Archives: Cancer Types

Osteosarcoma Treatment (PDQ®)–Patient Version

Osteosarcoma Treatment (PDQ®)–Patient Version

General Information About Osteosarcoma and Undifferentiated Pleomorphic Sarcoma (UPS) of Bone

Go to Health Professional Version

Key Points

  • Osteosarcoma and undifferentiated pleomorphic sarcoma (UPS) of bone are diseases in which cancer cells form in bone.
  • Having past treatment with chemotherapy or radiation can increase the risk of osteosarcoma.
  • Symptoms of osteosarcoma and UPS include swelling over a bone or a bony part of the body and joint pain.
  • Tests are used to diagnose osteosarcoma and UPS.
  • After osteosarcoma or UPS has been diagnosed, imaging tests are done to find out if cancer cells have spread within the bone or to other parts of the body.
  • You may want to get a second opinion.
  • Certain factors may affect prognosis (chance of recovery) and treatment options.

Osteosarcoma and undifferentiated pleomorphic sarcoma (UPS) of bone are diseases in which cancer cells form in bone.

Osteosarcoma is a rare type of bone cancer that starts in the cells called osteoblasts, which form new bone. In osteosarcoma, the cancer cells make osteoid, the early form of bone tissue. Osteosarcoma usually forms in the long bones of the arms and legs, and over half of the people with osteosarcoma have it in the long bones near the knee. While rare, it can also form in other bones or, in very unusual cases, in soft tissue or organs in the chest or abdomen.

This cancer is most common in adolescents and young adults. In the United States, about 440 cases of osteosarcoma are diagnosed each year in people 19 years and younger.

Undifferentiated pleomorphic sarcoma (UPS) is another rare cancer that can start in bones. UPS of the bone used to be called malignant fibrous histiocytoma. Under a microscope, UPS of the bone can look similar to osteosarcoma. However, UPS does not produce osteoid.

Osteosarcoma and UPS are treated the same way.

Ewing sarcoma is another kind of bone cancer. Learn more at Ewing Sarcoma Treatment.

Having past treatment with chemotherapy or radiation can increase the risk of osteosarcoma.

A risk factor is anything that increases the chance of getting a disease. Not every child with one or more of these risk factors will develop osteosarcoma. And it will develop in some children who don’t have a known risk factor. Risk factors for osteosarcoma include:

Talk with your child’s doctor if you think your child may be at risk.

Symptoms of osteosarcoma and UPS include swelling over a bone or a bony part of the body and joint pain.

The symptoms of osteosarcoma and UPS depend on which bone it forms in. It’s important to check with your child’s doctor if your child has:

  • swelling over a bone or bony part of the body
  • pain in a bone or joint
  • pain in the arm when lifting
  • stiffness in a joint
  • a limp or difficulty walking
  • a bone that breaks for no known reason

These symptoms may be caused by osteosarcoma, UPS, or other problems. The only way to know is for your child to see a doctor.

Tests are used to diagnose osteosarcoma and UPS.

If your child has symptoms that suggest bone cancer, the doctor will need to find out if they are due to cancer or another problem. The doctor will ask when the symptoms started and how often your child has been having them. They will also ask about your child’s personal and family health history and do a physical exam. Depending on these results, they may recommend other tests. If your child is diagnosed with osteosarcoma or UPS, the results of these tests will help you and your child’s doctor plan treatment.

The tests used to diagnose osteosarcoma or UPS may include:

  • X-ray is a type of radiation that can go through the body and onto film, making a picture of areas inside the body, such as the bones and organs.
  • 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. 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. Learn more about Computed Tomography (CT) Scans and Cancer.
  • MRI (magnetic resonance imaging) uses a magnet, radio waves, and a computer to make a series of detailed pictures of areas inside the body. This procedure is also called nuclear magnetic resonance imaging (NMRI).

Imaging tests are done before a biopsy.

  • Biopsy removes a sample of tissue from the tumor so that a pathologist can view it under a microscope to check for cancer. It is important that the biopsy be done by a surgeon who is an expert in treating cancer of the bone. It is best if that surgeon is also the one who removes the tumor. The biopsy and the surgery to remove the tumor are planned together because the way the biopsy is done affects which type of surgery can be done later.

    The type of biopsy depends on the size of the tumor and where it is in the body. There are two types of biopsy that may be used:

    • Core biopsy uses a wide needle to remove a sample of tissue.
    • Incisional biopsy removes a sample of tissue through an incision in the skin.

    The following test may be done on the tissue that is removed:

    • Electron microscopy: A laboratory test in which cells in a sample of tissue are viewed under regular and high-powered microscopes to look for certain changes in the cells. An electron microscope shows tiny details better than other types of microscopes.

After osteosarcoma or UPS has been diagnosed, imaging tests are done to find out if cancer cells have spread within the bone or to other parts of the body.

The process used to find out whether the cancer has spread within the bone 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 imaging tests and procedures may be used to find out if osteosarcoma or UPS has spread:

  • X-ray.
  • CT scan (CAT scan).
  • PET scan (positron emission tomography scan) uses a small amount of radioactive sugar (radioactive glucose) that is injected into a vein. The PET scanner rotates around the body and makes a picture of where sugar is being used in the body. Cancer cells show up brighter in the picture because they are more active and take up more sugar than normal cells do. This procedure is also called positron emission tomography (PET) scan.
  • PET-CT scan combines the pictures from a positron emission tomography (PET) scan and a computed tomography (CT) scan. The PET and CT scans are done at the same time on the same machine. The pictures from both scans are combined to make a more detailed picture than either test would make by itself.
  • MRI (magnetic resonance imaging).
  • Bone scan checks if there are rapidly dividing cells, such as cancer cells, in the bone. A very small amount of radioactive material is injected into a vein and travels through the bloodstream. The radioactive material collects in the bones with cancer and is detected by a scanner.

You may want to get a second opinion.

You may want to get a second opinion to confirm your child’s 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. This doctor may agree with the first doctor, suggest changes to the treatment plan, or provide more information about your child’s cancer.

To learn more about choosing a doctor and getting a second opinion, visit Finding Health Care Services. You can contact NCI’s Cancer Information Service via chat, email, or phone (both in English and Spanish) for help finding a doctor or hospital that can provide a second opinion. For questions you might want to ask at your child’s appointments, visit Questions to Ask Your Doctor About Cancer.

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

If your child has been diagnosed with osteosarcoma or UPS, you likely have questions about how serious the cancer is and your child’s chances of survival. The likely outcome or course of a disease is called prognosis.

Many factors affect prognosis and treatment options.

Factors that may affect your child’s prognosis before treatment include:

  • where the tumor is in the body and whether tumors formed in more than one bone
  • whether multiple tumors have formed in the same bone
  • the size of the tumor
  • whether the cancer has spread to other parts of the body and, if so, where it has spread
  • the type of tumor (based on how the cancer cells look under a microscope)
  • your child’s sex, age, and weight at the time of diagnosis
  • whether your child has been treated for a different cancer in the past
  • whether your child has certain genetic conditions

Factors that may affect your child’s prognosis after treatment include:

  • how well the chemotherapy worked
  • whether the tumor was completely removed by surgery
  • whether the cancer has recurred (come back) within 5 years of diagnosis

No two people are alike, and response to treatment can vary greatly. Your child’s cancer care team is in the best position to talk with you about your child’s prognosis.

Treatment options for osteosarcoma and UPS depend on:

  • where the tumor is in the body and if it has spread
  • the size of the tumor
  • the grade of the cancer
  • whether the bones are still growing
  • your child’s age and overall health
  • your child’s and family’s goals, such as being able to participate in sports, or concerns about physical appearance
  • whether the cancer is newly diagnosed or has recurred after treatment

Stages of Osteosarcoma and Undifferentiated Pleomorphic Sarcoma (UPS)

Key Points

  • After osteosarcoma or undifferentiated pleomorphic sarcoma (UPS) has been diagnosed, tests are done to find out if cancer cells have spread to other parts of the body.
  • Sometimes osteosarcoma and UPS of bone come back after treatment.

After osteosarcoma or undifferentiated pleomorphic sarcoma (UPS) has been diagnosed, tests are done to find out if cancer cells have spread to other parts of the body.

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. It is important to know the stage of the osteosarcoma to plan the best treatment. Instead of being grouped by stage, osteosarcoma and UPS are grouped according to whether the cancer is localized or metastatic.

  • Localized osteosarcoma or UPS has not spread out of the bone where the cancer started. There may be one or more areas of cancer in the bone that can be removed during surgery.
  • Metastatic osteosarcoma or UPS has spread from the bone in which the cancer began to other parts of the body. The cancer most often spreads to the lungs. It may also spread to other bones.

Sometimes osteosarcoma and UPS of bone come back after treatment.

The cancer may come back in the bone or in other parts of the body. Osteosarcoma and UPS most often recur in the lung, bone, or both. When osteosarcoma recurs, it is usually within 18 months after treatment is completed.

Treatment Option Overview

Key Points

  • There are different types of treatment for children with osteosarcoma or undifferentiated pleomorphic sarcoma (UPS).
  • Children with osteosarcoma or UPS should have their treatment planned by a team of health care providers who are experts in treating cancer in children.
  • The following types of treatment are used:
    • Surgery
    • Chemotherapy
    • Radiation therapy
    • Samarium
  • You may want to think about your child taking part in a clinical trial.
  • Treatment for osteosarcoma or UPS may cause side effects.
  • Follow-up care may be needed.

There are different types of treatment for children with osteosarcoma or undifferentiated pleomorphic sarcoma (UPS).

You and your child’s care team will work together to decide treatment. Many factors will be considered, such as where the cancer is located and your child’s age and overall health.

Your child’s treatment plan will include information about the tumor, the goals of treatment, treatment options, and the possible side effects. It will be helpful to talk with your child’s care team before treatment begins about what to expect. For help every step of the way, visit our booklet, Children with Cancer: A Guide for Parents.

Children with osteosarcoma or UPS should have their treatment planned by a team of health care providers who are experts in treating cancer in children.

A pediatric oncologist, a doctor who specializes in treating children with cancer, oversees treatment of osteosarcoma. The pediatric oncologist works with other health care providers who are experts in treating osteosarcoma and UPS and who specialize in certain areas of medicine. Other specialists may include:

The following types of treatment are used:

Surgery

Surgery to remove the entire tumor will be done when possible. Chemotherapy may be given before surgery to make the tumor smaller. This is called neoadjuvant chemotherapy. Chemotherapy is given so less bone tissue needs to be removed and there are fewer problems after surgery.

The following types of surgery may be done:

  • Wide local excision removes the cancer and some healthy tissue around it.
  • Limb-sparing surgery removes a tumor in an arm or leg without amputation. Limb-sparing surgery is often an option for children with osteosarcoma in an arm or leg. The tumor is removed by wide local excision. The removed tissue and bone may be replaced with a graft using tissue and bone taken from another part of the body, or with an implant such as artificial bone. If a fracture is found at the time of diagnosis or during chemotherapy before surgery, limb-sparing surgery may still be possible in some cases. If the surgeon is not able to remove all of the tumor and enough healthy tissue around it, an amputation may be done.
  • Amputation removes part or all of an arm or leg. This may be done when it is not possible to remove all of the tumor in limb-sparing surgery. If prosthesis is part of the plan, fitting and training will take place with a prosthetist (a specialist in artificial limbs) over several weeks to months.
  • Rotationplasty removes the tumor and the knee joint. The part of the leg that remains below the knee is then attached to the part of the leg that remains above the knee, with the foot facing backward and the ankle acting as a knee. A prosthesis may then be attached to the foot.

Studies have shown that survival is the same whether the first surgery done is a limb-sparing surgery or an amputation.

After the doctor removes all the cancer that can be seen at the time of the surgery, chemotherapy is given 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.

Chemotherapy

Chemotherapy (also called chemo) uses drugs to stop the growth of cancer cells. Chemotherapy either kills the cancer cells or stops them from dividing. Chemotherapy may be given alone or with other types of treatment.

Chemotherapy for osteosarcoma and UPS is injected into a vein. When given this way, the drugs enter the bloodstream and can reach cancer cells throughout the body. Chemotherapy is usually given before and after surgery to remove the tumor.

Chemotherapy drugs used alone or in combination to treat osteosarcoma include:

Other chemotherapy drugs not listed here may also be used.

Learn more about how chemotherapy works, how it is given, common side effects, and more at Chemotherapy to Treat Cancer.

Radiation therapy

Radiation therapy uses high-energy x-rays or other types of radiation to kill cancer cells or keep them from growing. Osteosarcoma is treated with external beam radiation therapy. This type of therapy uses a machine outside the body to send radiation toward the area of the body with cancer.

Osteosarcoma and UPS cells are not killed easily by external radiation therapy. It may be used when a small amount of cancer is left after surgery, used together with other treatments, or used as palliative therapy to relieve symptoms caused by the tumor in the bone.

Samarium

Samarium is a radioactive drug that targets tumor cells in a bone. It helps relieve pain caused by cancer in the bone and it also kills blood cells in the bone marrow. It is used to treat osteosarcoma that has come back in a different bone after treatment.

Treatment with samarium may be followed by stem cell transplant. Before treatment with samarium, stem cells (immature blood cells) are removed from the child’s blood or bone marrow and are frozen and stored. After treatment with samarium is complete, the stored stem cells are thawed and given back to the child through an infusion. These reinfused stem cells grow into (and restore) the body’s blood cells.

You may want to think about your child taking part in a clinical trial.

For some children, joining a clinical trial may be an option. There are different types of clinical trials for childhood 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 child’s 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 osteosarcoma or UPS may cause side effects.

Cancer treatments can cause side effects. Which side effects your child might have depends on the type of treatment they receive, the dose, and how their body reacts. Talk with your child’s treatment team about which side effects to look for and ways to manage them.

To learn more about side effects that begin during treatment for cancer, visit Side Effects.

Problems from cancer treatment that begin 6 months or later after treatment and continue for months or years are called late effects. Late effects of cancer treatment may include:

  • physical problems, such as infertility
  • changes in mood, feelings, thinking, learning, or memory
  • second cancers (new types of cancer), such as breast cancer or acute myeloid leukemia

Some late effects may be treated or controlled. It is important to talk with your child’s doctors about the effects cancer treatment can have on your child. Learn more about Late Effects of Treatment for Childhood Cancer.

Follow-up care may be needed.

As your child goes through treatment, they 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 child’s condition has changed or if the cancer has recurred (come back).

Treatment of Localized Osteosarcoma and Undifferentiated Pleomorphic Sarcoma (UPS) of Bone

Treatment of newly diagnosed localized osteosarcoma and UPS of bone may include:

  • surgery to remove the tumor
  • chemotherapy before or after surgery to remove the tumor
  • radiation therapy if surgery cannot be done or if the tumor was not completely removed by surgery

Learn 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 Metastatic Osteosarcoma and Undifferentiated Pleomorphic Sarcoma (UPS) of Bone

Lung Metastasis

When osteosarcoma or UPS spreads, it usually spreads to the lung. Treatment of newly diagnosed osteosarcoma and UPS that has spread to the lung may include chemotherapy followed by surgery to remove the primary cancer and more chemotherapy. Then, the doctor will remove the cancer in the lung and give additional chemotherapy.

Bone Metastasis or Bone with Lung Metastasis

Osteosarcoma and UPS may spread to a distant bone or to both the lung and a distant bone. Treatment of newly diagnosed osteosarcoma and UPS that has spread to a distant bone or to both the lung and a distant bone may include:

  • Chemotherapy followed by surgery to remove the primary cancer. More chemotherapy is given after surgery. This may be followed by surgery to remove cancer that has spread to other areas of the body.
  • Surgery to remove the primary cancer, followed by chemotherapy. Then the doctor will remove the cancer that has spread to other parts of the body and give combination chemotherapy.
  • Surgery alone to remove cancer that has spread to a distant bone.
  • Radiation therapy.

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 Recurrent Osteosarcoma and Undifferentiated Pleomorphic Sarcoma (UPS) of Bone

Treatment depends on where the cancer recurred and whether it has recurred more than once.

  • For tumors that have recurred in the same bone where the cancer started, treatment is surgery.
  • For tumors that have recurred in the lung only, treatment may include:
    • surgery to remove the tumor
    • chemotherapy
    • radiation therapy
  • For tumors that have recurred in bones other than where the cancer started, treatment may include:
  • For tumors that have recurred twice, treatment may include:
    • surgery to remove the cancer and chemotherapy
    • chemotherapy alone

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.

Related resources

For more childhood cancer information and other general cancer resources, 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 osteosarcoma and undifferentiated pleomorphic sarcoma (UPS) (formerly called malignant fibrous histiocytoma [MFH]) of bone. 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 Pediatric 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® Pediatric Treatment Editorial Board. PDQ Osteosarcoma Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/bone/patient/osteosarcoma-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389380]

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Osteosarcoma and Undifferentiated Pleomorphic Sarcoma of Bone Treatment (PDQ®)–Health Professional Version

Osteosarcoma and Undifferentiated Pleomorphic Sarcoma of Bone Treatment (PDQ®)–Health Professional Version

General Information About Osteosarcoma and Undifferentiated Pleomorphic Sarcoma (UPS) (Formerly Called Malignant Fibrous Histiocytoma [MFH]) of Bone

Go to Patient Version

Disease Overview

Osteosarcoma occurs predominantly in adolescents and young adults. Review of data from the National Cancer Institute’s National Childhood Cancer Registry resulted in an estimated osteosarcoma incidence rate of 5.4 cases per 1 million each year in people aged 0 to 19 years and 4 cases per 1 million each year in people younger than 40 years.[1] The U.S. Census Bureau estimated that there were 82 million people between the ages of 0 and 19 years, resulting in an incidence of roughly 440 cases per year in this age group.

Osteosarcoma accounts for approximately 5% of childhood tumors. In children and adolescents, more than 50% of these tumors arise from the long bones around the knee. Osteosarcoma is rarely observed in soft tissue or visceral organs. There appears to be no difference in presenting symptoms, tumor location, and outcome for younger patients (<12 years) compared with adolescents.[2,3]

Two trials conducted in the 1980s were designed to determine whether chemotherapy altered the natural history of osteosarcoma after surgical removal of the primary tumor. The outcome of these patients recapitulated the historical experience before 1970. More than one-half of these patients developed metastases within 6 months of diagnosis, and overall, approximately 90% developed recurrent disease within 2 years of diagnosis.[4] Overall survival (OS) for patients treated with surgery alone was statistically inferior.[5] The natural history of osteosarcoma has not changed over time, and fewer than 20% of patients with localized, resectable primary tumors treated with surgery alone can be expected to survive free of relapse.[4,6]; [7][Level of evidence A1]

In 2013, the World Health Organization (WHO) published an update to the Classification of Tumors of Soft Tissue and Bone.[8] They removed the term malignant fibrous histiocytoma (MFH) and replaced it with undifferentiated pleomorphic sarcoma (UPS). This type of sarcoma is much more common in soft tissues. However, it does arise in bone. In bone, it has features that are histologically similar to osteosarcoma, but it does not produce osteoid. Most of the literature describing the clinical behavior and response to therapy for this histology in bone was published before the 2013 WHO update, and a search for UPS of bone will not retrieve these articles. The citations in this summary appear with their titles as published. Therefore, many references will describe MFH of bone, a condition now called UPS of bone.

Diagnostic Evaluation

Osteosarcoma can be diagnosed by core needle biopsy or open surgical biopsy. It is preferable that the biopsy be performed by a surgeon skilled in the techniques of limb sparing (removal of the malignant bone tumor without amputation and replacement of bones or joints with allografts or prosthetic devices). In these cases, the original biopsy incision placement is crucial. Inappropriate alignment of the biopsy or inadvertent contamination of soft tissues can render subsequent limb-preserving reconstructive surgery impossible.

Prognostic Factors

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%.[1,9,10] For osteosarcoma, the 5-year relative survival rate increased over the same time from 40% to 72% in children younger than 15 years and from 56% to approximately 71% in adolescents aged 15 to 19 years. However, there has been no substantial improvement since the 1980s.[1,11]

In general, prognostic factors for osteosarcoma have not been helpful in identifying patients who might benefit from treatment intensification or who might require less therapy while maintaining an excellent outcome.

Factors that may influence outcome include the following:[12]

Primary tumor site

The site of the primary tumor is a significant prognostic factor for patients with localized disease. Among extremity tumors, distal sites have a more favorable prognosis than do proximal sites. Axial skeleton primary tumors are associated with the greatest risk of progression and death, primarily related to the inability to achieve a complete surgical resection.

Prognostic considerations for the axial skeleton and extraskeletal sites are as follows:

  • Pelvis: Pelvic osteosarcomas make up 7% to 9% of all osteosarcomas. Survival rates for patients with pelvic primary tumors are 20% to 47%.[13–15] Complete surgical resection is associated with a positive outcome for osteosarcoma of the pelvis in some cohorts of patients.[13,16]
  • Craniofacial/head and neck: In patients with craniofacial osteosarcoma, those with primary sites in the mandible and maxilla have a better prognosis than do patients with other primary sites in the head and neck.[17–19] For patients with osteosarcoma of craniofacial bones, complete resection of the primary tumor with negative margins is essential for cure.[20–22] When treated with surgery alone, patients who have osteosarcoma of the head and neck have a better prognosis than those who have appendicular lesions. However, surgery alone without adjuvant therapy is not recommended for high-grade osteosarcoma of the head and neck.

    Despite a relatively high rate of inferior necrosis after neoadjuvant chemotherapy, fewer patients with craniofacial primary tumors develop systemic metastases than do patients with osteosarcoma originating in the extremities. This may be the result of the inclusion of patients with lower-grade tumors in the cohorts reported.[23–25]

    A meta-analysis concluded that systemic adjuvant chemotherapy improves the prognosis for patients with osteosarcoma of the head and neck, while small series have not shown such a benefit.[23–25] Another large meta-analysis detected no benefit of chemotherapy for patients with osteosarcoma of the head and neck, but suggested that incorporating chemotherapy into the treatment plan for patients with high-grade tumors may improve survival.[22] A retrospective analysis identified a trend toward better survival in patients with high-grade osteosarcoma of the mandible and maxilla who received adjuvant chemotherapy.[22,26]

    Radiation therapy was found to improve local control, disease-specific survival, and OS in a retrospective study of patients with osteosarcoma of the craniofacial bones who had positive or uncertain margins after surgical resection.[27][Level of evidence C1] Radiation-associated craniofacial osteosarcomas are generally high-grade lesions, usually fibroblastic, and tend to recur locally with a high rate of metastasis.[28]

  • Extraskeletal: Osteosarcoma in extraskeletal sites is rare in children and young adults. With current combined-modality therapy, the outcome of patients with extraskeletal osteosarcoma appears to be similar to that of patients with primary tumors of bone.[29]

Size of the primary tumor

In some series, patients with larger tumors appeared to have a worse prognosis than patients with smaller tumors.[12,30,31] Tumor size has been assessed by longest single dimension, cross-sectional area, or estimate of tumor volume; all assessments have correlated with outcome.

Elevated serum lactate dehydrogenase (LDH), which also correlates with poorer outcome, is a likely surrogate for tumor volume.[14]

Presence of clinically detectable metastatic disease

Patients with localized disease have a much better prognosis than patients with overt metastatic disease. As many as 20% of patients have radiographically detectable metastases at diagnosis, with the lung being the most common site.[32] The prognosis for patients with metastatic disease appears to be determined largely by site(s) of metastases, number of metastases, and surgical resectability of the metastatic disease.[33,34]

  • Site of metastases: Prognosis appears more favorable for patients with fewer pulmonary nodules and for those with unilateral rather than bilateral pulmonary metastases.[33] Not all patients with suspected pulmonary metastases at diagnosis have osteosarcoma confirmed at the time of lung resection. In one large series, approximately 25% of patients had exclusively benign lesions removed at the time of surgery.[34]
  • Number of metastases: Patients with skip metastases (at least two discontinuous lesions in the same bone) have been reported to have inferior prognoses.[35] However, an analysis of the German Cooperative Osteosarcoma Study Group (COSS) suggests that skip lesions in the same bone do not confer an inferior prognosis if they are included in planned surgical resection. Skip metastasis in a bone other than the primary bone should be considered systemic metastasis.[36]

    Historically, metastasis across a joint was referred to as a skip lesion, but subsequent classification by the American Joint Committee on Cancer excluded such lesions as skip lesions.[37] They might be considered hematogenous spread and have a worse prognosis.[36]

    Patients with multifocal osteosarcoma (defined as multiple bone lesions without a clear primary tumor) have an extremely poor prognosis.[38,39]

  • Surgical resectability of metastases: Patients who have complete surgical ablation of the primary and metastatic tumor (when confined to the lung) after chemotherapy may attain long-term survival, although overall event-free survival (EFS) rates remain about 20% to 30% for patients with metastatic disease at diagnosis.[33,34,40,41] Patients with metastatic osteosarcoma were eligible for the European and American Osteosarcoma Study (EURAMOS) only if they had disease that was potentially resectable. Although the patients with metastatic disease had an overall 5-year EFS rate of only 28%, those who achieved a complete surgical remission at all sites (3–6 months after diagnosis) had a 5-year EFS rate of 64% and an OS rate of 79%.[31]

Surgical resectability of the primary tumor

Resectability of the tumor is a critical prognostic feature. Complete resection of the primary tumor and any skip lesions with adequate margins is generally considered essential for cure. For patients with axial skeletal primary tumors who either do not undergo surgery for their primary tumor or who undergo surgery that results in positive margins, radiation therapy may improve survival.[16,42]

A retrospective review of patients with craniofacial osteosarcoma performed by the cooperative German-Austrian-Swiss osteosarcoma study group reported that incomplete surgical resection was associated with inferior survival probability.[17][Level of evidence C1] In a European cooperative study, the size of the margin was not significant. However, prognosis was better when both the biopsy and resection were performed at a center with orthopedic oncology experience.[14]

Degree of tumor necrosis after neoadjuvant chemotherapy

Most treatment protocols for osteosarcoma use an initial period of systemic chemotherapy before definitive resection of the primary tumor (or resection of sites of metastases). The pathologist assesses necrosis in the resected tumor. Patients with at least 90% necrosis in the primary tumor after induction chemotherapy have a better prognosis than do patients with less necrosis.[30] Patients with less necrosis (<90%) in the primary tumor after initial chemotherapy have a higher rate of recurrence within the first 2 years than do patients with a more favorable amount of necrosis (≥90%).[43]

Less necrosis should not be interpreted to mean that chemotherapy has been ineffective. Cure rates for patients with little or no necrosis after induction chemotherapy are much higher than cure rates for patients who receive no chemotherapy. The EFS rate for patients who receive no adjuvant chemotherapy is approximately 11%.[44] Many large published series of patients treated with chemotherapy have reported EFS rates of 40% to 50% for patients with little or no necrosis in the primary tumor after initial systemic chemotherapy.[45–47] A review of two consecutive prospective trials performed by the Children’s Oncology Group showed that histological necrosis in the primary tumor after initial chemotherapy was affected by the duration and intensity of the initial period of chemotherapy. More necrosis was associated with better outcome in both trials, but the magnitude of the difference between patients with more and less necrosis was diminished with a longer and more intensive period of initial chemotherapy.[48][Level of evidence B1]

Age and sex

Patients in the older adolescent and young adult age group, typically defined as age 18 to 40 years, tend to have a worse prognosis. In addition, male sex has been associated with a worse prognosis.[31,49,50] Compared with the other prognostic factors listed, both age and sex have a relatively minor impact on outcome.

Impact of time on prognostic factors

An analysis of the EURAMOS found that the predictive power of initial prognostic factors modify with time.[51] They applied a landmarking approach to 1,965 patients. The results showed that local recurrence and new metastases negatively affected 5-year OS (local recurrence hazard ratio [HR], 2.634; 95% CI, 1.845–3.761; and metastases HR, 8.558; 95% CI, 7.367–9.942). Baseline factors with strong negative prognostic value (HRs >2) included poor histological response (≥10% viable tumor), axial tumor location, and the presence of lung metastases. The effect of poor versus good histological response changed over time, becoming nonsignificant 3.25 years after surgery and onward.

The German COSS searched their database of 5,503 patients with osteosarcoma who were registered between 1980 and 2019. They identified 2,009 patients surviving more than 5 years from diagnostic biopsy to assess prognostic factors for long-term survival.[52] The authors confirmed the known predictors of treatment failure, including lower necrosis after initial chemotherapy, older age at diagnosis, unfavorable tumor site, and presentation as a secondary malignancy. The OS rates beyond 5 years were reported (see Table 1).

Table 1. Survival Results From the Analysis of the German COSS Database
COSS = Cooperative Osteosarcoma Study Group; No. = number; OS = overall survival.
Additional follow-up 5 y 10 y 15 y 20 y
No. of patients analyzed at each time interval 161 808 288 125
OS rate 91.7% 88.9% 85.8% 83.4%

In a multivariate analysis, the factors that retained significance for worse long-term survival included having a recurrence in years 1 to 5, older age at diagnosis, and presentation as a secondary malignancy. Extent of tumor necrosis after initial chemotherapy was no longer valid after 5 years of follow-up.[52]

Other possible prognostic factors

Other factors that may be prognostic but with either limited or conflicting data include the following:

  • Subsequent neoplasms. Patients with osteosarcoma as a subsequent neoplasm, including tumors arising in a radiation field, share the same prognosis as patients with de novo osteosarcoma if they are treated aggressively with complete surgical resection and multiagent chemotherapy.[53,54]

    In a German series, approximately 25% of patients with craniofacial osteosarcoma had osteosarcoma as a second tumor, and in 8 of these 13 patients, osteosarcoma arose after treatment for retinoblastoma. In this series, there was no difference in outcome for primary or secondary craniofacial osteosarcoma.[17]

  • Laboratory abnormalities. Possible prognostic factors identified for patients with conventional localized high-grade osteosarcoma include LDH level, alkaline phosphatase level, and histological subtype.[30,46,49,55–58]
  • Body mass index. Higher body mass index at initial presentation is associated with worse OS.[59]
  • Pathological fracture. Some studies have suggested that a pathological fracture at diagnosis or during preoperative chemotherapy does not have adverse prognostic significance.[6]; [60,61][Level of evidence C1]; [62][Level of evidence C2]

    However, a systematic review of nine cohort studies examined the impact of pathological fractures on outcome in patients with osteosarcoma. The review included 2,187 patients, 311 of whom had a pathological fracture. The presence of a pathological fracture correlated with decreased EFS and OS.[63] In two additional series, a pathological fracture at diagnosis was associated with a worse overall outcome.[64]; [65][Level of evidence C1] A retrospective analysis of 2,847 patients with osteosarcoma from the German COSS identified 321 patients (11.3%) with a pathological fracture before the initiation of systemic therapy.[66][Level of evidence C1] In pediatric patients, OS and EFS did not differ significantly between patients with and without a pathological fracture. In adults, the 5-year OS rate in patients with a pathological fracture was 46% versus 69% for patients without a pathological fracture (P < .001). The 5-year EFS rate in adults was 36% for patients with a pathological fracture versus 56% for patients without a pathological fracture (P < .001). In a multivariable analysis, the presence of a pathological fracture was not a statistically significant factor for OS or EFS in the total cohort or in pediatric patients. In adult patients, presence of a pathological fracture remained an independent prognostic factor for OS (HR, 1.893; P = .013).

  • Time to definitive surgery. In a large series, a delay of 21 days or longer from the time of definitive surgery to the resumption of chemotherapy was an adverse prognostic factor.[67]
  • Genetic factors.
    • ERBB2 expression. There are conflicting data concerning the prognostic significance of this human epidermal growth factor.[68–70]
    • Tumor cell ploidy.[71]
    • Specific chromosomal gains or losses.[72]
    • Loss of heterozygosity of the RB1 gene.[73,74]
    • Loss of heterozygosity of the TP53 locus.[75]
    • Increased expression of p-glycoprotein.[76,77] A prospective analysis of p-glycoprotein expression determined by immunohistochemistry failed to identify prognostic significance for patients with newly diagnosed osteosarcoma, although earlier studies suggested that overexpression of p-glycoprotein predicted poor outcome.[78]

    For more information, see the Genomics of Osteosarcoma section.

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Genomics of Osteosarcoma

Molecular Features of Osteosarcoma

The genomic landscape of osteosarcoma is distinct from that of other childhood cancers. Compared with many adult cancers, it is characterized by an exceptionally high number of structural variants with a relatively small number of single nucleotide variants.[1,2]

Key observations regarding the genomic landscape of osteosarcoma include the following:

  • The number of structural variants observed for osteosarcoma is high, at more than 200 structural variants per genome.[1,2] Thus, osteosarcoma has the most chaotic genome among childhood cancers. The Circos plots shown in Figure 1 illustrate the exceptionally high number of intra- and inter-chromosomal translocations that typify osteosarcoma genomes.

    EnlargeDiagrams of osteosarcoma cases from the NCI TARGET project.
    Figure 1. Circos plots of osteosarcoma cases from the National Cancer Institute’s Therapeutically Applicable Research to Generate Effective Treatments (TARGET) project. The red lines in the interior circle connect chromosome regions involved in either intra- or inter-chromosomal translocations. Osteosarcoma is distinctive from other childhood cancers because it has a large number of intra- and inter-chromosomal translocations. Credit: National Cancer Institute.

  • The tumor mutational burden (TMB) for children and adolescents with osteosarcoma is approximately 2 mutations per megabase and is higher than that of some other childhood cancers (e.g., Ewing sarcoma and rhabdoid tumors).[1,2] However, this rate is well below that for adult cancers such as melanoma and non-small cell lung cancer, which are responsive to checkpoint inhibitors.
  • Rather than activating variants in oncogenes and inactivating variants in tumor suppressor genes, as observed in many cancer types, the genomic landscape for osteosarcoma is driven by copy number gain/amplification in chromosome regions that include oncogenes and copy number loss (deletions) in chromosome regions that include tumor suppressor genes. Recurring copy number gains and losses that affect known oncogenes and tumor suppressor genes, respectively, are described below.

    Estimates of the frequency of specific genomic alterations in osteosarcoma vary from report to report. This finding could be a result of different definitions being used to define copy number alterations, different methods being used for their detection, or differences in tumor biology across patient populations (e.g., newly diagnosed versus relapsed, localized versus metastatic, or pediatric versus adult).

  • Genomic alterations in TP53, leading to loss of TP53 function, are present in most osteosarcoma cases.[1] A distinctive form of TP53 inactivation occurs through structural variations in the first intron of TP53 that lead to disruption of the TP53 gene.[1] Other mechanisms of TP53 inactivation are also observed, including missense and nonsense variants and deletions of the TP53 gene.[1,2] The combination of these various mechanisms for loss of TP53 function leads to its biallelic inactivation in most cases of osteosarcoma. Because many of the structural variations leading to TP53 inactivation are best detected through whole-genome sequencing, results based on clinical genomic testing panels may show lower rates of TP53 alterations because they do not detect these changes.[3]
  • MDM2 amplification, which is another genomic alteration that leads to loss of TP53 function, is observed in a minority of osteosarcoma cases (approximately 5%).[1–4]
  • RB1 is commonly inactivated in osteosarcoma, sometimes by deleterious variants but more commonly by chromosomal deletion of the chromosome 13q14 region that includes RB1.[1,2,5]
  • Chromosomal deletions involving chromosome 9p21 lead to CDN2A deletion in approximately 20% of osteosarcoma cases.[1,2,5]
  • Among tumor oncogenes, MYC at chromosome 8q24 shows gain/amplification in approximately 10% of patients.[3,5,6] In one study, MYC gain/amplification appeared to be associated with inferior prognosis. In a second study, MYC gain/amplification was enriched in children, compared with adults.[6]
  • CCNE1 at chromosome 19q12 is another tumor oncogene that shows gain/amplification in approximately 10% of patients.[3,5,6] Other oncogene-containing chromosomal regions showing chromosomal gain/amplification in a minority of osteosarcoma cases include the CDK4-harboring region at chromosome 12q14,[4,5,7] the VEGFA– and CCND3-harboring regions at chromosome 6p12,[3–5,7] the CCND1-harboring region at chromosome 11q13,[4] and the PDGFRA-, KIT-, and KDR-harboring regions at chromosome 4q12.[3–5]
  • Alternative lengthening of telomeres (ALT) is the telomere maintenance mechanism employed by the majority of osteosarcoma tumors.[1,8,9] ATRX inactivating variants and gene deletions are associated with the ALT telomere maintenance mechanism. ATRX genomic alterations are present in a subset of osteosarcoma tumors that use this telomere maintenance mechanism.[1,3,9]
  • Many of the genomic alterations reported for osteosarcoma tumors at diagnosis do not provide obvious therapeutic targets, as they reflect loss of tumor suppressor genes (e.g., TP53, RB1, PTEN) rather than activation of targetable oncogenes. In addition, there has been limited success across cancer diagnoses in using gains/amplifications of the oncogenes relevant to osteosarcoma to identify patients that may benefit from targeted therapy.

Genetic predisposition to osteosarcoma

Germline variants in several genes are associated with susceptibility to osteosarcoma. Table 2 summarizes the syndromes and associated genes for these conditions. A recent multi-institutional genomic study of more than 1,200 patients with osteosarcoma revealed pathogenic or likely pathogenic germline variants in autosomal dominant cancer-susceptibility genes in 18% of patients. The frequency of these cancer-susceptibility genes was higher in children aged 10 years or younger.[10]

TP53 variants

Variants in TP53 are the most common germline alterations associated with osteosarcoma. Variants in this gene are found in approximately 70% of patients with Li-Fraumeni syndrome (LFS), which is associated with increased risk of osteosarcoma, breast cancer, various brain cancers, soft tissue sarcomas, and other cancers. While rhabdomyosarcoma is the most common sarcoma arising in patients aged 5 years and younger with TP53-associated LFS, osteosarcoma is the most common sarcoma in children and adolescents aged 6 to 19 years.[11] One study observed a high frequency of young patients (age <30 years) with osteosarcoma carrying a known LFS-associated or likely LFS-associated TP53 variant (3.8%) or rare exonic TP53 variant (5.7%), with an overall TP53 variant frequency of 9.5%.[12] Other groups have reported lower rates (3%–7%) of TP53 germline variants in patients with osteosarcoma.[10,13,14]

RECQL4 variants

Investigators analyzed whole-exome sequencing from the germline of 4,435 pediatric cancer patients at the St. Jude Children’s Research Hospital and 1,127 patients from the National Cancer Institute’s Therapeutically Applicable Research to Generate Effective Treatment (TARGET) database. They identified 24 patients (0.43%) who harbored loss-of-function RECQL4 variants, including 5 of 249 patients (2.0%) with osteosarcoma.[15] These RECQL4 variants were significantly overrepresented in children with osteosarcoma, the cancer most frequently observed in patients with Rothmund-Thomson syndrome, compared with 134,187 noncancer controls in the Genome Aggregation Database (gnomAD v2.1; P = .00087; odds ratio, 7.1; 95% confidence interval, 2.9–17). Nine of the 24 individuals (38%) possessed the same c.1573delT (p.Cys525Alafs) variant located in the highly conserved DNA helicase domain, suggesting that disruption of this domain is central to oncogenesis.

