 3-year EFS rates were 69% for those with an Oberlin risk factor score of zero or one and 60% for patients younger than 10 years with embryonal rhabdomyosarcoma.[203][Level of evidence C2]
    • However, patients with more than two Oberlin risk factors had a 3-year EFS rate of 20%, comparable to historical outcomes. This intensive protocol did not appear to improve outcome for the highest-risk patients.
  7. The EpSSG performed a randomized prospective phase III trial of patients with high-risk rhabdomyosarcoma. They compared a standard arm comprising nine cycles of IVA with an investigational arm comprising four cycles of IVA plus doxorubicin, followed by five cycles of IVA.[190][Level of evidence C1]
    • The investigational therapy was associated with increased toxicity, including treatment-related mortality, and was not associated with improvement in either EFS or OS.
  8. The COG performed two nonrandomized pilot trials in patients with high-risk rhabdomyosarcoma. All patients received 54 weeks of chemotherapy, including VI, interval-compressed VDC alternating with IE, and vincristine/dactinomycin/cyclophosphamide.[204][Level of evidence C2]
    1. In pilot 1, patients received intravenous cixutumumab (3, 6, or 9 mg/kg) once weekly throughout therapy. Cixutumumab is a monoclonal antibody against the insulin-like growth factor 1 receptor.
    2. In pilot 2, patients received oral temozolomide (100 mg/m2) daily for 5 days with irinotecan.

    The following results were observed:

    • With a median follow-up of 2.9 years, the 3-year EFS rate was 16% (95% CI, 7%–25%) for patients who received cixutumumab and 18% (95% CI, 2%–35%) for patients who received temozolomide.
    • These results did not differ from the results observed in the ARST0431 (NCT00354744) trial that used the same chemotherapy regimen.
  9. A European multinational collaboration investigated an intensive induction regimen followed by 1 year of maintenance therapy for patients with high-risk rhabdomyosarcoma who were aged 21 years or younger. Induction therapy consisted of four cycles of ifosfamide, vincristine, dactinomycin, and doxorubicin followed by five cycles of ifosfamide, vincristine, and dactinomycin. Maintenance therapy comprised 48 weeks of low-dose intravenous vinorelbine and low-dose oral cyclophosphamide. There were 270 evaluable patients.[205]
    • The 3-year EFS rate was 34.9% (95% CI, 29.1%–40.8%), and the OS rate was 47.9% (95% CI, 41.6%–53.9%).
    • The investigators simultaneously conducted a prospective randomized trial that tested the addition of bevacizumab to chemotherapy. In a subset of 102 patients, 50 were assigned to receive bevacizumab. The addition of bevacizumab did not improve EFS or OS.

Other Therapeutic Approaches

  • High-dose chemotherapy with autologous and allogeneic stem cell rescue has been evaluated in a limited number of patients with rhabdomyosarcoma.[206–208] The use of this modality has failed to improve the outcomes of patients with newly diagnosed or recurrent rhabdomyosarcoma.[208]
  • The National Cancer Institute’s (NCI) intramural Pediatric Oncology Branch conducted a pilot study of cytoreductive treatment followed by consolidative immunotherapy incorporating T-cell reconstitution, plus a dendritic-cell and tumor-peptide vaccine that was given with minimal toxicity to patients with translocation-positive metastatic or recurrent Ewing sarcoma (n = 37) and alveolar rhabdomyosarcoma (n = 15). Ten patients with alveolar rhabdomyosarcoma had improved survival, compared with five patients who did not receive immunotherapy.[209][Level of evidence C1]

Treatment Options Under Clinical Evaluation for Childhood Rhabdomyosarcoma

Information about NCI-supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, see the ClinicalTrials.gov website.

The following is an example of a national and/or institutional clinical trial that is currently being conducted:

  • ARST2032 (NCT05304585) (Chemotherapy for the Treatment of Patients With Newly Diagnosed Very Low-Risk and Low-Risk, Fusion-Negative Rhabdomyosarcoma): The COG redefined low-risk rhabdomyosarcoma using both clinical and molecular criteria. The new criteria will be used in this study. Patients are required to enroll in the COG APEC14B1 trial and the Molecular Characterization Initiative. Low-risk patients have both fusion-negative and wild-type MYOD1 and TP53. In this trial, very low-risk patients will receive 24 weeks of VA therapy, and low-risk patients will receive four cycles of VAC followed by VA for a total of 24 weeks.
    Table ARST2032 Risk Assignment for Low-Risk Patients
    Subset Fusion status Tumor Site  Tumor Size  Surgical-pathological Group  MYOD1 or TP53 Status
    Very Low Risk Negative Favorable  Any  I Wild-type
    Low Risk Negative Favorable Any II Wild-type
    Unfavorable >5 cm I, II
    Orbit Any III

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

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  163. Kato MA, Flamant F, Terrier-Lacombe MJ, et al.: Rhabdomyosarcoma of the larynx in children: a series of five patients treated in the Institut Gustave Roussy (Villejuif, France). Med Pediatr Oncol 19 (2): 110-4, 1991. [PUBMED Abstract]
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  165. Cribbs RK, Shehata BM, Ricketts RR: Primary ovarian rhabdomyosarcoma in children. Pediatr Surg Int 24 (5): 593-5, 2008. [PUBMED Abstract]
  166. Affinita MC, Merks JHM, Chisholm JC, et al.: Rhabdomyosarcoma with unknown primary tumor site: A report from European pediatric Soft tissue sarcoma Study Group (EpSSG). Pediatr Blood Cancer 69 (12): e29967, 2022. [PUBMED Abstract]
  167. Ben Arush M, Minard-Colin V, Mosseri V, et al.: Does aggressive local treatment have an impact on survival in children with metastatic rhabdomyosarcoma? Eur J Cancer 51 (2): 193-201, 2015. [PUBMED Abstract]
  168. Vaarwerk B, Bisogno G, McHugh K, et al.: Indeterminate Pulmonary Nodules at Diagnosis in Rhabdomyosarcoma: Are They Clinically Significant? A Report From the European Paediatric Soft Tissue Sarcoma Study Group. J Clin Oncol 37 (9): 723-730, 2019. [PUBMED Abstract]
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  174. Bergeron C, Jenney M, De Corti F, et al.: Embryonal rhabdomyosarcoma completely resected at diagnosis: The European paediatric Soft tissue sarcoma Study Group RMS2005 experience. Eur J Cancer 146: 21-29, 2021. [PUBMED Abstract]
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  179. Spunt SL, Smith LM, Ruymann FB, et al.: Cyclophosphamide dose intensification during induction therapy for intermediate-risk pediatric rhabdomyosarcoma is feasible but does not improve outcome: a report from the soft tissue sarcoma committee of the children’s oncology group. Clin Cancer Res 10 (18 Pt 1): 6072-9, 2004. [PUBMED Abstract]
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  182. Pappo AS, Lyden E, Breneman J, et al.: Up-front window trial of topotecan in previously untreated children and adolescents with metastatic rhabdomyosarcoma: an intergroup rhabdomyosarcoma study. J Clin Oncol 19 (1): 213-9, 2001. [PUBMED Abstract]
  183. Saylors RL, Stine KC, Sullivan J, et al.: Cyclophosphamide plus topotecan in children with recurrent or refractory solid tumors: a Pediatric Oncology Group phase II study. J Clin Oncol 19 (15): 3463-9, 2001. [PUBMED Abstract]
  184. Walterhouse DO, Lyden ER, Breitfeld PP, et al.: Efficacy of topotecan and cyclophosphamide given in a phase II window trial in children with newly diagnosed metastatic rhabdomyosarcoma: a Children’s Oncology Group study. J Clin Oncol 22 (8): 1398-403, 2004. [PUBMED Abstract]
  185. Arndt CA, Stoner JA, Hawkins DS, et al.: Vincristine, actinomycin, and cyclophosphamide compared with vincristine, actinomycin, and cyclophosphamide alternating with vincristine, topotecan, and cyclophosphamide for intermediate-risk rhabdomyosarcoma: children’s oncology group study D9803. J Clin Oncol 27 (31): 5182-8, 2009. [PUBMED Abstract]
  186. Arndt CA, Hawkins DS, Meyer WH, et al.: Comparison of results of a pilot study of alternating vincristine/doxorubicin/cyclophosphamide and etoposide/ifosfamide with IRS-IV in intermediate risk rhabdomyosarcoma: a report from the Children’s Oncology Group. Pediatr Blood Cancer 50 (1): 33-6, 2008. [PUBMED Abstract]
  187. Oberlin O, Rey A, Sanchez de Toledo J, et al.: Randomized comparison of intensified six-drug versus standard three-drug chemotherapy for high-risk nonmetastatic rhabdomyosarcoma and other chemotherapy-sensitive childhood soft tissue sarcomas: long-term results from the International Society of Pediatric Oncology MMT95 study. J Clin Oncol 30 (20): 2457-65, 2012. [PUBMED Abstract]
  188. Hawkins DS, Chi YY, Anderson JR, et al.: Addition of Vincristine and Irinotecan to Vincristine, Dactinomycin, and Cyclophosphamide Does Not Improve Outcome for Intermediate-Risk Rhabdomyosarcoma: A Report From the Children’s Oncology Group. J Clin Oncol 36 (27): 2770-2777, 2018. [PUBMED Abstract]
  189. Bisogno G, De Salvo GL, Bergeron C, et al.: Vinorelbine and continuous low-dose cyclophosphamide as maintenance chemotherapy in patients with high-risk rhabdomyosarcoma (RMS 2005): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol 20 (11): 1566-1575, 2019. [PUBMED Abstract]
  190. Bisogno G, Jenney M, Bergeron C, et al.: Addition of dose-intensified doxorubicin to standard chemotherapy for rhabdomyosarcoma (EpSSG RMS 2005): a multicentre, open-label, randomised controlled, phase 3 trial. Lancet Oncol 19 (8): 1061-1071, 2018. [PUBMED Abstract]
  191. Sparber-Sauer M, Ferrari A, Kosztyla D, et al.: Long-term results from the multicentric European randomized phase 3 trial CWS/RMS-96 for localized high-risk soft tissue sarcoma in children, adolescents, and young adults. Pediatr Blood Cancer 69 (9): e29691, 2022. [PUBMED Abstract]
  192. Gupta AA, Xue W, Harrison DJ, et al.: Addition of temsirolimus to chemotherapy in children, adolescents, and young adults with intermediate-risk rhabdomyosarcoma (ARST1431): a randomised, open-label, phase 3 trial from the Children’s Oncology Group. Lancet Oncol 25 (7): 912-921, 2024. [PUBMED Abstract]
  193. Rodeberg DA, Stoner JA, Hayes-Jordan A, et al.: Prognostic significance of tumor response at the end of therapy in group III rhabdomyosarcoma: a report from the children’s oncology group. J Clin Oncol 27 (22): 3705-11, 2009. [PUBMED Abstract]
  194. Lautz TB, Chi YY, Tian J, et al.: Relationship between tumor response at therapy completion and prognosis in patients with Group III rhabdomyosarcoma: A report from the Children’s Oncology Group. Int J Cancer 147 (5): 1419-1426, 2020. [PUBMED Abstract]
  195. Crist W, Gehan EA, Ragab AH, et al.: The Third Intergroup Rhabdomyosarcoma Study. J Clin Oncol 13 (3): 610-30, 1995. [PUBMED Abstract]
  196. Breneman JC, Lyden E, Pappo AS, et al.: Prognostic factors and clinical outcomes in children and adolescents with metastatic rhabdomyosarcoma–a report from the Intergroup Rhabdomyosarcoma Study IV. J Clin Oncol 21 (1): 78-84, 2003. [PUBMED Abstract]
  197. Oberlin O, Rey A, Lyden E, et al.: Prognostic factors in metastatic rhabdomyosarcomas: results of a pooled analysis from United States and European cooperative groups. J Clin Oncol 26 (14): 2384-9, 2008. [PUBMED Abstract]
  198. Breitfeld PP, Lyden E, Raney RB, et al.: Ifosfamide and etoposide are superior to vincristine and melphalan for pediatric metastatic rhabdomyosarcoma when administered with irradiation and combination chemotherapy: a report from the Intergroup Rhabdomyosarcoma Study Group. J Pediatr Hematol Oncol 23 (4): 225-33, 2001. [PUBMED Abstract]
  199. Sandler E, Lyden E, Ruymann F, et al.: Efficacy of ifosfamide and doxorubicin given as a phase II “window” in children with newly diagnosed metastatic rhabdomyosarcoma: a report from the Intergroup Rhabdomyosarcoma Study Group. Med Pediatr Oncol 37 (5): 442-8, 2001. [PUBMED Abstract]
  200. Pappo AS, Lyden E, Breitfeld P, et al.: Two consecutive phase II window trials of irinotecan alone or in combination with vincristine for the treatment of metastatic rhabdomyosarcoma: the Children’s Oncology Group. J Clin Oncol 25 (4): 362-9, 2007. [PUBMED Abstract]
  201. Bergeron C, Thiesse P, Rey A, et al.: Revisiting the role of doxorubicin in the treatment of rhabdomyosarcoma: an up-front window study in newly diagnosed children with high-risk metastatic disease. Eur J Cancer 44 (3): 427-31, 2008. [PUBMED Abstract]
  202. McDowell HP, Foot AB, Ellershaw C, et al.: Outcomes in paediatric metastatic rhabdomyosarcoma: results of The International Society of Paediatric Oncology (SIOP) study MMT-98. Eur J Cancer 46 (9): 1588-95, 2010. [PUBMED Abstract]
  203. Weigel BJ, Lyden E, Anderson JR, et al.: Intensive Multiagent Therapy, Including Dose-Compressed Cycles of Ifosfamide/Etoposide and Vincristine/Doxorubicin/Cyclophosphamide, Irinotecan, and Radiation, in Patients With High-Risk Rhabdomyosarcoma: A Report From the Children’s Oncology Group. J Clin Oncol 34 (2): 117-22, 2016. [PUBMED Abstract]
  204. Malempati S, Weigel BJ, Chi YY, et al.: The addition of cixutumumab or temozolomide to intensive multiagent chemotherapy is feasible but does not improve outcome for patients with metastatic rhabdomyosarcoma: A report from the Children’s Oncology Group. Cancer 125 (2): 290-297, 2019. [PUBMED Abstract]
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  206. Admiraal R, van der Paardt M, Kobes J, et al.: High-dose chemotherapy for children and young adults with stage IV rhabdomyosarcoma. Cochrane Database Syst Rev (12): CD006669, 2010. [PUBMED Abstract]
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Treatment of Progressive or Recurrent Childhood Rhabdomyosarcoma

Prognosis and Prognostic Factors

Although patients with progressive or recurrent rhabdomyosarcoma sometimes achieve complete remission with secondary therapy, the long-term prognosis is usually poor.[1,2] Rhabdomyosarcoma may relapse locally or in the lung, bone, or bone marrow. Less commonly, the site of first recurrence can be the breast in adolescent females or the liver.[3]

The following studies reported on the prognostic factors associated with progressive or recurrent disease:

  • In a 1999 study of 605 children, the prognosis was most favorable (5-year survival rates, 50%–70%) for children who initially presented with Stage 1 or Group I disease and embryonal/botryoid histology with small tumors and for those with local or regional nodal recurrence. Patients with Group I alveolar rhabdomyosarcoma or undifferentiated sarcoma had 5-year overall survival (OS) rates of 40% to 50%. This population of patients with improved outcomes encompasses only 20% of all patients with a relapse.[1][Level of evidence C1]
  • In a 2014 study of 24 children, 22 (82%) children with initially localized orbital sarcoma survived at least 5 years after relapse following re-treatment with curative intent.[4][Level of evidence C1]
  • A 2005 study of 125 patients with nonmetastatic rhabdomyosarcoma whose disease recurred after previous complete remission observed that favorable factors at initial diagnosis included: nonalveolar histology; primary site in the orbit, genitourinary/nonbladder-prostate, or head/neck nonparameningeal regions; tumor size of 5 cm or smaller; local relapse; relapse after 18 months from the primary diagnosis; and lack of initial radiation therapy (RT).[2]
  • A report of 337 patients with nonmetastatic rhabdomyosarcoma in 2008 observed that favorable factors at initial diagnosis were age 10 years or younger, embryonal histology, tumor size of 5 cm or smaller, favorable site, and lack of initial RT.[5]
  • In a 2009 study of 234 patients who had a relapse after achieving complete remission and completing primary treatment, the favorable prognostic factors for 3-year OS were reported. These factors were favorable primary site, local relapse, time to relapse of more than 12 months, tumor size of 5 cm or smaller, and no previous RT.[6][Level of evidence C1]
  • A 2011 study of 474 patients with nonmetastatic rhabdomyosarcoma who had complete local control at the primary site noted the unfavorable factors for survival 3 years after first relapse. These unfavorable factors included relapse with metastatic disease, previous (initial) RT, tumor size more than 5 cm, time to relapse of less than 18 months, regional lymph node involvement, alveolar histology, and unfavorable disease at primary diagnosis.[7]
  • In 2013, 90 patients with nonmetastatic alveolar rhabdomyosarcoma were re-treated with additional chemotherapy, with or without local re-excision of the primary site (if indicated) and with or without RT. The four most important factors for survival after relapse were no lymph node involvement, no metastases, adequate local therapy, and a second complete remission. The OS rate at 5 years was 21%.[8][Level of evidence C1]
  • A single-institution, retrospective review identified 23 patients with central nervous system (CNS) relapse after initial treatment for rhabdomyosarcoma.[9][Level of evidence C1] High-risk features at initial presentation included 16 alveolar patients, 13 Stage 4 patients, and 13 patients with primary tumor in parameningeal locations. All of the patients died. Twenty-one patients died of CNS disease, and two died of metastatic disease at other sites. Median survival post-CNS relapse was 5 months (range, 0.1–49 months).

Treatment Options for Progressive or Recurrent Childhood Rhabdomyosarcoma

The selection of additional treatment depends on many factors, including the site(s) of progression or recurrence, previous treatment, and individual patient considerations.

Treatment options for progressive or recurrent childhood rhabdomyosarcoma include the following:

  1. Surgery. Treatment for local or regional recurrence may include wide local excision or aggressive surgical removal of tumor, particularly in the absence of widespread bony metastases.[10,11] Some survivors have also been reported after surgical removal of only one or a few metastases in the lung.[10] A review examined 108 Italian children with bladder or prostate tumors who did not achieve tumor eradication after chemotherapy, with or without RT. The study found that only two factors correlated with inability to achieve progression-free survival (PFS) at 5 or more years: initial histology showing undifferentiated sarcoma (P = .008) and diameter of the surgically removed tumor exceeding 5 cm. Positive tumor margins at the salvage operation did not predict ultimate failure.[12][Level of evidence C2]
  2. RT. RT should be considered for patients with rhabdomyosarcoma who have not already received RT in the area of recurrence, or selectively for those who have received previous RT, particularly for those in whom surgical excision is not possible. RT techniques may include external beam in fractionated or hypofractionated courses (e.g., stereotactic body radiation therapy, CyberKnife, or brachytherapy). The rationale is primarily to improve local control that can translate into a better quality of life. An impact on OS is unlikely because of the metastatic disease that often occurs. Even a benefit on local control is difficult to unequivocally demonstrate because of small patient numbers in available reports. For example, in a multi-institutional study of 23 patients with local relapse only (n = 19) or local relapse with distant failure (n = 4) who were managed with (n = 12) or without (n = 11) re-irradiation, the local failure-free survival and OS in re-irradiated versus unirradiated patients was 19.6 months versus 12.4 months (P = .1) and 26.1 months versus 18.8 months (P = .46). In this report, patients with favorable site and Group 3 disease local (only) failure, and/or embryonal histology had improved 3-year local relapse-free survival rates with re-irradiation (62.3% vs. 40%; P = .11).[13]
  3. Chemotherapy. A German study found that treatment with multiagent chemotherapy incorporating carboplatin and etoposide, plus RT, was efficacious for patients with embryonal rhabdomyosarcoma (5-year event-free survival [EFS] rate, 41%), but it was less effective for patients with alveolar rhabdomyosarcoma (5-year EFS rate, 25%).[14] Previously unused, active, single agents or combinations of drugs may also enhance the likelihood of disease control.

The following chemotherapy regimens have been used to treat progressive or recurrent rhabdomyosarcoma:

  1. Carboplatin and etoposide.[14]
  2. Ifosfamide, carboplatin, and etoposide.[15,16]
  3. Cyclophosphamide and topotecan.[17]
  4. Topotecan, carboplatin, cyclophosphamide, and etoposide.[18]
    1. In a 2018 Italian study, 38 patients with recurrent or refractory rhabdomyosarcoma were treated with topotecan, carboplatin, cyclophosphamide, and etoposide.[18][Level of evidence C1]
      • Nine of 32 patients had a complete or partial response. However, the 5-year OS rate was 17%, and the PFS rate was 14%.
  5. Single-agent vinorelbine.[19,20]
    • In one phase II trial, 4 of 11 patients with recurrent rhabdomyosarcoma responded to single-agent vinorelbine.[19]
    • In another trial, 6 of 12 young patients (aged 9–29 years) had a partial response.[20]
    • In a meta-analysis of five studies, patients with relapsed alveolar rhabdomyosarcoma responded better to vinorelbine, either alone or in combination with other agents, than patients with relapsed embryonal and unclassified rhabdomyosarcoma.[21]
  6. Vinorelbine and cyclophosphamide.[22,23]
    1. In a pilot study, three of nine patients with rhabdomyosarcoma had an objective response.[22]
    2. In a phase II study in France (N = 50), children with recurrent or refractory rhabdomyosarcoma were treated with vinorelbine and low-dose oral cyclophosphamide.[23][Level of evidence C3]
      • Four complete responses and 14 partial responses were observed, for an objective response rate of 36%.
  7. Gemcitabine and docetaxel.[24]
    • In a single-institution trial, two patients (N = 5) with recurrent rhabdomyosarcoma achieved an objective response.[24]
  8. Sirolimus.[25]
  9. Topotecan, vincristine, and doxorubicin.[26][Level of evidence C3]
  10. Vincristine, irinotecan, and temozolomide.[27–29]
    1. One of four patients with recurrent alveolar rhabdomyosarcoma had a complete radiographic response sustained for 27 weeks with no grade 3 or 4 toxicities.[27]; [28][Level of evidence C2]
    2. A group of 15 patients with relapsed rhabdomyosarcoma were treated with vincristine, irinotecan, and temozolomide. Many of the patients had received previous relapse therapy.[29][Level of evidence C1]
      • There were no complete or partial remissions; four patients had stable disease, and 11 patients had progressive disease.
  11. Vincristine, irinotecan, doxorubicin, cyclophosphamide, etoposide, ifosfamide, and tirapazamine.[30]
    1. In 2019, the Children’s Oncology Group (COG) reported three trials of patients with recurrent or refractory rhabdomyosarcoma with specific criteria for eligibility. Unfavorable-risk patients with measurable disease could undergo a 6-week phase II window study of vincristine and irinotecan (VI). Patients with at least a partial response then received 44 weeks of assigned chemotherapy. Unfavorable-risk patients without measurable disease, no radiographic response, or refusal to go on window therapy received 31 weeks of multiagent chemotherapy plus tirapazamine.[30][Level of evidence C1]
      • Favorable-risk patients had a 3-year failure-free survival (FFS) rate of 79% and an OS rate of 84%.
      • Thirty patients with unfavorable-risk disease who were not treated with VI had a 3-year FFS rate of 21% and an OS rate of 39%.
  12. Irinotecan with or without vincristine and with or without temozolomide.[31–36]
    1. A COG prospective, randomized, up-front window trial, COG-ARST0121, compared VI (20 mg/m2/d) daily × 5 days for 4 weeks per 6-week treatment cycle (Regimen 1A) and irinotecan (50 mg/m2/d) daily × 5 days for 2 weeks per 6-week treatment cycle (Regimen 1B) in poor-risk patients with relapsed or progressive rhabdomyosarcoma.[35][Level of evidence A1]
      • At 1 year after initiation of treatment for recurrence, the FFS rate was 37% and the OS rate was 55% for Regimen 1A.
      • At 1 year after initiation of treatment for recurrence, the FFS rate was 38% and OS rate was 60% for Regimen 1B.
      • The Soft Tissue Sarcoma Committee of the COG recommended the more convenient Regimen 1B for further investigation.
    2. In a European Soft Tissue Sarcoma Study Group study, 120 patients with recurrent or refractory rhabdomyosarcoma were randomly assigned to receive either VI or vincristine, irinotecan, and temozolomide (VIT).[37][Level of evidence A1]
      • The objective response rate was 44% (24 of 55 evaluable patients) for patients who received VIT, compared with 31% (18 of 58) for patients who received VI.
      • The patients in the VIT arm achieved significantly better OS (adjusted hazard ratio [HR], 0.55; 95% confidence interval [CI], 0.35–0.84; P = .006), than patients on the VI arm, with consistent PFS results (adjusted HR, 0.68; 95% CI, 0.46–1.01; P = .059).
      • Overall, patients experienced grade 3 or greater adverse events more frequently with VIT than VI (98% vs. 78%, respectively; P = .009), including a significant excess of hematological toxicity (81% vs. 61%; P = .025).
  13. Temsirolimus, irinotecan, and temozolomide.[38]
    1. In a phase I trial of these agents, four patients had rhabdomyosarcoma.[38]
      • The regimen was well tolerated.
      • One patient had a partial response, and another patient had stable disease.
  14. Temsirolimus, cyclophosphamide, and vinorelbine.[39]
    1. A COG randomized, phase II, selection-design study of patients with relapsed rhabdomyosarcoma compared bevacizumab with temsirolimus, both administered with cyclophosphamide and vinorelbine.[40][Level of evidence C2]
      • Patients on the temsirolimus arm had improved EFS (P = .003). The 6-month and 12-month EFS rates in the temsirolimus arm were 65% (95% CI, 44%–79%) and 40.5% (95% CI, 25.6%–55.3%), respectively, compared with 50% (95% CI, 32%–66%) and 18.2% (95% CI, 6.8%–29.6%) in the bevacizumab arm.
      • The complete response rate (complete remission plus partial remission) was higher on the temsirolimus arm (47%) than on the bevacizumab arm (28%). The difference was not statistically significant at the 0.05 level (P = .12).
      • These results are the basis for the subsequent COG trial randomizing the use of temsirolimus for newly diagnosed patients with nonmetastatic rhabdomyosarcoma (ARST1431 [NCT02567435]).
  15. Adriamycin, carboplatin, cyclophosphamide, topotecan, vincristine, and etoposide (ACCTTIVE) or topotecan, etoposide, carboplatin, and cyclophosphamide (TECC).
    1. The Cooperative Weichteilsarkom Studiengruppe (CWS) examined second-line treatment for patients who had recurrence of rhabdomyosarcoma after initial treatment. Second-line chemotherapy based on anthracyclines (ACCTTIVE) was recommended for patients in initial low-risk, standard-risk, and high-risk groups after their original treatment did not include anthracyclines. TECC was recommended for patients in the very high-risk group after their initial treatment included anthracycline-based regimens. The risk groups included low risk, standard risk, high risk, and very high risk.[41]
      • Initial risk stratification, pattern/time to relapse, and achievement of second complete remission were significant prognostic factors for postrelapse survival.
      • The 5-year OS rates were 80% (± 21%) for patients with relapsed disease in the standard-risk group, 20% (± 16%) for patients in the high-risk group, and 13% (± 23%) for patients in the very high-risk group (P = .008).