Table 2. Genetic Diseases That Predispose to Osteosarcomaa
Syndrome Description Location Gene Function
AML = acute myeloid leukemia; IL-1 = interleukin-1; MDS = myelodysplastic syndrome; RANKL = receptor activator of nuclear factor kappa beta ligand; TNF = tumor necrosis factor.
aAdapted from Kansara et al.[16]
Bloom syndrome [17] Rare inherited disorder characterized by short stature and sun-sensitive skin changes. Often presents with a long, narrow face, small lower jaw, large nose, and prominent ears. 15q26.1 BLM DNA helicase
Diamond-Blackfan anemia [18] Inherited pure red cell aplasia. Patients at risk for MDS and AML. Associated with skeletal abnormalities such as abnormal facial features (flat nasal bridge, widely spaced eyes).   Ribosomal proteins Ribosome production [18,19]
Li-Fraumeni syndrome [20] Inherited variant in TP53 gene. Affected family members at increased risk of bone tumors, breast cancer, leukemia, brain tumors, and sarcomas. 17p13.1 TP53 DNA damage response
Paget disease [21] Excessive breakdown of bone with abnormal bone formation and remodeling, resulting in pain from weak, malformed bone. 18q21-qa22 LOH18CR1 IL-1/TNF signaling; RANKL signaling pathway
5q31
5q35-qter
Retinoblastoma [22] Malignant tumor of the retina. Approximately 66% of patients are diagnosed by age 2 years and 95% of patients by age 3 years. Patients with heritable germ cell variants at greater risk of subsequent neoplasms. 13q14.2 RB1 Cell-cycle checkpoint
Rothmund-Thomson syndrome (also called poikiloderma congenitale) [23,24] Autosomal recessive condition. Associated with skin findings (atrophy, telangiectasias, pigmentation), sparse hair, cataracts, small stature, and skeletal abnormalities. Increased incidence of osteosarcoma at a younger age. 8q24.3 RECQL4 DNA helicase
Werner syndrome [25] Patients often have short stature and in their early twenties, develop signs of aging, including graying of hair and hardening of skin. Other aging problems such as cataracts, skin ulcers, and atherosclerosis develop later. 8p12-p11.2 WRN DNA helicase; exonuclease activity

For more information about these genetic syndromes, see the following summaries:

References
  1. Chen X, Bahrami A, Pappo A, et al.: Recurrent somatic structural variations contribute to tumorigenesis in pediatric osteosarcoma. Cell Rep 7 (1): 104-12, 2014. [PUBMED Abstract]
  2. Perry JA, Kiezun A, Tonzi P, et al.: Complementary genomic approaches highlight the PI3K/mTOR pathway as a common vulnerability in osteosarcoma. Proc Natl Acad Sci U S A 111 (51): E5564-73, 2014. [PUBMED Abstract]
  3. Marinoff AE, Spurr LF, Fong C, et al.: Clinical Targeted Next-Generation Panel Sequencing Reveals MYC Amplification Is a Poor Prognostic Factor in Osteosarcoma. JCO Precis Oncol 7: e2200334, 2023. [PUBMED Abstract]
  4. Suehara Y, Alex D, Bowman A, et al.: Clinical Genomic Sequencing of Pediatric and Adult Osteosarcoma Reveals Distinct Molecular Subsets with Potentially Targetable Alterations. Clin Cancer Res 25 (21): 6346-6356, 2019. [PUBMED Abstract]
  5. Nacev BA, Sanchez-Vega F, Smith SA, et al.: Clinical sequencing of soft tissue and bone sarcomas delineates diverse genomic landscapes and potential therapeutic targets. Nat Commun 13 (1): 3405, 2022. [PUBMED Abstract]
  6. De Noon S, Ijaz J, Coorens TH, et al.: MYC amplifications are common events in childhood osteosarcoma. J Pathol Clin Res 7 (5): 425-431, 2021. [PUBMED Abstract]
  7. 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]
  8. Sanders RP, Drissi R, Billups CA, et al.: Telomerase expression predicts unfavorable outcome in osteosarcoma. J Clin Oncol 22 (18): 3790-7, 2004. [PUBMED Abstract]
  9. de Nonneville A, Salas S, Bertucci F, et al.: TOP3A amplification and ATRX inactivation are mutually exclusive events in pediatric osteosarcomas using ALT. EMBO Mol Med 14 (10): e15859, 2022. [PUBMED Abstract]
  10. Mirabello L, Zhu B, Koster R, et al.: Frequency of Pathogenic Germline Variants in Cancer-Susceptibility Genes in Patients With Osteosarcoma. JAMA Oncol 6 (5): 724-734, 2020. [PUBMED Abstract]
  11. Ognjanovic S, Olivier M, Bergemann TL, et al.: Sarcomas in TP53 germline mutation carriers: a review of the IARC TP53 database. Cancer 118 (5): 1387-96, 2012. [PUBMED Abstract]
  12. Mirabello L, Yeager M, Mai PL, et al.: Germline TP53 variants and susceptibility to osteosarcoma. J Natl Cancer Inst 107 (7): , 2015. [PUBMED Abstract]
  13. Toguchida J, Yamaguchi T, Dayton SH, et al.: Prevalence and spectrum of germline mutations of the p53 gene among patients with sarcoma. N Engl J Med 326 (20): 1301-8, 1992. [PUBMED Abstract]
  14. McIntyre JF, Smith-Sorensen B, Friend SH, et al.: Germline mutations of the p53 tumor suppressor gene in children with osteosarcoma. J Clin Oncol 12 (5): 925-30, 1994. [PUBMED Abstract]
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  19. Idol RA, Robledo S, Du HY, et al.: Cells depleted for RPS19, a protein associated with Diamond Blackfan Anemia, show defects in 18S ribosomal RNA synthesis and small ribosomal subunit production. Blood Cells Mol Dis 39 (1): 35-43, 2007 Jul-Aug. [PUBMED Abstract]
  20. Li FP, Fraumeni JF, Mulvihill JJ, et al.: A cancer family syndrome in twenty-four kindreds. Cancer Res 48 (18): 5358-62, 1988. [PUBMED Abstract]
  21. Grimer RJ, Cannon SR, Taminiau AM, et al.: Osteosarcoma over the age of forty. Eur J Cancer 39 (2): 157-63, 2003. [PUBMED Abstract]
  22. Wong FL, Boice JD, Abramson DH, et al.: Cancer incidence after retinoblastoma. Radiation dose and sarcoma risk. JAMA 278 (15): 1262-7, 1997. [PUBMED Abstract]
  23. Wang LL, Gannavarapu A, Kozinetz CA, et al.: Association between osteosarcoma and deleterious mutations in the RECQL4 gene in Rothmund-Thomson syndrome. J Natl Cancer Inst 95 (9): 669-74, 2003. [PUBMED Abstract]
  24. Hicks MJ, Roth JR, Kozinetz CA, et al.: Clinicopathologic features of osteosarcoma in patients with Rothmund-Thomson syndrome. J Clin Oncol 25 (4): 370-5, 2007. [PUBMED Abstract]
  25. Goto M, Miller RW, Ishikawa Y, et al.: Excess of rare cancers in Werner syndrome (adult progeria). Cancer Epidemiol Biomarkers Prev 5 (4): 239-46, 1996. [PUBMED Abstract]

Cellular Classification of Osteosarcoma and UPS of Bone

Osteosarcoma is a malignant tumor that is characterized by the direct formation of bone or osteoid tissue by the tumor cells. The World Health Organization’s histological classification [1] of bone tumors separates the osteosarcomas into central (medullary) and surface (peripheral) tumors [2,3] and recognizes a number of subtypes within each group.

Central (Medullary) Tumors

  • Conventional central osteosarcomas. The most common pathological subtype is conventional central osteosarcoma, which is characterized by areas of necrosis, atypical mitoses, and malignant osteoid tissue and/or cartilage. The other subtypes are much less common, each occurring at a frequency of less than 5%.
  • Telangiectatic osteosarcomas.[4,5] Telangiectatic osteosarcoma may be confused radiographically with an aneurysmal bone cyst or giant cell tumor. This variant should be managed the same as a conventional osteosarcoma.[4,5]
  • Intraosseous well-differentiated (low-grade) osteosarcomas.
  • Small-cell osteosarcomas.

Surface (Peripheral) Tumors

The terms parosteal and periosteal osteosarcoma are embedded in the literature and widely used. They are confusing to patients and practitioners. It would be more helpful to divide osteosarcoma by location and histological grade. High-grade osteosarcoma, sometimes referred to as conventional osteosarcoma, typically arises centrally and grows outward, destroying surrounding cortex and soft tissues, but there are unequivocal cases of high-grade osteosarcoma in surface locations.[6] Similarly, there are reports of low-grade osteosarcoma arising in the medullary cavity.

  • Parosteal (juxtacortical) well-differentiated (low-grade) osteosarcomas.[7,8] Parosteal osteosarcoma is defined as a lesion arising from the surface of the bone with a well-differentiated appearance on imaging and low-grade histological features.[9] The most common site for parosteal osteosarcoma is the posterior distal femur. Parosteal osteosarcoma occurs more often in older patients than does conventional high-grade osteosarcoma and is most common in patients aged 20 to 30 years. Parosteal osteosarcoma can be treated successfully with wide excision of the primary tumor alone.[7,10]
  • Periosteal osteosarcomas (low-grade to intermediate-grade osteosarcomas).[11–13] Periosteal osteosarcoma typically appears as a broad-based soft tissue mass with extrinsic erosion of the underlying bony cortex.[12] Pathology shows an intermediate grade of differentiation. Wide resection is essential.

    A single-institution retrospective review identified 29 patients with periosteal osteosarcoma.[11] The 5-year disease-free survival rate was 83%. The authors could not make a definitive statement regarding the benefits of adjuvant chemotherapy.

    Another single-institution retrospective review identified 33 patients with periosteal osteosarcoma.[13] The 10-year overall survival (OS) rate was 84%. The 10-year OS rate was 83% for patients who were treated with surgery alone and 86% for patients who were treated with surgery and chemotherapy.

    The European Musculoskeletal Oncology Society retrospectively analyzed 119 patients with periosteal osteosarcoma; 17 patients had metastasis.[12] The OS rate was 89% at 5 years and 83% at 10 years. Eighty-one patients received chemotherapy; 50 of those patients received chemotherapy before definitive surgical resection. There was no difference in outcome between the patients who received chemotherapy and the patients who did not receive chemotherapy.

  • High-grade surface osteosarcomas.[3,6,14]

Extraosseous Osteosarcoma

Extraosseous osteosarcoma is a malignant mesenchymal neoplasm without direct attachment to the skeletal system. Previously, treatment for extraosseous osteosarcoma followed soft tissue sarcoma guidelines.[15] However, a retrospective analysis of the cooperative German-Austrian-Swiss osteosarcoma study group identified a favorable outcome for patients with extraosseous osteosarcoma who were treated with surgery and conventional osteosarcoma therapy.[16]

Undifferentiated Pleomorphic Sarcoma (UPS) of Bone

UPS of bone should be distinguished from angiomatoid fibrous histiocytoma, a low-grade tumor that is usually noninvasive, small, and associated with an excellent outcome using surgery alone.[17] One study suggests similar event-free survival rates for UPS and osteosarcoma.[18]

References
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  2. Antonescu CR, Huvos AG: Low-grade osteogenic sarcoma arising in medullary and surface osseous locations. Am J Clin Pathol 114 (Suppl): S90-103, 2000. [PUBMED Abstract]
  3. Kaste SC, Fuller CE, Saharia A, et al.: Pediatric surface osteosarcoma: clinical, pathologic, and radiologic features. Pediatr Blood Cancer 47 (2): 152-62, 2006. [PUBMED Abstract]
  4. Bacci G, Ferrari S, Ruggieri P, et al.: Telangiectatic osteosarcoma of the extremity: neoadjuvant chemotherapy in 24 cases. Acta Orthop Scand 72 (2): 167-72, 2001. [PUBMED Abstract]
  5. Weiss A, Khoury JD, Hoffer FA, et al.: Telangiectatic osteosarcoma: the St. Jude Children’s Research Hospital’s experience. Cancer 109 (8): 1627-37, 2007. [PUBMED Abstract]
  6. Okada K, Unni KK, Swee RG, et al.: High grade surface osteosarcoma: a clinicopathologic study of 46 cases. Cancer 85 (5): 1044-54, 1999. [PUBMED Abstract]
  7. Hoshi M, Matsumoto S, Manabe J, et al.: Oncologic outcome of parosteal osteosarcoma. Int J Clin Oncol 11 (2): 120-6, 2006. [PUBMED Abstract]
  8. Han I, Oh JH, Na YG, et al.: Clinical outcome of parosteal osteosarcoma. J Surg Oncol 97 (2): 146-9, 2008. [PUBMED Abstract]
  9. Kumar VS, Barwar N, Khan SA: Surface osteosarcomas: Diagnosis, treatment and outcome. Indian J Orthop 48 (3): 255-61, 2014. [PUBMED Abstract]
  10. Schwab JH, Antonescu CR, Athanasian EA, et al.: A comparison of intramedullary and juxtacortical low-grade osteogenic sarcoma. Clin Orthop Relat Res 466 (6): 1318-22, 2008. [PUBMED Abstract]
  11. Rose PS, Dickey ID, Wenger DE, et al.: Periosteal osteosarcoma: long-term outcome and risk of late recurrence. Clin Orthop Relat Res 453: 314-7, 2006. [PUBMED Abstract]
  12. Grimer RJ, Bielack S, Flege S, et al.: Periosteal osteosarcoma–a European review of outcome. Eur J Cancer 41 (18): 2806-11, 2005. [PUBMED Abstract]
  13. Cesari M, Alberghini M, Vanel D, et al.: Periosteal osteosarcoma: a single-institution experience. Cancer 117 (8): 1731-5, 2011. [PUBMED Abstract]
  14. Staals EL, Bacchini P, Bertoni F: High-grade surface osteosarcoma: a review of 25 cases from the Rizzoli Institute. Cancer 112 (7): 1592-9, 2008. [PUBMED Abstract]
  15. Wodowski K, Hill DA, Pappo AS, et al.: A chemosensitive pediatric extraosseous osteosarcoma: case report and review of the literature. J Pediatr Hematol Oncol 25 (1): 73-7, 2003. [PUBMED Abstract]
  16. Goldstein-Jackson SY, Gosheger G, Delling G, et al.: Extraskeletal osteosarcoma has a favourable prognosis when treated like conventional osteosarcoma. J Cancer Res Clin Oncol 131 (8): 520-6, 2005. [PUBMED Abstract]
  17. Daw NC, Billups CA, Pappo AS, et al.: Malignant fibrous histiocytoma and other fibrohistiocytic tumors in pediatric patients: the St. Jude Children’s Research Hospital experience. Cancer 97 (11): 2839-47, 2003. [PUBMED Abstract]
  18. Picci P, Bacci G, Ferrari S, et al.: Neoadjuvant chemotherapy in malignant fibrous histiocytoma of bone and in osteosarcoma located in the extremities: analogies and differences between the two tumors. Ann Oncol 8 (11): 1107-15, 1997. [PUBMED Abstract]

Staging and Site Information for Osteosarcoma and UPS of Bone

Historically, the Enneking staging system for skeletal malignancies was used to stage osteosarcoma and UPS of bone.[1] This system inferred the aggressiveness of the primary tumor by the descriptors intracompartmental or extracompartmental. The American Joint Committee on Cancer’s tumor-node-metastasis (TNM) staging system for malignant bone tumors is not widely used for pediatric osteosarcoma, and patients are not stratified on the basis of prognostic stage groups.

For the purposes of treatment, osteosarcoma is described as one of the following:

  • Localized. Patients without clinically detectable metastatic disease are considered to have localized osteosarcoma.
  • Metastatic. Patients with any site of metastasis at the time of initial presentation detected by routine clinical studies are considered to have metastatic osteosarcoma.

Localized Osteosarcoma

Localized tumors are limited to the bone of origin. Patients with skip lesions confined to the bone that includes the primary tumor are considered to have localized disease if the skip lesions can be included in the planned surgical resection.[2] Approximately one-half of the tumors arise in the femur; of these, 80% are in the distal femur. Other primary sites, in descending order of frequency, are the proximal tibia, proximal humerus, pelvis, jaw, fibula, and ribs.[3] Osteosarcoma of the head and neck is more likely to be low grade [4] and to arise in older patients than is osteosarcoma of the appendicular skeleton.

Metastatic Osteosarcoma

Radiological evidence of metastatic tumor deposits is found in approximately 20% of patients at diagnosis, with 85% to 90% of metastatic disease presenting in the lungs. The second most common site of metastasis is another bone, which may be solitary or multiple.[5]

The syndrome of multifocal osteosarcoma refers to a presentation with multiple foci of osteosarcoma without a clear primary tumor, often with symmetrical metaphyseal involvement.[3]

Staging Evaluation

For patients with confirmed osteosarcoma, in addition to plain radiographs of the primary site that include a single-plane view of the entire affected bone to assess for skip metastasis, pretreatment staging studies should include the following:[6]

  • Magnetic resonance imaging (MRI) of the primary site to include the entire bone.
  • Computed tomography (CT) scan, if MRI is not available.
  • Fluorine F 18-fludeoxyglucose (18F-FDG) positron emission tomography (PET)-CT or PET-MRI.[7,8]
  • Bone scan if PET scan is not available.
  • Posteroanterior and lateral chest radiograph.
  • CT scan of the chest.

A retrospective review of 206 patients with osteosarcoma compared bone scan, PET scan, and PET-CT scan for the detection of bone metastases.[9] PET-CT was more sensitive and accurate than bone scan (sensitivity of 92% vs. 74%), and the combined use of both imaging studies achieved the highest sensitivity for diagnosing bone metastases in osteosarcoma (100%). 18F-FDG PET is the preferred staging modality for the detection of bone lesions. CT scan remains necessary for evaluation of pulmonary metastasis.

References
  1. Enneking WF: A system of staging musculoskeletal neoplasms. Clin Orthop Relat Res (204): 9-24, 1986. [PUBMED Abstract]
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  3. Longhi A, Fabbri N, Donati D, et al.: Neoadjuvant chemotherapy for patients with synchronous multifocal osteosarcoma: results in eleven cases. J Chemother 13 (3): 324-30, 2001. [PUBMED Abstract]
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  8. Quartuccio N, Fox J, Kuk D, et al.: Pediatric bone sarcoma: diagnostic performance of ¹⁸F-FDG PET/CT versus conventional imaging for initial staging and follow-up. AJR Am J Roentgenol 204 (1): 153-60, 2015. [PUBMED Abstract]
  9. Byun BH, Kong CB, Lim I, et al.: Comparison of (18)F-FDG PET/CT and (99 m)Tc-MDP bone scintigraphy for detection of bone metastasis in osteosarcoma. Skeletal Radiol 42 (12): 1673-81, 2013. [PUBMED Abstract]

Treatment Option Overview for Osteosarcoma and UPS of Bone

It is imperative that patients with proven or suspected osteosarcoma have an initial evaluation by an orthopedic oncologist familiar with the surgical management of this disease. This evaluation, which includes imaging studies, should be done before the initial biopsy because an inappropriately performed biopsy may jeopardize a limb-sparing procedure. Additionally, protective weight bearing is recommended for patients with tumors of weight-bearing bones to prevent pathological fractures that could preclude limb-preserving surgery.

Successful treatment generally requires the combination of effective systemic chemotherapy and complete resection of all clinically detectable disease.

Randomized clinical trials have established that both neoadjuvant and adjuvant chemotherapy are effective in preventing relapse in patients with clinically nonmetastatic tumors.[1]; [2][Level of evidence A1] The Pediatric Oncology Group (POG) conducted a study in which patients were randomly assigned to either immediate amputation or amputation after neoadjuvant therapy. A large percentage of patients declined to be assigned randomly, and the study was terminated without approaching the stated accrual goals. In the small number of patients treated, there was no difference in outcome between those who received preoperative chemotherapy and those who received postoperative chemotherapy.[3]

The treatment of osteosarcoma also depends on the histological grade, as follows:

  • Low-grade osteosarcoma. Patients with low-grade osteosarcoma can be treated successfully by wide surgical resection alone, regardless of site of origin.
  • Intermediate-grade osteosarcoma. Pathologists sometimes characterize tumors as intermediate-grade osteosarcoma. It is difficult to make treatment decisions for patients with intermediate-grade tumors. When a tumor biopsy suggests an intermediate-grade osteosarcoma, an option is to proceed with wide resection. The availability of the entire tumor allows the pathologist to examine more tissue and evaluate soft tissue and lymphovascular invasion, which can often clarify the nature of the lesion.

    If the lesion proves to have high-grade elements, systemic chemotherapy is indicated, just as it would be for any high-grade osteosarcoma. The POG performed a study in which patients with high-grade osteosarcoma were randomly assigned to either immediate definitive surgery followed by adjuvant chemotherapy or to an initial period of chemotherapy followed by definitive surgery.[3] The outcome was the same for both groups. Although the strategy of initial chemotherapy followed by definitive surgery has become an almost universally applied approach for osteosarcoma, this study suggests that there is no increased risk of treatment failure if definitive surgery is done before chemotherapy begins; this can help to clarify equivocal diagnoses of intermediate-grade osteosarcoma.

  • High-grade osteosarcoma. Patients with high-grade osteosarcoma require surgery and systemic chemotherapy. This treatment is necessary whether the tumor arises in the conventional central location or on a bone surface.

Recognition of intraosseous well-differentiated osteosarcoma and parosteal osteosarcoma is important because patients with these tumor types have the most favorable prognosis and can be treated successfully with wide excision of the primary tumor alone.[4,5] Patients with periosteal osteosarcoma have a generally good prognosis [6] and treatment is guided by histological grade.[5,7]

Patients with undifferentiated pleomorphic sarcoma (UPS) of bone are treated according to osteosarcoma treatment protocols.[8] A sarcoma-specific survival rate of 70.7% has been reported using primarily cisplatin- and doxorubicin-based regimens.[9]

Imaging modalities such as dynamic magnetic resonance imaging or positron emission tomography scanning are noninvasive methods to assess response,[10–18] and are the preferred modalities in the Children’s Oncology Group AOST2032 (NCT05691478) trial.

Table 3 describes the treatment options for localized, metastatic, and recurrent osteosarcoma and UPS of bone.

Table 3. Treatment Options for Osteosarcoma and Undifferentiated Pleomorphic Sarcoma (UPS) of Bone
Treatment Group Treatment Options
Localized osteosarcoma and UPS of bone Surgical removal of primary tumor.
Chemotherapy.
Radiation therapy, if surgery is not feasible or surgical margins are inadequate.
Osteosarcoma and UPS of bone with metastatic disease at diagnosis: Chemotherapy.
  Lung-only metastases Preoperative chemotherapy followed by surgery to remove the tumor followed by postoperative combination chemotherapy.
  Bone metastases with or without lung metastases Preoperative chemotherapy followed by surgery to remove the primary tumor and all metastatic disease followed by postoperative combination chemotherapy.
Surgery to remove the primary tumor followed by chemotherapy and then surgical resection of metastatic disease followed by postoperative combination chemotherapy.
Resection of metastatic bone lesions if possible.
Radiation therapy to the extremities (may offer some local control).
Recurrent osteosarcoma and UPS of bone: Surgery to remove all sites of metastatic disease.
Chemotherapy and targeted therapy.
Radiopharmaceuticals and radiation therapy.
  Local recurrence Surgery to remove the tumor.
  Lung-only recurrence Surgery to remove the tumor.
Chemotherapy or targeted therapy.
Radiation therapy.
  Recurrence with bone-only metastases Surgery to remove the tumor.
153Sm-EDTMP with or without stem cell support.
Chemotherapy or targeted therapy.
Radiation therapy.
  Second recurrence of osteosarcoma Surgery to remove the tumor and/or chemotherapy.
Chemotherapy or targeted therapy.
153Sm-EDTMP = samarium Sm 153-ethylenediamine tetramethylene phosphonic acid.
References
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  6. Rose PS, Dickey ID, Wenger DE, et al.: Periosteal osteosarcoma: long-term outcome and risk of late recurrence. Clin Orthop Relat Res 453: 314-7, 2006. [PUBMED Abstract]
  7. Grimer RJ, Bielack S, Flege S, et al.: Periosteal osteosarcoma–a European review of outcome. Eur J Cancer 41 (18): 2806-11, 2005. [PUBMED Abstract]
  8. Picci P, Bacci G, Ferrari S, et al.: Neoadjuvant chemotherapy in malignant fibrous histiocytoma of bone and in osteosarcoma located in the extremities: analogies and differences between the two tumors. Ann Oncol 8 (11): 1107-15, 1997. [PUBMED Abstract]
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  17. Byun BH, Kong CB, Lim I, et al.: Combination of 18F-FDG PET/CT and diffusion-weighted MR imaging as a predictor of histologic response to neoadjuvant chemotherapy: preliminary results in osteosarcoma. J Nucl Med 54 (7): 1053-9, 2013. [PUBMED Abstract]
  18. Davis JC, Daw NC, Navid F, et al.: 18F-FDG Uptake During Early Adjuvant Chemotherapy Predicts Histologic Response in Pediatric and Young Adult Patients with Osteosarcoma. J Nucl Med 59 (1): 25-30, 2018. [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.

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.

Treatment of Localized Osteosarcoma and UPS of Bone

Patients with localized osteosarcoma who undergo surgery and chemotherapy have a 5-year overall survival (OS) rate of 62% to 65%.[1] Complete surgical resection is crucial for patients with localized osteosarcoma, but it is not sufficient as the only therapy. At least 80% of patients treated with surgery alone will develop metastatic disease.[2] Randomized clinical trials have established that adjuvant chemotherapy is effective in preventing relapse or recurrence in patients with localized resectable primary tumors.[2]; [3][Level of evidence A1]

Undifferentiated pleomorphic sarcoma (UPS) of bone is seen more commonly in older adults. Patients with UPS of bone are treated according to osteosarcoma treatment protocols. The outcome for patients with resectable UPS is similar to the outcome for patients with osteosarcoma.[4] As with osteosarcoma, patients with favorable necrosis (≥90% necrosis) have a longer survival than do those with an inferior necrosis (<90% necrosis).[5] Many patients with UPS will need preoperative chemotherapy to achieve a wide local excision.[6]

Treatment Options for Localized Osteosarcoma and UPS of Bone

Treatment options for patients with localized osteosarcoma or UPS of bone include the following:

  1. Surgical removal of primary tumor.
  2. Chemotherapy (may start before or after definitive surgical resection of the primary tumor).
  3. Radiation therapy, if surgery is not feasible or surgical margins are inadequate.

Surgical removal of primary tumor

Surgical resection of the primary tumor with adequate margins is an essential component of the curative strategy for patients with localized osteosarcoma. The type of surgery required for complete ablation of the primary tumor depends on a number of factors that must be evaluated on a case-by-case basis.[7]

Limb-sparing procedures

In general, more than 80% of patients with extremity osteosarcoma can be treated using a limb-sparing procedure and do not require amputation.[8] Limb-sparing procedures are planned only when the preoperative staging indicates that it would be possible to achieve wide surgical margins. In one study, patients who underwent limb-salvage procedures who had poor histological response and close surgical margins had a high rate of local recurrence.[9]

Reconstruction after limb-sparing surgery can be accomplished with many options, including metallic endoprosthesis, allograft, vascularized autologous bone graft, and rotationplasty. An additional option, osteogenesis distraction bone transport, is available for patients whose tumors do not involve the epiphysis of long bones.[10] This procedure results in a stable reconstruction that functionally restores the normal limb.

The choice of optimal surgical reconstruction involves many factors, including the following:[11][Level of evidence A1]

  • Site and size of the primary tumor.
  • Ability to preserve the neurovascular supply of the distal extremity.
  • Age of the patient and potential for additional growth.
  • Needs and desires of the patient and family for specific functions such as sports participation.

If a complicated reconstruction delays or prohibits the resumption of systemic chemotherapy, limb preservation may endanger the chance for cure. In retrospective analyses of 703 patients with localized osteosarcoma, the resumption of chemotherapy 21 days or more after definitive surgery was associated with an increased risk of death and adverse events (hazard ratio [HR], 1.57; 1.04–2.36).[11] Delays in total time to completion of chemotherapy have also been associated with inferior OS and event-free survival (EFS). In a retrospective multivariate analysis of 113 patients with localized osteosarcoma, a delay of time to completion of chemotherapy greater than 4 weeks was associated with an OS HR of 2.70 (1.11–6.76, P = .003) and an EFS HR of 1.13 (1.00–1.26, P = .016).[12]

Amputation

For some patients, amputation remains the optimal choice for management of the primary tumor. A pathological fracture noted at diagnosis or during preoperative chemotherapy does not preclude limb-salvage surgery if wide surgical margins can be achieved.[13] If the pathological examination of the surgical specimen shows inadequate margins, an immediate amputation should be considered, especially if the histological necrosis after preoperative chemotherapy was poor.[14]

Factors associated with an increased risk of local recurrence

Patients who undergo amputation have lower local recurrence rates than do patients who undergo limb-salvage procedures.[15] However, there is no difference in OS between patients initially treated with amputation and those treated with a limb-sparing procedure. Patients with tumors of the femur have a higher local recurrence rate than do patients with primary tumors of the tibia or fibula. Rotationplasty and other limb-salvage procedures have been evaluated for both their functional outcome and their effect on survival. While limb-sparing resection is the current practice for local control at most pediatric institutions, there are few data to indicate that salvage of the lower limb is substantially superior to amputation with regard to patient quality of life.[16]

The German Cooperative Osteosarcoma Study Group (COSS) performed a retrospective analysis of 1,802 patients with localized and metastatic osteosarcoma who underwent surgical resection of all clinically detectable disease.[17][Level of evidence C1] Local recurrence (n = 76) was associated with a high risk of death from osteosarcoma. Factors associated with an increased risk of local recurrence included nonparticipation in a clinical trial, pelvic primary site, limb-preserving surgery, soft tissue infiltration beyond the periosteum, poor pathological response to initial chemotherapy, failure to complete planned chemotherapy, and performing the biopsy at an institution different from where the definitive surgery is being performed.

Chemotherapy

Preoperative chemotherapy

Almost all patients receive intravenous preoperative chemotherapy as initial treatment. However, a standard chemotherapy regimen has not been determined. Current chemotherapy protocols include combinations of the following agents: high-dose methotrexate, doxorubicin, cyclophosphamide, cisplatin, ifosfamide, etoposide, and carboplatin.[18–26]

Evidence (preoperative chemotherapy):

  1. A meta-analysis of protocols for the treatment of osteosarcoma concluded the following:[27]
    • Regimens containing three active chemotherapy agents were superior to regimens containing two active agents.
    • Regimens with four active agents were not superior to regimens with three active agents.
    • Three-drug regimens that did not include high-dose methotrexate were inferior to three-drug regimens that did include high-dose methotrexate.
  2. An Italian study that used regimens containing fewer courses of high-dose methotrexate observed the following results:[28][Level of evidence B4]
    • There was a lower probability for EFS than found in earlier studies that used regimens containing more courses of high-dose methotrexate.
  3. The Children’s Oncology Group (COG) performed a prospective randomized trial in newly diagnosed children and young adults with localized osteosarcoma. All patients received cisplatin, doxorubicin, and high-dose methotrexate. One-half of the patients were randomly assigned to receive ifosfamide. In a second randomization, one-half of the patients were assigned to receive the biological compound muramyl tripeptide-phosphatidyl ethanolamine encapsulated in liposomes (L-MTP-PE) beginning after definitive surgical resection. Results showed that:[29][Level of evidence A1]
    • The addition of ifosfamide did not improve outcome.
    • The addition of L-MTP-PE produced improvement in the EFS rate, which did not meet the conventional test for statistical significance (P = .08), and a significant improvement in the OS rate (78% vs. 70%; P = .03).
    • There has been speculation regarding the potential contribution of postrelapse treatment, although there were no differences in the postrelapse surgical approaches in the relapsed patients. The appropriate role of L-MTP-PE in the treatment of osteosarcoma remains under discussion.[30]
  4. The COG performed a series of pilot studies in patients with newly diagnosed localized osteosarcoma.[31][Level of evidence B4]
    1. In pilot study 1, patients with lower degrees of necrosis after three-drug initial therapy received subsequent therapy with a higher cumulative dose of doxorubicin of 600 mg/m2.
    2. In pilot study 2, all patients received four-drug initial chemotherapy with cisplatin, doxorubicin, high-dose methotrexate, and ifosfamide. Patients with lower degrees of necrosis received subsequent chemotherapy with a higher cumulative dose of doxorubicin of 600 mg/m2.
    3. In pilot study 3, all patients received the same four-drug initial chemotherapy as pilot study 2. Patients with lower degrees of necrosis received higher doses of ifosfamide with the addition of etoposide in subsequent therapy.

    The results of these pilot studies were as follows:

    • Outcomes for all three pilot studies were similar to each other and to historical controls.
    • All patients received dexrazoxane before each dose of doxorubicin. The addition of dexrazoxane did not appear to decrease the rate of good necrosis after initial therapy or EFS.
    • Left ventricular fractional shortening, as measured by echocardiography, was minimally affected at 78 weeks from study entry.
    • There was no evidence for an increased risk of secondary leukemia.
  5. The international European and American Osteosarcoma Study (EURAMOS) Group consortium was formed to conduct a large, prospective, randomized trial to help determine whether modifying the chemotherapy regimen on the basis of the degree of necrosis would improve EFS. All patients received initial therapy with cisplatin, doxorubicin, and high-dose methotrexate (MAP). Patients with more than 90% necrosis were randomly assigned to continue the same chemotherapy after surgery or to receive the same chemotherapy with the addition of interferon alpha-2B. Patients with less than 90% necrosis were randomly assigned to continue the same chemotherapy or to receive the same chemotherapy with the addition of high-dose ifosfamide and etoposide (MAPIE).[32][Level of evidence A1]
    • At a median follow-up of 54 months for all registered patients (N = 2,260), the 3-year EFS rate was 59% (95% confidence interval [CI], 57%–61%), and the 5-year EFS rate was 54% (95% CI, 52%–56%).
    • The 3-year OS rate was 79% (95% CI, 77%–81%), and the 5-year OS rate was 71% (95% CI, 68%–73%).
    • Patients with localized disease at diagnosis (M0) who underwent complete surgical resection (n = 1,549) had 3-year EFS and OS rates from surgery of 70% and 88%, respectively; the 5-year EFS and OS rates from surgery were 64% and 79%, respectively.
    • Forty percent of patients/families who participated in the study declined randomization after definitive surgical resection, making interpretation of the outcome of the randomized study questions more difficult and challenging the generalizability of the results.
    • Of patients with more than 90% necrosis, 716 were randomly assigned to continue the same chemotherapy after surgery with or without the addition of interferon alpha-2B. The 3-year EFS rates were 74% (95% CI, 69%–79%) for patients who received MAP and 77% (95% CI, 72%–81%) for patients who received MAP plus interferon alpha-2B. The HR was 0.83 (95% CI, 0.61–1.12; P = .2).[33]
    • Of patients with less than 90% necrosis, 618 were randomly assigned to continue MAP chemotherapy or to receive MAPIE chemotherapy. The 3-year EFS estimates for patients with localized disease were 60% (95% CI, 54%–66%) for the MAP group and 57% (95% CI, 51%–63%) for the MAPIE group. The HR was 1.03 (0.81–1.33, P = .80).[34]
  6. In a French Sarcoma Group trial, high-dose methotrexate was omitted for adult patients with osteosarcoma. The cohort included 60 patients aged 16 to 63 years (median age, 27 years). Patients received initial therapy with ifosfamide and cisplatin. Doxorubicin was added after definitive surgery for patients who had less necrosis after initial chemotherapy.[35]
    • With a median follow-up of 322 months, the 5-year disease-free survival (DFS) rate was 51.8%, and the 5-year OS rate was 64.4%.
    • At 10 years, the DFS rate was 49.9%, and the OS rate was 64.4%.
    • At 25 years, the DFS rate was 47.8%, and the OS rate was 55.9%.
Postoperative chemotherapy

Historically, the extent of tumor necrosis was used in some clinical trials to determine what type of postoperative chemotherapy would be given. In general, if tumor necrosis exceeded 90%, the preoperative chemotherapy regimen was continued. If tumor necrosis was less than 90%, some groups incorporated drugs not previously used in the preoperative therapy.

Patients with less necrosis after initial chemotherapy have an inferior prognosis than patients with more necrosis. The prognosis is still substantially better than the prognosis for patients treated with surgery alone and no adjuvant chemotherapy.

Based on the following evidence, it is inappropriate to conclude that patients with less necrosis have not responded to chemotherapy and that adjuvant chemotherapy should be withheld for these patients. Chemotherapy after definitive surgery should include the agents used in the initial phase of treatment unless there is clear and unequivocal progressive disease during the initial phase of therapy.

Evidence (using the same agents for postoperative chemotherapy):

  1. Early reports from the Memorial Sloan Kettering Cancer Center (MSKCC) suggested that adding cisplatin to postoperative chemotherapy improved the outcome for patients with less than 90% tumor necrosis.[36]
    • With longer follow-up, the outcome for patients with less than 90% tumor necrosis treated at MSKCC was the same whether they did or did not receive cisplatin in the postoperative phase of treatment.[37]
  2. In an early experience, the German COSS performed a trial in which the chemotherapy regimen for patients with poor necrosis was changed after initial treatment.[38] The agents used before surgery were discontinued and other agents were substituted.
    • The results were substantially poorer for these patients than for patients who continued to receive the same agents.
  3. Subsequent trials performed by other groups failed to demonstrate improved EFS when drugs not included in the preoperative regimen (cisplatin) were added to postoperative therapy.[19,39]
  4. A limited-institution pilot trial tested the strategy of discontinuing the agents used in the initial phase of therapy for patients with poorer necrosis. Postoperative therapy consisted of melphalan with autologous stem cell reconstitution.[40]
    • The 5-year EFS rate for this group was 28%, which was lower than the EFS rates observed in many large series in which agents were continued despite a lesser degree of necrosis.
  5. The international EURAMOS group consortium was formed to conduct a large, prospective, randomized trial to help determine whether modifying the chemotherapy regimen on the basis of the degree of necrosis would improve EFS. All patients received initial therapy with cisplatin, doxorubicin, and high-dose methotrexate (MAP). Patients with more than 90% necrosis were randomly assigned to continue the same chemotherapy after surgery or to receive the same chemotherapy with the addition of interferon alpha-2b.[33][Level of evidence B1] In the same EURAMOS trial, patients with less than 90% necrosis were randomly assigned to continue the same chemotherapy or to receive the same chemotherapy with the addition of high-dose ifosfamide and etoposide (MAPIE).[34][Level of evidence B1]
    • The addition of interferon alpha-2b did not improve the probability of EFS.
    • With a median follow-up of over 61 months, the EFS did not differ between the two groups.
    • The intensification of treatment in the MAPIE group resulted in greater toxicity than did the treatment in the standard MAP arm.
Progression before local therapy

A single-institution retrospective analysis reported on early progression of osteosarcoma before local control.[41] Among 195 patients aged 18 years or younger, 25 (81%) had local-site progression only, and 6 patients had combined local- and metastatic-sites progression. The authors did not prospectively identify patients with clinical features that might suggest telangiectatic osteosarcoma with increased necrosis and hemorrhage, which might be an explanation for apparent progression. For the entire cohort, the 5-year EFS rate was 27.2%, and the OS rate was 31.3%. Patients with good necrosis had better 5-year EFS and OS rates (66.7% and 66.7%, respectively), compared with patients with a poor histological response (21.4% and 25.6%, respectively). However, these results did not reach statistical significance (P = .07 and P = .1).

Other chemotherapy approaches not considered effective

The Italian Sarcoma Group and the Scandinavian Sarcoma Group performed a clinical trial in patients with osteosarcoma who presented with clinically detectable metastatic disease.[42] Consolidation with high-dose etoposide and carboplatin followed by autologous stem cell reconstitution did not appear to improve outcome and the investigators did not recommend this strategy for the treatment of osteosarcoma.

Laboratory studies using cell lines and xenografts suggested that bisphosphonates had activity against osteosarcoma.[43] A single-institution clinical trial demonstrated that pamidronate could safely be administered along with multiagent chemotherapy to patients with newly diagnosed osteosarcoma.[43] The French pediatric and adult sarcoma cooperative groups performed a prospective trial for the treatment of osteosarcoma.[44] All patients received multiagent chemotherapy, and patients were randomly assigned to receive or not to receive zoledronate. The addition of zoledronate did not improve EFS.

Radiation therapy

If complete surgical resection is not feasible or if surgical margins are inadequate, radiation therapy may improve the local control rate.[45,46]; [47][Level of evidence C1] Radiation therapy should be considered in patients with osteosarcoma of the head and neck who have positive or uncertain resection margins.[48][Level of evidence C1]

Evidence (radiation therapy for local control):

  1. While it is accepted that the standard approach is primary surgical resection, a retrospective analysis of a small group of highly selective patients reported long-term EFS with external-beam radiation therapy for local control in some patients.[49][Level of evidence C1]
  2. Investigators from a single institution reported on 28 children and young adults with osteosarcoma who were treated with radiation therapy for local control. Sixteen patients received radiation therapy during the primary treatment course, and 12 patients received radiation therapy as part of therapy after recurrence.[50]
    • For patients who received radiation therapy during primary treatment, the cumulative incidence of local failure at 5 years was 25%.
    • For patients with recurrent disease, the cumulative incidence of local failure at 5 years was 44%.
    • Local tumor progression was observed in 3 of 13 patients (23%) who were treated with adjuvant radiation therapy after resection, while three of six patients (50%) who received definitive radiation therapy as a sole modality of local control experienced local progression.

Osteosarcoma of the Head and Neck

Osteosarcoma of the head and neck occurs in an older population than does osteosarcoma of the extremities.[48,51–54] In the pediatric age group, osteosarcomas of the head and neck are more likely to be low-grade or intermediate-grade tumors than are osteosarcomas of the extremities.[55,56] All reported series emphasize the need for complete surgical resection.[48,51–56][Level of evidence C1] The probability for cure with surgery alone is higher for osteosarcoma of the head and neck than it is for extremity osteosarcoma. When surgical margins are positive, there is a trend for improved survival with adjuvant radiation therapy.[48,53][Level of evidence C1]

There are no randomized trials to assess the efficacy of chemotherapy in patients with osteosarcoma of the head and neck, but several series suggest a benefit.[51,57] Chemotherapy should be considered for younger patients with high-grade osteosarcoma of the head and neck.[55,58]

Patients with osteosarcoma of the head and neck have a higher risk of developing a local recurrence and a lower risk of having distant metastasis than do patients with osteosarcoma of the extremities.[51,53,54,59]

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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  42. Boye K, Del Prever AB, Eriksson M, et al.: High-dose chemotherapy with stem cell rescue in the primary treatment of metastatic and pelvic osteosarcoma: final results of the ISG/SSG II study. Pediatr Blood Cancer 61 (5): 840-5, 2014. [PUBMED Abstract]
  43. Meyers PA, Healey JH, Chou AJ, et al.: Addition of pamidronate to chemotherapy for the treatment of osteosarcoma. Cancer 117 (8): 1736-44, 2011. [PUBMED Abstract]
  44. Piperno-Neumann S, Le Deley MC, Rédini F, et al.: Zoledronate in combination with chemotherapy and surgery to treat osteosarcoma (OS2006): a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol 17 (8): 1070-80, 2016. [PUBMED Abstract]
  45. Ozaki T, Flege S, Kevric M, et al.: Osteosarcoma of the pelvis: experience of the Cooperative Osteosarcoma Study Group. J Clin Oncol 21 (2): 334-41, 2003. [PUBMED Abstract]
  46. DeLaney TF, Park L, Goldberg SI, et al.: Radiotherapy for local control of osteosarcoma. Int J Radiat Oncol Biol Phys 61 (2): 492-8, 2005. [PUBMED Abstract]
  47. Ciernik IF, Niemierko A, Harmon DC, et al.: Proton-based radiotherapy for unresectable or incompletely resected osteosarcoma. Cancer 117 (19): 4522-30, 2011. [PUBMED Abstract]
  48. Guadagnolo BA, Zagars GK, Raymond AK, et al.: Osteosarcoma of the jaw/craniofacial region: outcomes after multimodality treatment. Cancer 115 (14): 3262-70, 2009. [PUBMED Abstract]
  49. Hundsdoerfer P, Albrecht M, Rühl U, et al.: Long-term outcome after polychemotherapy and intensive local radiation therapy of high-grade osteosarcoma. Eur J Cancer 45 (14): 2447-51, 2009. [PUBMED Abstract]
  50. Tinkle CL, Lu J, Han Y, et al.: Curative-intent radiotherapy for pediatric osteosarcoma: The St. Jude experience. Pediatr Blood Cancer 66 (8): e27763, 2019. [PUBMED Abstract]
  51. Canadian Society of Otolaryngology-Head and Neck Surgery Oncology Study Group: Osteogenic sarcoma of the mandible and maxilla: a Canadian review (1980-2000). J Otolaryngol 33 (3): 139-44, 2004. [PUBMED Abstract]
  52. Kassir RR, Rassekh CH, Kinsella JB, et al.: Osteosarcoma of the head and neck: meta-analysis of nonrandomized studies. Laryngoscope 107 (1): 56-61, 1997. [PUBMED Abstract]
  53. Laskar S, Basu A, Muckaden MA, et al.: Osteosarcoma of the head and neck region: lessons learned from a single-institution experience of 50 patients. Head Neck 30 (8): 1020-6, 2008. [PUBMED Abstract]
  54. Patel SG, Meyers P, Huvos AG, et al.: Improved outcomes in patients with osteogenic sarcoma of the head and neck. Cancer 95 (7): 1495-503, 2002. [PUBMED Abstract]
  55. Gadwal SR, Gannon FH, Fanburg-Smith JC, et al.: Primary osteosarcoma of the head and neck in pediatric patients: a clinicopathologic study of 22 cases with a review of the literature. Cancer 91 (3): 598-605, 2001. [PUBMED Abstract]
  56. Daw NC, Mahmoud HH, Meyer WH, et al.: Bone sarcomas of the head and neck in children: the St Jude Children’s Research Hospital experience. Cancer 88 (9): 2172-80, 2000. [PUBMED Abstract]
  57. Smeele LE, Snow GB, van der Waal I: Osteosarcoma of the head and neck: meta-analysis of the nonrandomized studies. Laryngoscope 108 (6): 946, 1998. [PUBMED Abstract]
  58. Smeele LE, Kostense PJ, van der Waal I, et al.: Effect of chemotherapy on survival of craniofacial osteosarcoma: a systematic review of 201 patients. J Clin Oncol 15 (1): 363-7, 1997. [PUBMED Abstract]
  59. Jasnau S, Meyer U, Potratz J, et al.: Craniofacial osteosarcoma Experience of the cooperative German-Austrian-Swiss osteosarcoma study group. Oral Oncol 44 (3): 286-94, 2008. [PUBMED Abstract]

Treatment of Osteosarcoma and UPS of Bone With Metastatic Disease at Diagnosis

Approximately 20% to 25% of patients with osteosarcoma present with clinically detectable metastatic disease. For patients with metastatic disease at initial presentation, roughly 20% will remain continuously free of disease, and roughly 30% will survive 5 years from diagnosis.[1]

The lungs are the most common site of initial metastatic disease.[2] Patients with metastases limited to the lungs have a better outcome than do patients with metastases to other sites or to the lungs combined with other sites.[1,3]

Treatment Options for Osteosarcoma and UPS of Bone With Metastatic Disease at Diagnosis

Treatment options for patients with osteosarcoma or undifferentiated pleomorphic sarcoma (UPS) of bone with metastatic disease at diagnosis include the following:

  1. Chemotherapy.

The chemotherapeutic agents used include high-dose methotrexate, doxorubicin, cisplatin, high-dose ifosfamide, etoposide, and, in some reports, carboplatin or cyclophosphamide.

Evidence (chemotherapy):

  1. In a trial that investigated high-dose ifosfamide (17.5 g per course) in combination with etoposide for patients with newly diagnosed metastatic osteosarcoma, the following was observed:[4]
    • The combination produced a complete response in 10% of the patients and a partial response in 49% of the patients.

    However, similar to localized disease, there is no evidence that the addition of ifosfamide or etoposide contributes to improved event-free survival (EFS) or overall survival (OS) in patients with metastatic disease.

  2. A study using a factorial design in patients with metastatic osteosarcoma (n = 91) evaluated the addition of either muramyl tripeptide or ifosfamide to a standard chemotherapy regimen that included cisplatin, high-dose methotrexate, and doxorubicin.[5]
    • There was a nominal advantage for the addition of muramyl tripeptide (but not for ifosfamide) in terms of EFS and OS, but criteria for statistical significance were not met.
  3. In the international European and American Osteosarcoma Study (EURAMOS) group consortium, 362 of 2,186 patients (17%) presented with metastasis at diagnosis. Patients were randomly assigned to receive either treatment with cisplatin, doxorubicin, and high-dose methotrexate or cisplatin, doxorubicin, high-dose methotrexate, and ifosfamide.[6][Level of evidence A1]
    • At a median follow-up of 47 months, the 3-year EFS rate was 32% (95% confidence interval [CI], 27%–37%), and the 5-year EFS rate was 28% (95% CI, 23%–33%).
    • The 3-year OS rate was 56% (95% CI, 50%–61%), and the 5-year OS rate was 45% (95% CI, 39%–50%).

The treatment options for UPS of bone with metastasis at initial presentation are the same as the treatment for osteosarcoma with metastasis. Patients with unresectable or metastatic UPS have a very poor outcome.[7]

Treatment Options for Lung-Only Metastases at Diagnosis

Treatment options for patients with metastatic lung lesions at diagnosis include the following:

  1. Preoperative chemotherapy followed by surgery to remove the tumor followed by postoperative combination chemotherapy.

Patients with metastatic lung lesions as the sole site of metastatic disease should have the lung lesions resected if possible. Generally, this is performed after the administration of preoperative chemotherapy. After definitive surgical resection of the primary tumor, most clinicians resume systemic chemotherapy before initiating lung surgery to avoid longer delays in the resumption of chemotherapy. In approximately 10% of patients, all lung lesions disappear after preoperative chemotherapy.[3] Complete resection of pulmonary metastatic disease can be achieved in a high percentage of patients with residual lung nodules after preoperative chemotherapy. The long-term survival is poor for patients who do not undergo complete surgical resection of pulmonary metastatic disease.[8,9][Level of evidence B4]

For patients who present with primary osteosarcoma and metastases limited to the lungs and who achieve complete surgical remission, the 5-year EFS rate is approximately 20% to 25%. Multiple metastatic nodules confer a worse prognosis than do one or two nodules, and bilateral lung involvement is worse than unilateral.[1] Patients with peripheral lung lesions may have a better prognosis than patients with central lesions.[10] Patients with fewer than three nodules confined to one lung may achieve a 5-year EFS rate of approximately 40% to 50%.[1]

A multi-institutional retrospective analysis compared thoracotomy with thoracoscopy for resection of pulmonary metastases in patients with osteosarcoma.[11] The analysis included patients who had pulmonary metastases at diagnosis, patients with pulmonary relapse after initial management of localized disease, and patients with disease progression while on therapy. The authors recognized a significant selection bias for the patients chosen to undergo thoracoscopy. In a Cox regression analysis, controlling for other factors impacting outcome, there was a significantly increased risk of mortality (hazard ratio [HR], 2.11; 95% CI, 1.09–4.09; P = .027) but not pulmonary recurrence (HR, 0.96; 95% CI, 0.52–1.79; P = .90) with a thoracoscopic approach. In a subset analysis limited to patients with oligometastatic disease, thoracoscopy did not increase the risk of mortality (HR, 1.16; 95% CI, 0.64–2.11; P = .62). The ongoing randomized trial (AOST2031 [NCT05235165]) was designed to definitively address this question and the selection bias. This trial will compare the effect of thoracotomy with thoracoscopic surgery.

Treatment Options for Bone Metastases With or Without Lung Metastases

The second most common site of metastasis is another bone that is distant from the primary tumor. Patients with metastasis to other bones distant from the primary tumor experience EFS and OS rates of approximately 10%.[1] In a study of patients who presented with primary extremity tumors and synchronous metastasis to other bones, only 3 of 46 patients remained continuously disease-free 5 years later.[12] Patients with transarticular skip lesions have a poor prognosis.[13]

Multifocal osteosarcoma is different from osteosarcoma that presents with a clearly delineated primary lesion and limited bone metastasis. Multifocal osteosarcoma classically presents with symmetrical, metaphyseal lesions, and it may be difficult to determine the primary lesion. Patients with multifocal bone disease at presentation have an extremely poor prognosis, but treatment with systemic chemotherapy and aggressive surgical resection may significantly prolong life.[14,15]

Treatment options for patients with bone metastases with or without lung metastases include the following:

  1. Preoperative chemotherapy followed by surgery to remove the primary tumor. After definitive surgical resection of the primary tumor, most clinicians resume systemic chemotherapy.

    The timing of surgery to remove metastatic tumors is not well defined. It is usually not attempted at the time of primary surgery because delays of more than 21 days until resumption of chemotherapy can increase the risk of adverse events and death.[16]

  2. Surgery to remove the primary tumor followed by chemotherapy and then surgical resection of metastatic disease followed by postoperative combination chemotherapy.

    When the usual treatment course of preoperative chemotherapy followed by surgical ablation of the primary tumor and resection of all overt metastatic disease followed by postoperative combination chemotherapy cannot be used, an alternative treatment approach may be used. This alternative treatment approach begins with surgery for the primary tumor, followed by chemotherapy, and then surgical resection of metastatic disease. This approach may be appropriate in patients with intractable pain, pathological fracture, or uncontrolled infection of the tumor when initiation of chemotherapy could create risk of sepsis.[17]

  3. Resection of metastatic bone lesions if possible.
  4. Radiation therapy to the extremities.

    There is evidence that radiation therapy to the extremities may offer some local control.[18]

Treatment Options Under Clinical Evaluation

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 are examples of national and/or institutional clinical trials that are currently being conducted:

  • AOST2031 (NCT05235165) (Thoracotomy Versus Thoracoscopic Management of Pulmonary Metastases in Patients With Osteosarcoma): This phase III trial compares the effect of thoracotomy with thoracoscopic surgery (video-assisted thoracoscopic surgery) in treating patients with osteosarcoma that has spread to the lung (pulmonary metastases). This trial is being done to evaluate the two different surgery methods for these patients and to determine which procedure is better.
  • AOST2032 (NCT05691478) (A Study to Test the Addition of the Drug Cabozantinib to Chemotherapy in Patients With Newly Diagnosed Osteosarcoma): This trial starts with a feasibility phase for patients with high-risk osteosarcoma who have a resectable primary tumor. The feasibility phase will be followed by a randomized study comparing chemotherapy using methotrexate, doxorubicin, and cisplatin (MAP) with MAP and cabozantinib for patients with newly diagnosed localized and metastatic osteosarcoma.

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. Kager L, Zoubek A, Pötschger U, et al.: Primary metastatic osteosarcoma: presentation and outcome of patients treated on neoadjuvant Cooperative Osteosarcoma Study Group protocols. J Clin Oncol 21 (10): 2011-8, 2003. [PUBMED Abstract]
  2. Kempf-Bielack B, Bielack SS, Jürgens H, et al.: Osteosarcoma relapse after combined modality therapy: an analysis of unselected patients in the Cooperative Osteosarcoma Study Group (COSS). J Clin Oncol 23 (3): 559-68, 2005. [PUBMED Abstract]
  3. Bacci G, Rocca M, Salone M, et al.: High grade osteosarcoma of the extremities with lung metastases at presentation: treatment with neoadjuvant chemotherapy and simultaneous resection of primary and metastatic lesions. J Surg Oncol 98 (6): 415-20, 2008. [PUBMED Abstract]
  4. Goorin AM, Harris MB, Bernstein M, et al.: Phase II/III trial of etoposide and high-dose ifosfamide in newly diagnosed metastatic osteosarcoma: a pediatric oncology group trial. J Clin Oncol 20 (2): 426-33, 2002. [PUBMED Abstract]
  5. Chou AJ, Kleinerman ES, Krailo MD, et al.: Addition of muramyl tripeptide to chemotherapy for patients with newly diagnosed metastatic osteosarcoma: a report from the Children’s Oncology Group. Cancer 115 (22): 5339-48, 2009. [PUBMED Abstract]
  6. Smeland S, Bielack SS, Whelan J, et al.: Survival and prognosis with osteosarcoma: outcomes in more than 2000 patients in the EURAMOS-1 (European and American Osteosarcoma Study) cohort. Eur J Cancer 109: 36-50, 2019. [PUBMED Abstract]
  7. Daw NC, Billups CA, Pappo AS, et al.: Malignant fibrous histiocytoma and other fibrohistiocytic tumors in pediatric patients: the St. Jude Children’s Research Hospital experience. Cancer 97 (11): 2839-47, 2003. [PUBMED Abstract]
  8. Yamamoto Y, Kanzaki R, Kanou T, et al.: Long-term outcomes and prognostic factors of pulmonary metastasectomy for osteosarcoma and soft tissue sarcoma. Int J Clin Oncol 24 (7): 863-870, 2019. [PUBMED Abstract]
  9. Slade AD, Warneke CL, Hughes DP, et al.: Effect of concurrent metastatic disease on survival in children and adolescents undergoing lung resection for metastatic osteosarcoma. J Pediatr Surg 50 (1): 157-60; discussion 160, 2015. [PUBMED Abstract]
  10. Letourneau PA, Xiao L, Harting MT, et al.: Location of pulmonary metastasis in pediatric osteosarcoma is predictive of outcome. J Pediatr Surg 46 (7): 1333-7, 2011. [PUBMED Abstract]
  11. Lautz TB, Farooqui Z, Jenkins T, et al.: Thoracoscopy vs thoracotomy for the management of metastatic osteosarcoma: A Pediatric Surgical Oncology Research Collaborative Study. Int J Cancer 148 (5): 1164-1171, 2021. [PUBMED Abstract]
  12. Bacci G, Fabbri N, Balladelli A, et al.: Treatment and prognosis for synchronous multifocal osteosarcoma in 42 patients. J Bone Joint Surg Br 88 (8): 1071-5, 2006. [PUBMED Abstract]
  13. Kager L, Zoubek A, Kastner U, et al.: Skip metastases in osteosarcoma: experience of the Cooperative Osteosarcoma Study Group. J Clin Oncol 24 (10): 1535-41, 2006. [PUBMED Abstract]
  14. Harris MB, Gieser P, Goorin AM, et al.: Treatment of metastatic osteosarcoma at diagnosis: a Pediatric Oncology Group Study. J Clin Oncol 16 (11): 3641-8, 1998. [PUBMED Abstract]
  15. Longhi A, Fabbri N, Donati D, et al.: Neoadjuvant chemotherapy for patients with synchronous multifocal osteosarcoma: results in eleven cases. J Chemother 13 (3): 324-30, 2001. [PUBMED Abstract]
  16. Imran H, Enders F, Krailo M, et al.: Effect of time to resumption of chemotherapy after definitive surgery on prognosis for non-metastatic osteosarcoma. J Bone Joint Surg Am 91 (3): 604-12, 2009. [PUBMED Abstract]
  17. Marina NM, Smeland S, Bielack SS, et al.: Comparison of MAPIE versus MAP in patients with a poor response to preoperative chemotherapy for newly diagnosed high-grade osteosarcoma (EURAMOS-1): an open-label, international, randomised controlled trial. Lancet Oncol 17 (10): 1396-1408, 2016. [PUBMED Abstract]
  18. Tinkle CL, Lu J, Han Y, et al.: Curative-intent radiotherapy for pediatric osteosarcoma: The St. Jude experience. Pediatr Blood Cancer 66 (8): e27763, 2019. [PUBMED Abstract]

Treatment of Recurrent Osteosarcoma and UPS of Bone

Approximately 50% of relapses in patients with recurrent osteosarcoma occur within 18 months of therapy termination, and only 5% of recurrences develop beyond 5 years.[1–4]

Prognostic Factors for Recurrence

Prognostic factors for recurrent osteosarcoma or undifferentiated pleomorphic sarcoma (UPS) of bone include the following:

  • Time from diagnosis. In 564 patients who experienced a recurrence, patients whose disease recurred within 2 years of diagnosis had a worse prognosis than patients whose disease recurred after 2 years.[1] In another series of 431 patients, recurrences occurring less than 2 years from diagnosis were also associated with worse outcomes.[5]
  • Age at initial diagnosis. Older age at initial study enrollment was associated with a worse prognosis after recurrence.[5]
  • Presence of metastatic disease at diagnosis. The presence of metastatic disease at initial presentation was associated with a worse prognosis after recurrence.[5]
  • Tumor response to preoperative chemotherapy. Patients with a good histological response to initial preoperative chemotherapy had a better overall survival (OS) after recurrence than did patients with a poor initial response.[1]
  • Site of metastases. In two large series, the incidence of recurrence by site was as follows: lung only (65%–80%), bone only (8%–10%), local recurrence only (4%–7%), and combined relapse (10%–15%).[4,6] Abdominal metastases are rare but may occur as late as 4 years after diagnosis.[7] The Children’s Oncology Group (COG) reported the outcomes of 431 young patients with recurrent osteosarcoma.[5][Level of evidence C3] Patients with recurrences in both lung and bone had worse outcomes than did patients with recurrences in lung only (P = .005).
  • Surgical resectability. Patients with recurrent osteosarcoma should be assessed for surgical resectability because they may sometimes be cured with aggressive surgical resection with or without chemotherapy.[8,6,9–12]

    Control of osteosarcoma after recurrence depends on complete surgical resection of all sites of clinically detectable metastatic disease. If surgical resection is not attempted or cannot be performed, progression and death are certain. The ability to achieve a complete resection of recurrent disease is the most important prognostic factor at first relapse, with a 5-year survival rate of 20% to 45% after complete resection of metastatic pulmonary tumors and a 20% survival rate after complete resection of metastases at other sites.[4,6,12,13]

Treatment Options for Recurrent Osteosarcoma and UPS of Bone

Treatment options for patients with recurrent osteosarcoma or UPS of bone include the following:

  1. Surgery to remove all sites of metastatic disease.
  2. Chemotherapy and targeted therapy.
  3. Radiopharmaceuticals and radiation therapy.

Surgery

Control of osteosarcoma after recurrence depends on complete surgical resection of all sites of clinically detectable metastatic disease.

A multi-institutional retrospective analysis compared thoracotomy with thoracoscopy for resection of pulmonary metastases in patients with osteosarcoma.[14] The analysis included patients who had pulmonary metastases at diagnosis, patients with pulmonary relapse after initial management of localized disease, and patients with disease progression while on therapy. The authors recognized a significant selection bias for the patients chosen to undergo thoracoscopy. In a Cox regression analysis, controlling for other factors impacting outcome, there was a significantly increased risk of mortality (hazard ratio [HR], 2.11; 95% confidence interval [CI], 1.09–4.09; P = .027) but not pulmonary recurrence (HR, 0.96; 95% CI, 0.52–1.79; P = .90) with a thoracoscopic approach. In a subset analysis limited to patients with oligometastatic disease, thoracoscopy did not increase the risk of mortality (HR, 1.16; 95% CI, 0.64–2.11; P = .62). The ongoing randomized trial (AOST2031 [NCT05235165]) was designed to definitively address this question and the selection bias. This trial will compare the effect of thoracotomy with thoracoscopic surgery.

Chemotherapy and targeted therapy

The role of systemic chemotherapy for the treatment of patients with recurrent osteosarcoma is not well defined. The selection of further systemic treatment depends on many factors, including the site of recurrence, the patient’s previous primary treatment, and individual patient considerations.

Osteosarcoma frequently has a stromal matrix that may further mineralize with tumor necrosis, leaving behind a mass seen on imaging that may or may not have a reduced number of tumor cells within it. Thus, standard Response Evaluation Criteria in Solid Tumors (RECIST) criteria may not be appropriate for evaluation of response to drugs in patients with osteosarcoma. The COG, in an attempt to establish baseline event-free survival (EFS) rates in patients with relapsed osteosarcoma, analyzed the outcomes of these patients from seven single-arm phase II trials. The drugs tested in each trial were determined to be inactive on the basis of radiographic response rates.[15]

  • The EFS rate for 96 patients with osteosarcoma and measurable disease was 12% at 4 months (95% CI, 6%–19%).
  • There was no significant difference in EFS between the trials according to the number of previous treatment regimens or patient age, sex, and ethnicity.

One additional phase II trial with a different study design was reported. In this trial, patients with osteosarcoma and metastases to the lung underwent surgical resection of all lung nodules and then were treated with adjuvant inhaled granulocyte-macrophage colony-stimulating factor (GM-CSF).[15]

  • The 12-month EFS rate for the 42 evaluable patients enrolled in this study was 20% (95% CI, 10%–34%).

The following chemotherapy and targeted therapy agents have been studied to treat recurrent osteosarcoma and UPS of bone:

  • Ifosfamide alone with mesna uroprotection, or in combination with etoposide. Ifosfamide alone with mesna uroprotection, or in combination with etoposide, has been active in as many as one-third of patients with recurrent osteosarcoma who have not previously received this drug.[16–21]
  • Gemcitabine and docetaxel. A nonrandomized comparison of two doses of gemcitabine, both given with docetaxel, suggested that a higher dose of gemcitabine (900 mg/m2) was associated with a better response rate and longer survival than was a lower dose of gemcitabine (675 mg/m2) for patients with recurrent or refractory osteosarcoma.[22][Level of evidence C1] The combination of gemcitabine (at a dose of 900 mg/m2) and docetaxel has also been reported to have activity in some studies that included patients with unresectable disease.[23–25]; [26][Level of evidence C3]
  • Cyclophosphamide and etoposide. Cyclophosphamide and etoposide have been shown to have activity in recurrent osteosarcoma.[23]
  • Sorafenib. The Italian Sarcoma Group reported rare objective responses and disease stabilization with sorafenib in patients with recurrent osteosarcoma.[27]
  • Sorafenib and everolimus. The Italian Sarcoma Group also reported the outcome of patients with metastatic recurrent osteosarcoma treated with the combination of sorafenib and everolimus. They observed two partial responses and two minor responses in 38 patients; 17 of 38 patients were progression free at 6 months from study entry but toxicity was greater than with sorafenib monotherapy.[28][Level of evidence B4]
  • Regorafenib. Two prospective, randomized, double-blind trials have evaluated the role of regorafenib in the treatment of metastatic recurrent osteosarcoma. Both studies used the approved treatment regimen of 160 mg by mouth daily for 21 days followed by 7 days without treatment. The trial conducted in France included patients who were randomly assigned 2:1 between regorafenib and placebo and allowed crossover for patients assigned to placebo.[29] Seventeen of 26 patients (65%; one-sided 95% CI, 47%) in the regorafenib group did not have disease progression at 8 weeks, compared with 0 of 12 patients in the placebo group. The Sarcoma Alliance for Research Collaboration (SARC) group randomly assigned adult patients 1:1 between regorafenib and placebo.[30] Median progression-free survival (PFS) was significantly improved with regorafenib versus placebo: 3.6 months (95% CI, 2.0–7.6 months) versus 1.7 months (95% CI, 1.2–1.8 months), respectively (HR, 0.42; 95% CI, 0.21–0.85; P = .017).
  • Dinutuximab in combination with GM-CSF. The COG performed a phase II study of dinutuximab, an antidisialoganglioside antibody, in combination with GM-CSF for patients with recurrent osteosarcoma. Of 39 patients, 28 experienced an event, and only 28.2% (95% CI, 15%–44.9%) of patients were event-free at the 12-month benchmark. Dinutuximab did not demonstrate sufficient evidence of efficacy.[31]
  • Denosumab. The COG performed a phase II study of denosumab, a fully human monoclonal antibody to the receptor activator of nuclear factor-kappa beta ligand (RANKL). Patients aged 11 to 49 years with recurrent osteosarcoma were eligible for the study. Patients with measurable disease were eligible for cohort 1, and patients who underwent complete surgical resection of all sites of recurrent disease were eligible for cohort 2. The event-free rate did not exceed the historical rate experienced in previous COG trials to meet the study defined efficacy criteria in either cohort.[32]
  • Lenvatinib with ifosfamide and etoposide. A multi-institutional group performed a phase I/II study using a combination of lenvatinib, ifosfamide, and etoposide to treat patients with relapsed or refractory osteosarcoma.[33][Level of evidence B4] The study suggested phase II doses for each drug: 1) 14 mg/m2 per day of lenvatinib (with a daily dose cap of 24 mg), 2) 100 mg/m2 per day of etoposide, and 3) 3,000 mg/m2 per day of ifosfamide. These drugs were given to patients intravenously on days 1 to 3 of each 3-week cycle for five cycles at most. Thirty-five patients from the phase I (cohort 3A; n = 15) and phase II (cohort 3B; n = 20) trials were treated at the recommended phase II doses, and their results were pooled. Eighteen of 35 patients had PFS rates of 51% (95% CI, 34%–69%) after 4 months, per the binomial estimate.
  • Cabozantinib. A phase II clinical trial of this VEGFR2 and MET inhibitor evaluated 43 patients aged 12 years and older with relapsed osteosarcoma, 39 of whom had pulmonary metastases. The 6-month PFS rate was 33%, and five patients (12%) had a partial response.[34]
  • Apatinib. A phase II clinical trial of this VEGFR2 inhibitor enrolled 37 patients aged 16 years and older. Sixteen patients (43%) had a partial response, and the 4-month PFS rate was 57%.[35] In a retrospective review of 19 patients with osteosarcoma who were treated with apatinib, 3 patients had a partial response (16%).[36]
  • Anlotinib. A retrospective analysis reported the efficacy of the multitargeted tyrosine kinase inhibitor anlotinib in patients with recurrent metastatic osteosarcoma.[37] The study included 15 patients who were treated in China between June 2018 and April 2020. The median PFS was 9.8 months (± 0.9 months). The 6-month PFS rate was 73%, and the 10-month PFS rate was 33%. The median OS was 11.4 months (± 0.6 months). No patients achieved complete responses.
  • Immunotherapy. Osteosarcoma frequently expresses PD-1, but trials of PD-1 inhibitors have been disappointing.[38–40] In these three studies, objective responses were observed in 1 of 14, 0 of 10, and 1 of 19 patients. HER2-expressing chimeric antigen receptor (CAR) T-cell therapy is also being studied.[41]
  • High-dose chemotherapy with autologous hematopoietic stem cell transplant (HSCT). A study analyzed the addition of high-dose chemotherapy with autologous HSCT to treat Korean patients with relapsed osteosarcoma who achieved a complete response to salvage therapy.[42] Among 25 patients who achieved a complete response with salvage therapy, 15 were assigned to receive high-dose chemotherapy with autologous HSCT by investigator choice. In a subgroup analysis of outcomes in patients who achieved a complete response, there were no significant differences in the 5-year OS rates between patients who did and did not receive high-dose chemotherapy with autologous HSCT (83.9% ± 0.1% for 13 of 15 patients vs. 80.0% ± 0.1% for 8 of 10 patients, respectively; P = .923).

Radiopharmaceuticals and radiation therapy

High-dose samarium Sm 153-ethylenediamine tetramethylene phosphonic acid (153Sm-EDTMP) coupled with peripheral blood stem cell support may provide significant pain palliation in patients with bone metastases.[43–46] Toxicity of 153Sm-EDTMP is primarily hematologic.[47][Level of evidence C2]

A single-institution retrospective review reported that high-dose fraction radiation therapy (2 Gy/fraction) was a useful form of palliation for patients with recurrent osteosarcoma.[48][Level of evidence C3] Thirty-two courses of palliative radiation therapy were given to 20 patients with symptomatic metastatic and/or locally recurrent primary disease. Twenty-four of the 32 courses (75%) were associated with symptom improvement. Higher doses of radiation therapy correlated with longer durations of symptom response.

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.[49]

Treatment Options for Local Recurrence

Treatment options for patients with osteosarcoma or UPS of bone that has recurred locally include the following:

  1. Surgery to remove the tumor.

The postrelapse outcome of patients who have a local recurrence is quite poor.[50–52] Survival of patients with local recurrences and either previous or concurrent systemic metastases is poor.[53]

Two retrospective, single-institution series reported a survival rate of 10% to 40% after local recurrence without associated systemic metastasis.[53–56]

A retrospective review from the Italian Sarcoma Group identified 62 patients (median age, 21 years) with local recurrences.[57] With a median follow-up of 43 months (range, 5–235 months), the 5-year post–local relapse survival rate was 37%, significantly better for patients with a longer local recurrence–free interval (≤24 months, 31% vs. >24 months, 61.5%; P = .03), absence of distant metastases (no distant metastases, 56% vs. distant metastases, 11.5%; P = .0001), and achievement of second complete remission (CR) by surgical resection (no second CR, 0% vs. second CR, 58.5%; P = .0001). No difference in post–local relapse survival was found according to age, and there was no benefit from chemotherapy administration.

The incidence of local relapse was higher in patients who had a poor pathological response to chemotherapy in the primary tumor and in patients with inadequate surgical margins.[50,55]

Treatment Options for Lung-Only Recurrence

Treatment options for patients with osteosarcoma and UPS of bone that has recurred in the lung only include the following:

  1. Surgery to remove the tumor.
  2. Chemotherapy or targeted therapy. For more information, see the Chemotherapy and targeted therapy section.
  3. Radiation therapy.

Repeated resections of pulmonary recurrences can lead to extended disease control and, possibly, cure for some patients.[13,58] The survival rate is less than 5% for patients with unresectable metastatic disease.[6,59] The 5-year EFS rate ranges from 20% to 45% for patients who have complete surgical resection of all pulmonary metastases.[4,12,13]; [60][Level of evidence C1]

Factors associated with a better outcome include the following:[4,6,61–63]

  • Fewer pulmonary nodules.
  • Unilateral pulmonary metastases.
  • Longer intervals between primary tumor resection and metastases.
  • Tumor location in the periphery of the lung.

Approximately 50% of patients with one isolated pulmonary lesion more than 1 year after diagnosis were long-term survivors after metastasectomy. Chemotherapy did not appear to offer an advantage.[64][Level of evidence C1]

Control of osteosarcoma requires surgical resection of all macroscopic tumors. However, recommendations are conflicting regarding the surgical approach to the treatment of pulmonary metastases in osteosarcoma. Several options are available to resect pulmonary nodules in a patient with osteosarcoma, including thoracoscopy and thoracotomy with palpation of the collapsed lung. When patients have nodules identified only in one lung, some surgeons advocate thoracoscopy, some advocate unilateral thoracotomy, and some advocate bilateral thoracotomy. Bilateral thoracotomy can be performed as a single surgical procedure with a median sternotomy or a clamshell approach, or by staged bilateral thoracotomies.

Evidence (surgical approach for lung-only recurrence of osteosarcoma and UPS of bone):

  1. The St. Jude Children’s Research Hospital reported on 81 patients who had pulmonary nodules identified at initial presentation in only one lung by computed tomography (CT) scan.[65] They performed unilateral thoracotomy and did not explore the contralateral hemithorax. At the time of thoracotomy, 44 of 81 patients had a solitary nodule identified; 15 of 81 patients had two nodules identified; 16 of 81 patients had three to five nodules identified; and 6 of 81 patients had more than five nodules identified. Additional patients who were considered unresectable were not included in the analysis.
    • Thirty-nine of 81 patients had subsequent pulmonary recurrence; for most patients, recurrence occurred within 6 months.
    • Within the first 6 months, 9 of 81 patients had ipsilateral recurrence, and 10 of 81 patients had a contralateral recurrence. By 2 years after initial thoracotomy, 13 of 81 patients had ipsilateral recurrence; 19 of 81 patients had contralateral recurrence; and 2 of 81 patients had bilateral recurrence.
    • OS was similar for patients with ipsilateral and bilateral recurrence.
  2. The Memorial Sloan Kettering Cancer Center reported on pulmonary metastatic disease recurrence after initial therapy for osteosarcoma. Fourteen patients had pulmonary nodules identified in only one lung by CT scan. Nine patients were identified less than 2 years from initial diagnosis (early metastases), and five patients were identified more than 2 years from initial diagnosis (late metastases).[62] Seven of nine patients with early metastases had staged contralateral thoracotomies, and six of seven had nodules removed from the contralateral lung, despite negative CT scan findings.
    • The lack of a comparison group precludes evaluation of the impact of the contralateral thoracotomy on subsequent EFS or OS.
    • The same group expanded their analysis to include a retrospective review of 161 thoracotomies performed in 88 patients with osteosarcoma metastatic to the lung.[66] In this expanded series, CT failed to identify one-third of pulmonary metastases confirmed by pathological examination.

The COG is conducting a randomized trial (AOST2031 [NCT05235165]) to compare the effect of thoracotomy with thoracoscopic surgery to remove lung metastases. For more information, see the Treatment Options Under Clinical Evaluation section.

External-beam radiation therapy can provide local control of recurrent unresectable disease, symptomatic, and/or metastatic disease. Radiation therapy techniques allow for the delivery of very conformal high doses, known as stereotactic ablative radiation therapy (SABR) or stereotactic body radiation therapy (SBRT). SBRT and SABR administer treatment with high conformality and precision over a short period of time, providing good palliation and local control.[67]

Treatment Options for Recurrence With Bone-Only Metastases

Treatment options for patients with osteosarcoma or UPS of bone that has recurred in the bone only include the following:

  1. Surgery to remove the tumor.
  2. 153Sm-EDTMP with or without stem cell support.
  3. Chemotherapy or targeted therapy. For more information, see the Chemotherapy and targeted therapy section.
  4. Radiation therapy.