Very intensive chemotherapy followed by autologous bone marrow reinfusion is also under investigation for patients with recurrent rhabdomyosarcoma. However, a review of the published data did not determine a significant benefit for patients who underwent this salvage treatment approach.[42–44]

Patients or families who desire additional disease-directed therapy should consider entering trials of novel therapeutic approaches because no standard agents have demonstrated clinically significant activity.

Regardless of whether a decision is made to pursue disease-directed therapy at the time of progression, palliative care remains a central focus of management. This ensures that quality of life is maximized while attempting to reduce symptoms and stress related to the terminal illness.

Palliation of painful lesions in children with recurrent or progressive disease can be achieved using a short course (10 or fewer fractions) of radiation therapy. In a retrospective study of 213 children with various malignancies, who were treated with short course radiation therapy, 85% of patients had complete or partial pain relief, with low levels of toxicity.[45]

Treatment Options Under Clinical Evaluation for Progressive or Recurrent Childhood Rhabdomyosarcoma

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, see the ClinicalTrials.gov website.

The following is an example of a national and/or institutional clinical trial that is currently being conducted:

  • ADVL1621 (NCT02332668) (A Study of Pembrolizumab [MK-3475] in Pediatric Participants With Advanced Melanoma or Advanced, Relapsed, or Refractory PD-L1-Positive Solid Tumors or Lymphoma [MK-3475-051/KEYNOTE-051]): This is a two-part study of pembrolizumab in pediatric participants who have either advanced melanoma or a programmed cell death ligand 1–positive advanced, relapsed, or refractory solid tumor or lymphoma. Part 1 will find the maximum tolerated dose/maximum administered dose, confirm the dose, and find the recommended phase II dose for pembrolizumab therapy. Part 2 will further evaluate the safety and efficacy at the pediatric recommended phase II dose.

New agents under clinical evaluation in phase I and phase II trials should be considered for relapsed patients.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References
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  3. Audino AN, Setty BA, Yeager ND: Rhabdomyosarcoma of the Breast in Adolescent and Young Adult (AYA) Women. J Pediatr Hematol Oncol 39 (1): 62-66, 2017. [PUBMED Abstract]
  4. Raney B, Huh W, Hawkins D, et al.: Outcome of patients with localized orbital sarcoma who relapsed following treatment on Intergroup Rhabdomyosarcoma Study Group (IRSG) Protocols-III and -IV, 1984-1997: a report from the Children’s Oncology Group. Pediatr Blood Cancer 60 (3): 371-6, 2013. [PUBMED Abstract]
  5. Dantonello TM, Int-Veen C, Winkler P, et al.: Initial patient characteristics can predict pattern and risk of relapse in localized rhabdomyosarcoma. J Clin Oncol 26 (3): 406-13, 2008. [PUBMED Abstract]
  6. Mattke AC, Bailey EJ, Schuck A, et al.: Does the time-point of relapse influence outcome in pediatric rhabdomyosarcomas? Pediatr Blood Cancer 52 (7): 772-6, 2009. [PUBMED Abstract]
  7. Chisholm JC, Marandet J, Rey A, et al.: Prognostic factors after relapse in nonmetastatic rhabdomyosarcoma: a nomogram to better define patients who can be salvaged with further therapy. J Clin Oncol 29 (10): 1319-25, 2011. [PUBMED Abstract]
  8. Dantonello TM, Int-Veen C, Schuck A, et al.: Survival following disease recurrence of primary localized alveolar rhabdomyosarcoma. Pediatr Blood Cancer 60 (8): 1267-73, 2013. [PUBMED Abstract]
  9. De B, Kinnaman MD, Wexler LH, et al.: Central nervous system relapse of rhabdomyosarcoma. Pediatr Blood Cancer 65 (1): , 2018. [PUBMED Abstract]
  10. Hayes-Jordan A, Doherty DK, West SD, et al.: Outcome after surgical resection of recurrent rhabdomyosarcoma. J Pediatr Surg 41 (4): 633-8; discussion 633-8, 2006. [PUBMED Abstract]
  11. De Corti F, Bisogno G, Dall’Igna P, et al.: Does surgery have a role in the treatment of local relapses of non-metastatic rhabdomyosarcoma? Pediatr Blood Cancer 57 (7): 1261-5, 2011. [PUBMED Abstract]
  12. Angelini L, Bisogno G, Alaggio R, et al.: Prognostic factors in children undergoing salvage surgery for bladder/prostate rhabdomyosarcoma. J Pediatr Urol 12 (4): 265.e1-8, 2016. [PUBMED Abstract]
  13. Wakefield DV, Eaton BR, Dove APH, et al.: Is there a role for salvage re-irradiation in pediatric patients with locoregional recurrent rhabdomyosarcoma? Clinical outcomes from a multi-institutional cohort. Radiother Oncol 129 (3): 513-519, 2018. [PUBMED Abstract]
  14. Klingebiel T, Pertl U, Hess CF, et al.: Treatment of children with relapsed soft tissue sarcoma: report of the German CESS/CWS REZ 91 trial. Med Pediatr Oncol 30 (5): 269-75, 1998. [PUBMED Abstract]
  15. Kung FH, Desai SJ, Dickerman JD, et al.: Ifosfamide/carboplatin/etoposide (ICE) for recurrent malignant solid tumors of childhood: a Pediatric Oncology Group Phase I/II study. J Pediatr Hematol Oncol 17 (3): 265-9, 1995. [PUBMED Abstract]
  16. Van Winkle P, Angiolillo A, Krailo M, et al.: Ifosfamide, carboplatin, and etoposide (ICE) reinduction chemotherapy in a large cohort of children and adolescents with recurrent/refractory sarcoma: the Children’s Cancer Group (CCG) experience. Pediatr Blood Cancer 44 (4): 338-47, 2005. [PUBMED Abstract]
  17. Saylors RL, Stine KC, Sullivan J, et al.: Cyclophosphamide plus topotecan in children with recurrent or refractory solid tumors: a Pediatric Oncology Group phase II study. J Clin Oncol 19 (15): 3463-9, 2001. [PUBMED Abstract]
  18. Compostella A, Affinita MC, Casanova M, et al.: Topotecan/carboplatin regimen for refractory/recurrent rhabdomyosarcoma in children: Report from the AIEOP Soft Tissue Sarcoma Committee. Tumori 105 (2): 138-143, 2019. [PUBMED Abstract]
  19. Kuttesch JF, Krailo MD, Madden T, et al.: Phase II evaluation of intravenous vinorelbine (Navelbine) in recurrent or refractory pediatric malignancies: a Children’s Oncology Group study. Pediatr Blood Cancer 53 (4): 590-3, 2009. [PUBMED Abstract]
  20. Casanova M, Ferrari A, Spreafico F, et al.: Vinorelbine in previously treated advanced childhood sarcomas: evidence of activity in rhabdomyosarcoma. Cancer 94 (12): 3263-8, 2002. [PUBMED Abstract]
  21. Allen-Rhoades W, Lupo PJ, Scheurer ME, et al.: Alveolar rhabdomyosarcoma has superior response rates to vinorelbine compared to embryonal rhabdomyosarcoma in patients with relapsed/refractory disease: A meta-analysis. Cancer Med 12 (9): 10222-10229, 2023. [PUBMED Abstract]
  22. Casanova M, Ferrari A, Bisogno G, et al.: Vinorelbine and low-dose cyclophosphamide in the treatment of pediatric sarcomas: pilot study for the upcoming European Rhabdomyosarcoma Protocol. Cancer 101 (7): 1664-71, 2004. [PUBMED Abstract]
  23. Minard-Colin V, Ichante JL, Nguyen L, et al.: Phase II study of vinorelbine and continuous low doses cyclophosphamide in children and young adults with a relapsed or refractory malignant solid tumour: good tolerance profile and efficacy in rhabdomyosarcoma–a report from the Société Française des Cancers et leucémies de l’Enfant et de l’adolescent (SFCE). Eur J Cancer 48 (15): 2409-16, 2012. [PUBMED Abstract]
  24. Rapkin L, Qayed M, Brill P, et al.: Gemcitabine and docetaxel (GEMDOX) for the treatment of relapsed and refractory pediatric sarcomas. Pediatr Blood Cancer 59 (5): 854-8, 2012. [PUBMED Abstract]
  25. Houghton PJ, Morton CL, Kolb EA, et al.: Initial testing (stage 1) of the mTOR inhibitor rapamycin by the pediatric preclinical testing program. Pediatr Blood Cancer 50 (4): 799-805, 2008. [PUBMED Abstract]
  26. Meazza C, Casanova M, Zaffignani E, et al.: Efficacy of topotecan plus vincristine and doxorubicin in children with recurrent/refractory rhabdomyosarcoma. Med Oncol 26 (1): 67-72, 2009. [PUBMED Abstract]
  27. McNall-Knapp RY, Williams CN, Reeves EN, et al.: Extended phase I evaluation of vincristine, irinotecan, temozolomide, and antibiotic in children with refractory solid tumors. Pediatr Blood Cancer 54 (7): 909-15, 2010. [PUBMED Abstract]
  28. Mixon BA, Eckrich MJ, Lowas S, et al.: Vincristine, irinotecan, and temozolomide for treatment of relapsed alveolar rhabdomyosarcoma. J Pediatr Hematol Oncol 35 (4): e163-6, 2013. [PUBMED Abstract]
  29. Setty BA, Stanek JR, Mascarenhas L, et al.: VIncristine, irinotecan, and temozolomide in children and adolescents with relapsed rhabdomyosarcoma. Pediatr Blood Cancer 65 (1): , 2018. [PUBMED Abstract]
  30. Mascarenhas L, Lyden ER, Breitfeld PP, et al.: Risk-based treatment for patients with first relapse or progression of rhabdomyosarcoma: A report from the Children’s Oncology Group. Cancer 125 (15): 2602-2609, 2019. [PUBMED Abstract]
  31. Cosetti M, Wexler LH, Calleja E, et al.: Irinotecan for pediatric solid tumors: the Memorial Sloan-Kettering experience. J Pediatr Hematol Oncol 24 (2): 101-5, 2002. [PUBMED Abstract]
  32. Pappo AS, Lyden E, Breitfeld P, et al.: Two consecutive phase II window trials of irinotecan alone or in combination with vincristine for the treatment of metastatic rhabdomyosarcoma: the Children’s Oncology Group. J Clin Oncol 25 (4): 362-9, 2007. [PUBMED Abstract]
  33. Vassal G, Couanet D, Stockdale E, et al.: Phase II trial of irinotecan in children with relapsed or refractory rhabdomyosarcoma: a joint study of the French Society of Pediatric Oncology and the United Kingdom Children’s Cancer Study Group. J Clin Oncol 25 (4): 356-61, 2007. [PUBMED Abstract]
  34. Furman WL, Stewart CF, Poquette CA, et al.: Direct translation of a protracted irinotecan schedule from a xenograft model to a phase I trial in children. J Clin Oncol 17 (6): 1815-24, 1999. [PUBMED Abstract]
  35. Mascarenhas L, Lyden ER, Breitfeld PP, et al.: Randomized phase II window trial of two schedules of irinotecan with vincristine in patients with first relapse or progression of rhabdomyosarcoma: a report from the Children’s Oncology Group. J Clin Oncol 28 (30): 4658-63, 2010. [PUBMED Abstract]
  36. Defachelles AS, Bogart E, Casanova M, et al.: Randomized phase 2 trial of the combination of vincristine and irinotecan with or without temozolomide, in children and adults with refractory or relapsed rhabdomyosarcoma (RMS). [Abstract] J Clin Oncol 37 (Suppl 15): A-10000, 2019. Also available online. Last accessed June 13, 2022.
  37. Defachelles AS, Bogart E, Casanova M, et al.: Randomized Phase II Trial of Vincristine-Irinotecan With or Without Temozolomide, in Children and Adults With Relapsed or Refractory Rhabdomyosarcoma: A European Paediatric Soft Tissue Sarcoma Study Group and Innovative Therapies for Children With Cancer Trial. J Clin Oncol 39 (27): 2979-2990, 2021. [PUBMED Abstract]
  38. Bagatell R, Norris R, Ingle AM, et al.: Phase 1 trial of temsirolimus in combination with irinotecan and temozolomide in children, adolescents and young adults with relapsed or refractory solid tumors: a Children’s Oncology Group Study. Pediatr Blood Cancer 61 (5): 833-9, 2014. [PUBMED Abstract]
  39. Mascarenhas L, Meyer WH, Lyden E, et al.: Randomized phase II trial of bevacizumab and temsirolimus in combination with vinorelbine (V) and cyclophosphamide (C) for first relapse/disease progression of rhabdomyosarcoma (RMS): a report from the Children’s Oncology Group (COG). [Abstract] J Clin Oncol 32 (Suppl 5): A-10003, 2014. Also available online. Last accessed June 13, 2022.
  40. Mascarenhas L, Chi YY, Hingorani P, et al.: Randomized Phase II Trial of Bevacizumab or Temsirolimus in Combination With Chemotherapy for First Relapse Rhabdomyosarcoma: A Report From the Children’s Oncology Group. J Clin Oncol 37 (31): 2866-2874, 2019. [PUBMED Abstract]
  41. Heinz AT, Ebinger M, Schönstein A, et al.: Second-line treatment of pediatric patients with relapsed rhabdomyosarcoma adapted to initial risk stratification: Data of the European Soft Tissue Sarcoma Registry (SoTiSaR). Pediatr Blood Cancer 70 (7): e30363, 2023. [PUBMED Abstract]
  42. Weigel BJ, Breitfeld PP, Hawkins D, et al.: Role of high-dose chemotherapy with hematopoietic stem cell rescue in the treatment of metastatic or recurrent rhabdomyosarcoma. J Pediatr Hematol Oncol 23 (5): 272-6, 2001 Jun-Jul. [PUBMED Abstract]
  43. Admiraal R, van der Paardt M, Kobes J, et al.: High-dose chemotherapy for children and young adults with stage IV rhabdomyosarcoma. Cochrane Database Syst Rev (12): CD006669, 2010. [PUBMED Abstract]
  44. Peinemann F, Kröger N, Bartel C, et al.: High-dose chemotherapy followed by autologous stem cell transplantation for metastatic rhabdomyosarcoma–a systematic review. PLoS One 6 (2): e17127, 2011. [PUBMED Abstract]
  45. Sudmeier LJ, Madden N, Zhang C, et al.: Palliative radiotherapy for children: Symptom response and treatment-associated toxicity according to radiation therapy dose and fractionation. Pediatr Blood Cancer 70 (4): e30195, 2023. [PUBMED Abstract]

Latest Updates to This Summary (04/11/2025)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

General Information About Childhood Rhabdomyosarcoma

Added bone marrow involvement as a prognostic factor for children and adolescents with rhabdomyosarcoma.

Added Bone marrow involvement as a new subsection.

Treatment of Childhood Rhabdomyosarcoma

Added text about the results of a retrospective study that analyzed patients with rhabdomyosarcoma and lung metastases who were enrolled in four Children’s Oncology Group studies that required lung irradiation for patients with metastases (cited Luo et al. as reference 36).

Revised text about the 178 patients with Group 1 N0 disease who were enrolled in subgroups A and B of the European Paediatric Soft Tissue Sarcoma Study Group (EpSSG) RMS-2005 study. Also added text about the results of the 359 patients with localized, node-negative, IRS Group II/III, nonalveolar rhabdomyosarcoma at favorable sites who were enrolled in subgroup C of the EpSSG RMS-2005 study (cited Mandeville et al. as reference 175 and level of evidence B4).

This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood rhabdomyosarcoma. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Childhood Rhabdomyosarcoma Treatment are:

  • Louis S. Constine, MD (James P. Wilmot Cancer Center at University of Rochester Medical Center)
  • Holcombe Edwin Grier, MD
  • Andrea A. Hayes-Dixon, MD, FACS, FAAP (Howard University)
  • William H. Meyer, MD
  • Paul A. Meyers, MD (Memorial Sloan-Kettering Cancer Center)
  • Malcolm A. Smith, MD, PhD (National Cancer Institute)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website’s Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

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The preferred citation for this PDQ summary is:

PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Rhabdomyosarcoma Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/soft-tissue-sarcoma/hp/rhabdomyosarcoma-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389243]

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Childhood Liver Cancer Treatment (PDQ®)–Health Professional Version

Childhood Liver Cancer Treatment (PDQ®)–Health Professional Version

General Information About Childhood Liver Cancer

Liver cancer is a rare malignancy in children and adolescents and is divided into the following two major histological subgroups:

Other less common histologies include the following:

Harmonization of Childhood Liver Cancer Data and Definitions

Historically, four major study groups have performed prospective clinical trials in children with liver tumors: The International Childhood Liver Tumors Strategy Group (previously known as Société Internationale d’Oncologie Pédiatrique–Epithelial Liver Tumor Study Group [SIOPEL]), the Gesellschaft für Pädiatrische Onkologie und Hämatologie (Society for Paediatric Oncology and Haematology [GPOH]), the Japanese Study Group for Pediatric Liver Tumors (JPLT), and the Children’s Oncology Group (COG), including its predecessor groups the Children’s Cancer Group (CCG) and Pediatric Oncology Group (POG). These groups historically had disparate risk stratification categories, data elements that were monitored, and pathological and radiological definitions, making it difficult to compare outcomes across continents.

A collaborative effort among all four study groups collated their disparate data into a unified database called the Children’s Hepatic Tumor International Collaboration (CHIC). The CHIC group analyzed clinical features and outcomes in a database that included 1,605 patients with hepatoblastoma treated in eight separate multicenter clinical trials, with central review of all tumor imaging and histological details.[1] Patients who underwent orthotopic liver transplant were also included.[2]

References
  1. Czauderna P, Haeberle B, Hiyama E, et al.: The Children’s Hepatic tumors International Collaboration (CHIC): Novel global rare tumor database yields new prognostic factors in hepatoblastoma and becomes a research model. Eur J Cancer 52: 92-101, 2016. [PUBMED Abstract]
  2. Otte JB, Pritchard J, Aronson DC, et al.: Liver transplantation for hepatoblastoma: results from the International Society of Pediatric Oncology (SIOP) study SIOPEL-1 and review of the world experience. Pediatr Blood Cancer 42 (1): 74-83, 2004. [PUBMED Abstract]

Cellular Classification of Childhood Liver Cancer

Liver tumors are rare in children. A definitive pathological diagnosis may be challenging because of the rarity of the tumor and the lack of a universal classification system before the Children’s Hepatic Tumor International Collaboration (CHIC) harmonization efforts. Systematic central histopathological review of these tumors, performed as part of pediatric collaborative therapeutic protocols, has allowed the identification of histological subtypes with distinct clinical associations.

The Children’s Oncology Group (COG) Liver Tumor Committee sponsored an International Pathology Symposium in 2011 to discuss the histopathology and classification of pediatric liver tumors (hepatoblastoma, in particular) and develop an International Pediatric Liver Tumors Consensus Classification that would be required for international collaborative projects. The results were published in 2014.[1] In a post-hoc expert consensus review of 599 hepatoblastoma cases treated across five multicenter trials, 570 (95%) were validated and independently re-confirmed to be hepatoblastoma using the CHIC pathology guidelines.[2] This standardized, clinically meaningful classification has allowed the integration of new biological parameters and tumor genetics within a common pathological language to help improve future patient management and outcomes.

For information about the histology of each childhood liver cancer subtype, see the following sections:

References
  1. López-Terrada D, Alaggio R, de Dávila MT, et al.: Towards an international pediatric liver tumor consensus classification: proceedings of the Los Angeles COG liver tumors symposium. Mod Pathol 27 (3): 472-91, 2014. [PUBMED Abstract]
  2. Cho SJ, Ranganathan S, Alaggio R, et al.: Consensus classification of pediatric hepatocellular tumors: A report from the Children’s Hepatic tumors International Collaboration (CHIC). Pediatr Blood Cancer : e30505, 2023. [PUBMED Abstract]

Tumor Stratification by Imaging

A main treatment goal for children and adolescents with liver cancer is surgical extirpation of the primary tumor. Risk grouping depends heavily on factors determined by imaging that are related to safe surgical resection of the tumor, as well as the PRETEXT grouping. These imaging findings include the section or sections of the liver that are involved with the tumor and additional findings, called annotation factors, that impact surgical decision making and prognosis.

Risk stratification of children and adolescents with liver cancer involves the use of high-quality, cross-sectional imaging. Three-phase computed tomography scanning (noncontrast, arterial, and venous) or magnetic resonance imaging (MRI) with contrast agents are used. MRI with gadoxetate disodium, a gadolinium-based agent that is preferentially taken up and excreted by hepatocytes, is being used with increased frequency and may improve detection of multifocal disease.[1]

PRETEXT and POSTTEXT Group Definitions

The imaging grouping systems used to radiologically define the extent of liver involvement by the tumor are designated as the following:

  • PRETEXT (PRE-Treatment EXTent of disease): The extent of liver involvement is defined before therapy.
  • POSTTEXT (POST-Treatment EXTent of disease): The extent of liver involvement is defined in response to therapy.

PRETEXT

Major multicenter trial groups use PRETEXT as a central component of risk stratification schemes that guide treatment of hepatoblastoma. PRETEXT is based on the Couinaud eight-segment anatomical structure of the liver using cross-sectional imaging.

The PRETEXT system divides the liver into four parts, called sections. The left lobe of the liver consists of a lateral section (Couinaud segments I, II, and III) and a medial section (segment IV), whereas the right lobe consists of an anterior section (segments V and VIII) and a posterior section (segments VI and VII) (see Figure 1). PRETEXT groups were devised by the Société Internationale d’Oncologie Pédiatrique–Epithelial Liver Tumor Study Group (SIOPEL) for their first trial, SIOPEL-1,[2] and revised for the SIOPEL-3 trial in 2007.[3]

EnlargeDrawing showing 4 sections of the liver: the right posterior section, the right anterior section, the left medial section, and the left lateral section. Also shown are 8 segments (I-VIII), each corresponding to a specific section of the liver. The boundaries of each section are separated by the right hepatic vein, middle hepatic vein, and left hepatic vein. The vena cava and portal vein are also shown.
Figure 1. The liver is divided into four sections: the right posterior section, the right anterior section, the left medial section, and the left lateral section. Each section of the liver is further divided into segments: segments VI and VII make up the right posterior section, segments V and VIII make up the right anterior section, segment IV makes up the left medial section, and segments II and III make up the left lateral section. Segment I is found deep in the left side of the liver, in front of the inferior vena cava and behind the right, middle, and left hepatic veins.

PRETEXT group assignment I, II, III, or IV is determined by the number of uninvolved sections of the liver. PRETEXT is further described by annotation factors. Annotation factors include findings that are important for surgical management and evidence of tumor extension beyond the hepatic parenchyma of the major sections, including metastatic disease. For detailed descriptions of the PRETEXT groups, see Table 1. For descriptions of the annotation factors, see Table 2.

Annotation factors identify the extent of tumor involvement of the major vessels and its effect on venous inflow and outflow. These factors provide critical knowledge for the surgeon and can affect surgical outcomes. At one time, definitions of gross vascular involvement used by the Children’s Oncology Group (COG) and major liver surgery centers in the United States differed from those used by SIOPEL and in Europe. These differences have been resolved, and the new definitions are being used in an international trial.[4]

Although PRETEXT can be used to predict tumor resectability, it has limitations. It can be difficult to distinguish real invasion beyond the anatomical border of a given hepatic section from compression and displacement by the tumor, especially at diagnosis. Additionally, it can be difficult to distinguish between vessel encroachment and involvement, particularly if imaging is inadequate. The PRETEXT group assignment has a moderate degree of interobserver variability. In a report using data from the SIOPEL-1 study, the preoperative PRETEXT group aligned with postoperative pathological findings only 51% of the time, with overstaging in 37% of patients and understaging in 12% of patients.[5]

Because distinguishing PRETEXT group assignment is difficult, central review of imaging is critical and is generally performed in all major clinical trials. For patients not enrolled in clinical trials, expert radiological review should be considered in questionable cases in which the PRETEXT group assignment affects choice of treatment.

Table 1. Definitions of PRETEXT and POSTTEXT Groupsa
PRETEXT and POSTTEXT Groups Definition Image
aAdapted from Roebuck et al.[3]
I One section involved; three adjoining sections are tumor free.
EnlargeLiver PRETEXT and POSTTEXT I; drawing shows two livers. Dotted lines divide each liver into four vertical sections of about the same size. In the first liver, cancer is shown in the section on the far left. In the second liver, cancer is shown in the section on the far right.
II One or two sections involved; two adjoining sections are tumor free.
EnlargeLiver PRETEXT and POSTTEXT II; drawing shows five livers. Dotted lines divide each liver into four vertical sections that are about the same size. In the first liver, cancer is shown in the two sections on the left. In the second liver, cancer is shown in the two sections on the right. In the third liver, cancer is shown in the far left and far right sections. In the fourth liver, cancer is shown in the second section from the left. In the fifth liver, cancer is shown in the second section from the right.
III Two or three sections involved; one adjoining section is tumor free.
EnlargeLiver PRETEXT and POSTTEXT III; drawing shows seven livers. Dotted lines divide each liver into four vertical sections that are about the same size. In the first liver, cancer is shown in three sections on the left. In the second liver, cancer is shown in the two sections on the left and in the section on the far right. In the third liver, cancer is shown in the section on the far left and in the two sections on the right. In the fourth liver, cancer is shown in three sections on the right. In the fifth liver, cancer is shown in the two middle sections. In the sixth liver, cancer is shown in the section on the far left and in the second section from the right. In the seventh liver, cancer is shown in the section on the far right and in the second section from the left.
IV Four sections involved.
EnlargeLiver PRETEXT and POSTTEXT IV; drawing shows two livers. Dotted lines divide each liver into four vertical sections that are about the same size. In the first liver, cancer is shown across all four sections. In the second liver, cancer is shown in the two sections on the left and spots of cancer are shown in the two sections on the right.
Table 2. Annotation Factors for Describing PRETEXT and POSTTEXT Groupsa
Annotation Factors Definition
CT = computed tomography; MRI = magnetic resonance imaging; HU = Hounsfield unit.
aAdapted from Roebuck et al.[3]
bAdditional details describing the annotation factors have been published.[4]
Vb Venous involvement: Vascular involvement of the retrohepatic vena cava or involvement of all three major hepatic veins (right, middle, and left).
V0   Tumor within 1 cm.
V1   Tumor abutting.
V2   Tumor compressing or distorting.
V3   Tumor ingrowth, encasement, or thrombus.
Pb Portal involvement: Vascular involvement of the main portal vein and/or both right and left portal veins.
P0   Tumor within 1 cm.
P1   Tumor abutting the main portal vein, the right and left portal veins, or the portal vein bifurcation.
  P2   Tumor compressing the main portal vein, the right and left portal veins, or the portal vein bifurcation.
P3   Tumor ingrowth, encasement (>50% or >180 degrees), or intravascular thrombus within the main portal vein, the right and left portal veins, or the portal vein bifurcation.
Eb Extrahepatic spread of disease. Any one of the following criteria is met:
E1   Tumor crosses boundaries/tissue planes.
E2   Tumor is surrounded by normal tissue more than 180 degrees.
  E3   Peritoneal nodules (not lymph nodes) are present so that there is at least one nodule measuring ≥10 mm or at least two nodules measuring ≥5 mm.
Mb Distant metastases. Any one of the following criteria is met:
  M1   One noncalcified pulmonary nodule ≥5 mm in diameter.
  M2   Two or more noncalcified pulmonary nodules, each ≥3 mm in diameter.
  M3   Pathologically proven metastatic disease.
C Tumor involving the caudate.
F Multifocality. Two or more discrete hepatic tumors with normal intervening liver tissue.
Nb Lymph node metastases. Any one of the following criteria is met:
  N1   Lymph node with short-axis diameter of >1 cm.
  N2   Portocaval lymph node with short-axis diameter >1.5 cm.
  N3   Spherical lymph node shape with loss of fatty hilum.
Rb Tumor rupture. Free fluid in the abdomen or pelvis with one or more of the following findings of hemorrhage:
  R1   Internal complexity/septations within fluid.
  R2   High-density fluid on CT (>25 HU).
  R3   Imaging characteristics of blood or blood degradation products on MRI.
  R4   Heterogeneous fluid on ultrasound with echogenic debris.
  R5   Visible defect in tumor capsule OR tumor cells are present within the peritoneal fluid OR rupture diagnosed pathologically in patients who have received an upfront resection.

POSTTEXT

The POSTTEXT group is determined after patients receive chemotherapy. The greatest chemotherapy response, measured as decreases in tumor size and alpha-fetoprotein (AFP) level, occurs after the first two cycles of chemotherapy.[6,7] A study that evaluated surgical resectability after two versus four cycles of chemotherapy showed that many tumors may be resectable after two cycles.[6]

Evans Surgical Staging for Childhood Liver Cancer

The COG/Evans staging system, based on operative findings and surgical resectability, was used for many years in the United States to group and determine treatment for children with liver cancer (see Table 3).[8–10] Currently, other risk stratification systems are predominantly used to classify patients and determine treatment strategy, although the Paediatric Hepatic International Tumour Trial (PHITT) uses the Evans system for patients with hepatocellular carcinoma. For more information, see Table 5.

Table 3. Definition of Evans Surgical Staging
Evans Surgical Stage Definition
Stage I The tumor is completely resected.
Stage II Microscopic residual tumor remains after resection.
Stage III There are no distant metastases and at least one of the following is true: (1) the tumor is either unresectable or the tumor is resected with gross residual tumor; (2) there are positive extrahepatic lymph nodes.
Stage IV There is distant metastasis, regardless of the extent of liver involvement.
References
  1. Meyers AB, Towbin AJ, Geller JI, et al.: Hepatoblastoma imaging with gadoxetate disodium-enhanced MRI–typical, atypical, pre- and post-treatment evaluation. Pediatr Radiol 42 (7): 859-66, 2012. [PUBMED Abstract]
  2. Brown J, Perilongo G, Shafford E, et al.: Pretreatment prognostic factors for children with hepatoblastoma– results from the International Society of Paediatric Oncology (SIOP) study SIOPEL 1. Eur J Cancer 36 (11): 1418-25, 2000. [PUBMED Abstract]
  3. Roebuck DJ, Aronson D, Clapuyt P, et al.: 2005 PRETEXT: a revised staging system for primary malignant liver tumours of childhood developed by the SIOPEL group. Pediatr Radiol 37 (2): 123-32; quiz 249-50, 2007. [PUBMED Abstract]
  4. Towbin AJ, Meyers RL, Woodley H, et al.: 2017 PRETEXT: radiologic staging system for primary hepatic malignancies of childhood revised for the Paediatric Hepatic International Tumour Trial (PHITT). Pediatr Radiol 48 (4): 536-554, 2018. [PUBMED Abstract]
  5. Aronson DC, Schnater JM, Staalman CR, et al.: Predictive value of the pretreatment extent of disease system in hepatoblastoma: results from the International Society of Pediatric Oncology Liver Tumor Study Group SIOPEL-1 study. J Clin Oncol 23 (6): 1245-52, 2005. [PUBMED Abstract]
  6. Lovvorn HN, Ayers D, Zhao Z, et al.: Defining hepatoblastoma responsiveness to induction therapy as measured by tumor volume and serum alpha-fetoprotein kinetics. J Pediatr Surg 45 (1): 121-8; discussion 129, 2010. [PUBMED Abstract]
  7. Venkatramani R, Stein JE, Sapra A, et al.: Effect of neoadjuvant chemotherapy on resectability of stage III and IV hepatoblastoma. Br J Surg 102 (1): 108-13, 2015. [PUBMED Abstract]
  8. Ortega JA, Krailo MD, Haas JE, et al.: Effective treatment of unresectable or metastatic hepatoblastoma with cisplatin and continuous infusion doxorubicin chemotherapy: a report from the Childrens Cancer Study Group. J Clin Oncol 9 (12): 2167-76, 1991. [PUBMED Abstract]
  9. Douglass EC, Reynolds M, Finegold M, et al.: Cisplatin, vincristine, and fluorouracil therapy for hepatoblastoma: a Pediatric Oncology Group study. J Clin Oncol 11 (1): 96-9, 1993. [PUBMED Abstract]
  10. Ortega JA, Douglass EC, Feusner JH, et al.: Randomized comparison of cisplatin/vincristine/fluorouracil and cisplatin/continuous infusion doxorubicin for treatment of pediatric hepatoblastoma: A report from the Children’s Cancer Group and the Pediatric Oncology Group. J Clin Oncol 18 (14): 2665-75, 2000. [PUBMED Abstract]

Treatment Option Overview for Childhood Liver Cancer

Many of the improvements in survival in childhood cancer have been made using new therapies that have attempted to improve on the best available, accepted therapy. Clinical trials in pediatrics are designed to compare potentially better therapy with therapy that is currently accepted as standard. This comparison may be done in a randomized study of two treatment arms or by evaluating a single new treatment and comparing the results with those previously obtained with standard therapy.

Because of the relative rarity of cancer in children, all children with liver cancer should be considered for a clinical trial if available. Treatment planning by a multidisciplinary team of cancer specialists with experience treating tumors of childhood is required to determine and implement optimal treatment.[1]

Surgery

Historically, complete surgical resection of the primary tumor has been essential for cure of malignant liver tumors in children.[2–6]; [7][Level of evidence C1] This approach continues to be the goal of definitive surgical procedures, which are often combined with chemotherapy. The surgeon performs a highly sophisticated liver resection in children and adolescents with primary liver tumors after the diagnosis is confirmed by pathological investigation of intraoperative frozen sections. While complete surgical resection is important for all liver tumors, it is especially important for hepatocellular carcinoma because curative chemotherapy is not available. In patients with advanced hepatoblastoma, postoperative complications are associated with worsened overall survival (OS).[8]

The three surgical options to treat primary pediatric liver cancer include the following:

  • Initial surgical resection (alone or with adjuvant chemotherapy).
  • Delayed surgical resection (with neoadjuvant chemotherapy).
  • Orthotopic liver (cadaveric and living donor) transplant (most often with neoadjuvant chemotherapy).

The decision on which surgical approach to use (e.g., partial hepatectomy, extended resection, or transplant) depends on many factors, including the following:

  • PRE-Treatment EXTent of disease (PRETEXT) group and POST-Treatment EXTent of disease (POSTTEXT) group.
  • Size of the primary tumor.
  • Presence of multifocal hepatic disease.
  • Gross vascular involvement.
  • Alpha-fetoprotein (AFP) levels.
  • Whether preoperative chemotherapy is likely to convert an unresectable tumor into a resectable tumor.
  • Whether hepatic disease meets surgical and histopathological criteria for orthotopic liver transplant.

Timing of the surgical approach is critical. Surgeons who have experience performing pediatric liver resections and transplants are involved early in the decision-making process to determine optimal timing and extent of resection.

Early involvement, preferably at diagnosis, with an experienced pediatric liver surgeon is especially important in patients with PRETEXT group III or IV or involvement of major liver vessels (positive annotation factors V [venous] or P [portal]).[9] Although vascular involvement was initially thought to be a contraindication to resection, experienced liver surgeons are sometimes able to successfully resect the tumor and avoid performing a transplant.[10–12]; [13][Level of evidence C1] Patients with vascular involvement and tumors that have been deemed nonresectable by the pediatric surgical expert should be referred to a transplant center to avoid unnecessary delays in evaluation and listing for transplant.

Intraoperative ultrasonography may result in further delineation of tumor extent and location and can affect intraoperative management.[14] Preoperative infusion of indocyanine green, a fluoroactive agent that is concentrated in the liver and retained by abnormal liver tumors, has also been used to provide visual intraoperative guidance to locate the tumor and assess proximity to surgical margins.[15,16]

If the tumor is determined to be unresectable, measures to reduce the tumor size to make a complete surgical resection possible need to be considered. These measures include preoperative intravenous chemotherapy, transarterial chemotherapy, or transarterial radioactive therapy. These efforts must be carefully coordinated with the surgical team to facilitate planning of resection. Prolonged chemotherapy can lead to unnecessary delays and, in rare cases, tumor progression. If the tumor can be completely excised by an experienced surgical team, less postoperative chemotherapy may be needed. Incomplete resection must be avoided because patients who undergo rescue transplants of incompletely resected tumors have an inferior outcome, compared with patients who undergo transplant as the primary surgical therapy.[17][Level of evidence C1] Accomplishing the appropriate surgery at resection is critical.

The approach taken by the Children’s Oncology Group (COG) in North American clinical trials is to perform surgery initially when a complete resection can be done with a simple, negative-margin hemihepatectomy. The COG AHEP0731 (NCT00980460) trial studied the use of PRETEXT and POSTTEXT to determine the optimal approach and timing of surgery. POSTTEXT imaging grouping was performed after two and four cycles of chemotherapy to determine the optimal time for definitive surgery.[6,18] For more information, see the Tumor Stratification by Imaging section.

Orthotopic liver transplant

Liver transplants have been associated with significant success in the treatment of children with unresectable hepatic tumors.[19]; [20–22][Level of evidence C1] A review of the world experience has documented a posttransplant survival rate of 70% to 80% for children with hepatoblastomas.[17,23–25] Intravenous vascular invasion, positive lymph nodes, and contiguous extrahepatic spread did not have significant adverse effects on outcome. Adjuvant chemotherapy after transplant may decrease the risk of tumor recurrence, but its use has not been studied definitively in a randomized clinical trial.[26]

Evidence (orthotopic liver transplant):

  1. The United Network for Organ Sharing (UNOS) database was queried for all patients younger than 18 years with a primary malignant liver tumor who underwent an orthotopic liver transplant between 1987 and 2012 (N = 544). The patients were diagnosed with hepatoblastoma (n = 376, 70%), hepatocellular carcinoma (n = 84, 15%), and other tumors (n = 84, 15%). Patients with hepatocellular carcinoma were older, more often hospitalized at the time of transplant, and more likely to receive a cadaveric organ than were patients with hepatoblastoma.[27]
    1. The 5-year patient survival rate was 73%, and the graft survival rate was 74% for the entire cohort, with most deaths resulting from malignancy. On multivariate analysis, independent predictors of 5-year patient and graft survival included the following:
      1. Diagnosis.
        • For the study period of 1987 to 2012, the 5-year survival rate was 76% and the graft survival rate was 77% for patients with hepatoblastoma. The survival and graft survival rates were 63% for patients with hepatocellular carcinoma.
        • For the study period of 2009 to 2012, the 3-year survival and graft survival rates were 84% for patients with hepatoblastoma. The survival and graft survival rates were 85% for patients with hepatocellular carcinoma.
      2. Transplant era.
        • The death rate by hazard ratio was 1.0 for the period before 2002, 0.72 for the period of 2002 to 2009, and 0.54 for the period of 2009 to 2012.
      3. Medical condition at transplant.
        • For hepatoblastoma patients, the survival rate by hazard ratio was 1.0 for hospitalized patients versus 1.81 for nonhospitalized patients at the time of transplant.
        • For hepatocellular carcinoma patients, the survival rate by hazard ratio was 1.0 for hospitalized patients versus 1.92 for nonhospitalized patients.
        • Patients hospitalized in the intensive care unit did not fare worse than patients not in the intensive care unit.
  2. A report of 149 patients with hepatocellular carcinoma younger than 21 years who underwent transplants between 1987 and 2015 used detailed data collected at all U.S. pediatric transplant centers.[19]
    • The 1-year graft survival rate of about 85% did not differ from the survival rate for patients with hepatoblastoma or biliary atresia. Survival rates continued to decline over time, from 85% at 1 year to 52% at 5 years and 43% at 10 years, a more dramatic decline than that seen for hepatoblastoma or biliary atresia.
    • The survival after transplant did not differ from that of adults who underwent transplant for hepatocellular carcinoma.
    • Of the patients with hepatocellular carcinoma, 22 received a diagnosis after transplant for medical cirrhotic disease such as tyrosinemia. They had a superior outcome, but it was not statistically significant compared with the rest of the patients.
  3. A review of the Surveillance, Epidemiology, and End Results (SEER) Program database and many single-institution series have reported results similar to the UNOS database study described above.[11,20–22,28]; [25][Level of evidence C1]
  4. In a three-institution study of children with hepatocellular carcinoma, the overall 5-year disease-free survival rate was approximately 60%.[29]
  5. In a study that used the Society of Pediatric Liver Transplantation (SPLIT) database to identify patients who underwent liver transplant between 2011 and 2019, the following was reported:[30][Level of evidence C2]
    • The 3-year event-free survival (EFS) rate was 81% for patients with hepatoblastoma who received a transplant (n = 157).
    • The 3-year EFS rate was 62% for patients with hepatocellular carcinoma who received a transplant (n = 18).
    • Of the patients who received a transplant to treat hepatoblastoma, 6.9% had PRETEXT II disease and 15.3% had POSTTEXT I/II disease.
    • Tumor extent did not impact survival (P = NS).
    • Patients who received transplants for salvage (n = 13) and patients who received transplants for primary hepatoblastoma had similar 3-year EFS rates (62% vs. 78%; P = NS).
    • Among patients who received transplants for hepatocellular carcinoma, the 3-year EFS rate was poorer in older patients (38% for patients aged ≥8 years vs. 86% for patients aged <8 years; P < .001).

Application of the Milan criteria for UNOS selection of recipients of deceased donor livers is controversial.[31,32] The Milan criteria for liver transplant are directed toward adults with cirrhosis and hepatocellular carcinoma. The criteria do not apply to children and adolescents with hepatocellular carcinoma, especially those without cirrhosis.

Cirrhosis is an underlying risk factor for the development of hepatocellular carcinoma in children who suffer from certain diseases or conditions. These diseases include perinatally acquired hepatitis B, hepatorenal tyrosinemia, progressive familial intrahepatic cholestasis, glycogen storage disease, Alagille syndrome, and other conditions. Improvements in screening methodology have allowed for earlier identification and treatment of some of these conditions, as well as monitoring for development of hepatocellular carcinoma. Nevertheless, because of the poor prognosis of patients with hepatocellular carcinoma, liver transplant should be considered for diseases or conditions that have resulted in early findings of cirrhosis, before the development of liver failure or malignancy.[33]

Living-donor liver transplant for hepatic malignancy is more common in children than adults, and the outcome is similar to those undergoing cadaveric liver transplant.[34,35] In patients with hepatocellular carcinoma, gross vascular invasion, distant metastases, lymph node involvement, tumor size, and male sex were significant risk factors for recurrence. In one report, 33 patients with hepatoblastoma and 10 patients with hepatocellular carcinoma were treated with living-donor liver transplants. For the hepatoblastoma patients, the 5-year OS rate was 87.4%, and the EFS rate was 75.8%. The 5-year OS and EFS rates were 75.4% for the patients with hepatocellular carcinoma. The presence of renal vein invasion was associated with an increased incidence of recurrence and death (P = .28).[36][Level of evidence C1]

Surgical resection for metastatic disease

Surgical resection of metastatic disease is often recommended, but the rate of cure in children with hepatoblastoma has not been fully determined. Resection of metastases may be done for areas of locally invasive disease (e.g., diaphragm) and isolated brain metastases. Resection of pulmonary metastases should be considered if the number of metastases is limited.[37–40] In a North American study of 38 patients who presented with pulmonary metastases at diagnosis, only nine patients underwent surgical resection. The timing of pulmonary resection in relation to definitive resection of the primary tumor varied (two patients before, five patients simultaneously, and two patients after primary resection). Eight of the nine patients survived. Of 20 children with relapse restricted to the lungs, all patients received salvage chemotherapy, 8 patients had a thoracotomy and pulmonary metastasectomy, and 5 patients had a thoracotomy and biopsy. Among the 13 patients who had surgery, only 4 were long-term survivors, 2 of whom presented with stage I disease and 2 of whom presented with stage IV disease.[39]

Radiofrequency ablation has also been used to treat oligometastatic hepatoblastoma when patients prefer to avoid surgical metastasectomy.[41][Level of evidence C1]

Chemotherapy

Chemotherapy regimens used in the treatment of hepatoblastoma and hepatocellular carcinoma are described in their respective sections. Chemotherapy has been much more successful in the treatment of hepatoblastoma than in the treatment of hepatocellular carcinoma.[6,28,42] For more information, see the sections on Treatment of Hepatoblastoma and Treatment of Hepatocellular Carcinoma.

The standard of care in the United States is preoperative chemotherapy when the tumor is unresectable and postoperative chemotherapy after complete resection, even if preoperative chemotherapy has already been given.[43] Preoperative chemotherapy has been shown to benefit children with hepatoblastoma. However, postoperative chemotherapy after definitive surgical resection or liver transplant has not been investigated in a randomized fashion.

Radiation Therapy

Radiation therapy, even in combination with chemotherapy, has not cured children with unresectable hepatic tumors. A study of 154 patients with hepatoblastoma showed that radiation therapy and/or second resection of positive margins may not be necessary in some patients with incompletely resected hepatoblastoma and microscopic residual tumor.[44] Although there is no standard indication, radiation therapy may have a role in the management of patients with incompletely resected hepatoblastomas.[45] Stereotactic body radiation therapy is a safe and effective alternative treatment that has been successfully used in adult patients with hepatocellular carcinoma who are unable to undergo liver ablation/resection.[46] This highly conformal radiotherapeutic technique, when available, may be considered on an individual basis in children with hepatocellular carcinoma.

Other Treatment Approaches

Other treatment approaches include the following:

  • Transarterial chemoembolization (TACE): TACE is an image-guided, minimally invasive, nonsurgical procedure that is used to treat malignant lesions in the liver. The procedure uses a catheter to deliver both chemotherapy medication and embolization materials into the blood vessels that lead to the tumor. The arterial catheter route is image guided, most often via the hepatic artery, and perfusion of the tumor by the targeted artery may be confirmed by imaging before therapeutic injection. This procedure allows for the treatment of tumors that are not accessible with conventional surgery or radiation treatments. TACE has been used for patients with inoperable hepatoblastoma.[47–49] This procedure has also been used in a few children to successfully shrink tumors to permit resections.[48]
  • Transarterial radioembolization (TARE): TARE is an image-guided, minimally invasive, nonsurgical procedure that delivers radiation therapy to treat tumors in the liver. This procedure delivers radioactive beads and blocks arterial flow within the tumor to keep the radiation inside the tumor. Glass or resin microspheres, coated most commonly with yttrium Y 90 (90Y), are delivered to the tumor via catheters placed in arteries that supply the tumor. Usually, the hepatic artery or its branches are used, but tumors may be partially supplied by parasitized surrounding vessels. Because of the risk of radiation delivery to the nearby lung, technetium Tc 99m microaggregated albumin imaging is performed with delivery via the catheter that is in place before the administration of radioactive beads to carefully measure radiation exposure to the lung. If calculations determine that lung exposure is unsafe, TARE is not pursued. TARE with 90Y has been used in children with hepatoblastoma (n = 2) and hepatocellular carcinoma (n = 2) who have unresectable tumors. After treatment with 90Y TARE, all tumors were completely resected.[50][Level of evidence C3]; [51][Level of evidence C2] This approach has also been used for palliation in children with hepatocellular carcinoma.[52] For more information, see Primary Liver Cancer Treatment.
  • High-intensity focused ultrasonography (HIFU): HIFU is a noninvasive treatment for a wide range of tumors and diseases. HIFU uses an ultrasound transducer, similar to the ones used for diagnostic imaging, but with much higher energy. The transducer focuses sound waves to generate heat at a single point in the body and destroy the target tissue. The tissue can get as hot as 66°C in only 20 seconds. This process is repeated as many times as necessary until the target tissue is destroyed. Magnetic resonance imaging is used to plan the treatment and monitor the amount of heat in real time. A combination of chemotherapy followed by TACE and HIFU showed promising results in China for children with PRETEXT III and PRETEXT IV malignant liver tumors, some of whom had resectable tumors but did not undergo surgery because of parent refusal.[53]
References
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  34. Sevmis S, Karakayali H, Ozçay F, et al.: Liver transplantation for hepatocellular carcinoma in children. Pediatr Transplant 12 (1): 52-6, 2008. [PUBMED Abstract]
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  36. Pire A, Tambucci R, De Magnée C, et al.: Living donor liver transplantation for hepatic malignancies in children. Pediatr Transplant 25 (7): e14047, 2021. [PUBMED Abstract]
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  39. Meyers RL, Katzenstein HM, Krailo M, et al.: Surgical resection of pulmonary metastatic lesions in children with hepatoblastoma. J Pediatr Surg 42 (12): 2050-6, 2007. [PUBMED Abstract]
  40. O’Neill AF, Towbin AJ, Krailo MD, et al.: Characterization of Pulmonary Metastases in Children With Hepatoblastoma Treated on Children’s Oncology Group Protocol AHEP0731 (The Treatment of Children With All Stages of Hepatoblastoma): A Report From the Children’s Oncology Group. J Clin Oncol 35 (30): 3465-3473, 2017. [PUBMED Abstract]
  41. Yevich S, Calandri M, Gravel G, et al.: Reiterative Radiofrequency Ablation in the Management of Pediatric Patients with Hepatoblastoma Metastases to the Lung, Liver, or Bone. Cardiovasc Intervent Radiol 42 (1): 41-47, 2019. [PUBMED Abstract]
  42. Weeda VB, Murawski M, McCabe AJ, et al.: Fibrolamellar variant of hepatocellular carcinoma does not have a better survival than conventional hepatocellular carcinoma–results and treatment recommendations from the Childhood Liver Tumour Strategy Group (SIOPEL) experience. Eur J Cancer 49 (12): 2698-704, 2013. [PUBMED Abstract]
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  46. Wang PM, Chung NN, Hsu WC, et al.: Stereotactic body radiation therapy in hepatocellular carcinoma: Optimal treatment strategies based on liver segmentation and functional hepatic reserve. Rep Pract Oncol Radiother 20 (6): 417-24, 2015 Nov-Dec. [PUBMED Abstract]
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Special Considerations for the Treatment of Children With Cancer

Cancer in children and adolescents is rare, although the overall incidence has slowly increased since 1975.[1] Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the following pediatric specialists and others to ensure that children receive treatment, supportive care, and rehabilitation to achieve optimal survival and quality of life:

  • Primary care physicians.
  • Pediatric surgeons.
  • Transplant surgeons.
  • Pathologists.
  • Pediatric radiation oncologists.
  • Pediatric medical oncologists and hematologists.
  • Ophthalmologists.
  • Rehabilitation specialists.
  • Pediatric oncology nurses.
  • Social workers.
  • Child-life professionals.
  • Psychologists.
  • Nutritionists.

For specific information about supportive care for children and adolescents with cancer, see the summaries on Supportive and Palliative Care.

The American Academy of Pediatrics has outlined guidelines for pediatric cancer centers and their role in the treatment of children and adolescents with cancer.[2] At these centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate is offered to most patients and their families. Clinical trials for children and adolescents diagnosed with cancer are generally designed to compare potentially better therapy with current standard therapy. Other types of clinical trials test novel therapies when there is no standard therapy for a cancer diagnosis. Most of the progress in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI website.

Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2020, childhood cancer mortality decreased by more than 50%.[3–5] Childhood and adolescent cancer survivors require close monitoring because side effects of cancer therapy may persist or develop months or years after treatment. For specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors, see Late Effects of Treatment for Childhood Cancer.