Patients with osteosarcoma who develop bone metastases have a poor prognosis. In one large series, the 5-year EFS rate was 11%.[68] Patients with late solitary bone relapse have a 5-year EFS rate of approximately 30%.[68–71]

For patients with multiple unresectable bone lesions, 153Sm-EDTMP with or without stem cell support may produce stable disease and/or provide pain relief.[47]

External-beam radiation therapy can provide local control of recurrent unresectable disease, symptomatic, and/or metastatic disease. Radiation therapy techniques allow for the delivery of very conformal high doses, known as SABR or SBRT. SBRT and SABR administer treatment with high conformality and precision over a short period of time, providing good palliation and local control.[67]

Treatment Options for Second Recurrence of Osteosarcoma

Treatment options for patients with osteosarcoma or UPS of bone that has recurred twice include the following:

  1. Surgery to remove the tumor and/or chemotherapy.
  2. Chemotherapy or targeted therapy. For more information, see the Chemotherapy and targeted therapy section.

Evidence (surgery and/or chemotherapy):

  1. The cooperative German-Austrian-Swiss osteosarcoma study group reported on 249 patients who had a second recurrence of osteosarcoma. The main therapy was repeated surgical resection of recurrent disease.[72]
    • Of these patients, 197 died and 37 were alive in CR (24 patients after a third complete response and 13 patients after a fourth or subsequent complete response).
    • Fifteen patients who did not achieve surgical remission remained alive, but follow-up for these patients was extremely short.
  2. The Spanish Group for Research on Sarcoma reported the results of a phase II trial of patients with relapsed or refractory osteosarcoma who were treated with gemcitabine and sirolimus.[73][Level of evidence C3]
    • The PFS rate at 4 months was 44%.
    • After central radiological review of 33 assessable patients, 2 partial responses and 14 disease stabilizations (48.5%) were reported.
  3. The COG reported the outcomes of patients with recurrent osteosarcoma from seven phase II trials, all of which were assessed to have shown no treatment benefit.[15]
    • The EFS rate for 96 patients with osteosarcoma and measurable disease was 12% at 4 months (95% CI, 6%–19%).
    • There was no significant difference in EFS between the trials according to the number of previous treatment regimens or patient age, sex, and ethnicity.
  4. One additional phase II trial with a different study design was reported. In this trial, patients with osteosarcoma and metastases to the lung underwent surgical resection of all lung nodules and then were treated with adjuvant inhaled GM-CSF.[15]
    • The 12-month EFS rate for the 42 evaluable patients enrolled in this study was 20% (95% CI, 10%–34%).

Treatment Options Under Clinical Evaluation

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 are examples of national and/or institutional clinical trials that are currently being conducted:

  • GD2-CAR PERSIST (NCT04539366) (Testing a New Immune Cell Therapy, GD2-Targeted Modified T-cells (GD2CART), in Children, Adolescents, and Young Adults with Relapsed/Refractory Osteosarcoma and Neuroblastoma): This is a phase I trial to determine the side effects and best dose of GD2CART to be effective against GD2-positive tumor cells.
  • AOST2031 (NCT05235165) (Thoracotomy Versus Thoracoscopic Management of Pulmonary Metastases in Patients With Osteosarcoma): This phase III trial compares the effect of thoracotomy with thoracoscopic surgery (video-assisted thoracoscopic surgery) in treating patients with osteosarcoma that has spread to the lung (pulmonary metastases). This trial is being done to evaluate the two different surgery methods for these patients and to determine which procedure is better.
  • NCT03811886 (Natalizumab for the Treatment of Recurrent, Refractory, or Progressive Pulmonary Metastatic Osteosarcoma): This is a phase I/II trial evaluating the safety of and response to natalizumab for patients with lung metastases that have progressed, relapsed, or become refractory to systemic therapy.

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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  34. Italiano A, Mir O, Mathoulin-Pelissier S, et al.: Cabozantinib in patients with advanced Ewing sarcoma or osteosarcoma (CABONE): a multicentre, single-arm, phase 2 trial. Lancet Oncol 21 (3): 446-455, 2020. [PUBMED Abstract]
  35. Xie L, Xu J, Sun X, et al.: Apatinib for Advanced Osteosarcoma after Failure of Standard Multimodal Therapy: An Open Label Phase II Clinical Trial. Oncologist 24 (7): e542-e550, 2019. [PUBMED Abstract]
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  47. Loeb DM, Garrett-Mayer E, Hobbs RF, et al.: Dose-finding study of 153Sm-EDTMP in patients with poor-prognosis osteosarcoma. Cancer 115 (11): 2514-22, 2009. [PUBMED Abstract]
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Latest Updates to This Summary (12/02/2024)

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.

General Information About Osteosarcoma and Undifferentiated Pleomorphic Sarcoma (UPS) (Formerly Called Malignant Fibrous Histiocytoma [MFH]) of Bone

Added Impact of time on prognostic factors as a new subsection.

Added Bielack et al. as reference 54.

Treatment of Localized Osteosarcoma and UPS of Bone

Added text about the results of a French Sarcoma Group trial that omitted high-dose methotrexate for adult patients with osteosarcoma (cited Blay et al. as reference 35).

Treatment of Recurrent Osteosarcoma and UPS of Bone

Added Tirtei et al. as reference 21.

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 osteosarcoma and undifferentiated pleomorphic sarcoma of bone. 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 Osteosarcoma and Undifferentiated Pleomorphic Sarcoma of Bone Treatment are:

  • Holcombe Edwin Grier, MD
  • Karen J. Marcus, MD, FACR (Dana-Farber of Boston Children’s Cancer Center and Blood Disorders Harvard Medical School)
  • William H. Meyer, MD
  • Paul A. Meyers, MD (Memorial Sloan-Kettering Cancer Center)
  • Thomas A. Olson, MD (Aflac Cancer and Blood Disorders Center of Children’s Healthcare of Atlanta – Egleston Campus)
  • Nita Louise Seibel, MD (National Cancer Institute)
  • 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.

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The preferred citation for this PDQ summary is:

PDQ® Pediatric Treatment Editorial Board. PDQ Osteosarcoma and Undifferentiated Pleomorphic Sarcoma of Bone Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/bone/hp/osteosarcoma-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389179]

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Ewing Sarcoma and Undifferentiated Small Round Cell Sarcomas of Bone and Soft Tissue Treatment (PDQ®)–Health Professional Version

Ewing Sarcoma and Undifferentiated Small Round Cell Sarcomas of Bone and Soft Tissue Treatment (PDQ®)–Health Professional Version

General Information About Ewing Sarcoma and Undifferentiated Small Round Cell Sarcomas of Bone and Soft Tissue

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Dramatic 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] For Ewing sarcoma, the 5-year survival rate has increased from 59% to a range of 80% to 85% for children younger than 15 years and from 20% to 69% for adolescents aged 15 to 19 years.[1,2]

Studies using immunohistochemical markers,[4] cytogenetics,[5,6] molecular genetics, and tissue culture [7] indicate that Ewing sarcoma originates from a primordial bone marrow–derived mesenchymal stem cell.[8,9] Older terms such as peripheral primitive neuroectodermal tumor, Askin tumor (Ewing sarcoma of chest wall), and extraosseous Ewing sarcoma (often combined in the term Ewing sarcoma family of tumors) refer to this same tumor.

The World Health Organization (WHO) classification of tumors of soft tissue and bone was modified in 2020 to introduce a new chapter on undifferentiated small round cell sarcomas of bone and soft tissue. This WHO chapter consists of Ewing sarcoma and three main categories, including round cell sarcomas with EWSR1::non-ETS fusions, CIC-rearranged sarcoma, and sarcomas with BCOR genetic alterations.[10]

Before the widespread availability of genomic testing, Ewing sarcoma was identified by the appearance of small, round, blue cells on light microscopic examination, along with positive staining for CD99 by immunohistochemistry. The identification of the recurring t(11;22) translocation in most Ewing sarcoma tumors led to the discovery that most tumors classified as Ewing sarcoma had a translocation that juxtaposed a portion of the EWSR1 gene to a portion of a gene in the ETS family, resulting in a transforming transcript. Not all undifferentiated small round cell sarcomas of bone and soft tissue have such a translocation. Further research identified additional genetic changes, including tumors with translocations of the CIC gene or the BCOR gene. These groups of tumors occur much less frequently than Ewing sarcoma, and data on these patients are based on smaller sample sizes and less homogeneous treatment; therefore, patient outcomes are harder to quantify with precision. Most of these tumors have been treated with regimens designed for Ewing sarcoma, and the consensus was that they were often included in clinical trials for the treatment of Ewing sarcoma, sometimes referred to as translocation-negative Ewing sarcoma. It is now agreed that these tumors are sufficiently different from Ewing sarcoma and that they should be stratified and analyzed separately from Ewing sarcoma, even if they are treated with similar therapy. In this summary, these tumors are described separately. For more information about these smaller groups of tumors, see the following sections:

Incidence

In the United States between 2016 and 2020, the National Childhood Cancer Registry (NCCR) reported an incidence rate of Ewing sarcoma and related sarcomas of bone of 3.0 cases per 1 million in children and adolescents younger than 20 years.[2] This incidence is unchanged from that reported between 1973 and 2004.[11] The incidence rates by age groups in the U.S. pediatric population for Ewing sarcoma and related sarcomas of bone are shown in Table 1 and Figure 1. While well-characterized cases of Ewing sarcoma in neonates and infants have been described, the incidence is low in infants and young children and then increases in adolescents.[12,13]

Table 1. 5-Year Age-Adjusted Incidence Rates for Ewing Sarcoma by Age (2016–2020)a
Age (years) Rate per 1,000,000 95% Confidence Interval
aSource: National Childhood Cancer Registry (NCCR) Explorer.[2]
<1 0.5 0.2–1.1
1–4 1 0.7–1.3
5–9 2.3 1.9–2.6
10–14 4.3 3.9–4.9
15–19 4.5 4.0–5.0
EnlargeGraph showing the incidence rates of Ewing tumor and related sarcomas of bone by age at diagnosis in the National Childhood Cancer Registry from 2016 to 2020.
Figure 1. Incidence rates of Ewing tumor and related sarcomas of bone by age at diagnosis in the National Childhood Cancer Registry (NCCR) from 2016 to 2020. Credit: NCCR*Explorer: An interactive website for NCCR cancer statistics [Internet]. National Cancer Institute; 2023 Sep 7. [updated: 2023 Sep 8; cited 2024 Sep 4]. Available from: https://nccrexplorer.ccdi.cancer.gov.

The incidence of Ewing sarcoma in the United States is nine times greater in White people than in Black people, with an intermediate incidence in Asian people.[14,15] The relative paucity of Ewing sarcoma in people of African or Asian descent may be explained, in part, by a specific polymorphism in the EGR2 gene.[16]

Based on data from 1,426 patients entered on European Intergroup Cooperative Ewing Sarcoma Studies, 59% of patients are male and 41% are female.[17] These results match the 58%-to-42% male-to-female distribution in the United States (age <20 years) in the NCCR dataset (3.5 and 2.5 cases per million incidence rate for males and females, respectively).[2]

Genetic Predisposition to Ewing Sarcoma

Conventional understanding of translocation-driven sarcoma such as Ewing sarcoma suggests that these patients do not have a genetic predisposition.[18] A retrospective European-focused and panancestry case-controlled analysis was performed. The purpose of this study was to screen for enrichment of pathogenic germline variants in 141 known cancer predisposition genes in 1,147 pediatric patients diagnosed with sarcomas (226 Ewing sarcomas, 438 osteosarcomas, 180 rhabdomyosarcomas, and 303 other sarcomas), and compared the results to identically processed cancer-free control individuals. A distinct pattern of pathogenic germline variants was seen in Ewing sarcoma compared with other sarcoma types. FANCC was the only gene with an enrichment signal for heterozygous pathogenic variants in the European Ewing sarcoma discovery cohort (three individuals; odds ratio [OR], 12.6; 95% confidence interval [CI], 3.0–43.2; P = .003; false discovery rate, 0.40). This enrichment in FANCC heterozygous pathogenic variants was again observed in the European Ewing sarcoma validation cohort (three individuals; OR, 7.0; 95% CI, 1.7–23.6; P = .014).

Genome-wide association studies have identified susceptibility loci for Ewing sarcoma at 1p36.22, 10q21, and 15q15.[16,19,20] Deep sequencing through the 10q21.3 region identified a polymorphism in the EGR2 gene, which appears to cooperate with and magnify the enhanced activity of the gene product of the EWSR1::FLI1 fusion gene that is seen in most patients with Ewing sarcoma.[16] The polymorphism associated with the increased risk is found at a much higher frequency in White people than in Black or Asian people, possibly contributing to the epidemiology of the relative infrequency of Ewing sarcoma in the latter populations. Three new susceptibility loci have been identified at 6p25.1, 20p11.22, and 20p11.23.[20]

Clinical Presentation

Clinical presentation of Ewing sarcoma varies and depends on the tumor’s size and location.

Primary sites of bone disease are listed in Table 2.[21]

Table 2. Incidence Rates of Primary Sites of Bone Disease
Primary Site Incidence Rate
Skull 5%
Spine 7%
Rib 11%
Sternum, scapula, and clavicle 5%
Humerus 7%
Radius, ulna, hand 2%
Pelvis 18%
Femur 11%
Tibia, fibula, patella, foot 14%
Soft tissue 19%

The time from the first symptom to diagnosis of Ewing sarcoma is often long, with a median interval reported from 2 to 5 months. Longer times are associated with older age and pelvic primary sites. Time from the first symptom to diagnosis has not been associated with metastasis, surgical outcome, or survival.[22]

Approximately 25% of patients with Ewing sarcoma have metastatic disease at the time of diagnosis, with lung, bone, and bone marrow being the most common metastatic sites.[11]

A retrospective analysis examined patients treated on two Children’s Oncology Group (COG) studies, INT-0154 and AEWS0031 (NCT00006734). This study compared the clinical characteristics of 213 patients with extraskeletal primary Ewing sarcoma with those of 826 patients with primary Ewing sarcoma of bone.[23] Patients with extraskeletal tumors were more likely to be non-White, have axial primary tumors, and have smaller tumors than patients with primary Ewing sarcoma of bone.

The Surveillance, Epidemiology, and End Results (SEER) Program database was used to compare patients younger than 40 years with Ewing sarcoma who presented with skeletal and extraosseous primary sites (see Table 3).[24] Patients with extraosseous Ewing sarcoma were more likely to be older, female, of non-White race, and have axial primary sites, and they were less likely to have pelvic primary sites than were patients with skeletal Ewing sarcoma.

Table 3. Characteristics of Patients With Extraosseous Ewing Sarcoma and Skeletal Ewing Sarcomaa
Characteristic Extraosseous Ewing Sarcoma Skeletal Ewing Sarcoma P Value
aAdapted from Applebaum et al.[24]
Mean age (range), years 20 (0–39) 16 (0–39) <.001
Male 53% 63% <.001
White race 85% 93% <.001
Axial primary sites 73% 54% <.001
Pelvic primary sites 20% 27% .001

Diagnostic Evaluation

The following tests and procedures may be used to diagnose or stage Ewing sarcoma:

  • Physical examination and history.
  • Magnetic resonance imaging (MRI) of primary tumor site.
  • Computed tomography (CT) scan of chest.
  • Positron emission tomography (PET) scan.
  • Bone scan. Bone scan was traditionally routinely performed on all patients with Ewing sarcoma for staging. However, many investigators believe that the PET scan can replace the bone scan.[25,26]
  • Bone marrow aspiration and biopsy.
  • X-ray of primary bone sites.
  • Complete blood count.
  • Blood chemistry studies, such as lactate dehydrogenase (LDH).

Skip metastasis evaluation is important for primary appendicular bone tumors. Thus, imaging of the entire involved bone is standardly performed. In one retrospective study, skip metastasis was seen in 15.8% of patients. The presence of skip metastasis was associated with an increased risk of distant metastatic disease.[27]

Omission of bone marrow biopsy and aspiration may be considered, when fluorine F 18-fludeoxyglucose (18F-FDG) PET imaging is used, in patients with otherwise localized disease after initial staging studies. A systematic review of Ewing sarcoma studies was performed to assess the incidence of bone marrow metastasis and the role of 18F-FDG PET imaging to detect bone marrow metastasis.[28] The review reported a pooled incidence of bone marrow metastasis of 4.8% in all patients with newly diagnosed Ewing sarcoma and 17.5% in patients with metastatic disease. Only 1.2% of patients had bone marrow metastasis as their sole metastatic site. Compared with bone marrow biopsy and aspiration, 18F-FDG PET detection of bone marrow metastasis demonstrated pooled 100% sensitivity and 96% specificity, positive predictive value of 75%, and negative predictive value of 100%. For more information about diagnostic biopsy, see the Treatment Option Overview for Ewing Sarcoma section.

Prognostic Factors

The two major types of prognostic factors for patients with Ewing sarcoma are grouped as follows:

Pretreatment factors

  • Metastases: The presence or absence of metastatic disease is the single most powerful predictor of outcome. Any metastatic disease defined by standard imaging techniques or bone marrow aspirate/biopsy by morphology is an adverse prognostic factor. Metastases at diagnosis are detected in about 25% of patients.[11]

    Patients with metastatic disease confined to the lung have a better prognosis than patients with extrapulmonary metastatic sites.[29–32] The number of pulmonary lesions does not seem to correlate with outcome, but patients with unilateral lung involvement have a better prognosis than patients with bilateral lung involvement.[33]

    Patients with metastasis to only bone seem to have a better outcome than patients with metastases to both bone and lung.[34,35]

    Based on an analysis from the SEER database, regional lymph node involvement in patients is associated with an inferior overall outcome when compared with patients without regional lymph node involvement.[36]

  • Site of tumor: Patients with Ewing sarcoma in the distal extremities have more favorable outcomes. Patients with Ewing sarcoma in the proximal extremities have an intermediate prognosis, followed by patients with central or pelvic sites.[29,31,32,37] However, a trial from the COG showed similar outcomes for patients with pelvic primary tumors compared with other sites.[21]

    One study retrospectively analyzed a single-institution’s experience with visceral Ewing sarcoma. The study focused on surgical management and compared the outcomes of patients with visceral Ewing sarcoma with those of patients with osseous and soft tissue Ewing sarcoma.[38] There were 156 patients with Ewing sarcoma identified: 117 osseous Ewing sarcomas, 20 soft tissue Ewing sarcomas, and 19 visceral Ewing sarcomas. Visceral Ewing sarcomas arose in the kidneys (n = 5), lungs (n = 5), intestines (n = 2), esophagus (n = 1), liver (n = 1), pancreas (n = 1), adrenal gland (n = 1), vagina (n = 1), brain (n = 1), and spinal cord (n = 1). Visceral Ewing sarcoma was more frequently metastatic at presentation (63.2%; P = .005). However, there was no significant difference in overall survival (OS) or relapse-free survival among the Ewing sarcoma groups, with similar follow-up intervals.

  • Extraskeletal versus skeletal primary tumors: The COG performed a retrospective analysis from two large cooperative trials that used similar treatment regimens.[23] They identified 213 patients with extraskeletal primary tumors and 826 patients with skeletal primary tumors. Patients with extraskeletal primary tumors were more likely to have an axial primary site, less likely to have large primary tumors, and had a statistically significant better prognosis than did patients with skeletal primary tumors.
  • Tumor size or volume: Most studies have shown that tumor size or volume is an important prognostic factor. Cutoffs of a volume of 100 mL or 200 mL and/or single dimension greater than 8 cm are used to define larger tumors. Larger tumors tend to occur in unfavorable sites.[31,32,39]
  • Age: Younger patients generally have a better prognosis than older patients, as noted in the following studies:[13,29,32,37,40–42]
    • In North American studies, patients younger than 10 years had a better outcome than those aged 10 to 17 years at diagnosis (relative risk [RR], 1.4). Patients older than 18 years had an inferior outcome (RR, 2.5).[43–45]
    • A retrospective review of two consecutive German trials for Ewing sarcoma identified 47 patients older than 40 years.[46] With adequate multimodal therapy, survival was comparable to the survival observed in adolescents treated on the same trials.
    • Review of the SEER database from 1973 to 2011 identified 1,957 patients with Ewing sarcoma.[47] Thirty-nine of these patients (2.0%) were younger than 12 months at diagnosis. Infants were less likely to receive radiation therapy and more likely to have soft tissue primary sites. Early death was more common in infants, but the OS did not differ significantly from that of older patients.
    • A European retrospective review identified 2,635 patients with Ewing sarcoma of bone.[48] Sites of primary and metastatic tumors differed according to the age groups of young children (0–9 years), early adolescence (10–14 years), late adolescence (15–19 years), young adults (20–24 years), and adults (older than 24 years). Young children had the most striking differences in site of disease, with a lower proportion of pelvic primary and axial tumors. Young children also presented less often with metastatic disease at diagnosis.
  • Sex: Females with Ewing sarcoma have a better prognosis than males with Ewing sarcoma.[14,32,37]
  • Serum LDH: Increased serum LDH levels before treatment are associated with inferior prognosis. Increased LDH levels are also associated with large primary tumors and metastatic disease.[37]
  • Pathological fracture: A single-institution retrospective analysis of 78 patients with Ewing sarcoma suggested that pathological fracture at initial presentation was associated with inferior event-free survival (EFS) and OS.[49][Level of evidence C1] Another study found that pathological fracture at the time of diagnosis did not preclude surgical resection and was not associated with an adverse outcome.[50]
  • Previous treatment for cancer: In the SEER database, 58 patients with Ewing sarcoma were diagnosed after treatment for a previous malignancy (2.1% of patients with Ewing sarcoma). These patients were compared with 2,756 patients with Ewing sarcoma as a first cancer over the same period. Patients with Ewing sarcoma as a second malignant neoplasm were older (secondary Ewing sarcoma, mean age of 47.8 years; primary Ewing sarcoma, mean age of 22.5 years), more likely to have a primary tumor in an axial or extraskeletal site, and had a worse prognosis (5-year OS rates of 43.5% for patients with secondary Ewing sarcoma and 64.2% for patients with primary Ewing sarcoma).[51]
  • Chromosomal alterations:
    • Complex karyotype (defined as the presence of five or more independent chromosome abnormalities at diagnosis) and modal chromosome numbers lower than 50 appear to have adverse prognostic significance.[52]
    • Gain of chromosome 1q and/or deletion of chromosome 16q has been associated with inferior prognosis for patients with Ewing sarcoma in several cohorts.[53–55] These two chromosomal alterations commonly occur together across a range of cancer types, including Ewing sarcoma.[56] Their co-occurrence is likely a result of their derivation from an unbalanced t(1;16) translocation resulting in gain of chromosome 1q together with loss of chromosomal material from 16q.[57,58]
  • Detectable Ewing sarcoma cells, fusion transcripts, or circulating tumor DNA (ctDNA) in peripheral blood: Several techniques to evaluate the presence of Ewing sarcoma in the peripheral blood have been proposed. Flow cytometry for cells that express the CD99 antigen was not sufficiently sensitive to serve as a reliable biomarker.[59,60] Reverse transcriptase–polymerase chain reaction (RT-PCR) for the EWSR1::FLI1 translocation was also not considered a reliable biomarker.[61]

    A more sensitive technique used patient-specific primers designed after identification of the specific translocation breakpoint in combination with droplet digital PCR to detect the EWSR1 fusion. This technique reported a sensitivity threshold of 0.009% to 0.018%.[62] Levels of circulating cell-free DNA were higher in patients with metastatic disease than in patients with localized disease.

    A next-generation sequencing hybrid capture assay and an ultra-low-pass whole-genome sequencing assay were used to detect the EWSR1 fusion in ctDNA in banked plasma from patients with Ewing sarcoma. Among patients with newly diagnosed localized Ewing sarcoma, detectable ctDNA was associated with inferior 3-year EFS rates (48.6% vs. 82.1%; P = .006) and OS rates (79.8% vs. 92.6%; P = .01).[63]

    ctDNA was separately assayed by digital-droplet PCR in 102 patients who were treated in the EWING2008 (NCT00987636) trial.[64] Pretreatment ctDNA copy numbers correlated with EFS and OS. A reduction in ctDNA levels below the detection limit was observed in most patients after only two blocks of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) induction chemotherapy. The persistence of ctDNA after two blocks of VIDE was a strong predictor of poor outcomes.

  • Detectable fusion transcripts in morphologically normal marrow: RT-PCR can be used to detect fusion transcripts in bone marrow. In a single retrospective study using patients with normal marrow morphology and no other metastatic site, fusion transcript detection in marrow or peripheral blood was associated with an increased risk of relapse.[60] However, a larger cohort (n = 225) of patients with localized Ewing sarcoma did not show a difference in EFS or OS based on the detection of fusion transcripts in blood or bone marrow.[65]
  • Gene alterations: A prospective analysis of TP53 variants and/or CDKN2A deletions was done in patients with Ewing sarcoma enrolled on COG clinical trials. The analysis found no association of these alterations with EFS.[66]

    In a study of 299 patients with Ewing sarcoma, 41 patients (14%) had STAG2 variants and 16 patients (5%) had TP53 variants.[55] There was no association with OS for patients with either the STAG2 or TP53 variant alone. However, the nine patients (3%) with tumors that had both STAG2 and TP53 variants had a significantly decreased OS rate (<20% at 4 years).

    The COG analyzed STAG2 expression by immunohistochemistry in children with Ewing sarcoma who participated in frontline treatment trials.[67] STAG2 was lost in 29 of 108 patients with localized disease and in 6 of 27 patients with metastatic disease. Among patients who had immunohistochemistry and sequencing performed, no cases (0 of 17) with STAG2 expression had STAG2 variants, and 2 of 7 cases with STAG2 loss had STAG2 variants. Among patients with localized disease, the 5-year EFS rate was 54% (95% CI, 34%–70%) for those with STAG2 loss, compared with 75% (95% CI, 63%–84%) for those with STAG2 expression (P = .0034).

The following are not considered to be adverse prognostic factors for Ewing sarcoma:

  • Histopathology: The degree of neural differentiation is not a prognostic factor in Ewing sarcoma.[68,69]
  • Fusion subtype: The EWSR1::ETS translocation associated with Ewing sarcoma can occur at several potential breakpoints in each of the genes that join to form the novel segment of DNA. Once thought to be significant,[70] two large series have shown that the EWSR1::ETS translocation breakpoint site is not an adverse prognostic factor.[71,72]

Response to initial therapy factors

Multiple studies have shown that patients with minimal or no residual viable tumor after presurgical chemotherapy have a significantly better EFS than do patients with larger amounts of viable tumor.[21,73–76]; [77][Level of evidence C2] In particular, patients with localized disease who have no viable tumor seen at the time of local-control surgery appear to have markedly favorable outcomes.[21]; [77][Level of evidence C2] Female sex and younger age predict a good histological response to preoperative therapy.[78] For patients who receive preinduction- and postinduction-chemotherapy PET scans, decreased PET uptake after chemotherapy correlated with good histological response and better outcome.[79–81]

Patients with poor response to presurgical chemotherapy have an increased risk of local recurrence.[82]

A retrospective analysis of risk factors for recurrence was performed in patients who received initial chemotherapy and underwent surgical resection of the primary tumor.[83][Level of evidence C1] Among 982 patients with a median follow-up of 7.6 years, the following was reported:

  • Adverse risk factors for local recurrence were pelvic primary tumors (hazard ratio [HR], 2.04; 95% CI, 1.10–3.80) and marginal/intralesional resection (HR, 2.28; 95% CI, 1.25–4.16). The addition of radiation therapy was associated with improved outcome (HR, 0.52; 95% CI, 0.28–0.95).
  • Adverse risk factors for developing new pulmonary metastasis were less than 90% necrosis (HR, 2.13; 95% CI, 1.13–4.00) and previous pulmonary metastasis (HR, 4.90; 95% CI, 2.28–8.52).
  • Adverse risk factors for death included pulmonary metastasis (HR, 8.08; 95% CI, 4.01–16.29), bone or other metastasis (HR, 10.23; 95% CI, 4.90–21.36), and less than 90% necrosis (HR, 6.35; 95% CI, 3.18–12.69).
  • Early local recurrence (0–24 months) negatively influenced survival (HR, 3.79; 95% CI, 1.34–10.76).

In a retrospective cohort of 148 patients with pulmonary metastatic Ewing sarcoma, 41.2% had radiographic resolution of lung nodules after initial induction chemotherapy.[84] These patients had superior OS compared with patients who had residual nodules at end-induction (71.2% vs. 50.2% at 5 years). Particularly favorable outcomes were seen in the patients who had early clearance of lung nodules and received consolidative whole-lung radiation therapy (5-year OS rate, 85.2%).

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  41. Huh WW, Daw NC, Herzog CE, et al.: Ewing sarcoma family of tumors in children younger than 10 years of age. Pediatr Blood Cancer 64 (4): , 2017. [PUBMED Abstract]
  42. Ahmed SK, Randall RL, DuBois SG, et al.: Identification of Patients With Localized Ewing Sarcoma at Higher Risk for Local Failure: A Report From the Children’s Oncology Group. Int J Radiat Oncol Biol Phys 99 (5): 1286-1294, 2017. [PUBMED Abstract]
  43. Grier HE, Krailo MD, Tarbell NJ, et al.: Addition of ifosfamide and etoposide to standard chemotherapy for Ewing’s sarcoma and primitive neuroectodermal tumor of bone. N Engl J Med 348 (8): 694-701, 2003. [PUBMED Abstract]
  44. Granowetter L, Womer R, Devidas M, et al.: Dose-intensified compared with standard chemotherapy for nonmetastatic Ewing sarcoma family of tumors: a Children’s Oncology Group Study. J Clin Oncol 27 (15): 2536-41, 2009. [PUBMED Abstract]
  45. Womer RB, West DC, Krailo MD, et al.: Randomized controlled trial of interval-compressed chemotherapy for the treatment of localized Ewing sarcoma: a report from the Children’s Oncology Group. J Clin Oncol 30 (33): 4148-54, 2012. [PUBMED Abstract]
  46. Pieper S, Ranft A, Braun-Munzinger G, et al.: Ewing’s tumors over the age of 40: a retrospective analysis of 47 patients treated according to the International Clinical Trials EICESS 92 and EURO-E.W.I.N.G. 99. Onkologie 31 (12): 657-63, 2008. [PUBMED Abstract]
  47. Wong T, Goldsby RE, Wustrack R, et al.: Clinical features and outcomes of infants with Ewing sarcoma under 12 months of age. Pediatr Blood Cancer 62 (11): 1947-51, 2015. [PUBMED Abstract]
  48. Worch J, Ranft A, DuBois SG, et al.: Age dependency of primary tumor sites and metastases in patients with Ewing sarcoma. Pediatr Blood Cancer 65 (9): e27251, 2018. [PUBMED Abstract]
  49. Schlegel M, Zeumer M, Prodinger PM, et al.: Impact of Pathological Fractures on the Prognosis of Primary Malignant Bone Sarcoma in Children and Adults: A Single-Center Retrospective Study of 205 Patients. Oncology 94 (6): 354-362, 2018. [PUBMED Abstract]
  50. Bramer JA, Abudu AA, Grimer RJ, et al.: Do pathological fractures influence survival and local recurrence rate in bony sarcomas? Eur J Cancer 43 (13): 1944-51, 2007. [PUBMED Abstract]
  51. Applebaum MA, Goldsby R, Neuhaus J, et al.: Clinical features and outcomes in patients with secondary Ewing sarcoma. Pediatr Blood Cancer 60 (4): 611-5, 2013. [PUBMED Abstract]
  52. Roberts P, Burchill SA, Brownhill S, et al.: Ploidy and karyotype complexity are powerful prognostic indicators in the Ewing’s sarcoma family of tumors: a study by the United Kingdom Cancer Cytogenetics and the Children’s Cancer and Leukaemia Group. Genes Chromosomes Cancer 47 (3): 207-20, 2008. [PUBMED Abstract]
  53. Hattinger CM, Pötschger U, Tarkkanen M, et al.: Prognostic impact of chromosomal aberrations in Ewing tumours. Br J Cancer 86 (11): 1763-9, 2002. [PUBMED Abstract]
  54. Mackintosh C, Ordóñez JL, García-Domínguez DJ, et al.: 1q gain and CDT2 overexpression underlie an aggressive and highly proliferative form of Ewing sarcoma. Oncogene 31 (10): 1287-98, 2012. [PUBMED Abstract]
  55. Tirode F, Surdez D, Ma X, et al.: Genomic landscape of Ewing sarcoma defines an aggressive subtype with co-association of STAG2 and TP53 mutations. Cancer Discov 4 (11): 1342-53, 2014. [PUBMED Abstract]
  56. Mrózek K, Bloomfield CD: Der(16)t(1;16) is a secondary chromosome aberration in at least eighteen different types of human cancer. Genes Chromosomes Cancer 23 (1): 78-80, 1998. [PUBMED Abstract]
  57. Mugneret F, Lizard S, Aurias A, et al.: Chromosomes in Ewing’s sarcoma. II. Nonrandom additional changes, trisomy 8 and der(16)t(1;16). Cancer Genet Cytogenet 32 (2): 239-45, 1988. [PUBMED Abstract]
  58. Hattinger CM, Rumpler S, Ambros IM, et al.: Demonstration of the translocation der(16)t(1;16)(q12;q11.2) in interphase nuclei of Ewing tumors. Genes Chromosomes Cancer 17 (3): 141-50, 1996. [PUBMED Abstract]
  59. Dubois SG, Epling CL, Teague J, et al.: Flow cytometric detection of Ewing sarcoma cells in peripheral blood and bone marrow. Pediatr Blood Cancer 54 (1): 13-8, 2010. [PUBMED Abstract]
  60. Schleiermacher G, Peter M, Oberlin O, et al.: Increased risk of systemic relapses associated with bone marrow micrometastasis and circulating tumor cells in localized ewing tumor. J Clin Oncol 21 (1): 85-91, 2003. [PUBMED Abstract]
  61. Zoubek A, Ladenstein R, Windhager R, et al.: Predictive potential of testing for bone marrow involvement in Ewing tumor patients by RT-PCR: a preliminary evaluation. Int J Cancer 79 (1): 56-60, 1998. [PUBMED Abstract]
  62. Shukla NN, Patel JA, Magnan H, et al.: Plasma DNA-based molecular diagnosis, prognostication, and monitoring of patients with EWSR1 fusion-positive sarcomas. JCO Precis Oncol 2017: , 2017. [PUBMED Abstract]
  63. Shulman DS, Klega K, Imamovic-Tuco A, et al.: Detection of circulating tumour DNA is associated with inferior outcomes in Ewing sarcoma and osteosarcoma: a report from the Children’s Oncology Group. Br J Cancer 119 (5): 615-621, 2018. [PUBMED Abstract]
  64. Krumbholz M, Eiblwieser J, Ranft A, et al.: Quantification of Translocation-Specific ctDNA Provides an Integrating Parameter for Early Assessment of Treatment Response and Risk Stratification in Ewing Sarcoma. Clin Cancer Res 27 (21): 5922-5930, 2021. [PUBMED Abstract]
  65. Vo KT, Edwards JV, Epling CL, et al.: Impact of Two Measures of Micrometastatic Disease on Clinical Outcomes in Patients with Newly Diagnosed Ewing Sarcoma: A Report from the Children’s Oncology Group. Clin Cancer Res 22 (14): 3643-50, 2016. [PUBMED Abstract]
  66. Lerman DM, Monument MJ, McIlvaine E, et al.: Tumoral TP53 and/or CDKN2A alterations are not reliable prognostic biomarkers in patients with localized Ewing sarcoma: a report from the Children’s Oncology Group. Pediatr Blood Cancer 62 (5): 759-65, 2015. [PUBMED Abstract]
  67. Shulman DS, Chen S, Hall D, et al.: Adverse prognostic impact of the loss of STAG2 protein expression in patients with newly diagnosed localised Ewing sarcoma: A report from the Children’s Oncology Group. Br J Cancer 127 (12): 2220-2226, 2022. [PUBMED Abstract]
  68. Parham DM, Hijazi Y, Steinberg SM, et al.: Neuroectodermal differentiation in Ewing’s sarcoma family of tumors does not predict tumor behavior. Hum Pathol 30 (8): 911-8, 1999. [PUBMED Abstract]
  69. Luksch R, Sampietro G, Collini P, et al.: Prognostic value of clinicopathologic characteristics including neuroectodermal differentiation in osseous Ewing’s sarcoma family of tumors in children. Tumori 85 (2): 101-7, 1999 Mar-Apr. [PUBMED Abstract]
  70. de Alava E, Kawai A, Healey JH, et al.: EWS-FLI1 fusion transcript structure is an independent determinant of prognosis in Ewing’s sarcoma. J Clin Oncol 16 (4): 1248-55, 1998. [PUBMED Abstract]
  71. van Doorninck JA, Ji L, Schaub B, et al.: Current treatment protocols have eliminated the prognostic advantage of type 1 fusions in Ewing sarcoma: a report from the Children’s Oncology Group. J Clin Oncol 28 (12): 1989-94, 2010. [PUBMED Abstract]
  72. Le Deley MC, Delattre O, Schaefer KL, et al.: Impact of EWS-ETS fusion type on disease progression in Ewing’s sarcoma/peripheral primitive neuroectodermal tumor: prospective results from the cooperative Euro-E.W.I.N.G. 99 trial. J Clin Oncol 28 (12): 1982-8, 2010. [PUBMED Abstract]
  73. Paulussen M, Ahrens S, Dunst J, et al.: Localized Ewing tumor of bone: final results of the cooperative Ewing’s Sarcoma Study CESS 86. J Clin Oncol 19 (6): 1818-29, 2001. [PUBMED Abstract]
  74. Rosito P, Mancini AF, Rondelli R, et al.: Italian Cooperative Study for the treatment of children and young adults with localized Ewing sarcoma of bone: a preliminary report of 6 years of experience. Cancer 86 (3): 421-8, 1999. [PUBMED Abstract]
  75. Wunder JS, Paulian G, Huvos AG, et al.: The histological response to chemotherapy as a predictor of the oncological outcome of operative treatment of Ewing sarcoma. J Bone Joint Surg Am 80 (7): 1020-33, 1998. [PUBMED Abstract]
  76. Oberlin O, Deley MC, Bui BN, et al.: Prognostic factors in localized Ewing’s tumours and peripheral neuroectodermal tumours: the third study of the French Society of Paediatric Oncology (EW88 study). Br J Cancer 85 (11): 1646-54, 2001. [PUBMED Abstract]
  77. Lozano-Calderón SA, Albergo JI, Groot OQ, et al.: Complete tumor necrosis after neoadjuvant chemotherapy defines good responders in patients with Ewing sarcoma. Cancer 129 (1): 60-70, 2023. [PUBMED Abstract]
  78. Ferrari S, Bertoni F, Palmerini E, et al.: Predictive factors of histologic response to primary chemotherapy in patients with Ewing sarcoma. J Pediatr Hematol Oncol 29 (6): 364-8, 2007. [PUBMED Abstract]
  79. Hawkins DS, Schuetze SM, Butrynski JE, et al.: [18F]Fluorodeoxyglucose positron emission tomography predicts outcome for Ewing sarcoma family of tumors. J Clin Oncol 23 (34): 8828-34, 2005. [PUBMED Abstract]
  80. Denecke T, Hundsdörfer P, Misch D, et al.: Assessment of histological response of paediatric bone sarcomas using FDG PET in comparison to morphological volume measurement and standardized MRI parameters. Eur J Nucl Med Mol Imaging 37 (10): 1842-53, 2010. [PUBMED Abstract]
  81. Palmerini E, Colangeli M, Nanni C, et al.: The role of FDG PET/CT in patients treated with neoadjuvant chemotherapy for localized bone sarcomas. Eur J Nucl Med Mol Imaging 44 (2): 215-223, 2017. [PUBMED Abstract]
  82. Lin PP, Jaffe N, Herzog CE, et al.: Chemotherapy response is an important predictor of local recurrence in Ewing sarcoma. Cancer 109 (3): 603-11, 2007. [PUBMED Abstract]
  83. Bosma SE, Rueten-Budde AJ, Lancia C, et al.: Individual risk evaluation for local recurrence and distant metastasis in Ewing sarcoma: A multistate model: A multistate model for Ewing sarcoma. Pediatr Blood Cancer 66 (11): e27943, 2019. [PUBMED Abstract]
  84. Reiter AJ, Huang L, Craig BT, et al.: Survival outcomes in pediatric patients with metastatic Ewing sarcoma who achieve a rapid complete response of pulmonary metastases. Pediatr Blood Cancer 71 (7): e31026, 2024. [PUBMED Abstract]

Cellular Classification of Ewing Sarcoma

Ewing sarcoma belongs to the group of neoplasms commonly referred to as small round blue cell tumors of childhood. The individual cells of Ewing sarcoma contain round-to-oval nuclei, with fine dispersed chromatin without nucleoli. Occasionally, cells with smaller, more hyperchromatic, and probably degenerative nuclei are present, giving a light cell/dark cell pattern. The cytoplasm varies in amount, but in the classic case, it is clear and contains glycogen, which can be highlighted with a periodic acid-Schiff stain. The tumor cells are tightly packed and grow in a diffuse pattern without evidence of structural organization. Tumors with the requisite translocation that show neuronal differentiation are not considered a separate entity, but rather, part of a continuum of differentiation.