References
  1. Smith MA, Seibel NL, Altekruse SF, et al.: Outcomes for children and adolescents with cancer: challenges for the twenty-first century. J Clin Oncol 28 (15): 2625-34, 2010. [PUBMED Abstract]
  2. American Academy of Pediatrics: Standards for pediatric cancer centers. Pediatrics 134 (2): 410-4, 2014. Also available online. Last accessed February 25, 2025.
  3. Smith MA, Altekruse SF, Adamson PC, et al.: Declining childhood and adolescent cancer mortality. Cancer 120 (16): 2497-506, 2014. [PUBMED Abstract]
  4. National Cancer Institute: NCCR*Explorer: An interactive website for NCCR cancer statistics. Bethesda, MD: National Cancer Institute. Available online. Last accessed February 25, 2025.
  5. Surveillance Research Program, National Cancer Institute: SEER*Explorer: An interactive website for SEER cancer statistics. Bethesda, MD: National Cancer Institute. Available online. Last accessed December 30, 2024.

Hepatoblastoma

Incidence

The annual incidence of hepatoblastoma in the United States has increased (more than doubled), from 0.8 (1975–1983) to 2.3 (2020) cases per 1 million children aged 19 years and younger.[1–3] The cause for this increase is unknown, but the improved survival of premature infants with very low birth weight, which is known to be associated with hepatoblastoma, may contribute.[4] In Japan, the risk of hepatoblastoma in children who weighed less than 1,000 g at birth is 15 times the risk in children with normal birth weight.[5] Other data have confirmed the high incidence of hepatoblastoma in premature infants with very low birth weight.[6] Attempts to identify factors resulting from treatment of infants born prematurely have not revealed any suggestive causation of the increased incidence of hepatoblastoma.[4]

The age of onset of liver cancer in children is related to tumor histology. Hepatoblastomas usually occur before the age of 3 years, and approximately 90% of malignant liver tumors in children aged 4 years and younger are hepatoblastomas.[7]

Risk Factors

Conditions associated with an increased risk of hepatoblastoma are described in Table 4.

Table 4. Conditions Associated With an Increased Risk of Hepatoblastoma
Associated Disorder Clinical Findings
Aicardi syndrome [8] For more information, see the Aicardi syndrome section.
Beckwith-Wiedemann syndrome [9,10] For more information, see the Beckwith-Wiedemann syndrome and hemihyperplasia section.
Familial adenomatous polyposis [11–13] For more information, see the Familial adenomatous polyposis section.
Glycogen storage diseases I–IV [14] Symptoms vary by individual disorder.
Low-birth-weight infants [4–6,15,16] Preterm and small-for-gestation-age neonates.
Simpson-Golabi-Behmel syndrome [17] Macroglossia, macrosomia, renal and skeletal abnormalities, and increased risk of Wilms tumor.
Trisomy 18, other trisomies [18] Trisomy 18: Microcephaly and micrognathia, clenched fists with overlapping fingers, and failure to thrive. Most patients (>90%) die in the first year of life.

Aicardi syndrome

Aicardi syndrome is presumed to be an X-linked condition reported exclusively in females, leading to the hypothesis that an altered gene on the X chromosome causes lethality in males. The syndrome is classically defined as agenesis of the corpus callosum, chorioretinal lacunae, and infantile spasms, with a characteristic facies. Additional brain, eye, and costovertebral defects are often found.[8]

Beckwith-Wiedemann syndrome and hemihyperplasia

The incidence of hepatoblastoma increases 1,000-fold to 10,000-fold in infants and children with Beckwith-Wiedemann syndrome.[10,19] The risk of hepatoblastoma also increases in patients with hemihyperplasia, previously termed hemihypertrophy, a condition that results in asymmetry between the right and left side of the body when a body part grows faster than normal.[20,21]

Beckwith-Wiedemann syndrome is most commonly caused by epigenetic changes and is sporadic. The syndrome may also be caused by genetic variants and be familial. Either mechanism can be associated with an increased incidence of embryonal tumors, including Wilms tumor and hepatoblastoma.[10] The expression of both IGFR2 alleles and ensuing increased expression of insulin-like growth factor 2 (IGF-2) has been implicated in the macrosomia and embryonal tumors seen in patients with Beckwith-Wiedemann syndrome.[10,22] The types of embryonal tumors associated with sporadic Beckwith-Wiedemann syndrome have frequently undergone somatic changes in the Beckwith-Wiedemann syndrome locus and IGF-2.[23,24] The genetics of tumors in children with hemihyperplasia have not been clearly defined.

To detect abdominal malignancies at an early stage, all children with Beckwith-Wiedemann syndrome or isolated hemihyperplasia undergo regular screening for multiple tumor types by abdominal ultrasonography.[21] Screening using alpha-fetoprotein (AFP) levels has also been quite helpful in the early detection of hepatoblastoma in these children.[25] Because hepatoblastomas that are discovered early are small, treatment may minimize the use of adjuvant therapy after surgery.[19] However, a careful compilation of published data on 1,370 children with (epi)genotyped Beckwith-Wiedemann syndrome demonstrated that the prevalence of hepatoblastoma was 4.7% in those with Beckwith-Wiedemann syndrome caused by chromosome 11p15 paternal uniparental disomy, less than 1% in the two types of alteration in imprinting control regions, and absent in CDKN1C variants.[26] The authors recommended that only children with Beckwith-Wiedemann syndrome caused by uniparental disomy be screened for hepatoblastoma using abdominal ultrasonography and AFP levels every 3 months from age 3 months to 5 years.

Familial adenomatous polyposis

Hepatoblastoma is associated with familial adenomatous polyposis (FAP). Children in families that carry the APC gene have an 800-fold increased risk of hepatoblastoma. Screening for hepatoblastoma in members of families with FAP using ultrasonography and AFP levels is controversial because hepatoblastoma has been reported to occur in less than 1% of this group.[11–13,27] However, one study of 50 consecutive children with apparent sporadic hepatoblastoma reported that five children (10%) had APC germline variants.[27]

Current evidence cannot rule out the possibility that predisposition to hepatoblastoma may be limited to a specific subset of APC variants. Another study of children with hepatoblastoma found a predominance of the variant in the 5′ region of the gene, but some patients had variants closer to the 3′ region.[28] This preliminary study provides some evidence that screening children with hepatoblastoma for APC variants and colon cancer may be appropriate.

In the absence of APC germline variants, childhood hepatoblastomas do not have somatic variants in the APC gene. However, hepatoblastomas frequently have variants in the CTNNB1 gene, whose function is closely related to APC.[29]

Screening children predisposed to hepatoblastoma

An American Association for Cancer Research publication suggested that all children with genetic syndromes that lead to a risk of 1% or greater for developing hepatoblastoma undergo screening. This group includes patients with Beckwith-Wiedemann syndrome, hemihyperplasia, Simpson-Golabi-Behmel syndrome, and trisomy 18 syndrome. Screening is by abdominal ultrasonography and AFP determination every 3 months from birth (or diagnosis) through the fourth birthday, which will identify 90% to 95% of hepatoblastomas that develop in these children.[30]

Genomics of Hepatoblastoma

Molecular features of hepatoblastoma

Genomic findings related to hepatoblastoma include the following:

  • The frequency of variants in hepatoblastoma, as determined by three groups using whole-exome sequencing, was very low (approximately three variants per tumor) in children younger than 5 years.[31–34] A pediatric pan-cancer genomics study found that hepatoblastoma had the lowest gene variant rate among all childhood cancers studied.[35]
  • Hepatoblastoma is primarily a disease of WNT pathway activation. The primary mechanism for WNT pathway activation is CTNNB1 activating variants/deletions involving exon 3. CTNNB1 variants have been reported in more than 80% of cases.[31,33,34,36,37] A less common cause of WNT pathway activation in hepatoblastoma is variants in APC associated with familial adenomatosis polyposis coli.[36]
  • NFE2L2 variants were identified in 10 of 174 (6%), 4 of 88 (5%), and 5 of 112 (4%) cases of hepatoblastoma in three studies.[33,34,37] The presence of NFE2L2 variants was associated with a lower survival rate.[37]
  • Similar NFE2L2 variants have been found in many types of cancer, including hepatocellular carcinoma. These variants render NFE2L2 insensitive to KEAP1-mediated degradation, leading to activation of the NFE2L2-KEAP1 pathway, which activates resistance to oxidative stress and is believed to confer resistance to chemotherapy.
  • TERT and TP53 variants, which are common in adults with hepatocellular carcinoma,[38] are uncommon in children with hepatoblastoma.[31,33,34,36] Pediatric patients with TERT variants present with hepatoblastoma at a significantly older age, compared with patients without TERT variants (median age at diagnosis, approximately 10 years vs. 1.4 years).[37]
  • Uniparental disomy at 11p15.5 with loss of the maternal allele was reported in 6 of 15 cases of hepatoblastoma.[39] This finding has been confirmed in genomic characterization studies, in which 30% to 40% of cases showed allelic imbalance at the 11p15 locus.[34,36,37]

Gene expression and epigenetic profiling have been used to identify biological subtypes of hepatoblastoma and to evaluate the prognostic significance of these subtypes.[33,36,37,40]

  • A 16-gene expression signature divided hepatoblastoma cases into two subsets,[37,40] C1 and C2. The C1 subtype included most of the well-differentiated fetal (pure fetal) histology cases. The C2 subtype showed a more immature pattern and was associated with higher rates of metastatic disease at diagnosis. In a study of 174 patients with hepatoblastoma, the C2 subtype was a significant predictor of poor outcome in multivariable analysis.[37]
  • A second research group also found that gene expression profiling could be used to identify subsets of hepatoblastoma with favorable versus unfavorable prognosis.[33] The unfavorable prognosis group of patients showed elevated expression of genes associated with embryonic stem cell and progenitor cells (e.g., LIN28B, SALL4, and HMGA2). The favorable prognosis group of patients showed elevated expression of genes associated with liver differentiation (e.g., HNF1A).
  • A gene expression signature at chromosome 14q32 (e.g., DLK1) was identified, with a stronger expression signal being associated with higher risk of treatment failure.[34] A strong 14q32 expression signature was also observed in fetal liver tissue, further supporting the concept that patients with hepatoblastoma who have tumors with biological characteristics that are similar to those of hepatic precursor cells have an inferior prognosis.
  • Epigenetic profiling of hepatoblastoma has been used to identify molecularly defined hepatoblastoma subtypes. Tumors from 113 patients with hepatoblastoma were evaluated using DNA methylation arrays. Two distinctive subtypes were identified, epigenetic cluster A and B (Epi-CA and Epi-CB).[34] The methylation profile of Epi-CB resembled that of early embryonal/fetal phases of liver development. The methylation profile of Epi-CA was similar to that of late fetal or postnatal liver phases. Event-free survival was significantly lower for patients with the Epi-CB subtype than for those with the Epi-CA subtype.[34]

Delineating the clinical applications of these genomic, transcriptomic, and epigenomic profiling methods for the risk classification of patients with hepatoblastoma will require independent validation, which is one of the objectives of the Paediatric Hepatic International Tumour Trial (PHITT [NCT03017326]).

Diagnosis

Biopsy

A biopsy is always indicated to confirm the diagnosis of a pediatric liver tumor, except in the following circumstances:

  • Infantile hepatic hemangioma. Biopsy is not indicated for patients with infantile hemangioma of the liver with classic findings on magnetic resonance imaging (MRI). If the diagnosis is in doubt after high-quality imaging, a confirmatory biopsy is done.
  • Focal nodular hyperplasia. Biopsy may not be indicated or may be delayed for patients with focal nodular hyperplasia with classic features on MRI using hepatocyte-specific contrast agent. If the diagnosis is in doubt, a confirmatory biopsy is done.
  • Children’s Oncology Group (COG) surgical guidelines (AHEP0731 [NCT00980460] appendix) recommend tumor resection at diagnosis without preoperative chemotherapy in children with PRE-Treatment EXTent of disease (PRETEXT) group I tumors and PRETEXT group II tumors with greater than 1 cm radiographic margin on the vena cava and middle hepatic and portal veins. Therefore, biopsy is not usually recommended in this circumstance.
  • Infantile hepatic choriocarcinoma. In patients with infantile hepatic choriocarcinoma, which can be diagnosed by imaging and markedly elevated beta-human chorionic gonadotropin (beta-hCG), chemotherapy without biopsy is often indicated.[41]

Tumor markers

The AFP and beta-hCG tumor markers are helpful in the diagnosis and management of liver tumors. Although AFP is elevated in most children with hepatic malignancies, it is not pathognomonic for a malignant liver tumor.[42] The AFP level can be elevated with either a benign tumor or a malignant solid tumor. Markedly elevated AFP not caused by the tumor is normal in neonates and steadily falls after birth. The half-life of AFP is 5 to 7 days, and by age 1 year, it should be in the reference range, less than 10 ng/mL.[43,44] Beta-hCG levels may also be elevated in children with hepatoblastoma or hepatocellular carcinoma, which may result in isosexual precocity in boys.[45,46]

Prognosis and Prognostic Factors

Prognosis

The 5-year overall survival (OS) rate for children with hepatoblastoma is 70%.[47,48] Neonates with hepatoblastoma have outcomes comparable to those of older children up to age 5 years.[49]

Survival rates at 5 years, unrelated to annotation factors, were found to be the following:

  • 90% for patients with PRETEXT I group tumors.
  • 83% for patients with PRETEXT II group tumors.
  • 73% for patients with PRETEXT III group tumors.
  • 52% for patients with PRETEXT IV group tumors.

When each annotation factor was examined separately, regardless of the PRETEXT group or other annotation factors, the 5-year OS rates were found to be the following:

  • 51% for patients with positive V (involvement of all three hepatic veins and/or inferior vena cava).
  • 49% for patients with positive P (involvement of both right and left portal veins).
  • 53% for patients with positive E (contiguous extrahepatic tumor).
  • 52% for patients with positive F (multifocal).
  • 51% for patients with positive R (tumor rupture).
  • 41% for patients with positive M (distant metastasis).

For more information about PRETEXT grouping and annotation factors, see the PRETEXT and POSTTEXT Group Definitions section.

Hepatoblastoma prognosis by Evans surgical stage. Current study protocols use the PRETEXT staging for prognosis. The prognosis, based on Evans stage, is listed below. For more information, see the Evans Surgical Staging for Childhood Liver Cancer section.

  • Stages I and II.

    Approximately 20% to 30% of children with hepatoblastoma have stage I or II disease. Prognosis varies depending on the subtype of hepatoblastoma:

    • Patients with well-differentiated fetal (previously termed pure fetal) histology tumors (4% of hepatoblastomas) have a 3- to 5-year OS rate of 100% with minimal or no chemotherapy, whether PRETEXT I, II, or III.[50–52]
    • Patients with non–well-differentiated fetal histology, non–small cell undifferentiated stage I and II hepatoblastomas have a 3- to 4-year OS rate of 90% to 100% with adjuvant chemotherapy.[50,51]
    • If any small cell undifferentiated elements are present in patients with stage I or II hepatoblastoma, the 3-year survival rate is 40% to 70%.[50,53]
  • Stage III.

    Approximately 50% to 70% of children with hepatoblastoma have stage III disease. The 3- to 5-year OS rate for these children is less than 70%.[50,51]

  • Stage IV.

    Approximately 10% to 20% of children with hepatoblastoma have stage IV disease. The 3- to 5-year OS rate for these children varies widely, from 20% to approximately 60%, based on published reports.[50,51,54–57] Postsurgical stage IV is equivalent to any PRETEXT group with annotation factor M.[58–60]

Prognostic factors

Individual childhood cancer study groups have attempted to define the relative importance of a variety of prognostic factors present at diagnosis and in response to therapy.[61,62] The CHIC study group retrospectively combined data from eight clinical trials (N = 1,605) conducted between 1988 and 2010. They published a univariate analysis of the effect of clinical prognostic factors present at the time of diagnosis on event-free survival (EFS).[58,63] The analysis confirmed many of the statistically significant adverse factors described below:[58]

  • Higher PRETEXT group.[58]
  • Positive PRETEXT annotation factors:[58]
    • V: Involvement of all three hepatic veins and/or intrahepatic inferior vena cava.
    • P: Involvement of both left and right portal veins.
    • E: Contiguous extrahepatic tumor extensions (e.g., diaphragm, adjacent organs).
    • F: Multifocal tumors.
    • R: Tumor rupture.
    • M: Distant metastases, usually lung.
  • Low AFP level (<100 ng/mL or 100–1,000 ng/mL to account for infants with elevated AFP levels).[63]
  • Older age. Patients aged 3 to 7 years have a worse outcome in the PRETEXT IV group.[58] Patients aged 8 years and older have a worse outcome than younger patients in all PRETEXT groups. In a subsequent report from the CHIC group, risk of an event increased with advancing age throughout all age cohorts.[64][Level of evidence C1] Increasing age attenuated the effect of other risk factors, including metastasis, AFP level less than 100 ng/mL, tumor rupture, and the presence of one annotation factor.

    In contrast, in the SIOPEL-2 and -3 studies, infants younger than 6 months had PRETEXT group, annotation factors, and outcomes similar to those of older children undergoing the same treatment.[65][Level of evidence C1]

In the CHIC study, sex, prematurity, birth weight, and Beckwith-Wiedemann syndrome had no effect on EFS.[58]

A multivariate analysis of these prognostic factors was published to help develop a new risk group classification for hepatoblastoma.[63] This classification was used to generate a risk stratification schema to be used in international clinical trials. For more information, see the International risk classification model section.

Other studies observed the following factors that affected prognosis:

  • PRETEXT group: In SIOPEL studies, having a low PRETEXT group at diagnosis (PRETEXT I, II, and III tumors) is a good prognostic factor, whereas PRETEXT IV is a poor prognostic factor.[58] For more information, see the Tumor Stratification by Imaging section.
  • Tumor stage: In COG studies, patients with classical hepatoblastoma histology and stage I tumors that were resected at diagnosis have a favorable outcome when treated with limited chemotherapy. Patients with tumors that have well-differentiated fetal histology have an excellent prognosis. These tumors are not generally treated with chemotherapy. Patients with tumors of other stages and histologies are treated more aggressively.[58]
  • Treatment-related factors:

    Chemotherapy: Chemotherapy often decreases the size and extent of hepatoblastoma tumors, allowing complete resection.[51,54,66–68] Favorable response of the primary tumor to chemotherapy predicts its resectability, with favorable response defined as either a 30% decrease in tumor size by Response Evaluation Criteria In Solid Tumors (RECIST) or 90% or greater decrease in AFP levels. In turn, this favorable response predicted OS among all CHIC risk groups treated with neoadjuvant chemotherapy in the JPLT-2 Japanese national clinical trial.[69][Level of evidence B4]

    Surgery: Cure of hepatoblastoma requires gross tumor resection. Hepatoblastoma is most often unifocal, so resection may be possible. Most patients survive if a hepatoblastoma is completely removed. However, because of vascular or other involvement, less than one-third of patients have lesions that are amenable to complete resection at diagnosis.[58] It is critically important that a child with probable hepatoblastoma be evaluated by a pediatric surgeon who is experienced in the techniques of extreme liver resection with vascular reconstruction. The child should also have access to a liver transplant program. In advanced tumors, surgical treatment of hepatoblastoma is a demanding procedure. Postoperative complications in high-risk patients decrease the OS rate.[70]

    Orthotopic liver transplant: Orthotopic liver transplant is an additional treatment option for patients whose tumor remains unresectable after preoperative chemotherapy.[71,72] However, the presence of microscopic residual tumor at the surgical margin does not preclude a favorable outcome.[73,74] This outcome may result from additional courses of chemotherapy administered before or after resection.[66,67,73]

    For more information about the outcomes associated with specific chemotherapy regimens, see Table 6.

  • Tumor marker–related factors:

    Ninety percent of children with hepatoblastoma and two-thirds of children with hepatocellular carcinoma exhibit elevated levels of the serum tumor marker AFP, which parallels disease activity. The level of AFP at diagnosis and rate of decrease in AFP levels during treatment are compared with the age-adjusted reference range. Lack of a significant decrease in AFP levels with treatment may predict a poor response to therapy.[75] In an exploratory study of 34 children with hepatoblastoma, the rate of decrease in AFP and tumor volume, but not in RECIST I measurements, following two courses of treatment after diagnosis was predictive of EFS and OS.[76]

    Absence of elevated AFP levels at diagnosis (AFP <100 ng/mL) occurs in a small percentage of children with hepatoblastoma and appears to be associated with very poor prognosis, as well as with the small cell undifferentiated variant of hepatoblastoma.[58] Some of these variants do not express SMARCB1 and may be considered rhabdoid tumors of the liver, which require alternative therapy. All small cell undifferentiated hepatoblastomas are tested for loss of SMARCB1 expression by immunohistochemistry to determine those that should be treated as a hepatoblastoma versus those that should be treated as rhabdoid tumors of the liver.[50,53,56,57,77,78]

    Beta-hCG levels may also be elevated in children with hepatoblastoma or hepatocellular carcinoma, which may result in isosexual precocity in boys.[45,46]

  • Tumor histology:

    For more information, see the Histology section in the Hepatoblastoma section.

Other variables have been proposed to be poor prognostic factors, but their significance has been difficult to define. In the SIOPEL-1 study, a multivariate analysis of prognosis after positive response to chemotherapy showed that only one variable, PRETEXT group, predicted OS, while metastasis and PRETEXT group predicted EFS.[77] In an analysis of the U.S. intergroup study from the time of diagnosis, well-differentiated fetal histology, small cell undifferentiated histology, and AFP less than 100 ng/mL were prognostic in a log rank analysis. PRETEXT group was prognostic among patients designated group III, but not group IV.[50,79] The CHIC study incorporated detailed hepatoblastoma patient data from multiple groups, establishing a solid foundation of risk factors.[79]

Histology

Hepatoblastoma arises from precursors of hepatocytes and can have several morphologies, including the following:[80]

  • Small cells that reflect neither epithelial nor stromal differentiation. It is critical to discriminate between small cell undifferentiated hepatoblastoma expressing SMARCB1 and rhabdoid tumor of the liver, which lacks the SMARCB1 gene and SMARCB1 expression. Both diseases may share similar histology. Optimal treatment of rhabdoid tumor of the liver and small cell undifferentiated hepatoblastoma may require different approaches and different chemotherapy. For a more extensive discussion on the differences of these two diseases, see the Small cell undifferentiated histology hepatoblastoma and rhabdoid tumors of the liver section.
  • Embryonal epithelial cells resembling the liver epithelium at 6 to 8 weeks of gestation.
  • Well-differentiated fetal hepatocytes morphologically indistinguishable from normal fetal liver cells.

Most often the tumor consists of a mixture of epithelial hepatocyte precursors. About 20% of tumors have stromal derivatives such as osteoid, chondroid, and rhabdoid elements. Occasionally, neuronal, melanocytic, squamous, and enteroendocrine elements are found. The following histological subtypes have clinical relevance:

Well-differentiated fetal (pure fetal) histology hepatoblastoma

An analysis of patients with initially resected hepatoblastoma tumors (before receiving chemotherapy) has suggested that patients with well-differentiated fetal (previously termed pure fetal) histology tumors have a better prognosis than patients with an admixture of more primitive and rapidly dividing embryonal components or other undifferentiated tissues. Studies have reported the following:

  1. A study of patients with hepatoblastoma and well-differentiated fetal histology tumors observed the following:[51]
    • The survival rate was 100% for patients who received four doses of single-agent doxorubicin. This finding suggested that patients with well-differentiated fetal histology tumors might not need chemotherapy after complete resection.[81,82]
  2. In a COG study (COG-P9645), 16 patients with well-differentiated fetal histology hepatoblastoma with two or fewer mitoses per 10 high-power fields were not treated with chemotherapy. Retrospectively, their PRETEXT groups were group I (n = 4), group II (n = 6), and group III (n = 2).[52]
    • The survival rate was 100%.
    • All 16 patients were alive with no evidence of disease at a median follow-up of 4.9 years (range, 9 months to 9.2 years).

Thus, complete resection of a well-differentiated fetal hepatoblastoma may preclude the need for chemotherapy.

Small cell undifferentiated histology hepatoblastoma and rhabdoid tumors of the liver

Small cell undifferentiated hepatoblastoma (SMARCB1 retained) is an uncommon hepatoblastoma variant. Histologically, small cell undifferentiated hepatoblastoma is typified by a diffuse population of small cells with scant cytoplasm resembling neuroblasts.[83] It is now recognized that small cell undifferentiated hepatoblastoma may be difficult to distinguish from malignant rhabdoid tumor of the liver, which has been conflated with small cell undifferentiated hepatoblastoma in past studies.

Small cell undifferentiated histology hepatoblastoma and rhabdoid tumors of the livers can be distinguished by the following characteristic abnormalities:

  • Chromosomal abnormalities. These abnormalities in rhabdoid tumors include translocations involving a breakpoint on chromosome 22q11 and homozygous deletion at the chromosome 22q12 region that harbors the SMARCB1 gene.[84,85]
  • Lack of SMARCB1 expression. Lack of detection of SMARCB1 by immunohistochemistry is characteristic of malignant rhabdoid tumors.[84]

Historically, small cell undifferentiated hepatoblastoma was reported to occur at a younger age (6–10 months) than other cases of hepatoblastoma [50,84] and was associated with AFP levels that are in the reference range for age at presentation.[53,84] However, in a prospective study by the COG (AHEP0731 [NCT00980460]), the presence of small cell undifferentiated histology did not correlate with age, sex, or AFP levels at diagnosis.[86]

The Paediatric Hepatic International Tumour Trial (PHITT) designates any childhood liver tumor as rhabdoid tumor of the liver if it contains cells that lack SMARCB1 expression. Patients with SMARCB1-negative tumors, which are presumed to be related to rhabdoid tumors, may not be enrolled in the international trial, which addresses treatment of hepatoblastoma that includes small cell undifferentiated histology, hepatocellular carcinoma, and hepatic malignancy of childhood, not otherwise specified (NOS), but not rhabdoid tumor of the liver. In this trial, all patients with histology consistent with pure small cell undifferentiated hepatoblastoma, as assessed by the institutional pathologist, are required to have testing for SMARCB1 by immunohistochemistry according to the practices at the institution. In addition, presence of a blastemal component indicates conventional hepatoblastoma.[80]

A characteristic shared by both small cell undifferentiated hepatoblastoma and malignant rhabdoid tumor is the poor prognosis associated with each.[50,84,87] However, because small cell undifferentiated hepatoblastoma and rhabdoid tumor of the liver have not been discriminated in past studies, some of the prognostic features attributed to the former may have been contributed in part by the latter. Published studies of prognostic features related to small cell undifferentiated histology include the following:

  • In 2009, the results of a study of 11 young children with low AFP levels and small cell morphology were reported. Ten children died of disease progression, and one child died of complications. Six of six children tested were SMARCB1 negative, but only one child had any rhabdoid morphology. This finding suggests that many or all liver tumors with small cell morphology and very low AFP levels in young children may be rhabdoid tumors of the liver. These tumors have a poor prognosis that is associated with the driver variant.[84]
  • A single-institution study of seven children with small cell morphology liver tumors found that all retained expression of SMARCB1. Six children survived, and one child died of complications from liver transplant.[88]
  • A study of 23 liver tumors from the Kiel tumor bank found 12 tumors with small cell morphology. Nine tumors had malignant rhabdoid tumor classic histology, and two tumors had mixed small cell and rhabdoid histologies. Outcomes were not provided, but it was noted that rhabdoid brain tumors had small cell, not classic, rhabdoid histology.[89]
  • In a single-institution study of six children with SMARCB1-negative liver tumors, two children with small cell morphology died. The remaining four children with classic rhabdoid histology were not treated with cisplatin-based therapy; three children survived, and one child died of complications from transplant.[90]
  • A report from the COG AHEP0731 (NCT00980460) trial identified 35 of 177 evaluable patients (19%) with small cell undifferentiated hepatoblastoma confirmed by central review.[86] SMARCB1 nuclear expression was retained in 33 of 35 patients. Unlike previous reports, the presence of small cell undifferentiated histology did not correlate with age, sex, or AFP levels at diagnosis. The 5-year EFS rates for patients with low-, intermediate-, and high-risk small cell undifferentiated hepatoblastoma were 86% (95% confidence interval [CI], 33%–98%), 81% (95% CI, 51%–92%), and 29% (95% CI, 4%–81%), respectively. The 5-year EFS rates for patients with low-, intermediate-, and high-risk hepatoblastoma without small cell undifferentiated histology were 87% (95% CI, 72%–95%), 88% (95% CI, 79%–95%), and 55% (95% CI, 33%–74%); P = .17), respectively. In this trial, concordance between local and central review was poor, and they agreed in only 9 of 35 cases (26%). All tumors were tested for SMARCB1 expression by immunohistochemistry. In this study, hepatoblastoma that would otherwise be considered very low risk or low risk was upgraded to intermediate risk if any small cell undifferentiated elements were found. For more information, see Table 5.

The outcomes of the CHIC trial of childhood liver tumors may clarify some of the questions regarding these different histological and genetic findings.

Risk Stratification

There are significant differences among childhood cancer study groups in risk stratification used to determine treatment, making it difficult to compare results of the different treatments. Table 5 shows the variability in the definitions of risk groups.

Table 5. A Comparison of the Use of PRETEXT in Risk Stratification Schemes for Hepatoblastomaa,b
  COG (AHEP-0731) SIOPEL (SIOPEL-3, -3HR, -4, -6) GPOH JPLT (JPLT-2 and -3)
AFP = alpha-fetoprotein; COG = Children’s Oncology Group; GPOH = Gesellschaft für Pädiatrische Onkologie und Hämatologie (Society for Paediatric Oncology and Haematology); JPLT = Japanese Study Group for Pediatric Liver Tumor; PRETEXT = PRE-Treatment EXTent of disease; SIOPEL = International Childhood Liver Tumors Strategy Group.
aAdapted from Czauderna et al.[79]
bFor more information about the annotations used in PRETEXT, see Table 2.
cThe COG and PRETEXT definitions of vascular involvement differ.
Very low risk PRETEXT I or II; well-differentiated fetal histology; primary resection at diagnosis      
Low risk/standard risk PRETEXT I or II of any histology with primary resection at diagnosis PRETEXT I, II, or III PRETEXT I, II, or III PRETEXT I, II, or III
Intermediate riskb PRETEXT II, III, or IV unresectable at diagnosis; or V+c, P+, E+     PRETEXT IV or any PRETEXT with rupture; or N1, P2, P2a, V3, V3a; or multifocal
High riskb Any PRETEXT with M+; AFP level <100 ng/mL Any PRETEXT; V+, P+, E+, M+; AFP level <100 ng/mL; tumor rupture Any PRETEXT with V+, E+, P+, M+ or multifocal Any PRETEXT with M1 or N2; or AFP level <100 ng/mL

International risk classification model

The CHIC group developed a novel risk stratification system for use in international clinical trials on the basis of prognostic features present at diagnosis. CHIC unified the disparate definitions and staging systems used by pediatric cooperative multicenter trial groups, enabling the comparison of studies conducted by heterogeneous groups in different countries.[63] Original detailed clinical patient data were extracted from eight published clinical trials using central review of imaging and histology, and prognostic factors were identified by univariate analysis.[58]

Based on the initial univariate analysis of the data combined with historical clinical treatment patterns and data from previous large clinical trials, five backbone groups were selected, which allowed for further risk stratification. Subsequent multivariate analysis on the basis of these backbone groups defined the following clinical prognostic factors: PRETEXT group (I, II, III, or IV), presence of metastasis (yes or no), and AFP (≤100 ng/mL). The backbone groups are as follows:[63]

  • Backbone 1: PRETEXT I/II, not metastatic, AFP greater than 100 ng/mL.
  • Backbone 2: PRETEXT III, not metastatic, AFP greater than 100 ng/mL.
  • Backbone 3: PRETEXT IV, not metastatic, AFP greater than 100 ng/mL.
  • Backbone 4: Any PRETEXT group, metastatic disease at diagnosis, AFP greater than 100 ng/mL.
  • Backbone 5: Any PRETEXT group, metastatic or not, AFP less than or equal to 100 ng/mL at diagnosis.

Other diagnostic factors (e.g., age) were queried for each of the backbone categories, including the presence of at least one of the following PRETEXT annotations (defined as VPEFR+, see Table 2) or AFP less than or equal to 100 ng/mL:[63]

  • V: Involvement of vena cava or all three hepatic veins, or both.
  • P: Involvement of portal bifurcation or both right and left portal veins, or both.
  • E: Extrahepatic contiguous tumor extension.
  • F: Multifocal liver tumor.
  • R: Tumor rupture at diagnosis.

An assessment of surgical resectability at diagnosis was added for PRETEXT I and II patients. Patients in each of the five backbone categories were stratified on the basis of backwards stepwise elimination multivariable analysis of additional patient characteristics, including age and presence or absence of PRETEXT annotation factors (V, P, E, F, and R). Each of these subcategories received one of four risk designations (very low, low, intermediate, or high). The result of the multivariate analysis was used to assign patients to very low-, low-, intermediate-, and high-risk categories, as shown in Figure 2. For example, the finding of an AFP level of 100 to 1,000 ng/mL was significant only among patients younger than 8 years in the backbone PRETEXT III group. The analysis enables prognostically similar risk groups to be assigned to the appropriate treatment groups on upcoming international protocols.[63]

EnlargeDiagram showing risk stratification trees for the Children’s Hepatic tumors International Collaboration—Hepatoblastoma Stratification (CHIC-HS).
Figure 2. Risk stratification trees for the Children’s Hepatic tumors International Collaboration—Hepatoblastoma Stratification (CHIC-HS). Very low-risk group and low-risk group are separated only by their resectability at diagnosis, which has been defined by international consensus as part of the surgical guidelines for the collaborative trial, Paediatric Hepatic International Tumour Trial (PHITT). Separate risk stratification trees are used for each of the four PRETEXT groups. AFP = alpha-fetoprotein. M = metastatic disease. PRETEXT = PRETreatment EXTent of disease. Reprinted from The Lancet Oncology, Volume 18, Meyers RL, Maibach R, Hiyama E, Häberle B, Krailo M, Rangaswami A, Aronson DC, Malogolowkin MH, Perilongo G, von Schweinitz D, Ansari M, Lopez-Terrada D, Tanaka Y, Alaggio R, Leuschner I, Hishiki T, Schmid I, Watanabe K, Yoshimura K, Feng Y, Rinaldi E, Saraceno D, Derosa M, Czauderna P, Risk-stratified staging in paediatric hepatoblastoma: a unified analysis from the Children’s Hepatic tumors International Collaboration, Pages 122–131, Copyright (2017), with permission from Elsevier.

Treatment of Hepatoblastoma

Treatment options for newly diagnosed hepatoblastoma depend on the following:

  • Whether the cancer is resectable at diagnosis.
  • The tumor histology.
  • How the cancer responds to chemotherapy.
  • Whether the cancer has metastasized.

Cisplatin-based chemotherapy has resulted in a survival rate of more than 90% for children with PRETEXT and POST-Treatment EXTent (POSTTEXT) group I and II resectable disease before or after chemotherapy.[54,56,67]

Chemotherapy regimens used in the treatment of hepatoblastoma and their respective outcomes are described in Table 6. For information describing each stage, see the Tumor Stratification by Imaging section.

Table 6. Outcomes for Hepatoblastoma Multicenter Trialsa
Study Chemotherapy Regimen Number of Patients Outcomes
AFP = alpha-fetoprotein; C5V = cisplatin, fluorouracil (5-FU), and vincristine; CARBO = carboplatin; CCG = Children’s Cancer Group; CDDP = cisplatin; CITA = pirarubicin-cisplatin; COG = Children’s Oncology Group; DOXO = doxorubicin; EFS = event-free survival; GPOH = Gesellschaft für Pädiatrische Onkologie und Hämatologie (Society for Paediatric Oncology and Haematology); H+ = rupture or intraperitoneal hemorrhage; HR = high risk; IFOS = ifosfamide; IPA = ifosfamide, cisplatin, and doxorubicin; ITEC = ifosfamide, pirarubicin, etoposide, and carboplatin; JPLT = Japanese Study Group for Pediatric Liver Tumor; LR = low risk; NR = not reported; OS = overall survival; PLADO = cisplatin and doxorubicin; POG = Pediatric Oncology Group; PRETEXT = PRE-Treatment EXTent of disease; SIOPEL = International Childhood Liver Tumors Strategy Group; SR = standard risk; SUPERPLADO = cisplatin, doxorubicin, and carboplatin; THP = tetrahydropyranyl-adriamycin (pirarubicin); VP = vinorelbine and cisplatin; VPE+ = venous, portal, and extrahepatic involvement; VP16 = etoposide.
aAdapted from Czauderna et al.,[79] Meyers et al.,[91] and Malogolowkin et al.[92]
bStudy closed early because of inferior results in the CDDP/CARBO arm.
INT0098 (CCG/POG) 1989–1992 C5V vs. CDDP/DOXO Stage I/II: 50 4-Year EFS/OS:
I/II = 88%/100% vs. 96%/96%
Stage III: 83 III = 60%/68% vs. 68%/71%
Stage IV: 40 IV = 14%/33% vs. 37%/42%
P9645 (COG)b 1999–2002 C5V vs. CDDP/CARBO Stage III: 38 3-year EFS/OS:
III/IV: C5V = 60%/74%; CDDP/CARBO = 38%/54%
Stage IV: 50
AHEP0731 (COG) 2010–2014 [93][Level of evidence C1] LR: C5V (2 cycles) LR (stage I/II): 49 5-year EFS: 88%; 5-year OS: 91%
HB 94 (GPOH) 1994–1997 I/II: IFOS/CDDP/DOXO Stage I: 27 4-Year EFS/OS:
I = 89%/96%
Stage II: 3 II = 100%/100%
III/IV: IFOS/CDDP/DOXO + VP/CARBO Stage III: 25 III = 68%/76%
Stage IV: 14 IV = 21%/36%
HB 99 (GPOH) 1999–2004 SR: IPA SR: 58 3-Year EFS/OS:
SR = 90%/88%
HR: CARBO/VP16 HR: 42 HR = 52%/55%
SIOPEL-2 1994–1998 SR: PLADO PRETEXT I: 6 3-Year EFS/OS:
SR: 73%/91%
PRETEXT II: 36
PRETEXT III: 25
HR: CDDP/CARBO/DOXO PRETEXT IV: 21 HR: IV = 48%/61%
Metastases: 25 HR: metastases = 36%/44%
SIOPEL-3 1998–2006 SR: CDDP vs. PLADO SR: PRETEXT I: 18 3-Year EFS/OS:
SR: CDDP = 83%/95%; PLADO = 85%/93%
PRETEXT II: 133
PRETEXT III: 104
HR: SUPERPLADO HR: PRETEXT IV: 74 HR: Overall = 65%/69%
VPE+: 70  
Metastases: 70 Metastases = 57%/63%
AFP <100 ng/mL: 12  
SIOPEL-4 2005–2009 HR: Block A: Weekly; CDDP/3 weekly DOXO; Block B: CARBO/DOXO PRETEXT I: 2 3-Year EFS/OS:
All HR = 76%/83%
PRETEXT II: 17
PRETEXT III: 27
PRETEXT IV: 16 HR: IV = 75%/88%
Metastases: 39 HR: Metastases = 77%/79%
JPLT-1 1991–1999 I/II: CDDP(30)/THP-DOXO Stage I: 9 5-Year EFS/OS:
I = NR/100%
Stage II: 32 II = NR/76%
III/IV: CDDP(60)/THP-DOXO Stage IIIa: 48 IIIa = NR/50%
Stage IIIb: 25 IIIb = NR/64%
Stage IV: 20 IV = NR/77%
JPLT-2 1999–2010 [94][Level of evidence C1] Initial surgery and 2 cycles of CITA Stratum 1: PRETEXT I/II, 0 annotation factors except H+ (n = 40) 5-Year EFS/OS:
74.2%/89.9%
2 cycles of CITA followed by surgery and 2–4 cycles of CITA Stratum 2: PRETEXT II with multifocality (n = 80) 84.8%/90.8%
2 cycles of CITA followed by 2 cycles of CITA (responders); attempted surgery including transplant Stratum 3: PRETEXT I/II (annotation factors present) and III/IV (n = 176) responders 71.6%/85.9%
2 cycles of CITA followed by 2 cycles of ITEC (nonresponders); attempted surgery including transplant Stratum 4: PRETEXT I/II (annotation factors present) and III/IV (n = 59) nonresponders 59.1%/67.3%

Treatment options for hepatoblastoma that is resectable at diagnosis

Approximately 20% to 30% of children with hepatoblastoma have resectable disease at diagnosis. COG surgical guidelines (AHEP0731 [NCT00980460] appendix) recommend tumor resection at diagnosis without preoperative chemotherapy in children with PRETEXT I tumors and PRETEXT II tumors with greater than 1 cm radiographic margin on the vena cava and middle hepatic and portal veins. Outcomes for patients after undergoing a complete resection at diagnosis, compared with patients who had positive microscopic margins found at resection, are similar after receiving chemotherapy.[56,57,73]; [95][Level of evidence C1]

Prognosis varies depending on the histological subtype, as follows:

  • Patients with well-differentiated fetal histology (4% of hepatoblastomas) have a 3- to 5-year OS rate of 100% with minimal or no adjuvant chemotherapy.[50–52,96]
  • Patients with non–well-differentiated fetal histology, non–small cell undifferentiated hepatoblastomas have a 3- to 4-year OS rate of 90% to 100% with adjuvant chemotherapy.[50,51,54,56,97]
  • If any small cell undifferentiated elements are present, the 3-year survival rate is 40% to 70%.[50,53]

Treatment options for hepatoblastoma resectable at diagnosis showing non–well-differentiated fetal histology include the following:

  1. Resection followed by two to four cycles of chemotherapy.[58]

Re-resection of positive microscopic margins may not be necessary. Conclusive evidence is lacking for tumors with resection at diagnosis compared with those with positive microscopic margins resected after preoperative chemotherapy.

Evidence (gross surgical resection, with or without microscopic margins, and postoperative chemotherapy):

  1. In the COG AHEP0731 (NCT00980460) trial, 49 of 51 patients with stage I or stage II hepatoblastoma (without pure fetal histology) received two cycles of adjuvant chemotherapy consisting of cisplatin, fluorouracil, and vincristine.[93][Level of evidence C1]
    • The 5-year EFS rate was 88%, and the 5-year OS rate was 91%.
    • This outcome is comparable to the outcomes for children treated with four cycles after initial resection, and to the outcomes for children treated with two cycles of neoadjuvant chemotherapy before resection followed by two cycles of chemotherapy after resection.
  2. There is no reliable data for local recurrence risk in patients with a positive microscopic margin status who underwent resection at diagnosis.[68] SIOPEL studies suggest that in patients who received preoperative chemotherapy, positive microscopic margin did not increase risk of local recurrence.[56,57,73]; [95][Level of evidence C1]
    • In a European study conducted between 1990 and 1994, 11 patients had tumor found at the surgical margins after hepatic resection and two patients died, neither of whom had a local recurrence. None of the 11 patients underwent a second resection, and only one patient received radiation therapy postoperatively. All of the patients were treated with four courses of cisplatin and doxorubicin before surgery and received two courses of postoperative chemotherapy.[73]
    • In another European study of high-risk hepatoblastoma, 11 patients had microscopic residual tumor remaining after initial surgery and received two to four postoperative cycles of chemotherapy with no additional surgery. Of these 11 patients, 9 survived.[57]
    • In the SIOPEL-2 study, 13 of 13 patients with microscopic positive resection margins survived.[56]
    • An unplanned retrospective study of the SIOPEL-2 and SIOPEL-3 trials found that after four courses of cisplatin for standard-risk patients and seven courses of cisplatin alternating with doxorubicin/carboplatin for high-risk patients, resection was performed where imaging suggested it would be safe. Of the 431 children treated in these trials, 58 patients had positive microscopic tumor margins, and 371 patients were in complete remission. There were no statistically significant differences in the rates of local recurrence, EFS, or OS between the two groups.[95][Level of evidence C1]
  3. A randomized clinical trial demonstrated comparable efficacy with postoperative cisplatin/vincristine/fluorouracil and cisplatin/doxorubicin in the treatment of patients with hepatoblastoma.[51]
    • Although survival outcomes were nominally higher for the children who received cisplatin/doxorubicin, this difference was not statistically significant.
    • The combination of cisplatin/vincristine/fluorouracil was significantly less toxic than were the doses of cisplatin/doxorubicin.

Results of chemotherapy clinical trials are described in Table 6.

Treatment options for hepatoblastoma of well-differentiated fetal (pure fetal) histology resectable at diagnosis include the following:

  1. Complete surgical resection followed by watchful waiting or chemotherapy.[52]

Evidence (complete surgical resection followed by watchful waiting or chemotherapy):

  1. In a COG prospective clinical trial (INT0098), nine children with stage I (completely resected) well-differentiated fetal histology and fewer than two mitoses per high-power field were treated with four cycles of adjuvant doxorubicin.[51]
    • At a median follow-up of 5.1 years, the EFS and OS rates were 100% for all nine children.
  2. In the COG P9645 (NCT00003994) study, 16 patients with stage I (completely resected) tumors had well-differentiated fetal histology and received no adjuvant chemotherapy. In a retrospective PRETEXT classification of 21 of these 25 patients with adequate data, PRETEXT I, II, and III tumors were found in 7, 10, and 4 patients, respectively.[52]
    • The EFS and OS rates were 100% for patients with stage I well-differentiated fetal histology, including one patient who had a second surgery to address a positive tumor margin.

Treatment options for hepatoblastoma that is not resectable or not resected at diagnosis

Approximately 70% to 80% of children with hepatoblastoma have tumors that are not resected at diagnosis. COG surgical guidelines (AHEP0731 [NCT00980460] appendix) recommend a diagnostic biopsy without an attempt to resect the tumor in children with PRETEXT II tumors with less than 1-cm radiographic margin on the vena cava and middle hepatic vein and in all children with PRETEXT III and IV tumors.

Treatment options for hepatoblastoma that is not resectable or is not resected at diagnosis include the following:

  1. Chemotherapy followed by reassessment of surgical resectability and complete surgical resection.
  2. Chemotherapy followed by reassessment of surgical resectability and orthotopic liver transplant.[54,71,98–103]
  3. Transarterial chemoembolization (TACE) and transarterial radioembolization (TARE). TACE and TARE may be used to improve resectability before definitive surgical approaches.[104–106]

Tumor rupture at presentation, resulting in major hemorrhage that can be controlled by transcatheter arterial embolization or partial resection to stabilize the patient, does not preclude a favorable outcome when followed by chemotherapy and definitive surgery.[107]

In recent years, most children with hepatoblastoma have been treated with chemotherapy. In European cancer centers, children with resectable hepatoblastoma at diagnosis are treated with preoperative chemotherapy, which may reduce the incidence of surgical complications at the time of resection.[54,56,73] Treatment with preoperative chemotherapy has been shown to benefit children with hepatoblastoma. In contrast, an American intergroup study of treatment of children with hepatoblastoma encouraged resection at the time of diagnosis for all tumors amenable to resection without undue risk. The study (COG-P9645) did not treat children with stage I tumors of well-differentiated fetal histology with preoperative or postoperative chemotherapy unless they developed progressive disease.[52] In this study, most patients with PRETEXT III and all PRETEXT IV tumors were treated with chemotherapy before resection or transplant.

Patients whose tumors remain unresectable after chemotherapy should consider a liver transplant.[54,71,98–102] In the presence of features predicting unresectability, early coordination with a pediatric liver transplant service is critical.[78] In the COG AHEP0731 (NCT00980460) study, early referral (i.e., based on imaging done after the second cycle of chemotherapy) to a liver specialty center with transplant capability was recommended for patients with POSTTEXT III tumors with positive V or P and POSTTEXT IV tumors with positive F.

Evidence (chemotherapy followed by reassessment of surgical resectability and complete surgical resection or liver transplant):

  1. In the SIOPEL-1 study, preoperative chemotherapy (doxorubicin and cisplatin) was given to all children with hepatoblastoma with or without metastases. After chemotherapy, and excluding those who underwent a liver transplant (<5% of patients), complete resection was performed.[54]
    • The chemotherapy was well tolerated.
    • Complete resection was obtained in 87% of children.
    • This strategy resulted in an OS rate of 75% at 5 years after diagnosis.
  2. Identical results were seen in a follow-up international study (SIOPEL-2).[56]
  3. The SIOPEL-3 study compared cisplatin alone with cisplatin and doxorubicin in patients with preoperative standard-risk hepatoblastoma. Standard risk was defined as tumor confined to the liver and involving as many as three sectors.[97][Level of evidence A1]
    • The resection rates and OS rates were similar for the cisplatin (95%) and cisplatin/doxorubicin (93%) groups.
  4. In a pilot study, SIOPEL-3HR, cisplatin alternating with carboplatin/doxorubicin was administered in a dose-intensive fashion to high-risk patients with hepatoblastoma.[57]
    • In 74 patients with PRETEXT IV tumors, 22 of whom also had metastases, 31 patients had tumors that became resectable, and 26 patients underwent transplant. The 3-year OS rate was 69% (± 11%).
    • Of the 70 patients with metastases enrolled in the trial, the 3-year EFS rate was 56%, and the OS rate was 62%. Of patients with lung metastases, 50% were able to achieve complete remission of metastases with chemotherapy alone (without lung surgery).
  5. SIOPEL-4 (NCT00077389) was a multinational feasibility trial of dose-dense cisplatin/doxorubicin chemotherapy and radical surgery for a group of children with high-risk hepatoblastoma. Surgical removal of all remaining tumor lesions after chemotherapy was performed if feasible (including liver transplant and metastasectomy, if needed). Patients who underwent liver resection or liver transplant after three cycles of chemotherapy subsequently received two postoperative cycles of carboplatin and doxorubicin. Patients whose tumors remained unresectable after three cycles of chemotherapy received two cycles of very intensive carboplatin and doxorubicin before surgery. The primary tumor masses were identified as PRETEXT groups II (27%), III (44%), and IV (26%).[74][Level of evidence B4]
    • Ninety-seven percent of patients (60 of 61) had a partial response with chemotherapy.
    • Eighty-five percent of patients (53) underwent complete macroscopic resection; tumor was microscopically present in five patients, all of whom are disease-free survivors.
    • Two patients died postoperatively.
    • There were 37 partial hepatectomies and 16 liver transplants.
    • The study had a total of 62 high-risk patients; 74% of patients (62%–84%) underwent resection.
      • The 3-year disease-free survival (DFS) rate was 76% (95% CI, 65%–87%).
      • The 3-year OS rate was 83% (95% CI, 73%–93%).
    • Of the 16 patients with PRETEXT IV tumors, 11 were downstaged after chemotherapy—6 patients to PRETEXT group III, 4 patients to PRETEXT group II, and 1 patient to PRETEXT group I. Twelve tumors became resectable; subsequently, four patients underwent a partial hepatectomy and eight patients underwent a liver transplant. For patients who presented with PRETEXT IV disease:
      • The 3-year DFS rate was 73% (95% CI, 51%–96%).
      • The 3-year OS rate was 80% (95% CI, 60%–100%).
  6. In approximately 75% of children and adolescents with initially unresectable hepatoblastoma, tumors can be rendered resectable with cisplatin-based preoperative chemotherapy, and 60% to 65% of patients will survive disease-free.[108]

In the United States, patients with unresectable tumors have been treated with chemotherapy before resection or transplant.[51,52,66,67] On the basis of radiographic imaging, most stage III and IV hepatoblastomas are rendered resectable after two cycles of chemotherapy.[109] A combination of ifosfamide, cisplatin, and doxorubicin followed by postinduction resection has also been used in the treatment of advanced-stage disease.[110] Some centers have also used extended resection of selected POSTTEXT III and IV tumors rather than liver transplant.[78,111–114] Other options, such as TARE and TACE, have been used to shrink residual tumor mass. TARE may also facilitate surgical resection by tumor shrinkage when added to chemotherapy.[106]

The COG conducted a single-arm phase III trial (AHEP0731 [NCT00980460]) for patients with intermediate-risk hepatoblastoma. The study included 93 patients with unresectable nonmetastatic disease and 9 patients with a complete resection at diagnosis. All of the tumors had small cell undifferentiated histology. The addition of doxorubicin to standard treatment (cisplatin, fluorouracil, and vincristine) was assessed for feasibility and efficacy. In the 93 patients with initially unresectable disease, the 5-year EFS rate was 85% (95% CI, 79%–93%), and the OS rate was 95% (95% CI, 87%–98%).[115]

Chemotherapy followed by TACE, then high-intensity focused ultrasound, showed promising results in China for patients with PRETEXT III and IV tumors, some of which were resectable. Patients did not undergo surgical resection because of parent refusal.[116]

Treatment options for hepatoblastoma with metastases at diagnosis

The outcomes of patients with metastatic hepatoblastoma at diagnosis are poor, but long-term survival and cure are possible.[51,66,67] Survival rates at 3 to 5 years range from 20% to 79%.[55,57,74,117] To date, the best outcomes for children with metastatic hepatoblastoma resulted from treatment with dose-dense cisplatin and doxorubicin, although significant toxicity was also noted (SIOPEL-4 [NCT00077389] trial).[74][Level of evidence B4]

Treatment options for hepatoblastoma with metastases at diagnosis include the following:

  1. Chemotherapy followed by reassessment of surgical resectability.
    • If the primary tumor and extrahepatic disease (usually pulmonary nodules) are resectable after chemotherapy, surgical resection is followed by additional chemotherapy.
    • If extrahepatic metastatic disease is in complete remission after chemotherapy and/or surgical resection of lung nodule but the primary tumor remains unresectable, orthotopic liver transplant is warranted.
  2. If extrahepatic metastatic disease is not resectable or the patient is not a transplant candidate, additional chemotherapy, TACE, TARE, or radiation therapy may be indicated.[106]

The standard combination chemotherapy regimen in North America is four courses of cisplatin/vincristine/fluorouracil [51] or doxorubicin/cisplatin,[52,54,55] followed by attempted complete tumor resection. If the tumor is completely removed, two postoperative courses of the same chemotherapy are usually given. Study results for different chemotherapy regimens have been reported. For more information, see Table 6.