CD99 is a surface membrane protein that is expressed in most cases of Ewing sarcoma and is useful in diagnosing these tumors when the results are interpreted in the context of clinical and pathological parameters.[1] CD99 positivity is not unique to Ewing sarcoma, and positivity by immunochemistry is found in several other tumors, including synovial sarcoma, non-Hodgkin lymphoma, and gastrointestinal stromal tumors. NKX2.2 is a nuclear antigen that is also commonly assessed by immunohistochemistry to support a diagnosis of Ewing sarcoma, although it is also not 100% specific for this diagnosis.[2]

For more information about the cellular classification of other undifferentiated small round cell sarcomas, see the Undifferentiated Small Round Cell (Ewing-Like) Sarcomas section.

References
  1. Parham DM, Hijazi Y, Steinberg SM, et al.: Neuroectodermal differentiation in Ewing’s sarcoma family of tumors does not predict tumor behavior. Hum Pathol 30 (8): 911-8, 1999. [PUBMED Abstract]
  2. Yoshida A, Sekine S, Tsuta K, et al.: NKX2.2 is a useful immunohistochemical marker for Ewing sarcoma. Am J Surg Pathol 36 (7): 993-9, 2012. [PUBMED Abstract]

Genomics of Ewing Sarcoma

Molecular Features of Ewing Sarcoma

The World Health Organization identifies the presence of a gene fusion involving EWSR1 or FUS and a gene in the ETS family as a defining element of Ewing sarcoma.[1] The EWSR1 gene located on chromosome 22 band q12 is a member of the FET family (FUS, EWSR1, TAF15) of RNA-binding proteins.[2] Characteristically, the amino terminus of the EWSR1 gene is juxtaposed with the carboxy terminus of a gene from the ETS family of DNA-binding transcription factors (see Table 4). The FLI1 gene located on chromosome 11 band q24 is a member of the ETS family and is the ETS family fusion partner for EWSR1 in 85% to 90% of pediatric cases of Ewing sarcoma.[3–5] Other ETS family members that may combine with the EWSR1 gene are ERG, ETV1, ETV4, and FEV.[6] Rarely, FUS, another FET family member, can substitute for EWSR1.[7] Finally, there are a few rare cases in which EWSR1 has translocated with partners that are not members of the ETS family of oncogenes. These tumors are thought to be distinct from Ewing sarcoma and are discussed separately. For more information, see the Undifferentiated Small Round Cell (Ewing-Like) Sarcomas section.

The EWSR1::FLI1 translocation associated with Ewing sarcoma can occur at several potential breakpoints in each of the genes that join to form the novel segment of DNA. Once thought to be significant,[8] two large series have shown that the EWSR1::FLI1 translocation breakpoint site is not an adverse prognostic factor.[9,10]

Besides the consistent aberrations involving the EWSR1 gene, secondary numerical and structural chromosomal aberrations are observed in most cases of Ewing sarcoma. Chromosome gains are more common than chromosome losses, and structural chromosome imbalances are also observed.[11] Two of the more common chromosome aberrations are those involving chromosome 8 or chromosomes 1 and 16.[11]

  • Gain of whole chromosome 8 (trisomy 8). Trisomy 8 is the most frequent chromosomal alteration in Ewing sarcoma, occurring in nearly 50% of tumors.[3,4] Gain of chromosome 8 does not appear to have prognostic significance.[3,12]
  • Gain of chromosome 1q and loss of chromosome 16q. These occur in approximately 20% of patients and often occur together. Gain of chromosome 1q and/or deletion of chromosome 16q has been associated with inferior prognosis for patients with Ewing sarcoma in several cohorts.[3,13,14] These two chromosomal alterations commonly occur together across a range of cancer types, including Ewing sarcoma.[15] Their co-occurrence is likely a result of their derivation from an unbalanced t(1;16) translocation resulting in gain of chromosome 1q together with loss of chromosomal material from 16q.[12,16]

The genomic landscape of Ewing sarcoma is characterized by a relatively silent genome, with a paucity of variants in pathways that might be amenable to treatment with novel targeted therapies.[3–5] Recurring genomic alterations are described below. For some of these genomic alterations, claims of prognostic significance have been made. However, these claims need to be viewed cautiously because of the relatively small size of most studies, the low frequency of many of the genomic alterations, the variable use of tumor tissue from diagnosis versus relapse specimens, and the need to consider clinical prognostic factors such as tumor size and the presence of metastatic disease.

  • STAG2 variants. Variants in STAG2, a member of the cohesin complex, occur in about 15% to 20% of the cases.[3–5] These variants lead to loss of STAG2 expression and function in tumor cells.[5] Loss of STAG2 expression (detected by immunohistochemistry [IHC]) has been observed in tumors in which a STAG2 variant cannot be detected. In one report, loss of STAG2 expression by IHC was associated with inferior prognosis.[17]
  • CDKN2A deletions. CDKN2A deletions have been noted in 12% to 22% of cases.[3–5]
  • TP53 variants. TP53 variants were identified in about 6% to 7% of Ewing sarcoma cases reported by pediatric research teams.[3–5] Higher rates of TP53 variants (up to 19%) have been described in cohorts from single institutions that contain higher proportions of adult patients.[18,19] The coexistence of STAG2 and TP53 variants has been associated with a poor clinical outcome in one retrospective report.
  • ERF alterations. Genomic alterations in ERF leading to loss of function (frameshift, missense, and deep deletion) were reported in 7% of Ewing sarcoma tumors.[18] A second report observed ERF alterations at a rate of 3% in another Ewing sarcoma cohort.[4]
  • Other genes with recurring genomic alterations in Ewing sarcoma. Recurring genomic alterations present in fewer than 5% of Ewing sarcoma patients were reported: EZH2,[3,19] BCOR,[3] SMARCA4,[19] CREBBP,[19] TERT, and FGFR1.[18]

Ewing sarcoma translocations can all be found with standard cytogenetic analysis. A fluorescence in situ hybridization (FISH) rapid analysis looking for a break apart of the EWSR1 gene is now frequently done to confirm the diagnosis of Ewing sarcoma molecularly.[20] This test result must be considered with caution, however. Ewing sarcomas that harbor FUS translocations will have negative tests because the EWSR1 gene is not translocated in those cases. In addition, other small round tumors also contain translocations of different ETS family members with EWSR1, such as desmoplastic small round cell tumor, clear cell sarcoma, extraskeletal myxoid chondrosarcoma, and myxoid liposarcoma, all of which may be positive with a EWSR1 FISH break-apart probe. A detailed analysis of 85 patients with small round blue cell tumors that were negative for EWSR1 rearrangement by FISH (with an EWSR1 break-apart probe) identified eight patients with FUS rearrangements.[21] Four patients who had EWSR1::ERG fusions were not detected by FISH with an EWSR1 break-apart probe. The authors do not recommend relying solely on EWSR1 break-apart probes for analyzing small round blue cell tumors with strong immunohistochemical positivity for CD99. Next-generation sequencing assays, including dedicated fusion panels, are now commonly used in the evaluation of these tumors.

Table 4. EWSR1 and FUS Fusions and Translocations in Ewing Sarcoma
FET Family Partner Fusion With ETS-Like Oncogene Partner Translocation Comment
aThese partners are not members of the ETS family of oncogenes; therefore, these tumors are not classified as Ewing sarcoma.
EWSR1 EWSR1::FLI1 t(11;22)(q24;q12) Most common; approximately 85% to 90% of cases
EWSR1::ERG t(21;22)(q22;q12) Second most common; approximately 10% of cases
EWSR1::ETV1 t(7;22)(p22;q12) Rare
EWSR1::ETV4 t(17;22)(q12;q12) Rare
EWSR1::FEV t(2;22)(q35;q12) Rare
EWSR1::NFATC2a t(20;22)(q13;q12) Rare
EWSR1::POU5F1a t(6;22)(p21;q12)  
EWSR1::SMARCA5a t(4;22)(q31;q12) Rare
EWSR1::PATZ1a t(6;22)(p21;q12)  
EWSR1::SP3a t(2;22)(q31;q12) Rare
FUS FUS::ERG t(16;21)(p11;q22) Rare
FUS::FEV t(2;16)(q35;p11) Rare
References
  1. WHO Classification of Tumours Editorial Board: WHO Classification of Tumours. Volume 3: Soft Tissue and Bone Tumours. 5th ed., IARC Press, 2020.
  2. Schwartz JC, Cech TR, Parker RR: Biochemical Properties and Biological Functions of FET Proteins. Annu Rev Biochem 84: 355-79, 2015. [PUBMED Abstract]
  3. Tirode F, Surdez D, Ma X, et al.: Genomic landscape of Ewing sarcoma defines an aggressive subtype with co-association of STAG2 and TP53 mutations. Cancer Discov 4 (11): 1342-53, 2014. [PUBMED Abstract]
  4. Crompton BD, Stewart C, Taylor-Weiner A, et al.: The genomic landscape of pediatric Ewing sarcoma. Cancer Discov 4 (11): 1326-41, 2014. [PUBMED Abstract]
  5. Brohl AS, Solomon DA, Chang W, et al.: The genomic landscape of the Ewing Sarcoma family of tumors reveals recurrent STAG2 mutation. PLoS Genet 10 (7): e1004475, 2014. [PUBMED Abstract]
  6. Hattinger CM, Rumpler S, Strehl S, et al.: Prognostic impact of deletions at 1p36 and numerical aberrations in Ewing tumors. Genes Chromosomes Cancer 24 (3): 243-54, 1999. [PUBMED Abstract]
  7. Sankar S, Lessnick SL: Promiscuous partnerships in Ewing’s sarcoma. Cancer Genet 204 (7): 351-65, 2011. [PUBMED Abstract]
  8. de Alava E, Kawai A, Healey JH, et al.: EWS-FLI1 fusion transcript structure is an independent determinant of prognosis in Ewing’s sarcoma. J Clin Oncol 16 (4): 1248-55, 1998. [PUBMED Abstract]
  9. van Doorninck JA, Ji L, Schaub B, et al.: Current treatment protocols have eliminated the prognostic advantage of type 1 fusions in Ewing sarcoma: a report from the Children’s Oncology Group. J Clin Oncol 28 (12): 1989-94, 2010. [PUBMED Abstract]
  10. Le Deley MC, Delattre O, Schaefer KL, et al.: Impact of EWS-ETS fusion type on disease progression in Ewing’s sarcoma/peripheral primitive neuroectodermal tumor: prospective results from the cooperative Euro-E.W.I.N.G. 99 trial. J Clin Oncol 28 (12): 1982-8, 2010. [PUBMED Abstract]
  11. Roberts P, Burchill SA, Brownhill S, et al.: Ploidy and karyotype complexity are powerful prognostic indicators in the Ewing’s sarcoma family of tumors: a study by the United Kingdom Cancer Cytogenetics and the Children’s Cancer and Leukaemia Group. Genes Chromosomes Cancer 47 (3): 207-20, 2008. [PUBMED Abstract]
  12. Hattinger CM, Rumpler S, Ambros IM, et al.: Demonstration of the translocation der(16)t(1;16)(q12;q11.2) in interphase nuclei of Ewing tumors. Genes Chromosomes Cancer 17 (3): 141-50, 1996. [PUBMED Abstract]
  13. Hattinger CM, Pötschger U, Tarkkanen M, et al.: Prognostic impact of chromosomal aberrations in Ewing tumours. Br J Cancer 86 (11): 1763-9, 2002. [PUBMED Abstract]
  14. Mackintosh C, Ordóñez JL, García-Domínguez DJ, et al.: 1q gain and CDT2 overexpression underlie an aggressive and highly proliferative form of Ewing sarcoma. Oncogene 31 (10): 1287-98, 2012. [PUBMED Abstract]
  15. Mrózek K, Bloomfield CD: Der(16)t(1;16) is a secondary chromosome aberration in at least eighteen different types of human cancer. Genes Chromosomes Cancer 23 (1): 78-80, 1998. [PUBMED Abstract]
  16. Mugneret F, Lizard S, Aurias A, et al.: Chromosomes in Ewing’s sarcoma. II. Nonrandom additional changes, trisomy 8 and der(16)t(1;16). Cancer Genet Cytogenet 32 (2): 239-45, 1988. [PUBMED Abstract]
  17. Shulman DS, Chen S, Hall D, et al.: Adverse prognostic impact of the loss of STAG2 protein expression in patients with newly diagnosed localised Ewing sarcoma: A report from the Children’s Oncology Group. Br J Cancer 127 (12): 2220-2226, 2022. [PUBMED Abstract]
  18. Ogura K, Elkrief A, Bowman AS, et al.: Prospective Clinical Genomic Profiling of Ewing Sarcoma: ERF and FGFR1 Mutations as Recurrent Secondary Alterations of Potential Biologic and Therapeutic Relevance. JCO Precis Oncol 6: e2200048, 2022. [PUBMED Abstract]
  19. Rock A, Uche A, Yoon J, et al.: Bioinformatic Analysis of Recurrent Genomic Alterations and Corresponding Pathway Alterations in Ewing Sarcoma. J Pers Med 13 (10): , 2023. [PUBMED Abstract]
  20. Monforte-Muñoz H, Lopez-Terrada D, Affendie H, et al.: Documentation of EWS gene rearrangements by fluorescence in-situ hybridization (FISH) in frozen sections of Ewing’s sarcoma-peripheral primitive neuroectodermal tumor. Am J Surg Pathol 23 (3): 309-15, 1999. [PUBMED Abstract]
  21. Chen S, Deniz K, Sung YS, et al.: Ewing sarcoma with ERG gene rearrangements: A molecular study focusing on the prevalence of FUS-ERG and common pitfalls in detecting EWSR1-ERG fusions by FISH. Genes Chromosomes Cancer 55 (4): 340-9, 2016. [PUBMED Abstract]

Stage Information for Ewing Sarcoma

Pretreatment staging studies for Ewing sarcoma may include the following:

  • Magnetic resonance imaging (MRI) of the primary site.
  • Computed tomography (CT) scan of the primary site and chest.
  • Positron emission tomography using fluorine F 18-fludeoxyglucose (18F-FDG PET) or 18F-FDG PET-CT.
  • Bone scan has traditionally been part of the staging evaluation for Ewing sarcoma. However, many investigators believe that PET scan can replace bone scan.[1,2]
  • Bone marrow aspiration and biopsy.

For patients with confirmed Ewing sarcoma, pretreatment staging studies include MRI and/or CT scan, depending on the primary site. Despite the fact that CT and MRI are both equivalent in terms of staging, use of both imaging modalities may help radiation therapy planning.[3] Whole-body MRI may provide additional information that could potentially alter therapy planning.[4] Additional pretreatment staging studies include bone scan and CT scan of the chest. In certain studies, determination of pretreatment tumor volume is an important variable.

18F-FDG PET-CT scans have demonstrated high sensitivity and specificity in Ewing sarcoma and are now routinely used to complete staging. In one institutional study, 18F-FDG PET had a very high correlation with bone scan; the investigators suggested that it could replace bone scan for the initial extent of disease evaluation.[5] This finding was confirmed in a single-institution retrospective review.[6] 18F-FDG PET-CT is more accurate than 18F-FDG PET alone in Ewing sarcoma.[7–9]

Bone marrow aspiration and biopsy have been considered the standard of care for Ewing sarcoma. However, two retrospective studies showed that for patients (N = 141) who were evaluated by bone scan and/or PET scan and lung CT without evidence of metastases, bone marrow aspirates and biopsies were negative in every case.[5,10] A single-institution retrospective review of 504 patients with Ewing sarcoma identified 12 patients with bone marrow metastasis.[11] Only one patient was found to have bone marrow involvement without any other sites of metastatic disease, for an incidence of 1 per 367 (0.3%) in patients with clinically localized disease. The need for routine use of bone marrow aspirates and biopsies in patients without bone metastases is now in question.

For Ewing sarcoma, tumors are practically staged as localized or metastatic, and other staging systems are not commonly used. The tumor is defined as localized when, by clinical and imaging techniques, there is no spread beyond the primary site or regional lymph node involvement. Continuous extension into adjacent soft tissue may occur. If there is a question of regional lymph node involvement, pathological confirmation is indicated.

References
  1. Costelloe CM, Chuang HH, Daw NC: PET/CT of Osteosarcoma and Ewing Sarcoma. Semin Roentgenol 52 (4): 255-268, 2017. [PUBMED Abstract]
  2. Tal AL, Doshi H, Parkar F, et al.: The Utility of 18FDG PET/CT Versus Bone Scan for Identification of Bone Metastases in a Pediatric Sarcoma Population and a Review of the Literature. J Pediatr Hematol Oncol 43 (2): 52-58, 2021. [PUBMED Abstract]
  3. Meyer JS, Nadel HR, Marina N, et al.: Imaging guidelines for children with Ewing sarcoma and osteosarcoma: a report from the Children’s Oncology Group Bone Tumor Committee. Pediatr Blood Cancer 51 (2): 163-70, 2008. [PUBMED Abstract]
  4. Mentzel HJ, Kentouche K, Sauner D, et al.: Comparison of whole-body STIR-MRI and 99mTc-methylene-diphosphonate scintigraphy in children with suspected multifocal bone lesions. Eur Radiol 14 (12): 2297-302, 2004. [PUBMED Abstract]
  5. Newman EN, Jones RL, Hawkins DS: An evaluation of [F-18]-fluorodeoxy-D-glucose positron emission tomography, bone scan, and bone marrow aspiration/biopsy as staging investigations in Ewing sarcoma. Pediatr Blood Cancer 60 (7): 1113-7, 2013. [PUBMED Abstract]
  6. Ulaner GA, Magnan H, Healey JH, et al.: Is methylene diphosphonate bone scan necessary for initial staging of Ewing sarcoma if 18F-FDG PET/CT is performed? AJR Am J Roentgenol 202 (4): 859-67, 2014. [PUBMED Abstract]
  7. 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]
  8. Gerth HU, Juergens KU, Dirksen U, et al.: Significant benefit of multimodal imaging: PET/CT compared with PET alone in staging and follow-up of patients with Ewing tumors. J Nucl Med 48 (12): 1932-9, 2007. [PUBMED Abstract]
  9. Treglia G, Salsano M, Stefanelli A, et al.: Diagnostic accuracy of ¹⁸F-FDG-PET and PET/CT in patients with Ewing sarcoma family tumours: a systematic review and a meta-analysis. Skeletal Radiol 41 (3): 249-56, 2012. [PUBMED Abstract]
  10. Kopp LM, Hu C, Rozo B, et al.: Utility of bone marrow aspiration and biopsy in initial staging of Ewing sarcoma. Pediatr Blood Cancer 62 (1): 12-5, 2015. [PUBMED Abstract]
  11. Cesari M, Righi A, Colangeli M, et al.: Bone marrow biopsy in the initial staging of Ewing sarcoma: Experience from a single institution. Pediatr Blood Cancer 66 (6): e27653, 2019. [PUBMED Abstract]

Treatment Option Overview for Ewing Sarcoma

It is important that patients be evaluated by specialists from the appropriate disciplines (e.g., medical oncologists, surgical or orthopedic oncologists, and radiation oncologists) as early as possible. Multidisciplinary review with radiologists and pathologists is often performed at sarcoma specialty centers.

Appropriate imaging studies of the suspected primary site are obtained before biopsy. To ensure that the biopsy incision is placed in an acceptable location, the surgical or orthopedic oncologist (who will perform the definitive surgery) is consulted on biopsy-incision placement. This is especially important if it is thought that the lesion can subsequently be totally excised after initial systemic therapy or if a limb salvage procedure may be attempted. It is almost never appropriate to attempt a primary resection of known Ewing sarcoma at initial diagnosis. With rare exceptions, Ewing sarcoma is sensitive to chemotherapy and will respond to initial systemic therapy. This therapy reduces the risk of tumor spread to surrounding tissues and makes ultimate surgery easier and safer. Biopsy should be from soft tissue as often as possible to avoid increasing the risk of fracture.[1] If the initial biopsy sample is obtained from bone, reserving some tissue without decalcification is required because decalcification denatures DNA and makes genomic profiling of tumor tissue impossible.[2] The pathologist is consulted before biopsy/surgery to ensure that the incision will not compromise the radiation port and that multiple types of adequate tissue samples are obtained. It is important to obtain fresh tissue, whenever possible, for cytogenetics and molecular pathology. A second option is to perform a needle biopsy, as long as adequate tissue is obtained for molecular studies.[3]

Table 5 describes the treatment options for localized, metastatic, and recurrent Ewing sarcoma.

Table 5. Standard Treatment Options for Ewing Sarcoma
Treatment Group Standard Treatment Options
Localized Ewing sarcoma Chemotherapy
Local-control measures:
  Surgery
  Radiation therapy
High-dose chemotherapy with autologous stem cell rescue
Metastatic Ewing sarcoma Chemotherapy
Surgery
Radiation therapy
Recurrent Ewing sarcoma Chemotherapy (not considered standard treatment)
Surgery (not considered standard treatment)
Radiation therapy (not considered standard treatment)
High-dose chemotherapy with stem cell support (not considered standard treatment)
Other therapies (not considered standard treatment)

The successful treatment of patients with Ewing sarcoma requires systemic chemotherapy [4–10] in conjunction with surgery and/or radiation therapy for local tumor control.[11–15] In general, patients receive chemotherapy before instituting local-control measures. In patients who undergo surgery, surgical margins and histological response are considered in planning postoperative therapy. Patients with metastatic disease often have a good initial response to preoperative chemotherapy, but in most cases, the disease is only partially controlled or recurs.[16–21] Patients with lung as the only metastatic site have a better prognosis than do patients with metastases to bone and/or bone marrow. Adequate local control for metastatic sites, particularly bone metastases, may be an important consideration.[22]

Chemotherapy for Ewing Sarcoma

Multidrug chemotherapy for Ewing sarcoma always includes vincristine, doxorubicin, ifosfamide, and etoposide. Most protocols also use cyclophosphamide and some incorporate dactinomycin. The mode of administration and dose intensity of cyclophosphamide within courses differs markedly between protocols. A European Intergroup Cooperative Ewing Sarcoma Study (EICESS) trial suggested that 1.2 g of cyclophosphamide produced a similar event-free survival (EFS) compared with 6 g of ifosfamide in patients with lower-risk disease. The trial also identified a trend toward better EFS for patients with localized Ewing sarcoma and higher-risk disease when treatment included etoposide (GER-GPOH-EICESS-92 [NCT00002516]).[23][Level of evidence A1]

Protocols in the United States generally alternate courses of vincristine, cyclophosphamide, and doxorubicin (VDC) with courses of ifosfamide and etoposide (IE),[8] using interval compression.[24–26] For many years, European protocols generally combined vincristine, doxorubicin, and an alkylating agent with or without etoposide in a single treatment cycle.[10] After the completion of the randomized EURO EWING 2012 (EE2012) trial (see below), European investigators shifted to therapy with cycles of VDC alternating with cycles of IE.[27][Level of evidence B1] The duration of primary chemotherapy ranges from 6 months to approximately 1 year.

Evidence (chemotherapy):

  1. An international consortium of European countries conducted the EURO-EWING-INTERGROUP-EE99 (NCT00020566) trial from 2000 to 2010.[28][Level of evidence A1] All patients received induction therapy with six cycles of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE), followed by local control, and then one cycle of vincristine, dactinomycin, and ifosfamide (VAI). Patients were classified as standard risk if they had localized disease and good histological response to therapy or if they had localized tumors less than 200 mL in volume at presentation; they were treated with radiation therapy alone as local treatment. Standard-risk patients (n = 856) were randomly assigned to receive maintenance therapy with either seven cycles of vincristine, dactinomycin, and cyclophosphamide (VAC) or VAI.
    • There was no significant difference in EFS or overall survival (OS) between patients who received VAC and patients who received VAI.
    • The 3-year EFS rate for this low-risk population was 77%.
    • It is difficult to compare this outcome with that of other large series because the study population excluded patients with poor response to initial therapy or patients with tumors more than 200 mL in volume who received local-control therapy with radiation alone. All other published series report results for all patients who present without clinically detectable metastasis; thus, these other series included patients with poor response and patients with larger primary tumors treated with radiation alone, all of whom were excluded from the EURO-EWING-INTERGROUP-EE99 study.
  2. In a Children’s Oncology Group (COG) study (COG-AEWS0031 [NCT00006734]), patients presenting without metastases were randomly assigned to receive cycles of VDC alternating with cycles of IE at either 2-week or 3-week intervals.[24]
    • The administration of cycles of VDC/IE at 2-week intervals achieved superior EFS (5-year EFS rate, 73%) than did alternating cycles at 3-week intervals (5-year EFS rate, 65%). With longer follow-up, the advantage of interval-compressed chemotherapy was confirmed.[25]
    • The 10-year EFS rate was 70% using interval-compressed chemotherapy, compared with 61% using standard-timing chemotherapy (P = .03). The 10-year OS rate was 76% using interval-compressed chemotherapy, compared with 69% using standard-timing chemotherapy (P = .04).
  3. The EE2012 trial was an international multicenter phase III study that included two randomized treatments, the European VIDE induction regimen and the North American standard VDC/IE induction regimen. Patients with both localized and metastatic Ewing sarcoma were eligible for the study.[27][Level of evidence B1]
    • The hazard ratios (HRs) for EFS (0.71) and OS (0.62) favored VDC/IE over VIDE. The posterior probabilities were 99% for both EFS and OS, which showed that VDC/IE was superior.
    • Rates of febrile neutropenia were higher with the VIDE regimen. There were no other major differences in acute toxicities between the two regimens.
    • The benefit of VDC/IE over VIDE was seen across subgroups defined by patient age, sex, stage, tumor volume, or country of residence.
  4. The Brazilian Cooperative Study Group performed a multi-institutional trial that incorporated carboplatin into a risk-adapted intensive regimen in 175 children with localized or metastatic Ewing sarcoma.[29][Level of evidence B4]
    • The investigators found significantly increased toxicity without an improvement in outcome with the addition of carboplatin.
  5. The COG performed a prospective randomized trial in patients with localized Ewing sarcoma. All patients received cycles of VDC and cycles of IE. Patients were then randomly assigned to receive or not receive additional experimental cycles of vincristine, cyclophosphamide, and topotecan.[26]
    • The 5-year EFS rate was 78% (95% confidence interval [CI], 72%–82%) for those treated with experimental therapy and 79% (95% CI, 74%–83%) for patients treated with standard therapy.
    • The experimental therapy did not significantly reduce the risk of events (EFS HR for experimental arm vs. standard arm, 0.86; 1-sided P = .19).

Local Control (Surgery and Radiation Therapy) for Ewing Sarcoma

Treatment approaches for Ewing sarcoma and therapeutic aggressiveness must be adjusted to maximize local control while also minimizing morbidity.

Surgery is the most commonly used form of local control.[30] Radiation therapy is an effective alternative modality for local control in cases where the functional or cosmetic morbidity of surgery is deemed too high by experienced surgical oncologists. However, in the immature skeleton, radiation therapy can cause subsequent deformities that may be more morbid than deformities from surgery. When complete surgical resection with pathologically negative margins is not anticipated, surgery is not typically performed, and definitive radiation is used instead. When pathologically positive margins are found, then postoperative radiation therapy is indicated. A multidisciplinary discussion between the experienced radiation oncologist and the surgeon is necessary to determine the best treatment options for local control for a given case. For some marginally resectable lesions, a combined approach of preoperative radiation therapy followed by resection can be used.

Timing of local control may impact outcome. A retrospective review from the National Cancer Database identified 1,318 patients with Ewing sarcoma.[31] Patients who initiated local therapy at 6 to 15 weeks had a 5-year OS rate of 78.7% and a 10-year OS rate of 70.3%, and patients who initiated local therapy after 16 weeks had a 5-year OS rate of 70.4% and a 10-year OS rate of 57.1% (P < .001). The difference in OS according to time to local therapy was more important in patients who received radiation therapy alone.

For patients with metastatic Ewing sarcoma, any benefit of combined surgery and radiation therapy compared with either therapy alone for local control is relatively less substantial because the overall prognosis of these patients is much worse than the prognosis of patients who have localized disease.

Randomized trials that directly compare surgery and radiation therapy do not exist, and their relative roles remain controversial. Although retrospective institutional series suggest better local control and survival with surgery than with radiation therapy, most of these studies are compromised by selection bias. An analysis using propensity scoring to adjust for clinical features that may influence the preference for surgery only, radiation only, or combined surgery and radiation demonstrated that similar EFS is achieved with each mode of local therapy.[30] Data for patients with pelvic primary Ewing sarcoma from a North American intergroup trial showed no difference in local control or survival based on local-control modality—surgery alone, radiation therapy alone, or surgery plus radiation therapy.[32]

The EURO-EWING-INTERGROUP-EE99 (NCT00020566) trial prospectively treated 180 patients with pelvic primary tumors without clinically detectable metastatic disease.[33][Level of evidence B4] A retrospective analysis of outcomes for these patients showed improved survival for patients whose tumors were treated with combined radiation therapy and surgery. The study did not prospectively define criteria for the selection of local-control modalities, and the investigators did not have access to information that would allow them to clarify how decisions for local-control modalities were made. In nonsacral tumors, combined local treatment was associated with a lower local recurrence probability (14% [95% CI, 5%–23%] vs. 33% [95% CI, 19%–47%] at 5 years; P = .015) and a higher OS probability (72% [95% CI, 61%–83%] vs. 47% [95% CI, 33%–62%] at 5 years; P = .024), compared with surgery alone. Even in a subgroup of patients with wide surgical margins and a good histological response to induction treatment, the combined local treatment was associated with a higher OS probability (87% [95% CI, 74%–100%] vs. 51% [95% CI, 33%–69%] at 5 years; P = .009), compared with surgery alone. In patients with bone tumors who underwent surgical treatment—after controlling for tumor site in the pelvis, tumor volume, and surgical margin status—those who did not undergo complete removal of the affected bone (HR, 5.04; 95% CI, 2.07–12.24; P < .001), those with a poor histological response to induction chemotherapy (HR, 3.72; 95% CI, 1.51–9.21; P = .004), and those who did not receive additional radiation therapy (HR, 4.34; 95% CI, 1.71–11.05; P = .002) had a higher risk of death.

For patients who undergo gross-total resection with microscopic residual disease, a radiation therapy dose of 50.4 Gy is recommended. For patients treated with primary radiation therapy, the radiation dose is 55.8 Gy (45 Gy to the initial tumor volume and an additional 10.8 Gy to the postchemotherapy volume).[14,34]

Evidence (postoperative radiation therapy):

  1. Investigators from St. Jude Children’s Research Hospital reported 39 patients with localized Ewing sarcoma who received both surgery and radiation.[14]
    • The local failure rate for patients with positive margins was 17%, and the OS rate was 71%.
    • The local failure rate for patients with negative margins was 5%, and the OS rate was 94%.
  2. In a large retrospective Italian study, 45 Gy of adjuvant radiation therapy for patients with inadequate margins did not appear to improve either local control or disease-free survival (DFS).[15]
    • These investigators concluded that patients who are anticipated to have suboptimal surgery should be considered for definitive radiation therapy.
  3. The EURO-EWING-INTERGROUP-EE99 (NCT00020566) study reported the outcomes of 599 patients who presented with localized disease and had surgical resection after initial chemotherapy with at least 90% necrosis of the primary tumor.[34][Level of evidence C2] The protocol recommended postoperative radiation therapy for patients with inadequate surgical margins, vertebral primary tumors, or thoracic tumors with pleural effusion, but the decision to use postoperative radiation therapy was left to the institutional investigator.
    • Patients who received postoperative radiation therapy (n = 142) had a lower risk of failure than patients who did not receive postoperative radiation therapy, even after controlling for known prognostic factors, including age, sex, tumor site, clinical response, quality of resection, and histological necrosis. Most of the improvement was seen in a decreased risk of local recurrence. The improvement was greater in patients who had large tumors (>200 mL) and were assessed to have 100% necrosis than in patients who were assessed to have 90% to 100% necrosis.
    • There is a clear interaction between systemic therapy and local-control modalities for both local control and DFS. The induction regimen used in the EURO-EWING-INTERGROUP-EE99 study is less intense than the induction regimen used in contemporaneous protocols in the COG, and it is not appropriate to extrapolate the results from the EURO-EWING-INTERGROUP-EE99 study to different systemic chemotherapy regimens.

Thoracic primary tumors

Evidence (surgery):

  1. The treatment and outcomes for 62 patients with thoracic Ewing sarcoma were reported from the Cooperative Weichteilsarkom Studiengruppe CWS-81, -86, -91, -96, and -2002P trials.[35]
    • The 5-year OS rate was 58.7% (95% CI, 52.7%–64.7%), and the EFS rate was 52.8% (95% CI, 46.8%–58.8%).
    • Patients with intrathoracic tumors (n = 24) had a worse outcome (EFS rate, 37.5% [95% CI, 27.5%–37.5%]) than patients with chest wall tumors (n = 38; EFS rate, 62.3% [95% CI, 54.3%–70.3%]; P = .008).
    • Patients aged 10 years and younger (n = 38) had a better survival (EFS rate, 65.7% [95% CI, 57.7%–73.7%]) than patients older than 10 years (EFS rate, 31.3% [95% CI, 21.3%–41.3%]; P = .01).
    • Tumor size of less than or equal to 5 cm (n = 15) was associated with significantly better survival (EFS rate, 93.3% [95% CI, 87.3%–99.3%]), compared with a tumor size greater than 5 cm (n = 47; EFS rate, 40% [95% CI, 33%–47%]; P = .002).
    • Primary resections were carried out in 36 patients, 75% of which were incomplete, resulting in inferior EFS (P = .006).
    • Complete secondary resections were performed in 22 of 40 patients.
  2. The COG reviewed its results for 98 patients with chest wall tumors who were treated on the INT-0091 and INT-0154 trials from 1988 to 1998 and found the following:[36]
    • The 5-year EFS rate was 56%.
    • Negative margins were more common in patients who received initial chemotherapy and then underwent resections (41 of 53 patients, 77%) than in patients who had up-front surgery (10 of 20 patients, 50%).
    • More patients who underwent up-front surgery received radiation therapy (71%) than patients who started with chemotherapy (48%).

In summary, surgery is chosen as definitive local therapy for suitable patients, but radiation therapy is appropriate for patients with unresectable disease or those who would experience functional or cosmetic compromise by definitive surgery. The possibility of impaired function or cosmesis needs to be measured against the possibility of second tumors in the radiation field. Adjuvant radiation therapy should be considered for patients with residual microscopic disease or inadequate margins.

When preoperative assessment has suggested a high probability that surgical margins will be close or positive, preoperative radiation therapy has achieved tumor shrinkage and allowed surgical resection with clear margins.[37]

Multiple analyses have evaluated diagnostic findings, treatment, and outcome of patients with bone lesions at the following anatomical primary sites:

  • Pelvis.[38–40]
  • Femur.[41,42]
  • Humerus.[43,44]
  • Hand and foot.[45,46]
  • Chest wall/rib.[36,47–49]
  • Head and neck.[50]
  • Spine/sacrum.[51–54]

High-Dose Chemotherapy With Stem Cell Support for Ewing Sarcoma

For patients with a high risk of relapse with conventional treatments, some investigators have used high-dose chemotherapy with hematopoietic stem cell transplant (HSCT) as consolidation treatment, in an effort to improve outcome.[19,55–67]

Evidence (high-dose therapy with stem cell support):

  1. In a prospective study, patients with bone and/or bone marrow metastases at diagnosis were treated with aggressive chemotherapy, surgery, and/or radiation therapy and HSCT if a good initial response was achieved.[60]
    • The study showed no benefit for HSCT compared with historical controls.
  2. A retrospective review using international bone marrow transplant registries compared the outcomes after treatment with either reduced-intensity conditioning or high-intensity conditioning followed by allogeneic HSCT for patients with Ewing sarcoma at high risk of relapse.[68][Level of evidence C1]
    • There was no difference in outcome, and the authors concluded that this suggested the absence of a clinically relevant graft-versus-tumor effect against Ewing sarcoma tumor cells with current approaches.
  3. The role of high-dose therapy with busulfan-melphalan (BuMel) followed by stem cell rescue was investigated in the prospective randomized EURO-EWING-INTERGROUP-EE99 (NCT00020566) trial for two distinct groups:[69]
    1. Patients who presented with isolated pulmonary metastases (R2pulm).
    2. Patients with localized tumors with poor response to initial chemotherapy (<90% necrosis) or with large tumors (>200 mL) (R2loc).

      Both study arms were compromised by the potential for selection bias for patients who were eligible for and accepted randomization, which may limit the generalizability of the results. Only 40% of eligible patients were randomized.