High-dose chemotherapy with stem cell rescue does not appear to be more effective than standard multiagent chemotherapy.[118]

Evidence (chemotherapy followed by surgery to treat metastatic disease at diagnosis):

  1. A subset of 39 patients presenting with metastases were enrolled in the SIOPEL-4 (NCT00077389) trial, a multinational feasibility trial of dose-dense cisplatin/doxorubicin chemotherapy and radical surgery for a group of children with high-risk hepatoblastoma. Patients who underwent liver resection or transplant after three cycles of chemotherapy subsequently received two postoperative cycles of carboplatin and doxorubicin. Patients whose tumors were unresectable after three cycles of chemotherapy received two additional cycles of very intensive carboplatin and doxorubicin before surgery.[74][Level of evidence B4]
    • After three cycles of chemotherapy, there was a complete response (only in the metastases) in 20 of 39 patients and a partial response in 18 of 39 patients. Nineteen of the patients who achieved a complete response were alive without disease 3 years after diagnosis.
    • Of the patients who achieved a partial response, seven patients underwent metastasectomy near the time of resection or liver transplant, with an OS rate of 100%. An additional seven patients with residual small pulmonary nodules underwent resection without metastasectomy; of those, six patients did well and one patient had a recurrence.
    • Two patients with initial metastases eventually experienced a recurrence.
    • Liver transplant, rather than resection alone, was needed to treat 7 of the 39 patients who presented with metastases.
    • For the subset of 39 patients presenting with metastases, the 3-year DFS rate was 77% (95% CI, 63%–90%), and the OS rate was 79% (95% CI, 66%–92%).

In patients with resected primary tumors, any remaining pulmonary metastases should be surgically removed, if possible.[55] Resection of pulmonary metastases may be facilitated by computed tomography needle localization or preoperative indocyanine green administration with intraoperative fluorescence localization.[119] A review of patients treated on a U.S. intergroup trial suggested that resection of metastasis may be done at the time of resection of the primary tumor.[117][Level of evidence C1]

If extrahepatic disease is in complete remission after chemotherapy, and the primary tumor remains unresectable, an orthotopic liver transplant may be performed.[52,57,74,110]

The outcome results are discrepant for patients with lung metastases at diagnosis who undergo orthotopic liver transplant after complete resolution of lung disease in response to pretransplant chemotherapy. Some studies have reported favorable outcomes for these patients,[57,74,102,110] while others have noted high rates of hepatoblastoma recurrence.[71,98,101,104] All of these studies are limited by small patient numbers. Additional studies are needed to better define outcomes for this subset of patients. Recent clinical trials have resulted in few pulmonary recurrences in children who presented with metastatic disease and underwent liver transplants.[57,59,74]

If extrahepatic disease is not resectable after chemotherapy or the patient is not a transplant candidate, alternative treatment approaches include the following:

  • Other chemotherapy agents. Chemotherapy agents such as irinotecan, high-dose cisplatin/etoposide, or continuous-infusion doxorubicin have been used.[120–122]; [123][Level of evidence C1]
  • TACE.[105,124]
  • Radiation therapy.[125]

Treatment of Progressive or Recurrent Hepatoblastoma

The prognosis for a patient with progressive or recurrent hepatoblastoma depends on several factors, including the following:[126]

  • Site of recurrence.
  • Previous treatment.
  • Individual patient considerations.

Treatment options for progressive or recurrent hepatoblastoma include the following:

  1. Surgical resection. In patients with hepatoblastoma that is completely resected at initial diagnosis, aggressive surgical treatment of isolated pulmonary metastases that develop in the course of the disease, in conjunction with an overall strategy that includes chemotherapy, may make extended DFS possible.[117,126,127]

    If possible, isolated metastases are resected completely in patients whose primary tumor is controlled.[128] A retrospective analysis of patients in the SIOPEL 1, 2, and 3 studies showed a 12% incidence of recurrence after complete remission by imaging and AFP levels. Outcome after recurrence was best if the tumor was amenable to surgery. Of patients who underwent chemotherapy and surgery, the 3-year EFS rate was 34%, and the OS rate was 43%.[126][Level of evidence C1]

    If all of the recurrent disease cannot be surgically removed, patients should consider enrolling in a clinical trial. Phase I and phase II clinical trials may be appropriate.

  2. Chemotherapy. Analysis of survival after recurrence demonstrated that some patients treated with cisplatin/vincristine/fluorouracil could be salvaged with doxorubicin-containing regimens, but patients treated with doxorubicin/cisplatin could not be salvaged with vincristine/fluorouracil.[129] The addition of doxorubicin to vincristine/fluorouracil/cisplatin was clinically evaluated in the COG study AHEP0731 (NCT00980460).

    Combined vincristine/irinotecan and single-agent irinotecan have been used with some success.[123]; [122][Level of evidence C1]

    A review of COG phase I and II studies found no promising agents for relapsed hepatoblastoma.[130]

  3. Liver transplant. Liver transplant should be considered for patients with nonmetastatic disease recurrence in the liver that is not amenable to resection.[71,98,101]
  4. Percutaneous ablation. Percutaneous radiofrequency ablation has been used as an alternative to surgical resection of oligometastatic hepatoblastoma.[131][Level of evidence C1] Percutaneous ablation techniques may also be considered for palliation.[132]

Treatment Options Under Clinical Evaluation for Hepatoblastoma

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, see the ClinicalTrials.gov website.

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Hepatocellular Carcinoma

Incidence

The annual incidence of hepatocellular carcinoma in the United States is 0.4 cases per 1 million children between the ages of 0 and 14 years and 1.5 cases per 1 million adolescents aged 15 to 19 years.[1] The incidence of hepatocellular carcinoma in adults in the United States has steadily increased since the 1970s, possibly because of the increased frequency of chronic hepatitis C infection.[2] However, the incidence of hepatocellular carcinoma in children has not increased. In several Asian countries, the incidence of hepatocellular carcinoma in children is 10 times higher than in North America. The high incidence appears to be related to the incidence of perinatally acquired hepatitis B virus (HBV), which can be prevented in most cases by vaccination and administration of hepatitis B immune globulin to the newborn child.[3]

Fibrolamellar carcinoma of the liver was thought to be a subtype of hepatocellular carcinoma. However, it is now recognized as a distinct cancer. For more information, see the Fibrolamellar Carcinoma section.

Risk Factors

Conditions associated with hepatocellular carcinoma are described in Table 7.

Table 7. Conditions Associated With Hepatocellular Carcinoma
Associated Disorder Clinical Findings
Alagille syndrome [4] Broad prominent forehead, deep-set eyes, and small prominent chin. Abnormality of bile ducts leads to intrahepatic scarring. For more information, see the Alagille syndrome section.
Glycogen storage diseases I–IV [5] Symptoms vary by individual disorder.
Hepatitis B and C [6–8] For more information, see the Hepatitis B and hepatitis C infection section.
Progressive familial intrahepatic cholestasis [9,10] Symptoms of jaundice, pruritus, and failure to thrive begin in infancy and progress to portal hypertension and liver failure.
Tyrosinemia [11] First few months of life: failure to thrive, vomiting, jaundice.

Alagille syndrome

Alagille syndrome is an autosomal dominant genetic syndrome that is usually caused by a variant in or deletion of the JAG1 gene. It involves the bile ducts of the liver, the heart, and blood vessels in the brain and kidney. Patients develop a characteristic facies.[4]

Hepatitis B and hepatitis C infection

In children, hepatocellular carcinoma is associated with perinatally acquired HBV. In adults, it is associated with chronic HBV and hepatitis C virus (HCV) infection.[6–8] Widespread hepatitis B immunization has decreased the incidence of hepatocellular carcinoma in Asia.[3] Compared with adults, the incubation period from hepatitis virus infection to the genesis of hepatocellular carcinoma is extremely short in a small subset of children with perinatally acquired virus. Variants in the MET gene could be one mechanism that results in a shortened incubation period.[12]

HCV infection is associated with development of cirrhosis and hepatocellular carcinoma that takes decades to develop and is generally not seen in children.[8] Unlike in adults, cirrhosis in children is much less commonly involved in the development of hepatocellular carcinoma and is found in only 20% to 35% of children with hepatocellular carcinoma tumors.

Nonviral liver injury

Specific types of nonviral liver injury and cirrhosis that are associated with hepatocellular carcinoma in children include the following:

  • Tyrosinemia. Patients with tyrosinemia are regularly screened for hepatocellular carcinoma, even if they are treated with nitisinone.[11] Nitisinone can prevent cirrhosis and decrease the incidence of hepatocellular carcinoma, especially when administered during infancy, after neonatal screening is used to diagnose tyrosinemia.[13] As of 2014, only a minority of state screening programs had adopted a highly recommended, new, more predictive newborn screen that is much more effective in newborn children aged 24 to 48 hours.[14]

    In an Iranian study, 36 children underwent liver transplant for tyrosinemia.[15] Twenty-two children had liver nodules greater than 10 cm, and in 20 children, the nodules were cirrhotic. Median age at transplant was 3.9 years. Five of 19 children older than 2 years had hepatocellular carcinoma, and no children younger than 2 years had hepatocellular carcinoma in the resected liver.

  • Aggressive familial intrahepatic cholestasis. Hepatocellular carcinoma may also arise in very young children with variants in the ABCB11 gene (encodes bile salt export pump protein), which causes progressive familial intrahepatic cholestasis.[9]

Genomics of Hepatocellular Carcinoma

Molecular features of hepatocellular carcinoma

Genomic findings related to hepatocellular carcinoma include the following:

  • One case of pediatric hepatocellular carcinoma was analyzed by whole-exome sequencing, which showed a higher variant rate (53 variants) and the coexistence of CTNNB1 and NFE2L2 variants.[16]
  • One study investigated pediatric (nonfibrolamellar) hepatocellular carcinoma tumors (N = 15) using multiple analytic tools. These tumors were found to frequently carry aberrations in a subset of genes that are commonly altered in adult hepatocellular carcinoma, including CTNNB1 and TERT. However, the molecular mechanisms of the variants are different. The TP53 variant was rare in this pediatric hepatocellular carcinoma cohort. Pediatric hepatocellular carcinoma that arose in the background of underlying metabolic disease had fewer variants and a distinct molecular profile. Typical driver variants were lacking in this group of patients.[17]
  • A rare, more aggressive subtype of childhood liver cancer (hepatocellular neoplasm, not otherwise specified, also termed transitional liver cell tumor) occurs in older children. It has clinical and histopathological findings of both hepatoblastoma and hepatocellular carcinoma.

    TERT variants were observed in two of four transitional liver cell tumor cases tested.[18] TERT variants are also commonly observed in adults with hepatocellular carcinoma.[19]

To date, these genetic variants have not been used to select therapeutic agents for investigation in clinical trials.

Diagnosis

For more information, see the Diagnosis section in the Hepatoblastoma section.

Prognosis and Prognostic Factors

Prognosis

In the United states, the 5-year relative survival rate is 55% for children and adolescents with hepatocellular carcinoma.[1] The 5-year survival for patients with hepatocellular carcinoma may depend on the stage of the disease. In an intergroup chemotherapy study conducted in the 1990s, seven of eight stage I patients survived, and less than 10% of stage III and IV patients survived.[20,21] An analysis of Surveillance, Epidemiology, and End Results (SEER) Program data found a 5-year overall survival (OS) rate of 24%, a 10-year rate of 23%, and a 20-year rate of 8% in patients aged 19 years and younger, suggesting improved outcome related to more recent treatment. In a multivariate analysis of the SEER data, surgical resection, localized tumor, and non-Hispanic ethnicity were all associated with improved outcome. Patients who had a complete surgical resection had an OS rate of 60%, compared with an OS rate of 0% for patients who had an incomplete resection.[22][Level of evidence C1]

The 5-year OS rates by PRE-Treatment EXTent of disease (PRETEXT) group for patients with hepatocellular carcinoma in the SIOPEL-1 trial were found to be the following:[23]

  • 44% for patients with PRETEXT I group tumors.
  • 44% for patients with PRETEXT II group tumors.
  • 22% for patients with PRETEXT III group tumors.
  • 8% for patients with PRETEXT IV group tumors.

For more information about PRETEXT grouping, see the PRETEXT and POSTTEXT Group Definitions section.

Hepatocellular carcinoma prognosis by Evans surgical stage. Several staging systems exist for hepatocellular carcinoma, including the American Joint Committee on Cancer (AJCC) tumor-node-metastasis staging system (TNM) and the Barcelona Clinic Liver Cancer Staging System. However, the international prospective collaborative Paediatric Hepatic International Tumour Trial (PHITT) used the Evans Surgical Staging for childhood liver cancer. For more information, see the Evans Surgical Staging for Childhood Liver Cancer section.

  • Stage I.

    Children with stage I hepatocellular carcinoma have a good outcome.[24]

  • Stage II.

    Stage II is too rarely seen to predict outcome.

  • Stages III and IV.

    Stages III and IV are usually fatal.[21,23]

Prognostic factors

Factors affecting prognosis include the following:

  • Treatment-related factors: Cure of hepatocellular carcinoma requires gross tumor resection. However, hepatocellular carcinoma is often extensively invasive or multicentric, and less than 30% of tumors are resectable. Orthotopic liver transplant has been successful in selected children with hepatocellular carcinoma.[25,26]
  • PRETEXT group: PRETEXT group (resectability) is also a prognostic factor. For more information, see the Tumor Stratification by Imaging section.
  • Tumor histology: For more information, see the Histology section.

Histology

The cells of hepatocellular carcinoma are epithelial in appearance. Hepatocellular carcinoma commonly arises in the right lobe of the liver.

Hepatocellular neoplasm, not otherwise specified (NOS)

Hepatocellular neoplasm, NOS, is also known as transitional liver cell tumor. This tumor, with characteristics of both hepatoblastoma and hepatocellular carcinoma, is a rare neoplasm found in older children and adolescents. It has a putative intermediate position between hepatoblasts and more mature hepatocyte-like tumor cells. The tumor cells may vary in regions of the tumor between classical hepatoblastoma and obvious hepatocellular carcinoma. In the international consensus classification, these tumors are referred to as hepatocellular neoplasm, NOS.[27] The tumors are usually unifocal and may have central necrosis at presentation. Response to chemotherapy has not been rigorously studied, but it is thought to be similar to that of hepatocellular carcinoma.[28]

Treatment of Hepatocellular Carcinoma

Treatment options for newly diagnosed hepatocellular carcinoma depend on the following:

  1. Whether the cancer is resectable at diagnosis.
  2. How the cancer responds to chemotherapy.
  3. Whether the cancer has metastasized.
  4. Whether the cancer is HBV related.

Treatment options for hepatocellular carcinoma that is resectable at diagnosis

Treatment options for hepatocellular carcinoma that is resectable at diagnosis include the following:

  1. Complete surgical resection of the primary tumor followed by chemotherapy.
  2. Chemotherapy followed by complete surgical resection of the primary tumor.[23]
  3. Complete surgical resection without chemotherapy.

Surgical resection and chemotherapy are the mainstays of treatment for resectable hepatocellular carcinoma.

Evidence (complete surgical resection followed by chemotherapy):

  1. Seven of eight patients with stage I hepatocellular carcinoma who received adjuvant cisplatin-based chemotherapy survived disease free.[21]
  2. In a survey of childhood liver tumors treated before the consistent use of chemotherapy, only 12 of 33 patients with hepatocellular carcinoma who had complete excision of the tumor survived.[29] This suggests that treatment with adjuvant chemotherapy may benefit children with completely resected hepatocellular carcinoma.
  3. In an analysis of SEER data for children and adolescents younger than 20 years who were diagnosed between 1976 and 2009, patients who underwent a complete resection had a 5-year OS rate of 60%, and patients who did not have a complete resection had a 5-year OS rate of 0%.[22][Level of evidence C1]

Cisplatin and doxorubicin may be administered as adjuvant therapy because these agents may have activity in the treatment of hepatocellular carcinoma.[23]

Evidence (complete surgical resection without chemotherapy):

  1. In a single-institution retrospective report, 12 patients with stage I hepatocellular carcinoma were treated with surgery. Ten patients received no chemotherapy and two patients received a short course of chemotherapy based on oncologist preference.[30][Level of evidence C1]
    • All 12 patients were alive without evidence of disease at a median of 54 months.

Despite improvements in surgical techniques, chemotherapy delivery, and patient supportive care in the past 20 years, clinical trials of chemotherapy have not shown improved survival rates for pediatric patients with hepatocellular carcinoma.[23] The International Childhood Liver Tumors Strategy Group (SIOPEL) studies in Europe have observed no improvement in 5-year OS since 1990. The only long-term survivors were patients whose tumors were resectable at diagnosis, which was less than 30% of children entered in the study.[31] However, some liver transplant studies (complete resection with transplant with or without neoadjuvant chemotherapy) have shown OS rates that are superior to the SIOPEL studies.[26,32–35]

Treatment options for nonmetastatic hepatocellular carcinoma that is not resectable at diagnosis

Treatment options for nonmetastatic hepatocellular carcinoma that is not resectable at diagnosis include the following:

  1. Chemotherapy followed by reassessment of surgical resectability. If the primary tumor is resectable, complete surgical resection.
  2. Chemotherapy with or without transarterial radioembolization (TARE) followed by reassessment of surgical resectability. If the primary tumor remains unresectable:
    • Orthotopic liver transplant.
    • Temporizing transarterial chemoembolization (TACE) or TARE followed by complete resection or liver transplant.
    • TACE or TARE alone.

The use of neoadjuvant chemotherapy or TACE to enhance resectability or liver transplant, which may result in complete resection of tumor, is necessary for a cure.

Evidence (chemotherapy followed by surgery):

  1. In a prospective study of 41 patients who received preoperative cisplatin/doxorubicin chemotherapy, the following was observed:[23]
    • Treatment resulted in a decrease in tumor size, with a decrease in alpha-fetoprotein (AFP) levels in about 50% of patients.
    • The patients who responded to chemotherapy had a superior tumor resectability and survival rate. However, the OS rate was 28%, and only those who underwent complete resection survived.

Evidence (chemotherapy, TARE, or TACE followed by reassessment of surgical resectability; treatment options, including liver transplant, for unresectable primary tumor after chemotherapy, TARE, or TACE):

  1. Liver transplant has been a successful therapy for children with unresectable hepatocellular carcinoma. The survival rate is about 60%, with most deaths resulting from tumor recurrence.[25,35–38]
  2. A review of SEER data for hepatocellular carcinoma treatment in patients younger than 20 years revealed that 75% of patients underwent resection and 25% underwent liver transplant.[39]
    • The 5-year OS rate was 53.4% with resection and 85.3% with transplant, suggesting that the criteria for transplant in hepatocellular carcinoma might be liberalized for overall patient benefit. This data has not been verified in a prospective clinical trial.
  3. TACE followed by complete surgical resection of the primary tumor may be an alternative to the use of chemotherapy followed by surgical resection.
    • Studies in adults in China suggest that repeated hepatic TACE before surgery may improve the outcome of subsequent hepatectomy.[40]
    • A meta-analysis found seven randomized trials that compared resection alone with TACE followed by resection. There was no difference in the 3-year event-free survival (EFS) and OS rates between the two groups, but the 5-year EFS and OS rates favored TACE followed by resection.[41]
  4. TARE has been used in the treatment of adult patients with hepatocellular carcinoma for some time. In a small number of patients, TARE has provided both a palliative benefit and a possible bridge to liver transplant.[42,43]

If the primary tumor is not resectable after chemotherapy and the patient is not a transplant candidate, alternative treatment approaches used in adults include the following:

  • Sorafenib.
  • TACE or TARE.
  • Cryosurgery.
  • Intratumoral injection of alcohol.
  • Radiation therapy.

There are limited data on the use of these alternative treatment approaches in children.

Limited data from a European pilot study suggest that sorafenib was well tolerated in 12 children and adolescents with newly diagnosed advanced hepatocellular carcinoma when given in combination with standard chemotherapy of cisplatin and doxorubicin.[44] Additional study is needed to define its role in the treatment of children with hepatocellular carcinoma.

Cryosurgery, intratumoral injection of alcohol, and radiofrequency ablation can successfully treat small (<5 cm) tumors in adults with cirrhotic livers.[40,45,46] Some local approaches such as cryosurgery, radiofrequency ablation, and TACE, which suppress hepatocellular carcinoma tumor progression, are used as bridging therapy in adults to delay tumor growth while on a waiting list for cadaveric liver transplant.[47] In a pediatric study of eight patients with hepatocellular carcinoma, two patients died of progressive disease without transplant. Treatment with TACE stabilized disease in six patients, for a mean of 141 days to reach transplant.[48][Level of evidence C1] Five patients were alive at the end of the observation period, and one patient died of disease. For more information, see Primary Liver Cancer Treatment.

Most of the information about the use of targeted therapy or immunotherapy for patients with nonresectable hepatocellular carcinoma or metastatic disease has been informed by trials in adults. To learn more about these treatments in adults, see the Treatment of Locally Advanced or Metastatic Primary Liver Cancer section in Primary Liver Cancer Treatment.

Treatment options for hepatocellular carcinoma with metastases at diagnosis

No specific treatment has proven effective for metastatic hepatocellular carcinoma in children and adolescents.

In two prospective trials, cisplatin plus either vincristine/fluorouracil or continuous-infusion doxorubicin was ineffective in adequately treating 25 patients with metastatic hepatocellular carcinoma.[21,23] Occasional patients may transiently benefit from treatment with cisplatin/doxorubicin therapy, especially if the localized hepatic tumor shrinks adequately enough to allow resection of disease and the metastatic disease disappears or becomes resectable.

Treatment options for HBV-related hepatocellular carcinoma

Although HBV-related hepatocellular carcinoma is not common in children in the United States, nucleotide/nucleoside analog HBV inhibitor treatment improves postoperative prognosis in children and adults treated in China.[49]

Treatment options for HBV-related hepatocellular carcinoma include the following:

  1. Antiviral therapy.

Evidence (antiviral therapy):

  1. In a randomized controlled trial, 163 patients post–radical hepatectomy were evaluated for response to one of three antiviral treatments.[49]
    • Antiviral treatment significantly decreased hepatocellular carcinoma recurrence, with a hazard ratio (HR) of 0.48 (95% confidence interval [CI], 0.32–0.70), and hepatocellular carcinoma–related death, with an HR of 0.26 (95% CI, 0.14–0.50), in multivariate Cox analyses.
    • Patients who received antiviral treatment had significantly decreased early recurrence (HR, 0.41; 95% CI, 0.27–0.62) and improved liver function 6 months after surgery than did the control patients (P < .001).

Treatment of Progressive or Recurrent Hepatocellular Carcinoma

The prognosis for a patient with recurrent or progressive hepatocellular carcinoma is extremely poor.[50]

Treatment options for progressive or recurrent hepatocellular carcinoma include the following:

  1. Chemoembolization temporization before transplant or immediate liver transplant, for those with isolated recurrence in the liver.[25,35,36,51]
  2. Radiofrequency ablation.

    In a retrospective single-institution study, ten children aged 6 to 17 years with recurrent hepatocellular carcinoma were treated with radiofrequency ablation. After one ablation, 14 of 15 target lesions had complete responses. None of these lesions progressed. The 1-year OS rate was 77.8%, and the 3-year OS rate was 44.4%.[52][Level of evidence C1]

  3. Phase I and phase II clinical trials may be appropriate and should be considered.

Treatment with sorafenib has resulted in improved progression-free survival in adults with advanced hepatocellular carcinoma. For adult patients who received sorafenib, the median survival and time to radiological progression were about 3 months longer than for patients who received a placebo.[53]

Treatment Options Under Clinical Evaluation for Hepatocellular Carcinoma

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, see the ClinicalTrials.gov website.