      • For R2pulm patients, there was no statistically significant difference in EFS or OS between the treatment groups.[70]
        • The EFS rates at 3 years were 50.6% for patients who received VAI plus whole-lung irradiation versus 56.6% for patients who received BuMel. The EFS rates at 8 years were 43.1% for patients who received VAI plus whole-lung irradiation versus 52.9% for patients who received BuMel.
        • The OS rates at 3 years were 68.0% for patients who received VAI plus whole-lung irradiation versus 68.2% for patients who received BuMel. The OS rates at 8 years were 54.2% for patients who received VAI plus whole-lung irradiation versus 55.3% for patients who received BuMel.
      • Among R2loc patients, the 3-year EFS rate was superior with BuMel compared with continued chemotherapy (66.9% vs. 53.1%; P = .019). The 3-year OS rate was 78.0% with BuMel and 72.2% with continued chemotherapy (P = .028).[69]

    The induction regimen employed in the EURO-EWING-INTERGROUP-EE99 trial was VIDE. This regimen is less dose intensive than the regimen employed in COG studies. This can be inferred from the intended dose intensity of the agents employed for the 21-week period that preceded randomization in the EURO-EWING-INTERGROUP-EE99 study (see Table 6). The lower dose intensity can also be inferred from the outcome of the EURO-EWING-INTERGROUP-EE99 study for patients in the localized disease stratum. Results from this study include the following:

    • Patients assigned to the most favorable risk stratum, R1, were patients with small primary tumors, less than 200 mL in volume. In addition, patients who had poor response to the initial six cycles of therapy with VIDE, as assessed by pathology or radiology, were removed from the R1 stratum and assigned to the R2 stratum. As a result, the R1 stratum includes only patients with small primary tumors and favorable response to initial therapy. The probability for EFS at 3 years for this favorable group was 76%, and the OS rate at 3 years was 85%.[28]
    • For all patients with localized Ewing sarcoma, including patients with large primary tumors and patients with poor response to initial therapy treated on the COG-AEWS1031 (NCT01231906) trial, the 5-year probability for EFS was 73%, and the 5-year OS rate was 88%.[24]

    The observation that high-dose therapy with autologous stem cell rescue improved outcomes for patients with a poor response to initial therapy in the EURO-EWING-INTERGROUP-EE99 study must be interpreted in this context. The advantage of high-dose therapy as consolidation for patients with a poor response to initial treatment with a less intensive regimen cannot be extrapolated to a population of patients who received a more intensive treatment regimen as initial therapy.

    Table 6. Comparison of the Dose Intensity of the EURO-EWING-INTERGROUP-EE99 Trial Versus COG Interval Dose Compression
    Chemotherapy Agent Prescribed Dose Intensity (mg/week)
      EURO-EWING-INTERGROUP-EE99 Trial [28] COG Interval Dose Compression [24]
    COG = Children’s Oncology Group.
    Vincristine 0.5 mg/m2 0.43 mg/m2
    Doxorubicin 17.1 mg/m2 21.4 mg/m2
    Ifosfamide 3,000 mg/m2 2,150 mg/m2
    Cyclophosphamide 0 343 mg/m2
    Cyclophosphamide equivalent dose (= cyclophosphamide dose + ifosfamide dose × 0.244) 732 mg/m2 868 mg/m2
  4. Multiple small studies that report benefit for HSCT have been published but are difficult to interpret because only patients who have a good initial response to standard chemotherapy are considered for HSCT.

Extraosseous Ewing Sarcoma

Extraosseous Ewing sarcoma is biologically similar to Ewing sarcoma arising in bone. Historically, most children and young adults with extraosseous Ewing sarcoma were treated on protocols designed for the treatment of rhabdomyosarcoma. This is important because many of the treatment regimens for rhabdomyosarcoma do not include an anthracycline, which is a critical component of current treatment regimens for Ewing sarcoma. Currently, patients with extraosseous Ewing sarcoma are eligible for studies that include Ewing sarcoma of bone.

Evidence (treatment of extraosseous Ewing sarcoma):

  1. From 1987 to 2004, 111 patients with nonmetastatic extraosseous Ewing sarcoma were enrolled on the RMS-88 and RMS-96 protocols.[71] Patients with initial complete tumor resection received ifosfamide, vincristine, and actinomycin (IVA) while patients with residual tumor received IVA plus doxorubicin (VAIA) or IVA plus carboplatin, epirubicin, and etoposide (CEVAIE). Seventy-six percent of patients received radiation.
    • The 5-year EFS rate was 59%, and the OS rate was 69%.
    • In a multivariate analysis, independent adverse prognostic factors included axial primary, tumor size greater than 10 cm, Intergroup Rhabdomyosarcoma Studies Group III, and lack of radiation therapy.
  2. In a retrospective French study, patients with extraosseous Ewing sarcoma were treated using a rhabdomyosarcoma regimen (no anthracyclines) or a Ewing sarcoma regimen (includes anthracyclines).[72,73]
    • Patients who received the anthracycline-containing regimen had a significantly better EFS and OS than patients who did not receive anthracyclines.
  3. Two North American Ewing sarcoma trials included patients with extraosseous Ewing sarcoma.[24,74] In a review of data from the POG-9354 (INT-0154) and EWS0031 (NCT00006734) studies, 213 patients with extraosseous Ewing sarcoma and 826 patients with Ewing sarcoma of bone were identified.[75][Level of evidence C2]
    • The HR for EFS of extraosseous Ewing sarcoma was superior (0.62), and extraosseous Ewing sarcoma was a favorable risk factor, independent of age, race, and primary site.
  4. In addition to the above review, the COG AEWS1031 (NCT01231906) trial subsequently treated patients using a compressed chemotherapy schedule (every 2 weeks). Patients were randomly assigned to receive standard cycles of vincristine, doxorubicin, and cyclophosphamide, alternating with either ifosfamide and etoposide or vincristine, topotecan and cyclophosphamide every third cycle. There were 116 patients with extraosseous tumors, 114 patients with pelvic bone tumors, and 399 patients with nonpelvic bone tumors.[26]
    • There were no differences in patient outcomes between the treatment regimens.
    • The 5-year EFS rates were 75% (95% CI, 65%–82%) for patients with pelvic bone tumors, 78% (95% CI, 73%–81%) for patients with nonpelvic bone tumors, and 85% (95% CI, 76%–90%) for patients with extraosseous primary sites (global P value = .124).
  5. The Cooperative Weichteilsarkomstudiengruppe (CWS) performed a retrospective analysis of 243 patients with nonmetastatic extraosseous Ewing sarcoma treated on three consecutive soft tissue sarcoma studies between 1991 and 2008. Several different drug regimens were used, all containing vincristine, doxorubicin, and alkylating agents.[76]
    • The outcome improved over time, but it was difficult to assign causality to any specific therapy with these historical comparisons.
    • Patients with extremity primary tumors (compared with other locations) and patients with smaller tumors had better outcomes.
    • The 5-year EFS rate varied, from 57% to 79%, with the better outcome seen in the most recent protocol.

Cutaneous Ewing sarcoma is a soft tissue tumor in the skin or subcutaneous tissue that seems to behave as a less-aggressive tumor than primary bone or soft tissue Ewing sarcoma. Tumors can form throughout the body, although the extremity is the most common site, and they are almost always localized.

Evidence (treatment of cutaneous Ewing sarcoma):

  1. In a review of 78 reported cases (some lacking molecular confirmation), the OS rate was 91%. Adequate local control, defined as a complete resection with negative margins, radiation therapy, or a combination, significantly reduced the incidence of relapse. Standard chemotherapy for Ewing sarcoma is often used for these patients because there are no data to suggest which patients could be treated less aggressively.[77,78]
  2. A series of 56 patients with cutaneous or subcutaneous Ewing sarcoma confirmed the excellent outcome with the use of standard systemic therapy and local control. Attempted primary definitive surgery often resulted in the need for either radiation therapy or more function-compromising surgery, supporting the recommendation of biopsy only as initial surgery, rather than up-front unplanned resection.[79][Level of evidence C2]
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  21. Miser JS, Goldsby RE, Chen Z, et al.: Treatment of metastatic Ewing sarcoma/primitive neuroectodermal tumor of bone: evaluation of increasing the dose intensity of chemotherapy–a report from the Children’s Oncology Group. Pediatr Blood Cancer 49 (7): 894-900, 2007. [PUBMED Abstract]
  22. Haeusler J, Ranft A, Boelling T, et al.: The value of local treatment in patients with primary, disseminated, multifocal Ewing sarcoma (PDMES). Cancer 116 (2): 443-50, 2010. [PUBMED Abstract]
  23. Paulussen M, Craft AW, Lewis I, et al.: Results of the EICESS-92 Study: two randomized trials of Ewing’s sarcoma treatment–cyclophosphamide compared with ifosfamide in standard-risk patients and assessment of benefit of etoposide added to standard treatment in high-risk patients. J Clin Oncol 26 (27): 4385-93, 2008. [PUBMED Abstract]
  24. Womer RB, West DC, Krailo MD, et al.: Randomized controlled trial of interval-compressed chemotherapy for the treatment of localized Ewing sarcoma: a report from the Children’s Oncology Group. J Clin Oncol 30 (33): 4148-54, 2012. [PUBMED Abstract]
  25. Cash T, Krailo MD, Buxton AB, et al.: Long-Term Outcomes in Patients With Localized Ewing Sarcoma Treated With Interval-Compressed Chemotherapy on Children’s Oncology Group Study AEWS0031. J Clin Oncol 41 (30): 4724-4728, 2023. [PUBMED Abstract]
  26. Leavey PJ, Laack NN, Krailo MD, et al.: Phase III Trial Adding Vincristine-Topotecan-Cyclophosphamide to the Initial Treatment of Patients With Nonmetastatic Ewing Sarcoma: A Children’s Oncology Group Report. J Clin Oncol 39 (36): 4029-4038, 2021. [PUBMED Abstract]
  27. Brennan B, Kirton L, Marec-Bérard P, et al.: Comparison of two chemotherapy regimens in patients with newly diagnosed Ewing sarcoma (EE2012): an open-label, randomised, phase 3 trial. Lancet 400 (10362): 1513-1521, 2022. [PUBMED Abstract]
  28. Le Deley MC, Paulussen M, Lewis I, et al.: Cyclophosphamide compared with ifosfamide in consolidation treatment of standard-risk Ewing sarcoma: results of the randomized noninferiority Euro-EWING99-R1 trial. J Clin Oncol 32 (23): 2440-8, 2014. [PUBMED Abstract]
  29. Brunetto AL, Castillo LA, Petrilli AS, et al.: Carboplatin in the treatment of Ewing sarcoma: Results of the first Brazilian collaborative study group for Ewing sarcoma family tumors-EWING1. Pediatr Blood Cancer 62 (10): 1747-53, 2015. [PUBMED Abstract]
  30. DuBois SG, Krailo MD, Gebhardt MC, et al.: Comparative evaluation of local control strategies in localized Ewing sarcoma of bone: a report from the Children’s Oncology Group. Cancer 121 (3): 467-75, 2015. [PUBMED Abstract]
  31. Lin TA, Ludmir EB, Liao KP, et al.: Timing of Local Therapy Affects Survival in Ewing Sarcoma. Int J Radiat Oncol Biol Phys 104 (1): 127-136, 2019. [PUBMED Abstract]
  32. Yock TI, Krailo M, Fryer CJ, et al.: Local control in pelvic Ewing sarcoma: analysis from INT-0091–a report from the Children’s Oncology Group. J Clin Oncol 24 (24): 3838-43, 2006. [PUBMED Abstract]
  33. Andreou D, Ranft A, Gosheger G, et al.: Which Factors Are Associated with Local Control and Survival of Patients with Localized Pelvic Ewing’s Sarcoma? A Retrospective Analysis of Data from the Euro-EWING99 Trial. Clin Orthop Relat Res 478 (2): 290-302, 2020. [PUBMED Abstract]
  34. Foulon S, Brennan B, Gaspar N, et al.: Can postoperative radiotherapy be omitted in localised standard-risk Ewing sarcoma? An observational study of the Euro-E.W.I.N.G group. Eur J Cancer 61: 128-36, 2016. [PUBMED Abstract]
  35. Seitz G, Urla C, Sparber-Sauer M, et al.: Treatment and outcome of patients with thoracic tumors of the Ewing sarcoma family: A report from the Cooperative Weichteilsarkom Studiengruppe CWS-81, -86, -91, -96, and -2002P trials. Pediatr Blood Cancer 66 (3): e27537, 2019. [PUBMED Abstract]
  36. Shamberger RC, LaQuaglia MP, Gebhardt MC, et al.: Ewing sarcoma/primitive neuroectodermal tumor of the chest wall: impact of initial versus delayed resection on tumor margins, survival, and use of radiation therapy. Ann Surg 238 (4): 563-7; discussion 567-8, 2003. [PUBMED Abstract]
  37. Wagner TD, Kobayashi W, Dean S, et al.: Combination short-course preoperative irradiation, surgical resection, and reduced-field high-dose postoperative irradiation in the treatment of tumors involving the bone. Int J Radiat Oncol Biol Phys 73 (1): 259-66, 2009. [PUBMED Abstract]
  38. Hoffmann C, Ahrens S, Dunst J, et al.: Pelvic Ewing sarcoma: a retrospective analysis of 241 cases. Cancer 85 (4): 869-77, 1999. [PUBMED Abstract]
  39. Sucato DJ, Rougraff B, McGrath BE, et al.: Ewing’s sarcoma of the pelvis. Long-term survival and functional outcome. Clin Orthop (373): 193-201, 2000. [PUBMED Abstract]
  40. Bacci G, Ferrari S, Mercuri M, et al.: Multimodal therapy for the treatment of nonmetastatic Ewing sarcoma of pelvis. J Pediatr Hematol Oncol 25 (2): 118-24, 2003. [PUBMED Abstract]
  41. Bacci G, Ferrari S, Longhi A, et al.: Local and systemic control in Ewing’s sarcoma of the femur treated with chemotherapy, and locally by radiotherapy and/or surgery. J Bone Joint Surg Br 85 (1): 107-14, 2003. [PUBMED Abstract]
  42. Ozaki T, Hillmann A, Hoffmann C, et al.: Ewing’s sarcoma of the femur. Prognosis in 69 patients treated by the CESS group. Acta Orthop Scand 68 (1): 20-4, 1997. [PUBMED Abstract]
  43. Ayoub KS, Fiorenza F, Grimer RJ, et al.: Extensible endoprostheses of the humerus after resection of bone tumours. J Bone Joint Surg Br 81 (3): 495-500, 1999. [PUBMED Abstract]
  44. Bacci G, Palmerini E, Staals EL, et al.: Ewing’s sarcoma family tumors of the humerus: outcome of patients treated with radiotherapy, surgery or surgery and adjuvant radiotherapy. Radiother Oncol 93 (2): 383-7, 2009. [PUBMED Abstract]
  45. Casadei R, Magnani M, Biagini R, et al.: Prognostic factors in Ewing’s sarcoma of the foot. Clin Orthop (420): 230-8, 2004. [PUBMED Abstract]
  46. Anakwenze OA, Parker WL, Wold LE, et al.: Ewing’s sarcoma of the hand. J Hand Surg Eur Vol 34 (1): 35-9, 2009. [PUBMED Abstract]
  47. Shamberger RC, Laquaglia MP, Krailo MD, et al.: Ewing sarcoma of the rib: results of an intergroup study with analysis of outcome by timing of resection. J Thorac Cardiovasc Surg 119 (6): 1154-61, 2000. [PUBMED Abstract]
  48. Sirvent N, Kanold J, Levy C, et al.: Non-metastatic Ewing’s sarcoma of the ribs: the French Society of Pediatric Oncology Experience. Eur J Cancer 38 (4): 561-7, 2002. [PUBMED Abstract]
  49. Schuck A, Ahrens S, Konarzewska A, et al.: Hemithorax irradiation for Ewing tumors of the chest wall. Int J Radiat Oncol Biol Phys 54 (3): 830-8, 2002. [PUBMED Abstract]
  50. Windfuhr JP: Primitive neuroectodermal tumor of the head and neck: incidence, diagnosis, and management. Ann Otol Rhinol Laryngol 113 (7): 533-43, 2004. [PUBMED Abstract]
  51. Venkateswaran L, Rodriguez-Galindo C, Merchant TE, et al.: Primary Ewing tumor of the vertebrae: clinical characteristics, prognostic factors, and outcome. Med Pediatr Oncol 37 (1): 30-5, 2001. [PUBMED Abstract]
  52. Marco RA, Gentry JB, Rhines LD, et al.: Ewing’s sarcoma of the mobile spine. Spine 30 (7): 769-73, 2005. [PUBMED Abstract]
  53. Schuck A, Ahrens S, von Schorlemer I, et al.: Radiotherapy in Ewing tumors of the vertebrae: treatment results and local relapse analysis of the CESS 81/86 and EICESS 92 trials. Int J Radiat Oncol Biol Phys 63 (5): 1562-7, 2005. [PUBMED Abstract]
  54. Bacci G, Boriani S, Balladelli A, et al.: Treatment of nonmetastatic Ewing’s sarcoma family tumors of the spine and sacrum: the experience from a single institution. Eur Spine J 18 (8): 1091-5, 2009. [PUBMED Abstract]
  55. Kushner BH, Meyers PA: How effective is dose-intensive/myeloablative therapy against Ewing’s sarcoma/primitive neuroectodermal tumor metastatic to bone or bone marrow? The Memorial Sloan-Kettering experience and a literature review. J Clin Oncol 19 (3): 870-80, 2001. [PUBMED Abstract]
  56. Marina N, Meyers PA: High-dose therapy and stem-cell rescue for Ewing’s family of tumors in second remission. J Clin Oncol 23 (19): 4262-4, 2005. [PUBMED Abstract]
  57. Burdach S: Treatment of advanced Ewing tumors by combined radiochemotherapy and engineered cellular transplants. Pediatr Transplant 8 (Suppl 5): 67-82, 2004. [PUBMED Abstract]
  58. McTiernan A, Driver D, Michelagnoli MP, et al.: High dose chemotherapy with bone marrow or peripheral stem cell rescue is an effective treatment option for patients with relapsed or progressive Ewing’s sarcoma family of tumours. Ann Oncol 17 (8): 1301-5, 2006. [PUBMED Abstract]
  59. Burdach S, Meyer-Bahlburg A, Laws HJ, et al.: High-dose therapy for patients with primary multifocal and early relapsed Ewing’s tumors: results of two consecutive regimens assessing the role of total-body irradiation. J Clin Oncol 21 (16): 3072-8, 2003. [PUBMED Abstract]
  60. Meyers PA, Krailo MD, Ladanyi M, et al.: High-dose melphalan, etoposide, total-body irradiation, and autologous stem-cell reconstitution as consolidation therapy for high-risk Ewing’s sarcoma does not improve prognosis. J Clin Oncol 19 (11): 2812-20, 2001. [PUBMED Abstract]
  61. Oberlin O, Rey A, Desfachelles AS, et al.: Impact of high-dose busulfan plus melphalan as consolidation in metastatic Ewing tumors: a study by the Société Française des Cancers de l’Enfant. J Clin Oncol 24 (24): 3997-4002, 2006. [PUBMED Abstract]
  62. Hawkins D, Barnett T, Bensinger W, et al.: Busulfan, melphalan, and thiotepa with or without total marrow irradiation with hematopoietic stem cell rescue for poor-risk Ewing-Sarcoma-Family tumors. Med Pediatr Oncol 34 (5): 328-37, 2000. [PUBMED Abstract]
  63. Rosenthal J, Bolotin E, Shakhnovits M, et al.: High-dose therapy with hematopoietic stem cell rescue in patients with poor prognosis Ewing family tumors. Bone Marrow Transplant 42 (5): 311-8, 2008. [PUBMED Abstract]
  64. Burdach S, Thiel U, Schöniger M, et al.: Total body MRI-governed involved compartment irradiation combined with high-dose chemotherapy and stem cell rescue improves long-term survival in Ewing tumor patients with multiple primary bone metastases. Bone Marrow Transplant 45 (3): 483-9, 2010. [PUBMED Abstract]
  65. Gaspar N, Rey A, Bérard PM, et al.: Risk adapted chemotherapy for localised Ewing’s sarcoma of bone: the French EW93 study. Eur J Cancer 48 (9): 1376-85, 2012. [PUBMED Abstract]
  66. Drabko K, Raciborska A, Bilska K, et al.: Consolidation of first-line therapy with busulphan and melphalan, and autologous stem cell rescue in children with Ewing’s sarcoma. Bone Marrow Transplant 47 (12): 1530-4, 2012. [PUBMED Abstract]
  67. Loschi S, Dufour C, Oberlin O, et al.: Tandem high-dose chemotherapy strategy as first-line treatment of primary disseminated multifocal Ewing sarcomas in children, adolescents and young adults. Bone Marrow Transplant 50 (8): 1083-8, 2015. [PUBMED Abstract]
  68. Thiel U, Wawer A, Wolf P, et al.: No improvement of survival with reduced- versus high-intensity conditioning for allogeneic stem cell transplants in Ewing tumor patients. Ann Oncol 22 (7): 1614-21, 2011. [PUBMED Abstract]
  69. Whelan J, Le Deley MC, Dirksen U, et al.: High-Dose Chemotherapy and Blood Autologous Stem-Cell Rescue Compared With Standard Chemotherapy in Localized High-Risk Ewing Sarcoma: Results of Euro-E.W.I.N.G.99 and Ewing-2008. J Clin Oncol : JCO2018782516, 2018. [PUBMED Abstract]
  70. Dirksen U, Brennan B, Le Deley MC, et al.: High-Dose Chemotherapy Compared With Standard Chemotherapy and Lung Radiation in Ewing Sarcoma With Pulmonary Metastases: Results of the European Ewing Tumour Working Initiative of National Groups, 99 Trial and EWING 2008. J Clin Oncol 37 (34): 3192-3202, 2019. [PUBMED Abstract]
  71. Spiller M, Bisogno G, Ferrari A, et al.: Prognostic factors in localized extraosseus Ewing family tumors. [Abstract] Pediatr Blood Cancer 46 (10) : A-PD.024, 434, 2006.
  72. Castex MP, Rubie H, Stevens MC, et al.: Extraosseous localized ewing tumors: improved outcome with anthracyclines–the French society of pediatric oncology and international society of pediatric oncology. J Clin Oncol 25 (10): 1176-82, 2007. [PUBMED Abstract]
  73. 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]
  74. Granowetter L, Womer R, Devidas M, et al.: Dose-intensified compared with standard chemotherapy for nonmetastatic Ewing sarcoma family of tumors: a Children’s Oncology Group Study. J Clin Oncol 27 (15): 2536-41, 2009. [PUBMED Abstract]
  75. Cash T, McIlvaine E, Krailo MD, et al.: Comparison of clinical features and outcomes in patients with extraskeletal versus skeletal localized Ewing sarcoma: A report from the Children’s Oncology Group. Pediatr Blood Cancer 63 (10): 1771-9, 2016. [PUBMED Abstract]
  76. Koscielniak E, Sparber-Sauer M, Scheer M, et al.: Extraskeletal Ewing sarcoma in children, adolescents, and young adults. An analysis of three prospective studies of the Cooperative Weichteilsarkomstudiengruppe (CWS). Pediatr Blood Cancer 68 (10): e29145, 2021. [PUBMED Abstract]
  77. Collier AB, Simpson L, Monteleone P: Cutaneous Ewing sarcoma: report of 2 cases and literature review of presentation, treatment, and outcome of 76 other reported cases. J Pediatr Hematol Oncol 33 (8): 631-4, 2011. [PUBMED Abstract]
  78. Terrier-Lacombe MJ, Guillou L, Chibon F, et al.: Superficial primitive Ewing’s sarcoma: a clinicopathologic and molecular cytogenetic analysis of 14 cases. Mod Pathol 22 (1): 87-94, 2009. [PUBMED Abstract]
  79. Di Giannatale A, Frezza AM, Le Deley MC, et al.: Primary cutaneous and subcutaneous Ewing sarcoma. Pediatr Blood Cancer 62 (9): 1555-61, 2015. [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.

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.

Treatment of Localized Ewing Sarcoma

Standard treatment options for localized Ewing sarcoma include the following:

  1. Chemotherapy.
  2. Local-control measures:
  3. High-dose chemotherapy with autologous stem cell rescue.

Because most patients with apparently localized disease at diagnosis have occult metastatic disease, multidrug chemotherapy and surgery and/or radiation therapy (to control local disease) is indicated in the treatment of all patients.[1–8] Patients with localized Ewing sarcoma who receive current treatment regimens achieve event-free survival (EFS) and overall survival (OS) rates of approximately 70% at 5 years after diagnosis.[9]

Chemotherapy

Current standard chemotherapy in the United States includes vincristine, doxorubicin, and cyclophosphamide (VDC), alternating with ifosfamide and etoposide (IE) or VDC/IE.[9]; [10][Level of evidence A1] With the outcome of the EURO EWING 2012 (EE2012) trial, which compared VDC/IE to VIDE (vincristine, ifosfamide, doxorubicin, etoposide), the VDC/IE regimen has become increasingly used internationally as initial therapy over the previous VIDE regimen.[11][Level of evidence B1] For more information about the EE2012 trial, see the Chemotherapy for Ewing Sarcoma section.

Evidence (chemotherapy):

  1. IE has shown activity in Ewing sarcoma. A large randomized clinical trial and a nonrandomized trial demonstrated that outcome was improved when IE was alternated with VDC.[9,12]
  2. The use of high-dose VDC has shown promising results in small numbers of patients. A single-institution study of 44 patients treated with high-dose VDC and IE showed a 4-year EFS rate of 82%.[13]
  3. However, in an intergroup trial of the Pediatric Oncology Group and the Children’s Cancer Group, which compared an alkylator dose-intensified VDC/IE regimen with standard alkylator doses of the same VDC/IE regimen, no differences in outcome were observed.[14] Unlike the single-institution trial, this trial did not maintain the dose intensity of cyclophosphamide for the duration of treatment.[13]
  4. In a Children’s Oncology Group (COG) trial (COG-AEWS0031 [NCT00006734]), 568 patients with newly diagnosed localized extradural Ewing sarcoma were randomly assigned to receive chemotherapy (VDC/IE) given either every 2 weeks (interval compression) or every 3 weeks (standard).[10]
    • Patients randomly assigned to the every-2-week interval of treatment had an improved 5-year EFS rate (73% vs. 65%, P = .048).
    • There was no increase in toxicity observed with the every-2-week schedule.
    • With longer follow-up of 10 years, interval-compressed VDC/IE continued to demonstrate superior EFS. OS was also significantly higher with this regimen than with VDC/IE given every 3 weeks.[15]
  5. The European Ewing 2008R1 trial evaluated 284 patients with standard-risk Ewing sarcoma, defined as localized disease with favorable histological response to initial chemotherapy and/or an initial tumor volume of less than 200 mL. All patients received VIDE chemotherapy followed by vincristine, dactinomycin, and ifosfamide (VAI) (male) or vincristine, dactinomycin, and cyclophosphamide (VAC) (female) consolidation therapy. During the sixth cycle of consolidation, patients were randomly assigned to therapy with either the addition of zoledronic acid for nine 28-day cycles or no maintenance therapy.[16]
    • Outcomes were similar between patients who received zoledronic acid and patients who did not receive maintenance therapy (3-year EFS rates, 84.0% vs. 81.7%).
    • Patients who received zoledronic acid experienced higher rates of renal, neurological, and gastrointestinal toxicities.
  6. EE2012 was a European investigator–initiated, open-label, randomized, controlled, phase III trial that took place in ten countries. Between 2014 and 2019, 640 patients were enrolled and were randomly allocated (1:1) to either the European or COG treatment regimens (320 patients in each treatment group). The European treatment regimen for induction included VIDE, and the consolidation regimen included vincristine, dactinomycin, with ifosfamide or cyclophosphamide, or busulfan and melphalan (group 1). The COG treatment regimen for induction included interval-compressed VDC/IE, and the consolidation regimen included vincristine and cyclophosphamide, with ifosfamide and etoposide or busulfan and melphalan (group 2).[11][Level of evidence B1]
    • The 3-year EFS rate was 61% for patients in group 1 and 67% for patients in group 2 (adjusted hazard ratio [HR], 0.71; 95% confidence interval [CI], 0.55–0.92 in favor of group 2).
    • The probability that the true HR for group 2 with interval-compressed VDC/IE was less than 1 was greater than 0.99.
    • The investigators concluded that dose-intensive induction chemotherapy with the VDC/IE regimen was more effective, less toxic, and shorter in duration for patients with all stages of newly diagnosed Ewing sarcoma than the VIDE regimen.

Local-Control Measures

Local control can be achieved by surgery and/or radiation therapy. Decisions regarding the optimal modality for local control for an individual patient involve consideration of the following:

  • The possibility of complete resection with adequate margins after an initial period of systemic therapy.
  • The predicted functional impact of a surgical procedure.
  • The predicted morbidity after radiation therapy.
  • The possibility of increased risk of second malignant neoplasms after radiation therapy.

An analysis using propensity scoring (a method that adjusts for the inherent selection bias of the location and size of the tumor) to adjust for clinical features that may influence the preference for surgery only, radiation only, or combined surgery and radiation demonstrated that similar EFS rates are achieved with each mode of local therapy after propensity adjustment.[17]

Surgery

Surgery is generally the preferred approach if the lesion is resectable.[18,19] The superiority of resection for local control has never been tested in a prospective randomized trial. The apparent superiority may represent selection bias.

  1. In past studies, smaller, more peripheral tumors were more likely to be treated with surgery, and larger, more central tumors were more likely to be treated with radiation therapy.[20]
  2. An Italian retrospective study showed that surgery improved outcome only in extremity tumors, although the number of patients with central axis Ewing sarcoma who achieved adequate margins was small.[8]
  3. In a series of 39 patients who received both surgery and radiation therapy at St. Jude Children’s Research Hospital, the 8-year local failure rate was 5% for patients with negative surgical margins and 17% for those with positive margins.[5]
  4. Data for patients with pelvic primary Ewing sarcoma from a North American intergroup trial showed no difference in local control or survival based on local-control modality—surgery alone, radiation therapy alone, or radiation plus surgery.[21]
  5. Patients with residual viable tumor in the resected specimen have a worse outcome than those with complete necrosis. In a French Ewing sarcoma study (EW88), the EFS rates were 75% for patients with less than 5% viable tumor, 48% for patients with 5% to 30% viable tumor, and 20% for patients with more than 30% viable tumor.[20]

A single-institution retrospective analysis of 78 patients with Ewing sarcoma suggested that pathological fracture at initial presentation was associated with inferior EFS and OS.[22][Level of evidence C1] Another study found that pathological fracture at the time of diagnosis did not preclude surgical resection and was not associated with adverse outcome.[23]

Radiation therapy

Radiation therapy is usually employed in the following cases:

  • Patients who do not have a surgical option that preserves function and cosmesis.
  • Patients whose tumors have been excised but with inadequate margins.
  • Preoperative radiation therapy if gross-total resection is possible but without adequate margins (and preservation of function and cosmesis).

Radiation therapy is delivered in a setting in which stringent planning techniques are applied by those experienced in the treatment of Ewing sarcoma. Such an approach will result in local control of the tumor with acceptable morbidity in most patients.[1,2,24]

The radiation dose may be adjusted depending on the extent of residual disease after the initial surgical procedure. When no surgical resection is performed, radiation therapy is generally administered in fractionated doses totaling approximately 55.8 Gy to the prechemotherapy tumor volume. A randomized study of 40 patients with Ewing sarcoma using 55.8 Gy to the prechemotherapy tumor extent with a 2-cm margin compared with the same total-tumor dose after 39.6 Gy to the entire bone showed no difference in local control or EFS.[3] Hyperfractionated radiation therapy has not been associated with improved local control or decreased morbidity.[1]

Preoperative radiation therapy is an approach that can be used when surgical resection is deemed possible but with the likelihood of microscopic residual disease. A panel of international expert clinicians used a three-stage modified Delphi technique to develop consensus statements about local treatment. The panel reached a strong consensus that preoperative radiation therapy may be given when an inadequate (marginal) margin at resection is foreseen on imaging.[25]

For patients with residual disease after an attempt at surgical resection, the Intergroup Ewing Sarcoma Study (INT-0091) recommended 45 Gy to the original disease site plus a 10.8 Gy boost for patients with gross residual disease and 45 Gy plus a 5.4 Gy boost for patients with microscopic residual disease. No radiation therapy was recommended for those who had no evidence of microscopic residual disease after surgical resection.[14]

For patients who are deemed to have unresectable disease after induction chemotherapy, radiation therapy is given, using the same doses as those administered for patients with partially resected disease.[26] Patients who have unresectable disease are typically those with extremity tumors that have persistent encasement of the neurovascular bundles and/or morbid surgical excision entailing loss of functionality. In a phase III randomized controlled clinical trial of patients with unresectable disease, patients were randomly assigned to receive either standard-dose radiation therapy (55.8 Gy in 1.8 Gy fractions) or escalated-dose radiation therapy (70.2 Gy in 1.8 Gy fractions).[26] From 2005 to 2015, the study accrued 47 patients who received standard-dose radiation therapy and 48 patients who received escalated-dose radiation therapy (interquartile age, 13–23 years). The median largest tumor dimension was 9.7 cm. At a median follow-up of 67 months, the 5-year local control rate was significantly better in the escalated arm than in the standard arm (76.4% vs. 49.4%; P = .02). The differences in disease-free survival (DFS) and OS at 5 years did not achieve statistical significance (DFS rates, 46.7% vs. 31.8%; P = .22; OS rates, 58.8% vs. 45.4%; P = .08), possibly because the rate of metastatic disease was not changed. A skin toxicity grade of more than 2 was greater in the high-dose arm (10.4% vs. 2.1%; P = .08).

In a single-institution nonrandomized study, patients who had primary tumors 8 cm or larger were treated with higher-dose radiation therapy (median dose, 64.8 Gy). The 5-year cumulative incidence of local failure rate was 6.6%, which compares favorably to other published local failure rates in this group of patients.[27]

Comparison of proton-beam radiation therapy and intensity-modulated radiation therapy (IMRT) treatment plans has shown that proton-beam radiation therapy can spare more normal tissue adjacent to Ewing sarcoma primary tumors than IMRT.[28] Follow-up remains relatively short, and there are no data to determine whether the reduction in dose to adjacent tissue will result in improved functional outcome or reduce the risk of secondary malignancy. Because patient numbers are small and follow-up is relatively short, it is not possible to determine whether the risk of local recurrence might be increased by reducing radiation dose in tissue adjacent to the primary tumor.

Higher rates of local failure are seen in patients older than 14 years who have tumors larger than 8 cm in length.[29] Among patients with pelvic tumors, a larger tumor volume, a periacetabular tumor site, and the use of definitive radiation therapy only (rather than a combined-modality approach) were associated with higher rates of local failure.[30] A retrospective analysis of patients with Ewing sarcoma of the chest wall compared patients who received hemithorax radiation therapy with those who received radiation therapy to the chest wall only. Patients with pleural invasion, pleural effusion, or intraoperative contamination were assigned to hemithorax radiation therapy. EFS was longer for patients who received hemithorax radiation, but the difference was not statistically significant. In addition, most patients with primary vertebral tumors did not receive hemithorax radiation and had a lower probability for EFS.[31]

Radiation therapy is associated with the development of subsequent neoplasms. A retrospective study noted that patients who received 60 Gy or more had an incidence of second malignancy of 20%. Patients who received 48 Gy to 60 Gy had an incidence of 5%, and those who received less than 48 Gy did not develop a second malignancy.[32]

High-Dose Chemotherapy With Autologous Stem Cell Rescue

Evidence (high-dose chemotherapy with autologous stem cell rescue):

  1. The role of high-dose therapy with busulfan-melphalan (BuMel) followed by stem cell rescue was investigated in the prospective randomized EURO-EWING-INTERGROUP-EE99 (NCT00020566) trial for two distinct groups:[33]
    1. Patients who presented with isolated pulmonary metastases (R2pulm).
    2. Patients with localized tumors with poor response to initial chemotherapy (<90% necrosis) or with large tumors (>200 mL) (R2loc).

      Both study arms were compromised by the potential for selection bias for patients who were eligible for and accepted randomization, which may limit the generalizability of the results. Only 40% of eligible patients were randomized.

      • For R2pulm patients, there was no statistically significant difference in EFS or OS between the treatment groups.[34]
        • The EFS rates at 3 years were 50.6% for patients who received vincristine, dactinomycin, and ifosfamide (VAI) plus whole-lung irradiation versus 56.6% for patients who received BuMel.
        • The EFS rates at 8 years were 43.1% for patients who received VAI plus whole-lung irradiation versus 52.9% for patients who received BuMel.
        • The OS rates at 3 years were 68.0% for patients who received VAI plus whole-lung irradiation versus 68.2% for patients who received BuMel.
        • The OS rates at 8 years were 54.2% for patients who received VAI plus whole-lung irradiation versus 55.3% for patients who received BuMel.
      • Among R2loc patients, the 3-year EFS rate was superior with BuMel compared with continued chemotherapy (66.9% vs. 53.1%; P = .019). The 3-year OS rate was 78.0% with BuMel and 72.2% with continued chemotherapy (P = .028).[33]

    The induction regimen employed in the EURO-EWING-INTERGROUP-EE99 trial included VIDE. This regimen is less dose intensive than the regimen employed in COG studies. This can be inferred from the intended dose intensity of the agents employed for the 21-week period that preceded randomization in the EURO-EWING-INTERGROUP-EE99 study (see Table 6). The lower dose intensity can also be inferred from the outcome of the EURO-EWING-INTERGROUP-EE99 study for patients in the localized disease stratum. Results from this study include the following:

    1. Patients assigned to the most favorable risk stratum, R1, were patients with small primary tumors, less than 200 mL in volume. In addition, patients who had poor response to the initial six cycles of therapy with VIDE, as assessed by pathology or radiology, were removed from the R1 stratum and assigned to the R2 stratum. As a result, the R1 stratum includes only patients with small primary tumors and favorable response to initial therapy.[35]
      • The probability for EFS at 3 years for this favorable group was 76%, and the OS rate at 3 years was 85%.
    2. For all patients with localized Ewing sarcoma, including patients with large primary tumors and patients with poor response to initial therapy treated on the COG-AEWS1031 (NCT01231906) trial, the 5-year probability for EFS was 73%, and the 5-year OS rate was 88%.[10]

    The observation that high-dose therapy with autologous stem cell rescue improved outcomes for patients with a poor response to initial therapy in the EURO-EWING-INTERGROUP-EE99 study must be interpreted in this context. The advantage of high-dose therapy as consolidation for patients with a poor response to initial treatment (with a less intensive regimen) cannot be extrapolated to a population of patients who received a more intensive treatment regimen as initial therapy.

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. Dunst J, Jürgens H, Sauer R, et al.: Radiation therapy in Ewing’s sarcoma: an update of the CESS 86 trial. Int J Radiat Oncol Biol Phys 32 (4): 919-30, 1995. [PUBMED Abstract]
  2. Donaldson SS, Torrey M, Link MP, et al.: A multidisciplinary study investigating radiotherapy in Ewing’s sarcoma: end results of POG #8346. Pediatric Oncology Group. Int J Radiat Oncol Biol Phys 42 (1): 125-35, 1998. [PUBMED Abstract]
  3. Craft A, Cotterill S, Malcolm A, et al.: Ifosfamide-containing chemotherapy in Ewing’s sarcoma: The Second United Kingdom Children’s Cancer Study Group and the Medical Research Council Ewing’s Tumor Study. J Clin Oncol 16 (11): 3628-33, 1998. [PUBMED Abstract]
  4. Nilbert M, Saeter G, Elomaa I, et al.: Ewing’s sarcoma treatment in Scandinavia 1984-1990–ten-year results of the Scandinavian Sarcoma Group Protocol SSGIV. Acta Oncol 37 (4): 375-8, 1998. [PUBMED Abstract]
  5. Krasin MJ, Davidoff AM, Rodriguez-Galindo C, et al.: Definitive surgery and multiagent systemic therapy for patients with localized Ewing sarcoma family of tumors: local outcome and prognostic factors. Cancer 104 (2): 367-73, 2005. [PUBMED Abstract]
  6. Bacci G, Forni C, Longhi A, et al.: Long-term outcome for patients with non-metastatic Ewing’s sarcoma treated with adjuvant and neoadjuvant chemotherapies. 402 patients treated at Rizzoli between 1972 and 1992. Eur J Cancer 40 (1): 73-83, 2004. [PUBMED Abstract]
  7. Rosito P, Mancini AF, Rondelli R, et al.: Italian Cooperative Study for the treatment of children and young adults with localized Ewing sarcoma of bone: a preliminary report of 6 years of experience. Cancer 86 (3): 421-8, 1999. [PUBMED Abstract]
  8. Bacci G, Longhi A, Briccoli A, et al.: The role of surgical margins in treatment of Ewing’s sarcoma family tumors: experience of a single institution with 512 patients treated with adjuvant and neoadjuvant chemotherapy. Int J Radiat Oncol Biol Phys 65 (3): 766-72, 2006. [PUBMED Abstract]
  9. Grier HE, Krailo MD, Tarbell NJ, et al.: Addition of ifosfamide and etoposide to standard chemotherapy for Ewing’s sarcoma and primitive neuroectodermal tumor of bone. N Engl J Med 348 (8): 694-701, 2003. [PUBMED Abstract]
  10. Womer RB, West DC, Krailo MD, et al.: Randomized controlled trial of interval-compressed chemotherapy for the treatment of localized Ewing sarcoma: a report from the Children’s Oncology Group. J Clin Oncol 30 (33): 4148-54, 2012. [PUBMED Abstract]
  11. Brennan B, Kirton L, Marec-Bérard P, et al.: Comparison of two chemotherapy regimens in patients with newly diagnosed Ewing sarcoma (EE2012): an open-label, randomised, phase 3 trial. Lancet 400 (10362): 1513-1521, 2022. [PUBMED Abstract]
  12. Ferrari S, Mercuri M, Rosito P, et al.: Ifosfamide and actinomycin-D, added in the induction phase to vincristine, cyclophosphamide and doxorubicin, improve histologic response and prognosis in patients with non metastatic Ewing’s sarcoma of the extremity. J Chemother 10 (6): 484-91, 1998. [PUBMED Abstract]
  13. Kolb EA, Kushner BH, Gorlick R, et al.: Long-term event-free survival after intensive chemotherapy for Ewing’s family of tumors in children and young adults. J Clin Oncol 21 (18): 3423-30, 2003. [PUBMED Abstract]
  14. Granowetter L, Womer R, Devidas M, et al.: Dose-intensified compared with standard chemotherapy for nonmetastatic Ewing sarcoma family of tumors: a Children’s Oncology Group Study. J Clin Oncol 27 (15): 2536-41, 2009. [PUBMED Abstract]
  15. Cash T, Krailo MD, Buxton AB, et al.: Long-Term Outcomes in Patients With Localized Ewing Sarcoma Treated With Interval-Compressed Chemotherapy on Children’s Oncology Group Study AEWS0031. J Clin Oncol 41 (30): 4724-4728, 2023. [PUBMED Abstract]
  16. Koch R, Haveman L, Ladenstein R, et al.: Zoledronic Acid Add-on Therapy for Standard-Risk Ewing Sarcoma Patients in the Ewing 2008R1 Trial. Clin Cancer Res 29 (24): 5057-5068, 2023. [PUBMED Abstract]
  17. DuBois SG, Krailo MD, Gebhardt MC, et al.: Comparative evaluation of local control strategies in localized Ewing sarcoma of bone: a report from the Children’s Oncology Group. Cancer 121 (3): 467-75, 2015. [PUBMED Abstract]
  18. Hoffmann C, Ahrens S, Dunst J, et al.: Pelvic Ewing sarcoma: a retrospective analysis of 241 cases. Cancer 85 (4): 869-77, 1999. [PUBMED Abstract]
  19. Shamberger RC, Laquaglia MP, Krailo MD, et al.: Ewing sarcoma of the rib: results of an intergroup study with analysis of outcome by timing of resection. J Thorac Cardiovasc Surg 119 (6): 1154-61, 2000. [PUBMED Abstract]
  20. Oberlin O, Deley MC, Bui BN, et al.: Prognostic factors in localized Ewing’s tumours and peripheral neuroectodermal tumours: the third study of the French Society of Paediatric Oncology (EW88 study). Br J Cancer 85 (11): 1646-54, 2001. [PUBMED Abstract]
  21. Yock TI, Krailo M, Fryer CJ, et al.: Local control in pelvic Ewing sarcoma: analysis from INT-0091–a report from the Children’s Oncology Group. J Clin Oncol 24 (24): 3838-43, 2006. [PUBMED Abstract]
  22. Schlegel M, Zeumer M, Prodinger PM, et al.: Impact of Pathological Fractures on the Prognosis of Primary Malignant Bone Sarcoma in Children and Adults: A Single-Center Retrospective Study of 205 Patients. Oncology 94 (6): 354-362, 2018. [PUBMED Abstract]
  23. Bramer JA, Abudu AA, Grimer RJ, et al.: Do pathological fractures influence survival and local recurrence rate in bony sarcomas? Eur J Cancer 43 (13): 1944-51, 2007. [PUBMED Abstract]
  24. Krasin MJ, Rodriguez-Galindo C, Billups CA, et al.: Definitive irradiation in multidisciplinary management of localized Ewing sarcoma family of tumors in pediatric patients: outcome and prognostic factors. Int J Radiat Oncol Biol Phys 60 (3): 830-8, 2004. [PUBMED Abstract]
  25. Gerrand C, Bate J, Seddon B, et al.: Seeking international consensus on approaches to primary tumour treatment in Ewing sarcoma. Clin Sarcoma Res 10 (1): 21, 2020. [PUBMED Abstract]
  26. Laskar S, Sinha S, Chatterjee A, et al.: Radiation Therapy Dose Escalation in Unresectable Ewing Sarcoma: Final Results of a Phase 3 Randomized Controlled Trial. Int J Radiat Oncol Biol Phys 113 (5): 996-1002, 2022. [PUBMED Abstract]
  27. Kacar M, Nagel MB, Liang J, et al.: Radiation therapy dose escalation achieves high rates of local control with tolerable toxicity profile in pediatric and young adult patients with Ewing sarcoma. Cancer 130 (10): 1836-1843, 2024. [PUBMED Abstract]
  28. Rombi B, DeLaney TF, MacDonald SM, et al.: Proton radiotherapy for pediatric Ewing’s sarcoma: initial clinical outcomes. Int J Radiat Oncol Biol Phys 82 (3): 1142-8, 2012. [PUBMED Abstract]
  29. Fuchs B, Valenzuela RG, Sim FH: Pathologic fracture as a complication in the treatment of Ewing’s sarcoma. Clin Orthop (415): 25-30, 2003. [PUBMED Abstract]
  30. Ahmed SK, Witten BG, Harmsen WS, et al.: Analysis of Local Control Outcomes and Clinical Prognostic Factors in Localized Pelvic Ewing Sarcoma Patients Treated With Radiation Therapy: A Report From the Children’s Oncology Group. Int J Radiat Oncol Biol Phys 115 (2): 337-346, 2023. [PUBMED Abstract]
  31. Schuck A, Ahrens S, Konarzewska A, et al.: Hemithorax irradiation for Ewing tumors of the chest wall. Int J Radiat Oncol Biol Phys 54 (3): 830-8, 2002. [PUBMED Abstract]
  32. Kuttesch JF, Wexler LH, Marcus RB, et al.: Second malignancies after Ewing’s sarcoma: radiation dose-dependency of secondary sarcomas. J Clin Oncol 14 (10): 2818-25, 1996. [PUBMED Abstract]
  33. Whelan J, Le Deley MC, Dirksen U, et al.: High-Dose Chemotherapy and Blood Autologous Stem-Cell Rescue Compared With Standard Chemotherapy in Localized High-Risk Ewing Sarcoma: Results of Euro-E.W.I.N.G.99 and Ewing-2008. J Clin Oncol : JCO2018782516, 2018. [PUBMED Abstract]
  34. Dirksen U, Brennan B, Le Deley MC, et al.: High-Dose Chemotherapy Compared With Standard Chemotherapy and Lung Radiation in Ewing Sarcoma With Pulmonary Metastases: Results of the European Ewing Tumour Working Initiative of National Groups, 99 Trial and EWING 2008. J Clin Oncol 37 (34): 3192-3202, 2019. [PUBMED Abstract]
  35. Le Deley MC, Paulussen M, Lewis I, et al.: Cyclophosphamide compared with ifosfamide in consolidation treatment of standard-risk Ewing sarcoma: results of the randomized noninferiority Euro-EWING99-R1 trial. J Clin Oncol 32 (23): 2440-8, 2014. [PUBMED Abstract]

Treatment of Metastatic Ewing Sarcoma

Approximately 25% of patients with Ewing sarcoma have metastases at diagnosis.[1] The prognosis is poor for patients with metastatic disease. With current therapies, patients who present with metastatic disease have a 6-year event-free survival (EFS) rate of approximately 28% and an overall survival (OS) rate of approximately 30%.[2,3] For patients with lung/pleural metastases only, the 6-year EFS rate is approximately 40% when using bilateral lung irradiation.[2,4] In contrast, patients with bone/bone marrow metastases have a 4-year EFS rate of approximately 28%, and patients with combined lung and bone/bone marrow metastases have a 4-year EFS rate of approximately 14%.[4,5]

The following factors independently predict a poor outcome in patients presenting with metastatic disease:[3]

  • Age older than 14 years.
  • Primary tumor volume of more than 200 mL.
  • More than one bone metastatic site.
  • Bone marrow metastases.
  • Additional lung metastases.
  • Pulmonary metastases lack of complete response to induction chemotherapy.[6]

Standard treatment options for metastatic Ewing sarcoma include the following:

  1. Chemotherapy.
  2. Surgery.
  3. Radiation therapy.

Chemotherapy

For patients with metastatic Ewing sarcoma, standard treatment that uses alternating cycles of vincristine/doxorubicin/cyclophosphamide and ifosfamide/etoposide (VDC/IE) combined with adequate local-control measures applied to both primary and metastatic sites often results in complete or partial responses. However, the overall cure rate is 20%.[5,7,8]

The following chemotherapy regimens have not shown benefit:

  • In the Intergroup Ewing Sarcoma Study, patients with metastatic disease showed no benefit from the addition of ifosfamide and etoposide to a standard regimen of vincristine, doxorubicin, cyclophosphamide, and dactinomycin.[8]
  • In another Intergroup study, increasing dose intensity of cyclophosphamide, ifosfamide, and doxorubicin did not improve outcome compared with regimens using standard-dose intensity. This regimen increased toxicity and risk of second malignancy without improving EFS or OS.[2]
  • Intensification of ifosfamide to 2.8 g/m2 per day for 5 days did not improve outcome when administered with standard chemotherapy in patients with newly diagnosed metastatic Ewing sarcoma.[9][Level of evidence C2]
  • A pilot study of low-dose anti-angiogenic therapy with vinblastine and celecoxib added to every-3-week therapy with VDC/IE did not improve outcomes for patients presenting with metastases.[10]
  • The Children’s Oncology Group performed a prospective randomized trial (AEWS1221 [NCT02306161]) that tested the addition of ganitumab to multiagent chemotherapy. Patients were randomly assigned (1:1) at enrollment to either the standard arm (interval-compressed VDC/IE) or the experimental arm (ganitumab is given with VDC/IE when the cycle starts and as monotherapy once every 3 weeks for 6 months after conventional therapy). The study enrolled 298 eligible patients (148 in standard arm; 150 in experimental arm).[11][Level of evidence B1]
    • The 3-year EFS rate estimates were 37.4% (95% confidence interval [CI], 29.3%–45.5%) for patients in the standard arm and 39.1% (95% CI, 31.3%–46.7%) for patients in the experimental arm (stratified EFS-event hazard ratio [HR] for experimental arm, 1.00; 95% CI, 0.76–1.33; 1-sided, P = .50).
    • Patients in the experimental arm reported more cases of pneumonitis after radiation therapy involving thoracic fields and nominally higher rates of febrile neutropenia and alanine transaminase elevation.
    • Ganitumab added to interval-compressed chemotherapy did not significantly reduce the risk of an EFS event in patients with newly diagnosed metastatic Ewing sarcoma. The outcomes of these patients were similar to those in previous trials who did not receive IGF-1R inhibition or interval compression.
    • The addition of ganitumab may be associated with increased toxicity.

Surgery and Radiation Therapy

Systematic use of surgery and radiation therapy for metastatic sites may improve overall outcome in patients with extrapulmonary metastases, although a randomized trial has not been done.

Evidence (surgery and radiation therapy):

  1. In a retrospective data analysis of 120 patients with multifocal metastatic Ewing sarcoma, patients who received local treatment to both the primary tumor and metastases had better outcomes than patients who received local treatment to the primary tumor only or with no local treatment (3-year EFS rate, 39% vs. 17% and 14%, respectively; P < .001).[12]
  2. A similar trend for better outcomes with irradiation of all sites of metastatic disease was seen in three retrospective analyses of smaller groups of patients who received radiation therapy to all tumor sites.[13–15]

    These results must be interpreted with caution. The patients who received local-control therapy to all known sites of metastatic disease were selected by the treating investigator, not randomly assigned. Patients with so many metastases that radiation to all sites would result in bone marrow failure were not selected to receive radiation to all sites of metastatic disease. Patients who did not achieve control of the primary tumor did not go on to have local control of all sites of metastatic disease. There was a selection bias. While all patients in these reports had multiple sites of metastatic disease, the patients who had surgery and/or radiation therapy to all sites of clinically detectable metastatic disease had better responses to systemic therapy and fewer sites of metastasis than patients who did not undergo similar therapy of metastatic sites.

Radiation therapy, delivered in a setting in which stringent planning techniques are applied by those experienced in the treatment of Ewing sarcoma, should be considered. Such an approach will result in local control of the tumor with acceptable morbidity in most patients.[16]

The radiation dose depends on the metastatic site of disease:

  • Bone and soft tissue. Stereotactic body radiation therapy has been used to treat metastatic sites in bone and soft tissue. The median total curative/definitive stereotactic body radiation therapy dose delivered was 40 Gy in five fractions (range, 30–60 Gy in 3–10 fractions). The median total palliative stereotactic body radiation therapy dose delivered was 40 Gy in five fractions (range, 16–50 Gy in 1–10 fractions). These short-course regimens with large-dose fractions are biologically equivalent to higher doses delivered with smaller-dose fractions given over longer treatment courses.[17][Level of evidence C1]
  • Pulmonary. For all patients with pulmonary metastases, whole-lung irradiation should be considered, even if complete resolution of overt pulmonary metastatic disease has been achieved with chemotherapy.[4,5,18] Radiation doses are modulated based on age, the amount of lung to be irradiated, and pulmonary function. Doses between 12 Gy and 15 Gy are generally used if whole lungs are treated. No randomized trial has been done to prove radiation therapy improves survival in this group of patients. An early trial from the intergroup Ewing sarcoma group in the 1970s showed that radiation to the lung improved survival in patients with nonmetastatic disease when added to vincristine, actinomycin, and cyclophosphamide (VAC) compared with VAC alone.[19] However, the addition of doxorubicin to the therapy produced better EFS than the VAC/radiation therapy regimen.

Other Therapies

More intensive therapies, many of which incorporate high-dose chemotherapy with or without total-body irradiation in conjunction with stem cell support, have not improved EFS rates for patients with bone and/or bone marrow metastases.[2,3,13,20–22]; [23][Level of evidence C2] For more information, see the High-Dose Therapy With Stem Cell Support for Ewing Sarcoma section.

  • High-dose chemotherapy with stem cell support.
    • Ewing 2008R3 (NCT00987636) was the first phase III, open-label, multicenter, randomized controlled trial conducted for newly diagnosed patients with disseminated Ewing sarcoma who had metastases to bone and/or other sites.[24][Level of evidence B1] The study evaluated the EFS and OS effect of treatment with treosulfan and melphalan high-dose chemotherapy (TreoMel-HDT) followed by infusion of autologous hematopoietic stem cells. After six cycles of chemotherapy (vincristine, ifosfamide, doxorubicin, and etoposide), consenting patients were randomly assigned to receive either eight cycles of consolidation therapy (vincristine, dactinomycin, and cyclophosphamide) or consolidation therapy with TreoMel-HDT followed by autologous stem cell reinfusion. Between 2009 and 2018, 109 patients were randomly assigned, 55 of whom received TreoMel-HDT. There was no significant difference in 3-year EFS rates between patients who received TreoMel-HDT and patients in the control arm (20.9% vs. 19.2%; median follow-up, 3.3 years).
    • One of the largest studies was the EURO-EWING-INTERGROUP-EE99 R3 trial that enrolled 281 patients with primary disseminated metastatic Ewing sarcoma. Patients were treated with six cycles of vincristine, ifosfamide, doxorubicin, and etoposide followed by high-dose therapy and autologous stem cell transplant. Patients had a 3-year EFS rate of 27% and an OS rate of 34%. Identified independent prognostic factors included the presence and number of bone lesions, primary tumor volume greater than 200 mL, age older than 14 years, additional pulmonary metastases, and bone marrow involvement.[3][Level of evidence C2]
    • The role of high-dose therapy with busulfan-melphalan (BuMel) followed by stem cell rescue was investigated in the prospective randomized EURO-EWING-INTERGROUP-EE99 (NCT00020566) trial. Among patients with isolated pulmonary metastases, there was no difference in 3-year EFS rates (55.7% with BuMel vs. 50.3% with continued chemotherapy and whole-lung radiation therapy; P = .21).[25]
  • Melphalan. At nonmyeloablative doses, melphalan proved to be an active agent in an up-front window study for patients with metastatic disease at diagnosis. However, the cure rate remained extremely low.[26]
  • Irinotecan. Irinotecan was administered as a single agent in an up-front window study for patients with newly diagnosed metastatic Ewing sarcoma and showed modest activity (partial response in 5 of 24 patients).[27][Level of evidence C3] Further investigation is needed to determine irinotecan dosing and combinations with other agents for patients with Ewing sarcoma.

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. Esiashvili N, Goodman M, Marcus RB: Changes in incidence and survival of Ewing sarcoma patients over the past 3 decades: Surveillance Epidemiology and End Results data. J Pediatr Hematol Oncol 30 (6): 425-30, 2008. [PUBMED Abstract]
  2. Miser JS, Goldsby RE, Chen Z, et al.: Treatment of metastatic Ewing sarcoma/primitive neuroectodermal tumor of bone: evaluation of increasing the dose intensity of chemotherapy–a report from the Children’s Oncology Group. Pediatr Blood Cancer 49 (7): 894-900, 2007. [PUBMED Abstract]
  3. Ladenstein R, Pötschger U, Le Deley MC, et al.: Primary disseminated multifocal Ewing sarcoma: results of the Euro-EWING 99 trial. J Clin Oncol 28 (20): 3284-91, 2010. [PUBMED Abstract]
  4. Paulussen M, Ahrens S, Craft AW, et al.: Ewing’s tumors with primary lung metastases: survival analysis of 114 (European Intergroup) Cooperative Ewing’s Sarcoma Studies patients. J Clin Oncol 16 (9): 3044-52, 1998. [PUBMED Abstract]
  5. Paulussen M, Ahrens S, Burdach S, et al.: Primary metastatic (stage IV) Ewing tumor: survival analysis of 171 patients from the EICESS studies. European Intergroup Cooperative Ewing Sarcoma Studies. Ann Oncol 9 (3): 275-81, 1998. [PUBMED Abstract]
  6. Halalsheh H, Kaste SC, Krasin MJ, et al.: Clinical impact of post-induction resolution of pulmonary lesions in metastatic Ewing sarcoma. Pediatr Blood Cancer 67 (4): e28150, 2020. [PUBMED Abstract]
  7. Pinkerton CR, Bataillard A, Guillo S, et al.: Treatment strategies for metastatic Ewing’s sarcoma. Eur J Cancer 37 (11): 1338-44, 2001. [PUBMED Abstract]
  8. Miser JS, Krailo MD, Tarbell NJ, et al.: Treatment of metastatic Ewing’s sarcoma or primitive neuroectodermal tumor of bone: evaluation of combination ifosfamide and etoposide–a Children’s Cancer Group and Pediatric Oncology Group study. J Clin Oncol 22 (14): 2873-6, 2004. [PUBMED Abstract]
  9. Magnan H, Goodbody CM, Riedel E, et al.: Ifosfamide dose-intensification for patients with metastatic Ewing sarcoma. Pediatr Blood Cancer 62 (4): 594-7, 2015. [PUBMED Abstract]
  10. Felgenhauer JL, Nieder ML, Krailo MD, et al.: A pilot study of low-dose anti-angiogenic chemotherapy in combination with standard multiagent chemotherapy for patients with newly diagnosed metastatic Ewing sarcoma family of tumors: A Children’s Oncology Group (COG) Phase II study NCT00061893. Pediatr Blood Cancer 60 (3): 409-14, 2013. [PUBMED Abstract]
  11. DuBois SG, Krailo MD, Glade-Bender J, et al.: Randomized Phase III Trial of Ganitumab With Interval-Compressed Chemotherapy for Patients With Newly Diagnosed Metastatic Ewing Sarcoma: A Report From the Children’s Oncology Group. J Clin Oncol 41 (11): 2098-2107, 2023. [PUBMED Abstract]
  12. Haeusler J, Ranft A, Boelling T, et al.: The value of local treatment in patients with primary, disseminated, multifocal Ewing sarcoma (PDMES). Cancer 116 (2): 443-50, 2010. [PUBMED Abstract]
  13. Burdach S, Thiel U, Schöniger M, et al.: Total body MRI-governed involved compartment irradiation combined with high-dose chemotherapy and stem cell rescue improves long-term survival in Ewing tumor patients with multiple primary bone metastases. Bone Marrow Transplant 45 (3): 483-9, 2010. [PUBMED Abstract]
  14. Paulino AC, Mai WY, Teh BS: Radiotherapy in metastatic ewing sarcoma. Am J Clin Oncol 36 (3): 283-6, 2013. [PUBMED Abstract]
  15. Casey DL, Wexler LH, Meyers PA, et al.: Radiation for bone metastases in Ewing sarcoma and rhabdomyosarcoma. Pediatr Blood Cancer 62 (3): 445-9, 2015. [PUBMED Abstract]
  16. Donaldson SS, Torrey M, Link MP, et al.: A multidisciplinary study investigating radiotherapy in Ewing’s sarcoma: end results of POG #8346. Pediatric Oncology Group. Int J Radiat Oncol Biol Phys 42 (1): 125-35, 1998. [PUBMED Abstract]
  17. Brown LC, Lester RA, Grams MP, et al.: Stereotactic body radiotherapy for metastatic and recurrent ewing sarcoma and osteosarcoma. Sarcoma 2014: 418270, 2014. [PUBMED Abstract]
  18. Spunt SL, McCarville MB, Kun LE, et al.: Selective use of whole-lung irradiation for patients with Ewing sarcoma family tumors and pulmonary metastases at the time of diagnosis. J Pediatr Hematol Oncol 23 (2): 93-8, 2001. [PUBMED Abstract]
  19. Nesbit ME, Perez CA, Tefft M, et al.: Multimodal therapy for the management of primary, nonmetastatic Ewing’s sarcoma of bone: an Intergroup Study. Natl Cancer Inst Monogr (56): 255-62, 1981. [PUBMED Abstract]
  20. Meyers PA, Krailo MD, Ladanyi M, et al.: High-dose melphalan, etoposide, total-body irradiation, and autologous stem-cell reconstitution as consolidation therapy for high-risk Ewing’s sarcoma does not improve prognosis. J Clin Oncol 19 (11): 2812-20, 2001. [PUBMED Abstract]
  21. Burdach S, Meyer-Bahlburg A, Laws HJ, et al.: High-dose therapy for patients with primary multifocal and early relapsed Ewing’s tumors: results of two consecutive regimens assessing the role of total-body irradiation. J Clin Oncol 21 (16): 3072-8, 2003. [PUBMED Abstract]
  22. Thiel U, Wawer A, Wolf P, et al.: No improvement of survival with reduced- versus high-intensity conditioning for allogeneic stem cell transplants in Ewing tumor patients. Ann Oncol 22 (7): 1614-21, 2011. [PUBMED Abstract]
  23. Loschi S, Dufour C, Oberlin O, et al.: Tandem high-dose chemotherapy strategy as first-line treatment of primary disseminated multifocal Ewing sarcomas in children, adolescents and young adults. Bone Marrow Transplant 50 (8): 1083-8, 2015. [PUBMED Abstract]
  24. Koch R, Gelderblom H, Haveman L, et al.: High-Dose Treosulfan and Melphalan as Consolidation Therapy Versus Standard Therapy for High-Risk (Metastatic) Ewing Sarcoma. J Clin Oncol 40 (21): 2307-2320, 2022. [PUBMED Abstract]
  25. Whelan J, Le Deley MC, Dirksen U, et al.: High-Dose Chemotherapy and Blood Autologous Stem-Cell Rescue Compared With Standard Chemotherapy in Localized High-Risk Ewing Sarcoma: Results of Euro-E.W.I.N.G.99 and Ewing-2008. J Clin Oncol : JCO2018782516, 2018. [PUBMED Abstract]
  26. Luksch R, Grignani G, Fagioli F, et al.: Response to melphalan in up-front investigational window therapy for patients with metastatic Ewing’s family tumours. Eur J Cancer 43 (5): 885-90, 2007. [PUBMED Abstract]
  27. Morland B, Platt K, Whelan JS: A phase II window study of irinotecan (CPT-11) in high risk Ewing sarcoma: a Euro-E.W.I.N.G. study. Pediatr Blood Cancer 61 (3): 442-5, 2014. [PUBMED Abstract]

Treatment of Recurrent Ewing Sarcoma

Recurrence of Ewing sarcoma is most common within 2 years of initial diagnosis (approximately 80%).[1,2] However, late relapses occurring more than 5 years from initial diagnosis are more common in Ewing sarcoma (13%; 95% confidence interval, 9.4%–16.5%) than in other pediatric solid tumors.[3] An analysis of the Surveillance, Epidemiology, and End Results (SEER) Program database identified 1,351 patients who survived more than 60 months from diagnosis.[4] Of these patients, 209 died; 144 of the deaths (69%) were attributed to recurrent, progressive Ewing sarcoma. Black race, male sex, older age at initial diagnosis, and primary tumors of the pelvis and axial skeleton were associated with a higher risk of late death. This analysis covered the period from 1973 to 2013, and the 1,351 patients represented only 38% of the patients in the original sample, which reflects the inferior treatment outcomes from the earlier era. It is possible that patients who reach the 5-year point after more contemporary treatment may not recapitulate this experience.

The overall prognosis for patients with recurrent Ewing sarcoma is poor. The 5-year survival rate after recurrence is approximately 10% to 15%.[2,5,6]; [1][Level of evidence C1] Patients with relapsed or progressive Ewing sarcoma with measurable disease have a 6-month event-free survival (EFS) rate of 13%.[7][Level of evidence C1]

Prognostic factors include the following:

  • Time to recurrence. Time to recurrence is the most important prognostic factor. Patients whose Ewing sarcoma recurred more than 2 years from initial diagnosis had a 5-year survival rate of 30%, versus 7% for patients whose disease recurred within 2 years.[1,2]
  • Local and distant recurrence. Patients with both local recurrence and distant metastases have a worse outcome than patients with either isolated local recurrence or metastatic recurrence alone.[1,2]
  • Isolated pulmonary recurrence. Isolated pulmonary recurrence was not an important prognostic factor in a North American series.[1] In the Italian/Scandinavian experience, younger age, longer disease-free interval, and lung-only recurrence were associated with longer progression-free survival (PFS) after recurrence. In this experience, patients with Ewing sarcoma that recurred after initial therapy, which included high-dose therapy with autologous stem cell rescue, were less likely to achieve a second complete remission.[8][Level of evidence C2]

The selection of treatment for patients with recurrent disease depends on many factors, including the following:

  • Site of recurrence.
  • Previous treatment.
  • Individual patient considerations.

There is no standardized second-line treatment for patients with relapsed or refractory Ewing sarcoma. Most patients in first relapse are treated with conventional systemic chemotherapy. Patients who demonstrate a response to therapy may undergo local control to sites of recurrence.

Treatment options for recurrent Ewing sarcoma include the following:

  1. Chemotherapy.
  2. Surgery.
  3. Radiation therapy.
  4. High-dose chemotherapy with stem cell support.
  5. Other therapies.

Chemotherapy

Combinations of chemotherapy, such as cyclophosphamide and topotecan or irinotecan and temozolomide with or without vincristine, are active in recurrent Ewing sarcoma and can be considered for these patients.[9–14]

Table 7. Results from Studies that Used Cyclophosphamide and Topotecan Regimens to Treat Patients With Relapsed and/or Refractory Ewing Sarcoma
Study Reference Trial Phase (Total No. of Patients) Median Age (Range) (y) CR/PR RR Cyclophosphamide (mg/m2)/Topotecan (mg/m2) × d Other Agents
II = phase II trial; CR = complete response; PR = partial response; R = retrospective; RR = objective response rate; VCR = vincristine.
Saylors et al.[9] II (17) 13.8 (1–21) 1/3 29% 250 × 5/0.75 × 5 None
Hunold et al.[11] R (54) 17.4 (3–49) 0/16 30% 250 × 5/0.75 × 5 None
Farhat et al.[15] R (14) 11 (2–19) 0/3 21% 250 × 5/0.75 × 5 None
Kebudi et al.[16] R (14) 13 (3–16) 2/5 50% 250 × 5/0.75 × 5 VCR

These studies were retrospective. Prospective trials with clearly defined eligibility cohorts and intent-to-treat analyses are lacking. When combined, these studies accrued 99 patients and observed 3 complete remissions and 27 partial remissions. The objective response rate was 30%.

Table 8. Results from Studies that Used Temozolomide and Irinotecan Regimens to Treat Patients With Relapsed and/or Refractory Ewing Sarcoma
Study Reference Trial Phase (Total No. of Patients) Median Age (Range) (y) CR/PR RR Temozolomide (mg/m2)/Irinotecan (mg/m2) × d × wk Other Agents
I = phase I trial; II = phase II trial; Acta Onc = Acta Oncologica; An Ped = Annals of Pediatrics; Clin Cancer Res = Clinical Cancer Research; Exp Opin = Expert Opinion Investigational Drugs; Clin Transl Oncol = Clinical and Translational Oncology; BEV = bevacizumab; CR = complete response; IV = intravenous; N/A = not applicable; PBC = Pediatric Blood and Cancer; Ped Hem Onc = Pediatric Hematology and Oncology; PO = oral; PR = partial response; R = retrospective trial; RR = objective response rate; TMS = temsirolimus; UK = unknown; VCR = vincristine.
Wagner et al. (PBC, 2007) [12] R (16) 18 (7–33) 1/3 29% 100 × 5/IV 10–20 × 5 × 2 None
Casey et al. (PBC, 2009) [13] R (19) 19.5 (2–40) 5/7 63% 100 × 5/IV 20 × 5 × 2 None
Hernandez-Marques et al. (An Ped, 2013) [17] R (8) 13 (6–18) 0/3 37% 80–100 × 5/IV 10–20 × 5 × 2 None
Raciborska et al. (PBC, 2013) [14] R (22) 14.3 5/7 54% 125 × 5/IV 50 × 5 VCR
McKnall-Knapp et al. (PBC, 2010) [18] I (1) N/A 0/1 100% 100 × 5/IV 20 × 5 × 2 VCR
Wagner et al. (PBC, 2010) [19] I (5) (<21) 1/1 40% 100–150 × 5/PO 35–90 × 5 VCR
Wagner et al. (PBC, 2013) [20] I (2) 20, 22 1/1 100% 150 × 5/PO 90 × 5 VCR, BEV
Bagatell et al. (PBC, 2014) [21] I (7) (<21) 0/1 14% 100–150 × 5/PO 50–90 × 5 TMS
Kurucu et al. (Ped Hem Onc, 2015) [22] R (20) 14 (1–18) UK 55% 100 × 5/IV 20 × 5 × 2 None
Anderson et al. (Exp Opin, 2008) [23] R (25) 15 7/9 64% 100 × 5/IV 10 × 5 × 2 None
Palmerini et al. (Acta Onc, 2018) [24] R (51) 21 (3–65) 5/12 34% 100 × 5/IV 40 × 5 None
Salah et al. (Clin Transl Oncol, 2021) [25] R (53) 20 (5–45) 1/11 28% 100 × 5/IV 40 × 5 in 21 patients; IV 50 × 5 in 24 patients; IV 20 × 5 × 2 in 6 patients None
Xu et al. (Clin Cancer Res, 2023) [26] 5-day schedule: II (24) 16.5 ± 7.9 1/4 20.8% 100 × 5/50 × 5 VCR 1.4 mg/m2 day 1
Xu et al. (Clin Cancer Res, 2023) [26] 10-day schedule: II (22) 15.2 ± 6.3 1/11 54.5% 100 × 5/20 × 5 × 2 VCR 1.4 mg/m2 days 1 and 8

Most of these studies were retrospective, not prospective. There are only four prospective trials with well-defined eligibility cohorts and report by intent to treat. In addition, there is significant variability among the reports in doses and dose schedules of irinotecan and temozolomide and the use of additional agents. When combined, these studies accrued 275 patients and observed 21 complete remissions and 82 partial remissions. The objective response rate was 37.5%.

Evidence (chemotherapy):

  1. One phase II study of topotecan and cyclophosphamide showed a response in 6 of 17 patients with Ewing sarcoma.[9] In a similar trial in Germany, 16 of 49 patients had a clinical response.[11]
  2. Several retrospective studies have demonstrated the activity of temozolomide and irinotecan in patients with recurrent Ewing sarcoma.[13,22,24]
    1. In the largest retrospective multicenter study of the combination of temozolomide and irinotecan in patients with recurrent and primary refractory Ewing sarcoma, 51 patients (66% of patients were aged ≥18 years; median age, 21 years) were treated with temozolomide (100 mg/m2/day orally) and irinotecan (40 mg/m2/day intravenously), on days 1 to 5, every 21 days. Twenty-five percent of the patients were in first relapse/progression, while the remainder of the patients were in second or greater relapse/progression.[24]
      • Five patients (10%) achieved complete remissions, 12 patients (24%) achieved partial remissions, and 19 patients (37%) had stable disease, with a disease control rate of 71%.
      • On univariate analysis, the only two factors predicting response to temozolomide and irinotecan in PFS were performance score and lactate dehydrogenase levels.
      • Two patients were rechallenged with temozolomide and irinotecan after disease remission was induced. Both patients achieved partial remissions on rechallenge. One patient’s remission lasted at least 15 cycles and the other remission lasted 22 cycles.[24]
    2. A prospective randomized trial compared two schedules of irinotecan given in combination with vincristine and temozolomide for the treatment of recurrent Ewing sarcoma. One schedule administered irinotecan 50 mg/m2 daily for 5 days (d × 5) and the other administered irinotecan 20 mg/m2 daily for 5 days for two consecutive weeks (10 doses; d × 5 × 2).[26]
      • The objective response rate at 12 weeks was lower for the patients treated on the d × 5 schedule (5 of 24; 20.8%) than for patients treated on the d × 5 × 2 schedule (12 of 22; 54.5%; P = .019).
    3. A retrospective review of published series compared the results of treatment with irinotecan and temozolomide with a 10-day schedule to treatment with a 5-day schedule.[27]
      • Among 89 patients treated with a 10-day irinotecan schedule, there were 47 objective responses (53%).
      • Among 180 patients treated with a 5-day irinotecan schedule, there were 52 responses (29%).
      • The two studies that used the 5-day irinotecan schedule reported median times to progression of 3.0 and 3.9 months, respectively.
      • The four studies that used the 10-day irinotecan schedule reported median times to progression of 4.6, 5.5, 8.3, and 9.5 months, respectively.
  3. The combination of docetaxel either with gemcitabine or irinotecan has achieved objective responses in patients with relapsed Ewing sarcoma.[28][Level of evidence C1]; [29,30][Level of evidence C3]
  4. High-dose ifosfamide (3 g/m2 per day for 5 days = 15 g/m2) has shown activity in patients whose Ewing sarcoma recurred after therapy that included standard ifosfamide (1.8 g/m2 per day for 5 days = 9 g/m2).[31][Level of evidence C3]
  5. European investigators are performing a prospective study to compare four regimens for the treatment of patients with recurrent Ewing sarcoma.[32] The rEECur phase II/III adaptive multiarm trial is the first to compare regimens in a randomized design. Patients aged 4 to 50 years with refractory or recurrent Ewing sarcoma and healthy enough to receive chemotherapy were randomly assigned to receive one of four regimens: topotecan and cyclophosphamide (TC), irinotecan and temozolomide (IT), gemcitabine and docetaxel (GD), or high-dose ifosfamide.[33]
    • Pairwise comparison showed that GD was the least effective.
    • Imaging response and survival outcomes after TC were marginally better than after IT. However, in a phase II comparison, ifosfamide had significantly better PFS and OS than TC. As a result, ifosfamide was the most effective regimen in this setting, although with significant renal and neurological toxicity.
    • The study is ongoing and has recruited over 570 patients. The study is now comparing ifosfamide and lenvatinib with ifosfamide, carboplatin, and etoposide.[34]

Local Therapy for Relapsed Disease

Surgery

Aggressive surgery (such as amputation or hemipelvectomy) may be considered for patients with nonmetastatic locally recurrent Ewing sarcoma, even if the prognosis is limited.[35]

The role of pulmonary metastasectomy in patients with relapsed disease and isolated lung metastases is controversial.[36,37]

Radiation therapy

Radiation therapy may be used (similar to first-line strategies) for patients who relapsed after the beginning of front-line therapy and/or who present only with relapsed pulmonary metastases.[36]; [38][Level of evidence C1] Radiation therapy to bone lesions may provide palliation, although radical resection may improve outcome.[2] Patients with pulmonary metastases who have not received radiation therapy to the lungs should be considered for whole-lung irradiation and/or treated with stereotactic body radiation therapy.[36,39]; [38][Level of evidence C1]; Residual disease in the lung may be surgically removed.