References
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Fibrolamellar Carcinoma

Fibrolamellar carcinoma was previously considered a rare subtype of hepatocellular carcinoma. It is also called fibrolamellar hepatocellular carcinoma and fibrolamellar liver cancer. With the 2014 discovery of a pathognomonic DNAJB::PRKACA chimera that defines this entity, it has been redefined as a distinct type of cancer, separate from hepatocellular carcinoma.[1]

Incidence

Fibrolamellar carcinoma most commonly arises in adolescents and adults, although it can also arise in young children and older adults.[2,3] The Surveillance, Epidemiology, and End Results (SEER) Program reports an annual fibrolamellar carcinoma incidence of 0.2 cases per 1 million based on pathology reporting. However, clinical practice estimates are much higher, and tiered computational analysis of clinical data places this estimate five to eight times higher.[4] Unlike hepatoblastoma in children and hepatocellular carcinoma in adults, fibrolamellar carcinoma in adolescents and young adults is not clearly increasing in incidence over time.[3,5] Fibrolamellar carcinoma, unlike hepatocellular carcinoma, is not strongly associated with a history of cirrhosis, hepatitis B virus (HBV), or hepatitis C virus (HCV) infection.[2]

Risk Factors

Carney complex is caused by heterozygous germline pathogenic variants in PRKAR1A and is an autosomal dominant genetic syndrome.[6] It is characterized by skin pigmentary abnormalities. It is also associated with cardiac, endocrine, cutaneous, and neural myxomatous tumors. Fibrolamellar carcinoma is observed, albeit rarely, in patients with Carney complex.[7] Fibrolamellar carcinoma arising in patients with Carney complex is negative for PRKACA rearrangements and instead shows loss of PRKAR1A protein expression.[7]

Diagnosis

Fibrolamellar carcinoma was first described as a distinct pathological entity by Edmonson in 1956. It is characterized by large cells with eosinophilic cytoplasm, central nuclei with vesiculated chromatin and prominent macronucleoli, along with dense bands of lamellar fibrosis that gives the tumor its name.[8]

Genomics of Fibrolamellar Carcinoma

Molecular features of fibrolamellar carcinoma

Fibrolamellar carcinoma is a rare subtype of hepatocellular carcinoma observed in older children and young adults. It is characterized by an approximately 400 kB deletion on chromosome 19, which produces a chimeric transcript. This chimeric RNA codes for a protein containing the amino-terminal domain of DNAJB1, a homolog of the molecular chaperone DNAJ, fused in frame with PRKACA, the catalytic domain of protein kinase A.[1]

Prognosis

Fibrolamellar carcinoma is not associated with cirrhosis of the liver. It was previously thought to confer a more favorable prognosis than hepatocellular carcinoma.[3,5,9] The improved outcomes of patients with fibrolamellar carcinoma in older studies may be related to a higher proportion of tumors being less invasive and more resectable in the absence of cirrhosis. However, the outcomes of patients with fibrolamellar carcinoma in recent prospective studies, when compared stage-to-stage and PRETEXT group–to–PRETEXT group, are the same as the outcomes of patients with conventional hepatocellular carcinomas.[10,11]; [12][Level of evidence C1]

Treatment of Fibrolamellar Carcinoma

Surgery is the standard of care for patients with radiographically localized fibrolamellar carcinoma. For patients with distant spread of disease, systemic therapy is based on the current treatments for pediatric or adult hepatocellular carcinoma, albeit with similarly poor effectiveness. For more information about the treatments used for fibrolamellar carcinoma, see the Treatment of Hepatocellular Carcinoma section.

Treatment Options Under Clinical Evaluation for Fibrolamellar Carcinoma

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, see the ClinicalTrials.gov website.

References
  1. Honeyman JN, Simon EP, Robine N, et al.: Detection of a recurrent DNAJB1-PRKACA chimeric transcript in fibrolamellar hepatocellular carcinoma. Science 343 (6174): 1010-4, 2014. [PUBMED Abstract]
  2. Cruz O, Laguna A, Vancells M, et al.: Fibrolamellar hepatocellular carcinoma in an infant and literature review. J Pediatr Hematol Oncol 30 (12): 968-71, 2008. [PUBMED Abstract]
  3. Eggert T, McGlynn KA, Duffy A, et al.: Fibrolamellar hepatocellular carcinoma in the USA, 2000-2010: A detailed report on frequency, treatment and outcome based on the Surveillance, Epidemiology, and End Results database. United European Gastroenterol J 1 (5): 351-7, 2013. [PUBMED Abstract]
  4. Zack T, Losert KP, Maisel SM, et al.: Defining incidence and complications of fibrolamellar liver cancer through tiered computational analysis of clinical data. NPJ Precis Oncol 7 (1): 29, 2023. [PUBMED Abstract]
  5. El-Serag HB, Davila JA, Petersen NJ, et al.: The continuing increase in the incidence of hepatocellular carcinoma in the United States: an update. Ann Intern Med 139 (10): 817-23, 2003. [PUBMED Abstract]
  6. Stratakis CA: Carney Complex. In: Adam MP, Feldman J, Mirzaa GM, et al., eds.: GeneReviews. University of Washington, Seattle, 1993-2024, pp. Available online. Last accessed February 29, 2024.
  7. Graham RP, Lackner C, Terracciano L, et al.: Fibrolamellar carcinoma in the Carney complex: PRKAR1A loss instead of the classic DNAJB1-PRKACA fusion. Hepatology 68 (4): 1441-1447, 2018. [PUBMED Abstract]
  8. EDMONDSON HA: Differential diagnosis of tumors and tumor-like lesions of liver in infancy and childhood. AMA J Dis Child 91 (2): 168-86, 1956. [PUBMED Abstract]
  9. Mayo SC, Mavros MN, Nathan H, et al.: Treatment and prognosis of patients with fibrolamellar hepatocellular carcinoma: a national perspective. J Am Coll Surg 218 (2): 196-205, 2014. [PUBMED Abstract]
  10. Czauderna P, Mackinlay G, Perilongo G, et al.: Hepatocellular carcinoma in children: results of the first prospective study of the International Society of Pediatric Oncology group. J Clin Oncol 20 (12): 2798-804, 2002. [PUBMED Abstract]
  11. Katzenstein HM, Krailo MD, Malogolowkin MH, et al.: Fibrolamellar hepatocellular carcinoma in children and adolescents. Cancer 97 (8): 2006-12, 2003. [PUBMED Abstract]
  12. Weeda VB, Murawski M, McCabe AJ, et al.: Fibrolamellar variant of hepatocellular carcinoma does not have a better survival than conventional hepatocellular carcinoma–results and treatment recommendations from the Childhood Liver Tumour Strategy Group (SIOPEL) experience. Eur J Cancer 49 (12): 2698-704, 2013. [PUBMED Abstract]

Undifferentiated Embryonal Sarcoma of the Liver

Incidence

Undifferentiated embryonal sarcoma of the liver (UESL) is a distinct clinical and pathological entity and accounts for 2% to 15% of pediatric hepatic malignancies.[1]

Diagnosis

UESL presents as an abdominal mass, often with pain or malaise, usually between the ages of 5 and 10 years. Widespread infiltration throughout the liver and pulmonary metastasis are common. It may appear solid or cystic on imaging, frequently with central necrosis. Undifferentiated sarcomas, like small cell undifferentiated hepatoblastomas, should be examined for loss of SMARCB1 expression by immunohistochemistry to help rule out rhabdoid tumor of the liver.

It is important to make the diagnostic distinction between UESL and biliary tract rhabdomyosarcoma because they share some common clinical and pathological features, but treatment differs between the two, as shown in Table 8.[1] For more information, see Childhood Rhabdomyosarcoma Treatment.

Table 8. Diagnostic Differences Between Undifferentiated Embryonal Sarcoma of the Liver and Biliary Tract Rhabdomyosarcomaa
  Undifferentiated Embryonal Sarcoma of the Liver Biliary Tract Rhabdomyosarcoma
aAdapted from Nicol et al.[1]
Median Age at Diagnosis 10.5 y 3.4 y
Tumor Location Often arises in the right lobe of the liver Often arises in the hilum of the liver
Biliary Obstruction Unusual Frequent; jaundice is a common presenting symptom
Treatment Surgery and chemotherapy Surgery (usually biopsy only), radiation therapy, and chemotherapy

Histology

Distinctive histological features of UESL include intracellular hyaline globules and marked anaplasia on a mesenchymal background.[2] Many UESL tumors contain diverse elements of mesenchymal cell maturation, such as smooth muscle and fat.

Strong clinical and histological evidence suggests that UESL can arise within preexisting mesenchymal hamartomas of the liver, which are large, benign, multicystic masses that present in the first 2 years of life.[1] In a report of 11 cases of UESL, 5 arose in association with mesenchymal hamartomas of the liver, and transition zones between the histologies were noted.[3] Many mesenchymal hamartomas of the liver have a characteristic translocation with a breakpoint at 19q13.4, and several UESLs have the same translocation.[4,5] Some UESLs arising from mesenchymal hamartomas of the liver may have complex karyotypes not involving 19q13.4.[4]

Prognosis and Prognostic Factors

The overall survival (OS) rates of children with UESL appear to be substantially higher than 50% when combining reports, although all series are small and may have selection bias.[6]; [7–17][Level of evidence C1]

The Childhood Cancer Database, which does not provide central review of pathology or reliable details of nonsurgical treatment, reported on 103 children with UESL diagnosed between 1998 and 2012. The 5-year OS rate was 86% for all patients and 92% for those treated with combination surgery and chemotherapy. A multivariate analysis of the nonsurgical data revealed statistically significant poorer outcomes for patients with tumors larger than 15 cm. Seven of ten children who presented with metastases and ten of ten children who underwent orthotopic liver transplant survived at least 5 years, but details of their treatment were not presented.[18]

A retrospective study combined data from three European studies to identify 64 patients with UESL.[19][Level of evidence C1] The tumors were staged according to Intergroup Rhabdomyosarcoma Study (IRS) clinical grouping. Fourteen patients had IRS group I disease, 9 had IRS group II disease, 38 had IRS group III disease, and 4 had IRS group IV disease. A variety of chemotherapy regimens were used, with either neoadjuvant or adjuvant chemotherapy. Most regimens included alkylators and anthracyclines. Some patients also received radiation therapy. The 5-year event-free survival (EFS) rate was 89.1% (95% confidence interval [CI], 78.4%–94.6%), and the OS rate was 90.1% (95% CI, 79.3%–95.3%).

Treatment Options for UESL

UESL is rare. Only small series have been published regarding treatment.[20]

Treatment options for UESL include the following:

  • Surgical resection and chemotherapy.
  • Liver transplant for unresectable tumors.

The generally accepted approach is resection of the primary tumor mass in the liver when possible.[18] Use of aggressive chemotherapy regimens seems to have improved the OS of patients with UESL. Neoadjuvant chemotherapy can be effective in decreasing the size of an unresectable primary tumor mass, resulting in resectability.[8–11] Most patients are treated with chemotherapy regimens used for pediatric rhabdomyosarcoma or Ewing sarcoma without cisplatin.[6]; [7–16,21][Level of evidence C1]

Evidence (surgical resection and chemotherapy):

  1. The Italian and German Soft Tissue Sarcoma Cooperative Groups prospectively studied patients with UESL. Patients were treated with conservative surgery or biopsy followed by neoadjuvant chemotherapy consisting of varying combinations of vincristine, cyclophosphamide, dactinomycin, doxorubicin, and ifosfamide. Disease evaluation, usually after four cycles of chemotherapy, was followed by second-look surgery when appropriate to try to remove residual primary tumor, followed by additional and/or adjuvant chemotherapy.[12]
    • Ten of 17 patients survived in first complete remission, and one patient survived in third complete remission.
  2. In a subset analysis from the Children’s Oncology Group ARST0332 (NCT00346164) study, 39 patients with embryonal sarcoma of the liver were available for analysis. Patients underwent upfront (n = 23) or delayed (n = 16) resection and received adjuvant or neoadjuvant chemotherapy (dose-intensive ifosfamide/doxorubicin). Eight patients received radiation therapy.[22]
    • The 5-year EFS rate was 79% (95% CI, 65%–93%), and the 5-year OS rate was 95% (95% CI, 87%–100%).
  3. In a single-center retrospective report, five patients with UESL were treated with surgery and adjuvant chemotherapy consisting of vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide. Four patients had stage I disease, and one patient had stage II disease. One patient received abdominal radiation for tumor rupture.[17][Level of evidence C1]
    • All patients were alive (range, 5–19 years), with EFS and OS rates of 100%.

Liver transplant has occasionally been used to successfully treat an otherwise unresectable primary tumor.[14,16,18,23]

Treatment Options Under Clinical Evaluation for UESL

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, see the ClinicalTrials.gov website.

References
  1. Nicol K, Savell V, Moore J, et al.: Distinguishing undifferentiated embryonal sarcoma of the liver from biliary tract rhabdomyosarcoma: a Children’s Oncology Group study. Pediatr Dev Pathol 10 (2): 89-97, 2007 Mar-Apr. [PUBMED Abstract]
  2. Stocker JT: Hepatic tumors in children. Clin Liver Dis 5 (1): 259-81, viii-ix, 2001. [PUBMED Abstract]
  3. Shehata BM, Gupta NA, Katzenstein HM, et al.: Undifferentiated embryonal sarcoma of the liver is associated with mesenchymal hamartoma and multiple chromosomal abnormalities: a review of eleven cases. Pediatr Dev Pathol 14 (2): 111-6, 2011 Mar-Apr. [PUBMED Abstract]
  4. Stringer MD, Alizai NK: Mesenchymal hamartoma of the liver: a systematic review. J Pediatr Surg 40 (11): 1681-90, 2005. [PUBMED Abstract]
  5. O’Sullivan MJ, Swanson PE, Knoll J, et al.: Undifferentiated embryonal sarcoma with unusual features arising within mesenchymal hamartoma of the liver: report of a case and review of the literature. Pediatr Dev Pathol 4 (5): 482-9, 2001 Sep-Oct. [PUBMED Abstract]
  6. Walther A, Geller J, Coots A, et al.: Multimodal therapy including liver transplantation for hepatic undifferentiated embryonal sarcoma. Liver Transpl 20 (2): 191-9, 2014. [PUBMED Abstract]
  7. Ismail H, Dembowska-Bagińska B, Broniszczak D, et al.: Treatment of undifferentiated embryonal sarcoma of the liver in children–single center experience. J Pediatr Surg 48 (11): 2202-6, 2013. [PUBMED Abstract]
  8. Chowdhary SK, Trehan A, Das A, et al.: Undifferentiated embryonal sarcoma in children: beware of the solitary liver cyst. J Pediatr Surg 39 (1): E9-12, 2004. [PUBMED Abstract]
  9. Baron PW, Majlessipour F, Bedros AA, et al.: Undifferentiated embryonal sarcoma of the liver successfully treated with chemotherapy and liver resection. J Gastrointest Surg 11 (1): 73-5, 2007. [PUBMED Abstract]
  10. Kim DY, Kim KH, Jung SE, et al.: Undifferentiated (embryonal) sarcoma of the liver: combination treatment by surgery and chemotherapy. J Pediatr Surg 37 (10): 1419-23, 2002. [PUBMED Abstract]
  11. Webber EM, Morrison KB, Pritchard SL, et al.: Undifferentiated embryonal sarcoma of the liver: results of clinical management in one center. J Pediatr Surg 34 (11): 1641-4, 1999. [PUBMED Abstract]
  12. Bisogno G, Pilz T, Perilongo G, et al.: Undifferentiated sarcoma of the liver in childhood: a curable disease. Cancer 94 (1): 252-7, 2002. [PUBMED Abstract]
  13. Urban CE, Mache CJ, Schwinger W, et al.: Undifferentiated (embryonal) sarcoma of the liver in childhood. Successful combined-modality therapy in four patients. Cancer 72 (8): 2511-6, 1993. [PUBMED Abstract]
  14. Okajima H, Ohya Y, Lee KJ, et al.: Management of undifferentiated sarcoma of the liver including living donor liver transplantation as a backup procedure. J Pediatr Surg 44 (2): e33-8, 2009. [PUBMED Abstract]
  15. Weitz J, Klimstra DS, Cymes K, et al.: Management of primary liver sarcomas. Cancer 109 (7): 1391-6, 2007. [PUBMED Abstract]
  16. Plant AS, Busuttil RW, Rana A, et al.: A single-institution retrospective cases series of childhood undifferentiated embryonal liver sarcoma (UELS): success of combined therapy and the use of orthotopic liver transplant. J Pediatr Hematol Oncol 35 (6): 451-5, 2013. [PUBMED Abstract]
  17. Mathias MD, Ambati SR, Chou AJ, et al.: A single-center experience with undifferentiated embryonal sarcoma of the liver. Pediatr Blood Cancer 63 (12): 2246-2248, 2016. [PUBMED Abstract]
  18. Shi Y, Rojas Y, Zhang W, et al.: Characteristics and outcomes in children with undifferentiated embryonal sarcoma of the liver: A report from the National Cancer Database. Pediatr Blood Cancer 64 (4): , 2017. [PUBMED Abstract]
  19. Guérin F, Martelli H, Rogers T, et al.: Outcome of patients with undifferentiated embryonal sarcoma of the liver treated according to European soft tissue sarcoma protocols. Pediatr Blood Cancer 70 (7): e30374, 2023. [PUBMED Abstract]
  20. Techavichit P, Masand PM, Himes RW, et al.: Undifferentiated Embryonal Sarcoma of the Liver (UESL): A Single-Center Experience and Review of the Literature. J Pediatr Hematol Oncol 38 (4): 261-8, 2016. [PUBMED Abstract]
  21. Merli L, Mussini C, Gabor F, et al.: Pitfalls in the surgical management of undifferentiated sarcoma of the liver and benefits of preoperative chemotherapy. Eur J Pediatr Surg 25 (1): 132-7, 2015. [PUBMED Abstract]
  22. Spunt SL, Xue W, Gao Z, et al.: Embryonal sarcoma of the liver in pediatric and young adult patients: A report from Children’s Oncology Group study ARST0332. Cancer 130 (15): 2683-2693, 2024. [PUBMED Abstract]
  23. Kelly MJ, Martin L, Alonso M, et al.: Liver transplant for relapsed undifferentiated embryonal sarcoma in a young child. J Pediatr Surg 44 (12): e1-3, 2009. [PUBMED Abstract]

Infantile Choriocarcinoma of the Liver

Choriocarcinoma of the liver is a very rare tumor that appears to originate in the placenta during gestation. It presents with a liver mass in the first few months of life. Metastasis from the placenta to maternal tissues occurs in many cases, necessitating beta-human chorionic gonadotropin (beta-hCG) testing of the mother. Infants are often unstable at diagnosis because of hemorrhage of the tumor.

Diagnosis

Clinical diagnosis may be made without biopsy on the basis of tumor imaging of the liver associated with extremely high serum beta-hCG levels and alpha-fetoprotein (AFP) levels in the reference range for age.[1]

Histology

Cytotrophoblasts and syncytiotrophoblasts are both present. The former are closely packed nests of medium-sized cells with clear cytoplasm, distinct cell margins, and vesicular nuclei. The latter are very large, multinucleated syncytia formed from the cytotrophoblasts.[2]

Prognosis

The prognosis of patients with infantile choriocarcinoma of the liver is often poor because of the instability at presentation from hemorrhage. A 2017 case report and literature review found 32 cases, with 6 long-term survivors. The authors emphasized the opportunity for early diagnosis and treatment of this very chemosensitive tumor.[3]

Treatment Options for Infantile Choriocarcinoma of the Liver

Treatment options for infantile choriocarcinoma of the liver include the following:

  1. Surgical resection.[1]
  2. Chemotherapy followed by surgical resection.
  3. Chemotherapy followed by liver transplant.

Initial surgical removal of the tumor mass may be difficult because of its friability and hemorrhagic tendency. Surgical removal of the primary tumor is often performed after neoadjuvant chemotherapy.[1]

Maternal gestational trophoblastic tumors are exquisitely sensitive to methotrexate. Many women, including those with distant metastases, are cured with single-agent chemotherapy. Maternal and infantile choriocarcinoma both come from the same placental malignancy. The combination of cisplatin, etoposide, and bleomycin, as used in other pediatric germ cell tumors, has been effective in some patients and is followed by resection of the residual mass. Use of neoadjuvant methotrexate in infantile choriocarcinoma, although often resulting in a response, has not been uniformly successful.[1]

A case report of neoadjuvant chemotherapy followed by successful liver transplant highlights the opportunity for this therapy in children whose tumors remain unresectable after chemotherapy.[4]

Treatment Options Under Clinical Evaluation for Infantile Choriocarcinoma of the Liver

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, see the ClinicalTrials.gov website.

References
  1. Yoon JM, Burns RC, Malogolowkin MH, et al.: Treatment of infantile choriocarcinoma of the liver. Pediatr Blood Cancer 49 (1): 99-102, 2007. [PUBMED Abstract]
  2. Olson T, Schneider D, Perlman E: Germ cell tumors. In: Pizzo PA, Poplack DG, eds.: Principles and Practice of Pediatric Oncology. 6th ed. Lippincott Williams and Wilkins, 2011, pp 1045-1067.
  3. Alsharif S, Karsou A: Infantile choriocarcinoma of the liver: case report and review of the literature. Oncol Cancer Case Rep 3 (1): 2017.
  4. Hanson D, Walter AW, Dunn S, et al.: Infantile choriocarcinoma in a neonate with massive liver involvement cured with chemotherapy and liver transplant. J Pediatr Hematol Oncol 33 (6): e258-60, 2011. [PUBMED Abstract]

Vascular Liver Tumors

Careful attention to clinical history, physical examination, laboratory evaluation, and radiological imaging is essential for an appropriate diagnosis of vascular liver tumors. If there is any doubt about the accuracy of the diagnosis, a biopsy should be performed.

The different diagnoses of vascular tumors of the liver include the following:

  • Benign tumors.
    • Focal congenital hemangiomas. For more information, see the Congenital Hemangiomas section in Childhood Vascular Tumors Treatment.
    • Multiple or diffuse infantile hemangiomas. For more information, see the Infantile Hemangioma section in Childhood Vascular Tumors Treatment.
  • Malignant tumors.
    • Epithelioid hemangioendothelioma. For more information, see the Epithelioid Hemangioendothelioma section in Childhood Vascular Tumors Treatment.
    • Angiosarcoma. For more information, see the Angiosarcoma section in Childhood Vascular Tumors Treatment.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Latest Updates to This Summary (01/06/2025)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Editorial changes were made to this summary.

This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood liver cancer. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

  • be discussed at a meeting,
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Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Childhood Liver Cancer Treatment are:

  • Denise Adams, MD (Children’s Hospital Boston)
  • Andrea A. Hayes-Dixon, MD, FACS, FAAP (Howard University)
  • Karen J. Marcus, MD, FACR (Dana-Farber of Boston Children’s Cancer Center and Blood Disorders Harvard Medical School)
  • Thomas A. Olson, MD (Aflac Cancer and Blood Disorders Center of Children’s Healthcare of Atlanta – Egleston Campus)
  • Michael V. Ortiz, MD (Memorial Sloan Kettering Cancer Center)
  • Stephen J. Shochat, MD (St. Jude Children’s Research Hospital)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website’s Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

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The preferred citation for this PDQ summary is:

PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Liver Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/liver/hp/child-liver-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389232]

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Rectal Cancer Treatment (PDQ®)–Patient Version

Rectal Cancer Treatment (PDQ®)–Patient Version

General Information About Rectal Cancer

Go to Health Professional Version

Key Points

  • Rectal cancer is a type of cancer that forms in the tissues of the rectum.
  • Health history affects the risk of developing rectal cancer.
  • Signs of rectal cancer include blood in the stool or a change in bowel habits.
  • Tests that examine the rectum and colon are used to diagnose rectal cancer.
  • After rectal cancer has been diagnosed, imaging tests are done to find out if cancer cells have spread within the rectum or to other parts of the body.
  • Some people decide to get a second opinion.
  • Certain factors affect prognosis (chance of recovery) and treatment options.

Rectal cancer is a type of cancer that forms in the tissues of the rectum.

The rectum is part of the body’s digestive system. The digestive system takes in nutrients (vitamins, minerals, carbohydrates, fats, proteins, and water) from foods and helps pass waste material out of the body. The digestive system is made up of the esophagus, stomach, and the small and large intestines. The colon (large bowel) is the main part of the large intestine and is about 5 feet long. Together, the rectum and anal canal make up the last part of the large intestine and are 6 to 8 inches long. The anal canal ends at the anus (the opening of the large intestine to the outside of the body).

EnlargeGastrointestinal (digestive) system anatomy; drawing shows the esophagus, liver, stomach, colon, small intestine, rectum, and anus.
Anatomy of the lower gastrointestinal (digestive) system showing the colon, rectum, and anus. Other organs that make up the digestive system are also shown.

Health history affects the risk of developing rectal cancer.

Colorectal cancer is caused by certain changes to the way colorectal cells function, especially how they grow and divide into new cells. There are many risk factors for colorectal cancer, but many do not directly cause cancer. Instead, they increase the chance of DNA damage in cells that may lead to colorectal cancer. To learn more about how cancer develops, see What Is Cancer?

A risk factor is anything that increases the chance of getting a disease. Some risk factors for colorectal cancer, like smoking, can be changed. However, risk factors also include things you cannot change, like your genetics, getting older, and your family history. Learning about risk factors for colorectal cancer can help you make changes that might lower your risk of getting it.

Risk factors for colorectal cancer include:

Older age is a main risk factor for most cancers. The chance of getting cancer increases as you get older.

Having one or more of these risk factors does not mean that you will get colorectal cancer. Many people with risk factors never develop colorectal cancer, while others with no known risk factors do. Talk with your doctor if you think you might be at increased risk.

Signs of rectal cancer include blood in the stool or a change in bowel habits.

These and other signs and symptoms may be caused by rectal cancer or by other conditions. Check with your doctor if you have:

  • blood (either bright red or very dark) in the stool
  • a change in bowel habits
    • diarrhea
    • constipation
    • feeling that the bowel does not empty completely
    • stools that are narrower or have a different shape than usual
  • general abdominal discomfort (frequent gas pains, bloating, fullness, or cramps)
  • change in appetite
  • weight loss for no known reason
  • fatigue

Tests that examine the rectum and colon are used to diagnose rectal cancer.

In addition to asking about your personal and family health history and doing a physical exam, your doctor may perform the following tests and procedures:

  • Digital rectal exam (DRE) is an exam of the rectum. The doctor or nurse inserts a lubricated, gloved finger into the lower part of the rectum to feel for lumps or anything else that seems unusual. In women, the vagina may also be examined.
  • Colonoscopy is a procedure that uses a colonoscope to look inside the rectum and colon for polyps (small pieces of bulging tissue), abnormal areas, or cancer. A colonoscope is a thin, tube-like instrument with a light and a lens for viewing. It may also have a tool to remove polyps or tissue samples, which are checked under a microscope for signs of cancer.
    EnlargeColonoscopy; drawing shows a colonoscope inserted through the anus and rectum and into the colon. An inset shows a patient lying on a table having a colonoscopy.
    Colonoscopy. A thin, lighted tube is inserted through the anus and rectum and into the colon to look for abnormal areas.
  • Biopsy is the removal of cells or tissues so they can be viewed under a microscope to check for signs of cancer. Tumor tissue that is removed during the biopsy may be checked to see if the patient is likely to have the gene mutation that causes Lynch syndrome (also known as hereditary nonpolyposis colorectal cancer). This may help to plan treatment. Learn about the type of information that can be found in a pathologist’s report about the cells or tissue removed during a biopsy at Pathology Reports.
  • Immunohistochemistry is a laboratory test that uses antibodies to check for certain antigens (markers) in a sample of a patient’s tissue. The antibodies are usually linked to an enzyme or a fluorescent dye. After the antibodies bind to a specific antigen in the tissue sample, the enzyme or dye is activated, and the antigen can then be seen under a microscope. This type of test is used to help diagnose cancer and to help tell one type of cancer from another type of cancer.
  • Microsatellite instability (MSI) is a laboratory test in which tumor tissue is checked for cells that may have a defect in genes involved in DNA repair. The findings may indicate whether or not the patient has a type of cancer linked to an inherited cancer syndrome such as Lynch syndrome.

After rectal cancer has been diagnosed, imaging tests are done to find out if cancer cells have spread within the rectum or to other parts of the body.

The process used to find out whether cancer has spread within the rectum or to other parts of the body is called staging. The information gathered from the staging process determines the stage of the disease. It is important to know the stage in order to plan treatment.

The following tests and procedures may be used in the staging process:

  • Chest x-ray is a type of radiation that can go through the body and make pictures of the organs and bones inside the chest.
  • CT scan (CAT scan) uses a computer linked to an x-ray machine to make a series of detailed pictures of areas inside the body, such as the abdomen, pelvis, or chest. The pictures are taken from different angles and are used to create 3-D views of tissues and organs. A dye may be injected into a vein or swallowed to help the organs or tissues show up more clearly. This procedure is also called computed tomography, computerized tomography, or computerized axial tomography.
  • MRI (magnetic resonance imaging) uses a magnet, radio waves, and a computer to make a series of detailed pictures of areas inside the rectum. A substance called gadolinium is injected into the patient through a vein. The gadolinium collects around the cancer cells so they show up brighter in the picture. This procedure is also called nuclear magnetic resonance imaging (NMRI).
  • PET scan (positron emission tomography scan) uses a small amount of radioactive sugar (also called glucose) that is injected into a vein. Then a scanner rotates around the body to make detailed, computerized pictures of areas inside the body where the glucose is taken up. Because cancer cells often take up more glucose than normal cells, the pictures can be used to find cancer cells in the body.
  • Endorectal ultrasound is used to examine the rectum and nearby organs. An ultrasound transducer (probe) is inserted into the rectum and used to bounce high-energy sound waves (ultrasound) off internal tissues or organs and make echoes. The echoes form a picture of body tissues called a sonogram. The doctor can identify tumors by looking at the sonogram. This procedure is also called transrectal ultrasound.
  • Carcinoembryonic antigen (CEA) assay is a test that measures the level of CEA in the blood. CEA is released into the bloodstream from both cancer cells and normal cells. When found in higher than normal amounts, it can be a sign of rectal cancer or other conditions.

Some people decide to get a second opinion.

You may want to get a second opinion to confirm your rectal cancer diagnosis and treatment plan. If you seek a second opinion, you will need to get medical test results and reports from the first doctor to share with the second doctor. The second doctor will review the pathology report, slides, and scans. They may agree with the first doctor, suggest changes or another treatment approach, or provide more information about your cancer.

Learn more about choosing a doctor and getting a second opinion at Finding Cancer Care. You can contact NCI’s Cancer Information Service via chat, email, or phone (both in English and Spanish) for help finding a doctor, hospital, or getting a second opinion. For questions you might want to ask at your appointments, visit Questions to Ask Your Doctor About Cancer.

Certain factors affect prognosis (chance of recovery) and treatment options.

The prognosis and treatment options depend on:

  • the stage of the cancer (whether it affects the inner lining of the rectum only, involves the whole rectum, or has spread to lymph nodes, nearby organs, or other places in the body)
  • whether the cancer is related to a defect in genes involved in DNA repair
  • whether the tumor has spread into or through the bowel wall
  • where the cancer is found in the rectum
  • whether the bowel is blocked or has a hole in it
  • whether all of the tumor can be removed by surgery
  • the patient’s general health
  • whether the cancer has just been diagnosed or has recurred (come back)

Stages of Rectal Cancer

Key Points

  • The following stages are used for rectal cancer:
    • Stage 0 (carcinoma in situ)
    • Stage I (also called stage 1) rectal cancer
    • Stage II (also called stage 2) rectal cancer
    • Stage III (also called stage 3) rectal cancer
    • Stage IV (also called stage 4) rectal cancer
  • Rectal cancer can recur (come back) after it has been treated.

Cancer stage describes the extent of cancer in the body, such as the size of the tumor, whether it has spread, and how far it has spread from where it first formed.

There are several staging systems for cancer that describe the extent of the cancer. Rectal cancer staging usually uses the TNM staging system. The cancer may be described by this staging system in your pathology report. Based on the TNM results, a stage (I, II, III, or IV, also written as 1, 2, 3, or 4) is assigned to your cancer. When talking to you about your diagnosis, your doctor may describe the cancer as one of these stages.

Learn about tests to stage rectal cancer. Learn more about Cancer Staging.

The following stages are used for rectal cancer:

Stage 0 (carcinoma in situ)

EnlargeStage 0 colorectal carcinoma in situ; drawing shows a cross-section of the colon/rectum. An inset shows the layers of the colon/rectum wall with abnormal cells in the mucosa layer. Also shown are the submucosa, muscle layers, serosa, a blood vessel, and lymph nodes.
Stage 0 (rectal carcinoma in situ). Abnormal cells are shown in the mucosa of the rectum wall.

In stage 0 rectal cancer, abnormal cells are found in the mucosa (innermost layer) of the rectum wall. These abnormal cells may become cancer and spread into nearby normal tissue. Stage 0 is also called carcinoma in situ.

Stage I (also called stage 1) rectal cancer

EnlargeStage I colorectal cancer; drawing shows a cross-section of the colon/rectum. An inset shows the layers of the colon/rectum wall with cancer in the mucosa and submucosa. Also shown are the muscle layers, serosa, a blood vessel, and lymph nodes.
Stage I rectal cancer. Cancer has spread from the mucosa of the rectum wall to the submucosa or to the muscle layer.

In stage I rectal cancer, cancer has formed in the mucosa (innermost layer) of the rectum wall and has spread to the submucosa (layer of tissue next to the mucosa) or to the muscle layer of the rectum wall.

Stage II (also called stage 2) rectal cancer

EnlargeStage II colorectal cancer; drawing shows a cross-section of the colon/rectum and a three-panel inset. Each panel shows the layers of the colon/rectum wall: the mucosa, submucosa, muscle layers, and serosa. Also shown are a blood vessel and lymph nodes. The first panel shows stage IIA with cancer in the mucosa, submucosa, muscle layers, and serosa. The second panel shows stage IIB with cancer in all layers and spreading through the serosa to the visceral peritoneum. The third panel shows stage IIC with cancer in all layers and spreading through the serosa to nearby organs.
Stage II rectal cancer. In stage IIA, cancer has spread through the muscle layer of the rectum wall to the serosa. In stage IIB, cancer has spread through the serosa but has not spread to nearby organs. In stage IIC, cancer has spread through the serosa to nearby organs.

Stage II rectal cancer is divided into stages IIA, IIB, and IIC.

  • Stage IIA: Cancer has spread through the muscle layer of the rectum wall to the serosa (outermost layer) of the rectum wall.
  • Stage IIB: Cancer has spread through the serosa (outermost layer) of the rectum wall to the tissue that lines the organs in the abdomen (visceral peritoneum).
  • Stage IIC: Cancer has spread through the serosa (outermost layer) of the rectum wall to nearby organs.

Stage III (also called stage 3) rectal cancer

Stage III rectal cancer is divided into stages IIIA, IIIB, and IIIC.

EnlargeStage IIIA colorectal cancer; drawing shows a cross-section of the colon/rectum and a two-panel inset. Each panel shows the layers of the colon/rectum wall: the mucosa, submucosa, muscle layers, and serosa. Also shown are a blood vessel and lymph nodes. The first panel shows cancer in the mucosa, submucosa, and muscle layers and in 2 lymph nodes. The second panel shows cancer in the mucosa and submucosa and in 5 lymph nodes.
Stage IIIA rectal cancer. Cancer has spread through the mucosa of the rectum wall to the submucosa and may have spread to the muscle layer, and has spread to one to three nearby lymph nodes or tissues near the lymph nodes. OR, cancer has spread through the mucosa to the submucosa and four to six nearby lymph nodes.

In stage IIIA, cancer has spread:

  • through the mucosa (innermost layer) of the rectum wall to the submucosa (layer of tissue next to the mucosa) or to the muscle layer of the rectum wall. Cancer has spread to one to three nearby lymph nodes, or cancer cells have formed in tissue near the lymph nodes; or
  • through the mucosa (innermost layer) of the rectum wall to the submucosa (layer of tissue next to the mucosa). Cancer has spread to four to six nearby lymph nodes.
EnlargeStage IIIB colorectal cancer; drawing shows a cross-section of the colon/rectum and a three-panel inset. Each panel shows the layers of the colon/rectum wall: the mucosa, submucosa, muscle layers, and serosa. Also shown are a blood vessel and lymph nodes. The first panel shows cancer in all layers, in 3 nearby lymph nodes, and in the visceral peritoneum. The second panel shows cancer in all layers and in 5 nearby lymph nodes. The third panel shows cancer in the mucosa, submucosa, and muscle layers and in 7 nearby lymph nodes.
Stage IIIB rectal cancer. Cancer has spread through the muscle layer of the rectum wall to the serosa or has spread through the serosa but not to nearby organs; cancer has spread to one to three nearby lymph nodes or to tissues near the lymph nodes. OR, cancer has spread to the muscle layer or to the serosa, and to four to six nearby lymph nodes. OR, cancer has spread through the mucosa to the submucosa and may have spread to the muscle layer; cancer has spread to seven or more nearby lymph nodes.

In stage IIIB, cancer has spread:

  • through the muscle layer of the rectum wall to the serosa (outermost layer) of the rectum wall or has spread through the serosa to the tissue that lines the organs in the abdomen (visceral peritoneum). Cancer has spread to one to three nearby lymph nodes, or cancer cells have formed in tissue near the lymph nodes; or
  • to the muscle layer or to the serosa (outermost layer) of the rectum wall. Cancer has spread to four to six nearby lymph nodes; or
  • through the mucosa (innermost layer) of the rectum wall to the submucosa (layer of tissue next to the mucosa) or to the muscle layer of the rectum wall. Cancer has spread to seven or more nearby lymph nodes.
EnlargeStage IIIC colorectal cancer; drawing shows a cross-section of the colon/rectum and a three-panel inset. Each panel shows the layers of the colon/rectum wall: the mucosa, submucosa, muscle layers, and serosa. Also shown are a blood vessel and lymph nodes. The first panel shows cancer in all layers, in 4 lymph nodes, and in the visceral peritoneum. The second panel shows cancer in all layers and in 7 lymph nodes. The third panel shows cancer in all layers, in 2 lymph nodes, and spreading to nearby organs.
Stage IIIC rectal cancer. Cancer has spread through the serosa of the rectum wall but not to nearby organs; cancer has spread to four to six nearby lymph nodes. OR, cancer has spread through the muscle layer to the serosa or has spread through the serosa but not to nearby organs; cancer has spread to seven or more nearby lymph nodes. OR, cancer has spread through the serosa to nearby organs and to one or more nearby lymph nodes or to tissues near the lymph nodes.

In stage IIIC, cancer has spread:

  • through the serosa (outermost layer) of the rectum wall to the tissue that lines the organs in the abdomen (visceral peritoneum). Cancer has spread to four to six nearby lymph nodes; or
  • through the muscle layer of the rectum wall to the serosa (outermost layer) of the rectum wall or has spread through the serosa to the tissue that lines the organs in the abdomen (visceral peritoneum). Cancer has spread to seven or more nearby lymph nodes; or
  • through the serosa (outermost layer) of the rectum wall to nearby organs. Cancer has spread to one or more nearby lymph nodes, or cancer cells have formed in tissue near the lymph nodes.

Stage IV (also called stage 4) rectal cancer

EnlargeStage IV rectal cancer; drawing shows other parts of the body where rectal cancer may spread, including the distant lymph nodes, lung, liver, abdominal wall, and prostate. An inset shows cancer cells spreading from the rectum, through the blood and lymph system, to another part of the body where metastatic cancer has formed.
Stage IV rectal cancer. The cancer has spread through the blood and lymph nodes to other parts of the body, such as the lung, liver, abdominal wall, or prostate.

Stage IV rectal cancer is divided into stages IVA, IVB, and IVC.

  • Stage IVA: Cancer has spread to one area or organ that is not near the rectum, such as the liver, lung, prostate, or a distant lymph node.
  • Stage IVB: Cancer has spread to more than one area or organ that is not near the rectum, such as the liver, lung, prostate, or a distant lymph node.
  • Stage IVC: Cancer has spread to the tissue that lines the wall of the abdomen and may have spread to other areas or organs.

Stage IV rectal cancer is also called metastatic rectal cancer. Metastatic cancer happens when cancer cells travel through the lymphatic system or blood and form tumors in other parts of the body. The metastatic tumor is the same type of cancer as the primary tumor. For example, if rectal cancer spreads to the liver, the cancer cells in the liver are actually rectal cancer cells. The disease is called metastatic rectal cancer, not liver cancer. Learn more in Metastatic Cancer: When Cancer Spreads.

Rectal cancer can recur (come back) after it has been treated.

Recurrent rectal cancer is cancer that has come back after it has been treated. If rectal cancer comes back, it may come back in the rectum or in other parts of the body, such as the colon, pelvis, liver, or lungs. Tests will be done to help determine where the cancer has returned. The type of treatment for recurrent rectal cancer will depend on where it has come back.

Learn more in Recurrent Cancer: When Cancer Comes Back.

Treatment Option Overview

Key Points

  • There are different types of treatment for people with rectal cancer.
  • The following types of treatment are used:
    • Surgery
    • Radiation therapy
    • Chemotherapy
    • Chemoradiation therapy
    • Active surveillance
    • Targeted therapy
    • Immunotherapy
  • New types of treatment are being tested in clinical trials.
  • Treatment for rectal cancer may cause side effects.
  • Follow-up care may be needed.

There are different types of treatment for people with rectal cancer.

Different types of treatments are available for rectal cancer. You and your cancer care team will work together to decide your treatment plan, which may include more than one type of treatment. Many factors will be considered, such as the stage of the cancer, your overall health, and your preferences. Your plan will include information about your cancer, the goals of treatment, your treatment options and the possible side effects, and the expected length of treatment.

Talking with your cancer care team before treatment begins about what to expect will be helpful. You’ll want to learn what you need to do before treatment begins, how you’ll feel while going through it, and what kind of help you will need. To learn more, visit Questions to Ask Your Doctor About Treatment.

The following types of treatment are used:

Surgery

Surgery is the most common treatment for all stages of rectal cancer. The cancer is removed using one of the following types of surgery:

  • Polypectomy: If the cancer is found in a polyp (a small piece of bulging tissue), the polyp is often removed during a colonoscopy.
  • Local excision: If the cancer is found on the inside surface of the rectum and has not spread into the wall of the rectum, the cancer and a small amount of surrounding healthy tissue are removed.
  • Resection: If the cancer has spread into the wall of the rectum, the section of the rectum with cancer and nearby healthy tissue are removed. Sometimes, the tissue between the rectum and the abdominal wall is also removed. The lymph nodes near the rectum are removed and checked under a microscope for signs of cancer.
  • Radiofrequency ablation: The use of a special probe with tiny electrodes that kill cancer cells. Sometimes, the probe is inserted directly through the skin, and only local anesthesia is needed. In other cases, the probe is inserted through an incision in the abdomen. This is done in the hospital with general anesthesia.
  • Cryosurgery: A treatment that uses an instrument to freeze and destroy abnormal tissue. This type of treatment is also called cryotherapy. Learn more about Cryosurgery to Treat Cancer.
  • Pelvic exenteration: If the cancer has spread to other organs near the rectum, the lower colon, rectum, and bladder are removed. In women, the cervix, vagina, ovaries, and nearby lymph nodes may be removed. In men, the prostate may be removed. Artificial openings (stoma) are made for urine and stool to flow from the body to a collection bag.

After the cancer is removed, the surgeon will either:

  • do an anastomosis (sew the healthy parts of the rectum together, sew the remaining rectum to the colon, or sew the colon to the anus);
    EnlargeThree-panel drawing showing rectal cancer surgery with anastomosis; the first panel shows area of rectum with cancer, the middle panel shows cancer and nearby tissue removed, and the last panel shows the colon and anus joined.
    Resection of the rectum with anastomosis. The rectum and part of the colon are removed, and then the colon and anus are joined.

    or

  • make a stoma (an opening) from the rectum to the outside of the body for waste to pass through. This procedure is done if the cancer is too close to the anus and is called a colostomy. A bag is placed around the stoma to collect the waste. Sometimes, the colostomy is needed only until the rectum has healed, and then it can be reversed. If the entire rectum is removed, however, the colostomy may be permanent.

Radiation therapy and/or chemotherapy may be given before surgery to shrink the tumor, make it easier to remove the cancer, and help with bowel control after surgery. Treatment given before surgery is called neoadjuvant therapy. After all the cancer that can be seen at the time of the surgery is removed, some patients may be given radiation therapy and/or chemotherapy after surgery to kill any cancer cells that are left. Treatment given after the surgery, to lower the risk that the cancer will come back, is called adjuvant therapy.

If the cancer has spread to the liver and cannot be removed by surgery, a total hepatectomy and liver transplant after chemotherapy may be done. Total hepatectomy and liver transplant is the removal of the entire liver by surgery, followed by a transplant of a healthy liver from a donor.

Radiation therapy

Radiation therapy uses high-energy x-rays or other types of radiation to kill cancer cells or keep them from growing. Rectal cancer is sometimes treated with external radiation therapy. This type of radiation therapy uses a machine outside the body to send radiation toward the area of the body with cancer.

Short-course preoperative radiation therapy is used in some types of rectal cancer. This type of external radiation therapy uses fewer and lower doses of radiation than standard treatment, followed by surgery several days after the last dose.

Learn more about External Beam Radiation Therapy for Cancer and Radiation Therapy Side Effects.

Chemotherapy

Chemotherapy (also called chemo) uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing.

Systemic chemotherapy is when chemotherapy drugs are taken by mouth or injected into a vein or muscle. When given this way, the drugs enter the bloodstream and can reach cancer cells throughout the body. Systemic chemotherapy used to treat rectal cancer includes:

Combinations of these drugs may be used. Other chemotherapy drugs not listed here may also be used.

Chemotherapy may also be combined with other kinds of drugs. For example, it might be combined with the targeted therapy drug bevacizumab, cetuximab, or panitumumab.

Regional chemotherapy for rectal cancer is when drugs are placed directly into the hepatic artery (the main artery that supplies blood to the liver) in a procedure called chemoembolization. Chemoembolization of the hepatic artery may be used to treat cancer that has spread to the liver. This is done by blocking the hepatic artery and injecting anticancer drugs between the blockage and the liver. The liver’s arteries then carry the drugs into the liver. Only a small amount of the drug reaches other parts of the body. The blockage may be temporary or permanent, depending on what is used to block the artery. The liver continues to receive some blood from the hepatic portal vein, which carries blood from the stomach and intestine.

The way the chemotherapy is given depends on the type and stage of the cancer being treated.

Learn more about how chemotherapy works, how it is given, common side effects, and more at Chemotherapy to Treat Cancer and Chemotherapy and You: Support for People With Cancer.

Chemoradiation therapy

Chemoradiation therapy combines chemotherapy and radiation therapy to increase the effects of both.

Active surveillance

Active surveillance is closely following a patient’s condition without giving any treatment unless there are changes in test results. It is used to find early signs that the condition is getting worse. In active surveillance, patients are given certain exams and tests to check if the cancer is growing. When the cancer begins to grow, treatment is given to cure the cancer. Tests include:

Targeted therapy

Targeted therapy uses drugs or other substances to identify and attack specific cancer cells. Your doctor may suggest biomarker tests to help predict your response to certain targeted therapy drugs. Learn more about Biomarker Testing for Cancer Treatment.

Targeted therapies used to treat rectal cancer include:

Learn more about Targeted Therapy to Treat Cancer.

Immunotherapy

Immunotherapy helps a person’s immune system fight cancer. Your doctor may suggest biomarker tests to help predict your response to certain immunotherapy drugs. Learn more about Biomarker Testing for Cancer Treatment.

Immunotherapy drugs used to treat rectal cancer include:

Learn more about Immunotherapy to Treat Cancer.

New types of treatment are being tested in clinical trials.

For some people, joining a clinical trial may be an option. There are different types of clinical trials for people with cancer. For example, a treatment trial tests new treatments or new ways of using current treatments. Supportive care and palliative care trials look at ways to improve quality of life, especially for those who have side effects from cancer and its treatment.

You can use the clinical trial search to find NCI-supported cancer clinical trials accepting participants. The search allows you to filter trials based on the type of cancer, your age, and where the trials are being done. Clinical trials supported by other organizations can be found on the ClinicalTrials.gov website.

Learn more about clinical trials, including how to find and join one, at Clinical Trials Information for Patients and Caregivers.

Treatment for rectal cancer may cause side effects.

For information about side effects caused by treatment for cancer, visit our Side Effects page.

Follow-up care may be needed.

As you go through treatment, you will have follow-up tests or check-ups. Some tests that were done to diagnose or stage the cancer may be repeated to see how well the treatment is working. Decisions about whether to continue, change, or stop treatment may be based on the results of these tests.

Some of the tests will continue to be done from time to time after treatment has ended. The results of these tests can show if your condition has changed or if the cancer has recurred (come back).

After treatment for rectal cancer, a blood test to measure amounts of carcinoembryonic antigen (a substance in the blood that may be increased when cancer is present) may be done to see if the cancer has come back.

Treatment of Stage 0 (carcinoma in situ)

Treatment of stage 0 may include the following types of surgery:

Learn more about these treatments in the Treatment Option Overview.

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

Treatment of Stage I Rectal Cancer

Treatment of stage I rectal cancer may include:

Learn more about these treatments in the Treatment Option Overview.

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

Treatment of Stages II and III Rectal Cancer

Treatment of stage II and stage III rectal cancer may include:

  • chemoradiation followed by surgery
  • chemotherapy alone followed by surgery, for people with lower-risk disease
  • short-course radiation therapy followed by surgery and chemotherapy
  • surgery followed by chemoradiation
  • surgery
  • chemoradiation followed by active surveillance and possibly surgery if the cancer recurs (comes back)
  • immunotherapy with dostarlimab (for treatment of tumors that may have a defect in genes involved in DNA repair)

Learn more about these treatments in the Treatment Option Overview.

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

Treatment of Stage IV and Recurrent Rectal Cancer

Treatment of stage IV and recurrent rectal cancer may include:

Treatment of rectal cancer that has spread to other organs depends on where the cancer has spread.

  • Treatment for areas of cancer that have spread to the liver may include:
    • chemotherapy to shrink the tumor, if needed, followed by surgery
    • cryosurgery or radiofrequency ablation
    • chemoembolization and/or systemic chemotherapy
    • liver transplant after chemotherapy for patients with liver metastases that cannot be removed by surgery
    • a clinical trial of chemoembolization combined with radiation therapy to the tumors in the liver

Learn more about these treatments in the Treatment Option Overview.

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

To Learn More About Rectal Cancer

For more information from the National Cancer Institute about rectal cancer, visit:

For general cancer information and other resources from the National Cancer Institute, visit:

About This PDQ Summary

About PDQ

Physician Data Query (PDQ) is the National Cancer Institute’s (NCI’s) comprehensive cancer information database. The PDQ database contains summaries of the latest published information on cancer prevention, detection, genetics, treatment, supportive care, and complementary and alternative medicine. Most summaries come in two versions. The health professional versions have detailed information written in technical language. The patient versions are written in easy-to-understand, nontechnical language. Both versions have cancer information that is accurate and up to date and most versions are also available in Spanish.

PDQ is a service of the NCI. The NCI is part of the National Institutes of Health (NIH). NIH is the federal government’s center of biomedical research. The PDQ summaries are based on an independent review of the medical literature. They are not policy statements of the NCI or the NIH.

Purpose of This Summary

This PDQ cancer information summary has current information about the treatment of rectal cancer. It is meant to inform and help patients, families, and caregivers. It does not give formal guidelines or recommendations for making decisions about health care.

Reviewers and Updates

Editorial Boards write the PDQ cancer information summaries and keep them up to date. These Boards are made up of experts in cancer treatment and other specialties related to cancer. The summaries are reviewed regularly and changes are made when there is new information. The date on each summary (“Updated”) is the date of the most recent change.

The information in this patient summary was taken from the health professional version, which is reviewed regularly and updated as needed, by the PDQ Adult Treatment Editorial Board.

Clinical Trial Information

A clinical trial is a study to answer a scientific question, such as whether one treatment is better than another. Trials are based on past studies and what has been learned in the laboratory. Each trial answers certain scientific questions in order to find new and better ways to help cancer patients. During treatment clinical trials, information is collected about the effects of a new treatment and how well it works. If a clinical trial shows that a new treatment is better than one currently being used, the new treatment may become “standard.” Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.

Clinical trials can be found online at NCI’s website. For more information, call the Cancer Information Service (CIS), NCI’s contact center, at 1-800-4-CANCER (1-800-422-6237).

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The best way to cite this PDQ summary is:

PDQ® Adult Treatment Editorial Board. PDQ Rectal Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/colorectal/patient/rectal-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389378]

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