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 such short course radiation therapy, 85% of patients had complete or partial pain relief, with low levels of toxicity.[40]

High-Dose Chemotherapy With Stem Cell Support

Aggressive attempts to control the disease, including myeloablative regimens, have been used, but there is no evidence at this time to conclude that myeloablative therapy is superior to standard chemotherapy.[41–43]; [44][Level of evidence C2]

Most published reports about the use of high-dose therapy and stem cell support for patients with high-risk Ewing sarcoma have significant flaws in methodology. The most common issue is the comparison of this high-risk group with an inappropriate control group. Patients with Ewing sarcoma at high risk of treatment failure who received high-dose therapy are compared with patients who did not receive high-dose therapy. Patients who undergo high-dose therapy must respond to systemic therapy, remain alive and respond to treatment long enough to reach the time at which stem cell therapy can be applied, be free of comorbid toxicity that precludes high-dose therapy, and have an adequate stem cell collection. Patients who undergo high-dose therapy and stem cell support are a highly selected group. Comparing this patient group with all patients with high-risk Ewing sarcoma is inappropriate and leads to the erroneous conclusion that this strategy improves outcome.

Surveys of patients who underwent allogeneic hematopoietic stem cell transplant (HSCT) for recurrent Ewing sarcoma did not show improved EFS when compared with patients who underwent autologous HSCT. In addition, allogeneic HSCT was associated with a higher complication rate.[41,45,46]

Other Therapies

Other therapies that have been studied in the treatment of recurrent Ewing sarcoma include the following:

  • Monoclonal antibody therapy. Monoclonal antibodies against the insulin-like growth factor 1 receptor (IGF1R) are reported to produce objective responses in approximately 10% of patients with metastatic recurrent Ewing sarcoma.[47–50][Level of evidence C3] These studies suggested that time-to-progression was prolonged compared with historical controls. Objective responses have been reported in studies combining the mTOR inhibitor temsirolimus with an IGF1R antibody. In a phase II trial of ten patients who were treated with an IGF1R antibody and a CDK4/6 inhibitor, no responses were reported.[51] Stratification by IGF1R expression (detected by immunohistochemistry) in one of the studies did not predict clinical outcome in patients with Ewing sarcoma.[52,53] Further studies are needed to identify patients who are likely to benefit from IGF1R therapy.
  • Immunotherapy. Immunotherapy with antigen-specific T cells is being studied in patients with Ewing sarcoma because immune-mediated killing attacks the tumor in a different way, unlike conventional therapies (that rely on pathways), which such tumors often resist. Several potential chimeric antigen receptors target antigens that have been identified for Ewing sarcomas. These include HER2 (human epidermal growth factor receptor 2),[54] GD2,[55] CD99 (MIC2 antigens),[56] and STEAP1 (six-transmembrane epithelial antigens of the prostate).[57] Some of these therapies are in early-phase testing in patients with sarcomas.[54]

    Treatment with single-agent and combined immune checkpoint inhibitors has shown no activity in patients with recurrent Ewing sarcoma. There were no responses in five patients with Ewing sarcoma treated on a clinical trial with single-agent nivolumab or the combination of nivolumab and ipilimumab.[58] A trial of pembrolizumab included 13 patients with Ewing sarcoma whose cancer did not respond to the treatment.[59] Another trial of nivolumab reported that there were no responses in 11 patients with Ewing sarcoma.[60] The Children’s Oncology Group (COG) conducted a phase I/II trial of the combination of nivolumab and ipilimumab in children with recurrent sarcomas.[61][Level of evidence B4] Only 1 of 14 patients with Ewing sarcoma exhibited a sustained partial response.

  • Multitargeted kinase inhibitors.
    • Regorafenib: A phase II study (SARC024 [NCT02048371]) evaluated regorafenib monotherapy in 30 patients with metastatic recurrent Ewing sarcoma and other translocation-positive tumors, including CIC::DUX4 sarcoma.[62] Modest activity was observed, with a 10% objective response rate by response evaluation criteria in solid tumors (RECIST). The median PFS was 14.8 weeks.

      A prospective, randomized, double-blind trial compared regorafenib with placebo in patients with recurrent Ewing sarcoma.[63] Of 36 patients who were evaluable for efficacy, 23 received regorafenib and 13 received placebo. The patients randomly assigned to regorafenib had an 8-week PFS rate of 56%, compared with 7.7% for patients randomly assigned to placebo. The median PFS was 11.4 weeks for patients who received regorafenib and 3.9 weeks for patients who received placebo. The response rate was 13% in patients treated with regorafenib. Ten patients in the placebo group crossed over to receive regorafenib after progression. Although the results were not significant, the authors suggested that this trial provided some evidence of benefit for the use of regorafenib in patients with relapsed Ewing sarcoma.

      In addition to this single-agent experience, regorafenib was shown to be tolerable on a sequential schedule with vincristine and irinotecan in 21 pediatric patients. Five patients with relapsed Ewing sarcoma were included as part of this phase I trial. Three of five patients had partial responses with this regimen.[64]

    • Anlotinib: A study completed in China evaluated treatment with anlotinib (an oral receptor tyrosine kinase inhibitor targeting vascular endothelial growth factor receptors 1–3, fibroblast growth factors 1–3, platelet-derived growth factor receptors alpha and beta, c-KIT, and RET) given along with vincristine and irinotecan for patients with relapsed or refractory Ewing sarcoma.[65][Level of evidence B4] Patients were treated in two cohorts. Cohort A included patients aged 16 years and older, and cohort B included patients younger than 16 years. At 12 weeks, patients in cohort A demonstrated an objective response rate of 62.5% (14 of 23 patients), and patients in cohort B demonstrated an objective response rate of 83.3% (11 of 12 patients). Anlotinib has not yet received approval from the U.S. Food and Drug Administration.
    • Cabozantinib: A real-world evidence analysis included 16 patients with relapsed or refractory Ewing sarcoma who were treated with cabozantinib. Four patients had objective responses (25% objective response rate).[66]

      Thirty-nine patients (older than 12 years) with relapsed Ewing sarcoma were assessable for response after cabozantinib monotherapy.[67] Patients younger than 16 years received 40 mg daily, and patients aged 16 years and older received 60 mg daily. Most patients were older than 18 years. Ten patients (26%) had responses (all partial responses).

  • Strategies to target fusion proteins.
    • Lurbinectedin: Lurbinectedin is structurally related to trabectedin, but it has been more effective in suppressing the activity of the oncogenic transcription factor EWS::FLI in mice in preclinical studies. In an open-label, single-arm, basket phase II trial, clinical antitumor activity was seen. In a cohort of 28 adult patients with confirmed Ewing sarcoma and relapsed disease, the objective response rate was 14.3%, the clinical benefit rate (response or disease stabilization for >4 months) was 39.3%, and the disease control rate (response or disease stabilization of any duration) was 57.1%.[68]
    • TK216: An agent known as TK216 is thought to interfere with interactions between the EWSR1::FLI1 fusion oncoprotein and key proteins critical for its oncogenic function, although it has also been shown to disrupt microtubules.[69] In a phase I/II trial of TK216 in combination with vincristine in patients with recurrent Ewing sarcoma, three responses were observed. However, the overall response rate was only 3.5% across the whole trial.[70]

Sequencing of recurrent and refractory Ewing sarcoma tumors from pediatric (n = 79) and young adult patients (n = 25) enrolled in the National Cancer Institute (NCI)-COG Pediatric Molecular Analysis for Therapeutic Choice (MATCH) trial revealed genomic alterations that were considered actionable for treatment on MATCH study arms in 8 of 104 tumors (7.7%), including EZH2 variants in 2 of 104 tumors (1.9%).[71]

Treatment Options Under Clinical Evaluation for Recurrent Ewing Sarcoma

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:

  • NCT04890093 (Vincristine and Temozolomide in Combination With PEN-866 for Adolescents and Young Adults With Relapsed or Refractory Solid Tumors): PEN-866 is a novel molecule consisting of SN-38 conjugated to a heat shock protein 90 (HSP90) inhibitor that has been shown to have a pharmacokinetic advantage over irinotecan in preclinical models. In preclinical models of Ewing sarcoma, PEN-866 had superior efficacy and pharmacodynamics compared with irinotecan. For the phase I portion of this trial, any patient aged 12 to 39 years with a relapsed or refractory solid tumor is eligible. The phase II portion of this trial will enroll only patients aged 12 to 39 years with relapsed or refractory Ewing sarcoma or rhabdomyosarcoma.

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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  47. Malempati S, Weigel B, Ingle AM, et al.: Phase I/II trial and pharmacokinetic study of cixutumumab in pediatric patients with refractory solid tumors and Ewing sarcoma: a report from the Children’s Oncology Group. J Clin Oncol 30 (3): 256-62, 2012. [PUBMED Abstract]
  48. Juergens H, Daw NC, Geoerger B, et al.: Preliminary efficacy of the anti-insulin-like growth factor type 1 receptor antibody figitumumab in patients with refractory Ewing sarcoma. J Clin Oncol 29 (34): 4534-40, 2011. [PUBMED Abstract]
  49. Pappo AS, Patel SR, Crowley J, et al.: R1507, a monoclonal antibody to the insulin-like growth factor 1 receptor, in patients with recurrent or refractory Ewing sarcoma family of tumors: results of a phase II Sarcoma Alliance for Research through Collaboration study. J Clin Oncol 29 (34): 4541-7, 2011. [PUBMED Abstract]
  50. Tap WD, Demetri G, Barnette P, et al.: Phase II study of ganitumab, a fully human anti-type-1 insulin-like growth factor receptor antibody, in patients with metastatic Ewing family tumors or desmoplastic small round cell tumors. J Clin Oncol 30 (15): 1849-56, 2012. [PUBMED Abstract]
  51. Shulman DS, Merriam P, Choy E, et al.: Phase 2 trial of palbociclib and ganitumab in patients with relapsed Ewing sarcoma. Cancer Med 12 (14): 15207-15216, 2023. [PUBMED Abstract]
  52. Naing A, LoRusso P, Fu S, et al.: Insulin growth factor-receptor (IGF-1R) antibody cixutumumab combined with the mTOR inhibitor temsirolimus in patients with refractory Ewing’s sarcoma family tumors. Clin Cancer Res 18 (9): 2625-31, 2012. [PUBMED Abstract]
  53. Schwartz GK, Tap WD, Qin LX, et al.: Cixutumumab and temsirolimus for patients with bone and soft-tissue sarcoma: a multicentre, open-label, phase 2 trial. Lancet Oncol 14 (4): 371-82, 2013. [PUBMED Abstract]
  54. Ahmed N, Brawley VS, Hegde M, et al.: Human Epidermal Growth Factor Receptor 2 (HER2) -Specific Chimeric Antigen Receptor-Modified T Cells for the Immunotherapy of HER2-Positive Sarcoma. J Clin Oncol 33 (15): 1688-96, 2015. [PUBMED Abstract]
  55. Pule MA, Savoldo B, Myers GD, et al.: Virus-specific T cells engineered to coexpress tumor-specific receptors: persistence and antitumor activity in individuals with neuroblastoma. Nat Med 14 (11): 1264-70, 2008. [PUBMED Abstract]
  56. Scotlandi K, Baldini N, Cerisano V, et al.: CD99 engagement: an effective therapeutic strategy for Ewing tumors. Cancer Res 60 (18): 5134-42, 2000. [PUBMED Abstract]
  57. Grunewald TG, Diebold I, Esposito I, et al.: STEAP1 is associated with the invasive and oxidative stress phenotype of Ewing tumors. Mol Cancer Res 10 (1): 52-65, 2012. [PUBMED Abstract]
  58. D’Angelo SP, Mahoney MR, Van Tine BA, et al.: Nivolumab with or without ipilimumab treatment for metastatic sarcoma (Alliance A091401): two open-label, non-comparative, randomised, phase 2 trials. Lancet Oncol 19 (3): 416-426, 2018. [PUBMED Abstract]
  59. Tawbi HA, Burgess M, Bolejack V, et al.: Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028): a multicentre, two-cohort, single-arm, open-label, phase 2 trial. Lancet Oncol 18 (11): 1493-1501, 2017. [PUBMED Abstract]
  60. Davis KL, Fox E, Merchant MS, et al.: Nivolumab in children and young adults with relapsed or refractory solid tumours or lymphoma (ADVL1412): a multicentre, open-label, single-arm, phase 1-2 trial. Lancet Oncol 21 (4): 541-550, 2020. [PUBMED Abstract]
  61. Davis KL, Fox E, Isikwei E, et al.: A Phase I/II Trial of Nivolumab plus Ipilimumab in Children and Young Adults with Relapsed/Refractory Solid Tumors: A Children’s Oncology Group Study ADVL1412. Clin Cancer Res 28 (23): 5088-5097, 2022. [PUBMED Abstract]
  62. Attia S, Bolejack V, Ganjoo KN, et al.: A phase II trial of regorafenib in patients with advanced Ewing sarcoma and related tumors of soft tissue and bone: SARC024 trial results. Cancer Med 12 (2): 1532-1539, 2023. [PUBMED Abstract]
  63. Duffaud F, Blay JY, Le Cesne A, et al.: Regorafenib in patients with advanced Ewing sarcoma: results of a non-comparative, randomised, double-blind, placebo-controlled, multicentre Phase II study. Br J Cancer 129 (12): 1940-1948, 2023. [PUBMED Abstract]
  64. Casanova M, Bautista F, Campbell-Hewson Q, et al.: Regorafenib plus Vincristine and Irinotecan in Pediatric Patients with Recurrent/Refractory Solid Tumors: An Innovative Therapy for Children with Cancer Study. Clin Cancer Res 29 (21): 4341-4351, 2023. [PUBMED Abstract]
  65. Xu J, Xie L, Sun X, et al.: Anlotinib, Vincristine, and Irinotecan for Advanced Ewing Sarcoma After Failure of Standard Multimodal Therapy: A Two-Cohort, Phase Ib/II Trial. Oncologist 26 (7): e1256-e1262, 2021. [PUBMED Abstract]
  66. Peretz Soroka H, Vora T, Noujaim J, et al.: Real-world experience of tyrosine kinase inhibitors in children, adolescents and adults with relapsed or refractory bone tumours: A Canadian Sarcoma Research and Clinical Collaboration (CanSaRCC) study. Cancer Med 12 (18): 18872-18881, 2023. [PUBMED Abstract]
  67. Italiano A, Mir O, Mathoulin-Pelissier S, et al.: Cabozantinib in patients with advanced Ewing sarcoma or osteosarcoma (CABONE): a multicentre, single-arm, phase 2 trial. Lancet Oncol 21 (3): 446-455, 2020. [PUBMED Abstract]
  68. Subbiah V, Braña I, Longhi A, et al.: Antitumor Activity of Lurbinectedin, a Selective Inhibitor of Oncogene Transcription, in Patients with Relapsed Ewing Sarcoma: Results of a Basket Phase II Study. Clin Cancer Res 28 (13): 2762-2770, 2022. [PUBMED Abstract]
  69. Povedano JM, Li V, Lake KE, et al.: TK216 targets microtubules in Ewing sarcoma cells. Cell Chem Biol 29 (8): 1325-1332.e4, 2022. [PUBMED Abstract]
  70. Meyers PA, Federman N, Daw N, et al.: Open-Label, Multicenter, Phase I/II, First-in-Human Trial of TK216: A First-Generation EWS::FLI1 Fusion Protein Antagonist in Ewing Sarcoma. J Clin Oncol 42 (31): 3725-3734, 2024. [PUBMED Abstract]
  71. 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]

Undifferentiated Small Round Cell (Ewing-Like) Sarcomas

There are undifferentiated small round cell sarcomas of bone and soft tissue that do not have the translocations of the EWSR1 gene and a gene in the ETS family. These sarcomas appear to be biologically distinctive from Ewing sarcoma with EWSR1 and ETS gene family member translocations. This includes tumors with translocations of the CIC gene or the BCOR gene, as well as tumors with EWSR1 translocations involving non-ETS gene family members. These groups occur much less frequently than Ewing sarcoma, and descriptions of clinical outcomes for these patients are based on smaller sample sizes and less homogeneous treatment. Therefore, patient outcomes are hard to quantitate with precision. Most of these tumors have been treated with regimens designed for Ewing sarcoma, and there is consensus that they were often included in past clinical trials for the treatment of Ewing sarcoma, sometimes called translocation-negative Ewing sarcoma. There is agreement that these tumors are sufficiently different from Ewing sarcoma; they should be stratified and analyzed separately from Ewing sarcoma with the common translocations, even if they are treated with similar therapy. The summary of these entities are presented below and follows the categorization of the 2020 World Health Organization (WHO) Classification of Tumours: Soft Tissue and Bone Tumours (5th edition).[1]

Undifferentiated Small Round Cell Sarcomas With BCOR Genetic Alterations

Clinical presentation

Undifferentiated round cell sarcomas with BCOR::CCNB3 rearrangements account for about 5% of all EWSR1-negative rearranged sarcomas and more commonly affects males. More than 70% of cases occur in patients younger than 18 years (median age at diagnosis, 13–15 years).[2,3][Level of evidence C1] These tumors more commonly arise in the bones of the pelvis and extremities, and metastases are present in approximately 30% of cases.

Genomic characteristics

The most common types of undifferentiated small round cell sarcoma with BCOR rearrangements are those with the BCOR::CCNB3 rearrangement.[2,4] The BCOR::MAML3 rearrangement is less commonly observed, but tumors with this translocation appear to have biological characteristics that are similar to tumors with the BCOR::CCNB3 rearrangement.[2,5,6]

BCOR internal tandem duplications (ITD) involving exon 15 are observed in infantile undifferentiated round cell sarcomas and primitive myxoid mesenchymal tumors of infancy (PMMTI).[7–9] These two entities have significant histological overlap and similar transcriptional profiles, and they are distinguished by more prominent myxoid stroma in PMMTI. BCOR ITD may be occasionally observed in undifferentiated round cell sarcomas arising in older children.[9]

BCOR ITD have been reported in 90% of cases of clear cell sarcoma of the kidney, with a smaller subset harboring YWHAE::NUTM2B/E or BCOR::CCNB3 gene fusions.[10,11] For more information, see the Clear Cell Sarcoma of the Kidney section in Wilms Tumor and Other Childhood Kidney Tumors Treatment.

The transcriptional profiles induced by BCOR gene fusions, BCOR ITD, and YWHAE::NUTM2B/E fusions appear to be similar to each other and distinctive from that of Ewing sarcoma.[2,6,7] As an example, elevated BCOR expression is observed across all of these entities, which can be useful in distinguishing these entities from other undifferentiated small round cell tumors.

Treatment of undifferentiated round cell sarcomas with BCOR genetic alterations

When treated with Ewing sarcoma–like therapies, 75% of patients show significant treatment-associated pathological responses. In one series of 36 cases, the 3-year and 5-year survival rates were 93% and 72%, respectively.[2][Level of evidence C1] In another series of 26 patients, the 5-year overall survival (OS) rate was 76.5%, and survival was better for patients who received induction therapy using an Ewing sarcoma–type regimen.[12][Level of evidence C1] Most of the tumors in these series arose in the bone. A retrospective survey of European cancer centers identified 148 patients with undifferentiated small round cell sarcomas who did not have an Ewing sarcoma–related fusion gene.[13] Of the 148 patients, 88 (60%) had CIC-rearranged sarcomas (median age, 32 years; range 7–78 years), 33 (22%) had BCOR::CCNB3-rearranged sarcomas (median age, 17 years; range 5–91 years), and 27 (18%) had unclassified undifferentiated small round cell sarcomas (median age, 37 years; range 4–70 years). Of the 148 patients, 101 (68.2%) presented with localized disease and 47 (31.8%) had metastasis at diagnosis. Male prevalence, younger age, bone primary site, and low rate of synchronous metastases were observed in BCOR::CCNB3-rearranged cases. The local treatment was surgery for 67 patients (45%) and surgery and radiation therapy for 52 patients (35%). Chemotherapy was given to 122 patients (82%). At a median follow-up of 42.7 months, the 3-year OS rate was 92.2% for patients with BCOR::CCNB3-rearranged sarcomas, 39.6% for patients with CIC-rearranged sarcomas, and 78.7% (P < .0001) for patients with unclassified undifferentiated small round cell sarcomas.

A multi-institution retrospective analysis of patients aged 0 to 24 years identified 29 patients with sarcomas and CIC gene fusions and 25 patients with BCOR-associated sarcomas (18 with BCOR::CCNB3 gene fusions and 7 with BCOR ITD).[14] Using a diverse range of treatments, the 3-year event-free survival (EFS) rates were 44.0% (95% confidence interval [CI], 28.7%–67.5%) for patients with CIC gene fusions and 41.2% (95% CI, 25.4%–67.0%) for patients with BCOR alterations (P = .97).

Undifferentiated Small Round Cell Sarcomas With CIC Genetic Alterations

CIC-rearranged sarcomas represent the second most common family of round cell sarcomas and are defined by the presence of CIC fusions at the molecular level.[1]

Clinical presentation

Undifferentiated small round cell sarcomas with CIC::DUX4 rearrangements most commonly affect young adults, with 50% of cases occurring between the ages of 21 and 40 years. In a series of 115 cases, the median age at diagnosis was 32 years, and 22% of cases occurred in patients younger than 18 years.[3,15] This entity more commonly affects males and usually originates from the soft tissues of the trunk and extremities.

Genomic characteristics

CIC-rearranged sarcomas most commonly have a CIC gene fusion with DUX4, FOXO4, or NUTM1.[15–17] The CIC gene fusion with DUX4 results from either a t(4;19)(q35;q13) or a t(10;19)(q26;q13) translocation.[16,18] CIC is located at chromosome 19q13.1 and DUX4 is located on either chromosome 4q35 or 10q26.3. Sarcomas with the CIC::DUX4 rearrangement have a transcriptional profile and DNA methylation profile that differs from that of Ewing sarcoma, supporting their characterization as a distinct entity.[6,19,20] For example, nearly all sarcomas with CIC::DUX4 rearrangements express WT1 and ETV4, in contrast to Ewing sarcoma and BCOR-rearranged tumors, making immunohistochemistry for these proteins useful in distinguishing between these diagnoses.[15,19]

Treatment of undifferentiated small round cell sarcomas with CIC genetic alterations

In a series of 115 cases of CIC-rearranged small round cell sarcomas, 57 patients had adequate follow-up information.[15] Nine patients presented with metastases, and 53% of patients with localized disease experienced a recurrence commonly involving the lung. Patients treated with neoadjuvant chemotherapy had an inferior survival than patients who were treated with up-front surgical resection. However, this difference in survival might have been related to a larger tumor size at presentation in the former group. The 2-year and 5-year survival rates were 53% and 43%, respectively.

An international retrospective cohort study further highlighted the poor outcomes for patients with CIC-rearranged sarcomas. The 3-year OS rate was 39.6%, which was significantly worse than outcomes for patients with other undifferentiated round cell sarcomas.[13] Likewise, these survival rates are significantly lower than the survival rates observed in patients with Ewing sarcoma. Further study is required to identify optimal treatments for this disease.

In another series of 79 patients with CIC-rearranged round cell sarcomas, outcomes were likewise poor, with a median OS of 18 months.[21] Patients treated with Ewing sarcoma–based chemotherapy regimens had nominally higher response rates compared with patients treated with soft tissue sarcoma–based regimens. However, OS rates were similar between these two groups.

A multi-institution retrospective analysis of patients aged 0 to 24 years identified 29 patients with sarcomas and CIC gene fusions and 25 patients with BCOR-associated sarcomas (18 with BCOR::CCNB3 gene fusions and 7 with BCOR ITD).[14] Using a diverse range of treatments, the 3-year EFS rates were 44.0% (95% CI, 28.7%–67.5%) for patients with CIC gene fusions and 41.2% (95% CI, 25.4%–67.0%) for patients with BCOR alterations (P = .97).

Undifferentiated small round cell sarcomas with CIC::NUTM1 rearrangements

Undifferentiated small round cell sarcomas with CIC::NUTM1 rearrangements occur much less frequently than undifferentiated round cell sarcomas with CIC::DUX4 rearrangements.[22–25] These tumors occur in younger patients, with a median age of 6 years, compared with an average age of 21.6 years for patients with CIC::DUX4 fusions. The primary tumors occur in the central nervous system (CNS) and in the periphery. The histological appearance of these tumors is similar to CIC::DUX4-rearranged sarcomas. The prognosis of patients with these tumors is reported to be very poor despite treatment with surgery, multiagent chemotherapy, and radiation therapy.

Undifferentiated small round cell sarcomas with ATXN1::NUTM2A or ATXN1L::NUTM2A fusions

In one report, three children had tumors with ATXN1::NUTM2A or ATXN1L::NUTM2A fusions.[26] Two of the patients were infants with CNS lesions, and the third patient was a neonate with skin involvement and multiple masses throughout the peritoneal cavity. The authors suggested that ATXN1– or ATXN1L-associated fusions disrupted their interaction with CIC and decreased the transcription repressor complex, leading to downstream PEA3 family gene overexpression.

Undifferentiated Small Round Cell Sarcomas With EWSR1::non-ETS Fusions

Sarcomas with EWSR1::NFATC2 and FUS::NFATC2 fusions

Sarcomas with EWSR1::NFATC2 and FUS::NFATC2 fusions typically arise in long bones, show a strong male predominance, and are more common in adults than in children.[27,28] These entities have transcriptional and DNA methylation profiles that distinguish them from Ewing sarcoma and other small round cell sarcomas.[6,20] Additionally, the transcriptional profiles for EWSR1::NFATC2 and FUS::NFATC2 differ from each other,[6] although the significance of this observation is unclear. The two entities also differ in that amplification of the EWSR1::NFATC2 gene fusion is commonly observed, but the FUS::NFATC2 gene fusion is generally not amplified.[20,27,29] Sarcomas with EWSR1::NFATC2 and FUS::NFATC2 fusions have metastatic potential and appear to respond poorly to chemotherapy regimens that are commonly used to treat other sarcomas.[27,28]

EWSR1::NFATC2 and FUS::NFATC2 rearrangements are also observed in a substantial proportion of solitary bone cysts (also known as simple bone cysts), a benign condition that typically presents in the metadiaphyses of the long bones of skeletally immature individuals.[30,31] Therefore, the presence of either EWSR1::NFATC2 or FUS::NFATC2 fusions should not be taken as an indicator of malignancy, but rather needs to be interpreted considering the clinical setting.

Sarcomas with EWSR1::PATZ1 fusions

Sarcomas with the EWSR1::PATZ1 fusion are very uncommon. In the small number of cases described, there appears to be gender balance, a propensity for presentation at truncal primary sites (particularly the chest), and a median age of presentation of between 40 to 50 years, with cases rarely occurring in the pediatric age range.[32–34] Sarcomas with the EWSR1::PATZ1 fusion have gene expression and DNA methylation profiles that distinguish them from other sarcomas,[6,20] and CDKN2A deletions appear to commonly occur as secondary genomic alterations.[32,33]

The EWSR1::PATZ1 fusion has been described more commonly in brain tumors. It has been suggested that this fusion may define a novel form of glioblastoma.[35] In a series of 11 cases of EWSR1::PATZ1 fusion–associated tumors, 3 were primary brain tumors, 7 were sarcomas, and 1 was classified as a soft tissue sarcoma in the CNS.[32] Patients were between the ages of 11 and 81 years. Treatment details were reported for only three adult patients, two of whom had mixed responses to chemotherapy followed by disease progression, and one patient who did not receive chemotherapy.

References
  1. WHO Classification of Tumours Editorial Board: WHO Classification of Tumours. Volume 3: Soft Tissue and Bone Tumours. 5th ed., IARC Press, 2020.
  2. Kao YC, Owosho AA, Sung YS, et al.: BCOR-CCNB3 Fusion Positive Sarcomas: A Clinicopathologic and Molecular Analysis of 36 Cases With Comparison to Morphologic Spectrum and Clinical Behavior of Other Round Cell Sarcomas. Am J Surg Pathol 42 (5): 604-615, 2018. [PUBMED Abstract]
  3. Machado I, Navarro S, Llombart-Bosch A: Ewing sarcoma and the new emerging Ewing-like sarcomas: (CIC and BCOR-rearranged-sarcomas). A systematic review. Histol Histopathol 31 (11): 1169-81, 2016. [PUBMED Abstract]
  4. Pierron G, Tirode F, Lucchesi C, et al.: A new subtype of bone sarcoma defined by BCOR-CCNB3 gene fusion. Nat Genet 44 (4): 461-6, 2012. [PUBMED Abstract]
  5. Specht K, Zhang L, Sung YS, et al.: Novel BCOR-MAML3 and ZC3H7B-BCOR Gene Fusions in Undifferentiated Small Blue Round Cell Sarcomas. Am J Surg Pathol 40 (4): 433-42, 2016. [PUBMED Abstract]
  6. 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]
  7. Kao YC, Sung YS, Zhang L, et al.: Recurrent BCOR Internal Tandem Duplication and YWHAE-NUTM2B Fusions in Soft Tissue Undifferentiated Round Cell Sarcoma of Infancy: Overlapping Genetic Features With Clear Cell Sarcoma of Kidney. Am J Surg Pathol 40 (8): 1009-20, 2016. [PUBMED Abstract]
  8. Kao YC, Sung YS, Zhang L, et al.: BCOR Overexpression Is a Highly Sensitive Marker in Round Cell Sarcomas With BCOR Genetic Abnormalities. Am J Surg Pathol 40 (12): 1670-1678, 2016. [PUBMED Abstract]
  9. Antonescu CR, Kao YC, Xu B, et al.: Undifferentiated round cell sarcoma with BCOR internal tandem duplications (ITD) or YWHAE fusions: a clinicopathologic and molecular study. Mod Pathol 33 (9): 1669-1677, 2020. [PUBMED Abstract]
  10. Ueno-Yokohata H, Okita H, Nakasato K, et al.: Consistent in-frame internal tandem duplications of BCOR characterize clear cell sarcoma of the kidney. Nat Genet 47 (8): 861-3, 2015. [PUBMED Abstract]
  11. Roy A, Kumar V, Zorman B, et al.: Recurrent internal tandem duplications of BCOR in clear cell sarcoma of the kidney. Nat Commun 6: 8891, 2015. [PUBMED Abstract]
  12. Cohen-Gogo S, Cellier C, Coindre JM, et al.: Ewing-like sarcomas with BCOR-CCNB3 fusion transcript: a clinical, radiological and pathological retrospective study from the Société Française des Cancers de L’Enfant. Pediatr Blood Cancer 61 (12): 2191-8, 2014. [PUBMED Abstract]
  13. Palmerini E, Gambarotti M, Italiano A, et al.: A global collaboRAtive study of CIC-rearranged, BCOR::CCNB3-rearranged and other ultra-rare unclassified undifferentiated small round cell sarcomas (GRACefUl). Eur J Cancer 183: 11-23, 2023. [PUBMED Abstract]
  14. Sparber-Sauer M, Corradini N, Affinita MC, et al.: Clinical characteristics and outcomes for children, adolescents and young adults with “CIC-fused” or “BCOR-rearranged” soft tissue sarcomas: A multi-institutional European retrospective analysis. Cancer Med 12 (13): 14346-14359, 2023. [PUBMED Abstract]
  15. Antonescu CR, Owosho AA, Zhang L, et al.: Sarcomas With CIC-rearrangements Are a Distinct Pathologic Entity With Aggressive Outcome: A Clinicopathologic and Molecular Study of 115 Cases. Am J Surg Pathol 41 (7): 941-949, 2017. [PUBMED Abstract]
  16. Italiano A, Sung YS, Zhang L, et al.: High prevalence of CIC fusion with double-homeobox (DUX4) transcription factors in EWSR1-negative undifferentiated small blue round cell sarcomas. Genes Chromosomes Cancer 51 (3): 207-18, 2012. [PUBMED Abstract]
  17. Dickson BC, Sung YS, Rosenblum MK, et al.: NUTM1 Gene Fusions Characterize a Subset of Undifferentiated Soft Tissue and Visceral Tumors. Am J Surg Pathol 42 (5): 636-645, 2018. [PUBMED Abstract]
  18. Kawamura-Saito M, Yamazaki Y, Kaneko K, et al.: Fusion between CIC and DUX4 up-regulates PEA3 family genes in Ewing-like sarcomas with t(4;19)(q35;q13) translocation. Hum Mol Genet 15 (13): 2125-37, 2006. [PUBMED Abstract]
  19. Specht K, Sung YS, Zhang L, et al.: Distinct transcriptional signature and immunoprofile of CIC-DUX4 fusion-positive round cell tumors compared to EWSR1-rearranged Ewing sarcomas: further evidence toward distinct pathologic entities. Genes Chromosomes Cancer 53 (7): 622-33, 2014. [PUBMED Abstract]
  20. Koelsche C, Kriegsmann M, Kommoss FKF, et al.: DNA methylation profiling distinguishes Ewing-like sarcoma with EWSR1-NFATc2 fusion from Ewing sarcoma. J Cancer Res Clin Oncol 145 (5): 1273-1281, 2019. [PUBMED Abstract]
  21. Brahmi M, Gaspar N, Gantzer J, et al.: Patterns of care and outcome of CIC-rearranged sarcoma patients: A nationwide study of the French sarcoma group. Cancer Med 12 (7): 7801-7807, 2023. [PUBMED Abstract]
  22. Le Loarer F, Pissaloux D, Watson S, et al.: Clinicopathologic Features of CIC-NUTM1 Sarcomas, a New Molecular Variant of the Family of CIC-Fused Sarcomas. Am J Surg Pathol 43 (2): 268-276, 2019. [PUBMED Abstract]
  23. Mangray S, Kelly DR, LeGuellec S, et al.: Clinicopathologic Features of a Series of Primary Renal CIC-rearranged Sarcomas With Comprehensive Molecular Analysis. Am J Surg Pathol 42 (10): 1360-1369, 2018. [PUBMED Abstract]
  24. Schaefer IM, Dal Cin P, Landry LM, et al.: CIC-NUTM1 fusion: A case which expands the spectrum of NUT-rearranged epithelioid malignancies. Genes Chromosomes Cancer 57 (9): 446-451, 2018. [PUBMED Abstract]
  25. Zhao L, He H, Ren J, et al.: CIC::NUTM1 sarcomas occurred in soft tissues of upper limbs : a rare case report and literature review. Diagn Pathol 19 (1): 76, 2024. [PUBMED Abstract]
  26. Xu F, Viaene AN, Ruiz J, et al.: Novel ATXN1/ATXN1L::NUTM2A fusions identified in aggressive infant sarcomas with gene expression and methylation patterns similar to CIC-rearranged sarcoma. Acta Neuropathol Commun 10 (1): 102, 2022. [PUBMED Abstract]
  27. Bode-Lesniewska B, Fritz C, Exner GU, et al.: EWSR1-NFATC2 and FUS-NFATC2 Gene Fusion-Associated Mesenchymal Tumors: Clinicopathologic Correlation and Literature Review. Sarcoma 2019: 9386390, 2019. [PUBMED Abstract]
  28. Wang GY, Thomas DG, Davis JL, et al.: EWSR1-NFATC2 Translocation-associated Sarcoma Clinicopathologic Findings in a Rare Aggressive Primary Bone or Soft Tissue Tumor. Am J Surg Pathol 43 (8): 1112-1122, 2019. [PUBMED Abstract]
  29. Szuhai K, Ijszenga M, de Jong D, et al.: The NFATc2 gene is involved in a novel cloned translocation in a Ewing sarcoma variant that couples its function in immunology to oncology. Clin Cancer Res 15 (7): 2259-68, 2009. [PUBMED Abstract]
  30. Pižem J, Šekoranja D, Zupan A, et al.: FUS-NFATC2 or EWSR1-NFATC2 Fusions Are Present in a Large Proportion of Simple Bone Cysts. Am J Surg Pathol 44 (12): 1623-1634, 2020. [PUBMED Abstract]
  31. Hung YP, Fisch AS, Diaz-Perez JA, et al.: Identification of EWSR1-NFATC2 fusion in simple bone cysts. Histopathology 78 (6): 849-856, 2021. [PUBMED Abstract]
  32. Bridge JA, Sumegi J, Druta M, et al.: Clinical, pathological, and genomic features of EWSR1-PATZ1 fusion sarcoma. Mod Pathol 32 (11): 1593-1604, 2019. [PUBMED Abstract]
  33. Michal M, Rubin BP, Agaimy A, et al.: EWSR1-PATZ1-rearranged sarcoma: a report of nine cases of spindle and round cell neoplasms with predilection for thoracoabdominal soft tissues and frequent expression of neural and skeletal muscle markers. Mod Pathol 34 (4): 770-785, 2021. [PUBMED Abstract]
  34. Dehner CA, Torres-Mora J, Gupta S, et al.: Sarcomas Harboring EWSR1::PATZ1 Fusions: A Clinicopathologic Study of 17 Cases. Mod Pathol 37 (2): 100400, 2024. [PUBMED Abstract]
  35. Siegfried A, Rousseau A, Maurage CA, et al.: EWSR1-PATZ1 gene fusion may define a new glioneuronal tumor entity. Brain Pathol 29 (1): 53-62, 2019. [PUBMED Abstract]

Latest Updates to This Summary (11/27/2024)

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.

Treatment of Recurrent Ewing Sarcoma

Added strategies to target fusion proteins to the list of other therapies that have been studied in the treatment of recurrent Ewing sarcoma.

Added text to state that lurbinectedin is structurally related to trabectedin, but it has been more effective in suppressing the activity of the oncogenic transcription factor EWS::FLI in mice in preclinical studies. Also added text about the results of an open-label, single-arm, basket phase II trial of lurbinectedin (cited Subbiah et al. as reference 68). Added text to state that an agent known as TK216 is thought to interfere with interactions between the EWSR1::FLI1 fusion oncoprotein and key proteins critical for its oncogenic function, although it has also been shown to disrupt microtubules (cited Povedano et al. as reference 69). Also added text about the results of a phase I/II trial of TK216 in combination with vincristine in patients with recurrent Ewing sarcoma (cited Meyers et al. as reference 70).

Added NCT04890093 as a treatment option under clinical evaluation for patients with recurrent Ewing sarcoma.

Undifferentiated Small Round Cell (Ewing-Like) Sarcomas

Added text to state that CIC-rearranged sarcomas represent the second most common family of round cell sarcomas and are defined by the presence of CIC fusions at the molecular level.

Revised text to state that CIC-rearranged sarcomas most commonly have a CIC gene fusion with DUX4, FOXO4, or NUTM1 (cited Dickson et al. as reference 17).

Added Zhao et al. as reference 25. Also revised text to state that tumors with CIC::NUTM1 rearrangements occur in younger patients, with a median age of 6 years, compared with an average age of 21.6 years for patients with CIC::DUX4 fusions.

Added Dehner et al. as reference 34.

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 Ewing sarcoma and undifferentiated small round cell sarcomas of bone and soft tissue. 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 Ewing Sarcoma and Undifferentiated Small Round Cell Sarcomas of Bone and Soft Tissue Treatment are:

  • Holcombe Edwin Grier, MD
  • 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)
  • William H. Meyer, MD
  • Paul A. Meyers, MD (Memorial Sloan-Kettering Cancer Center)
  • Thomas A. Olson, MD (Aflac Cancer and Blood Disorders Center of Children’s Healthcare of Atlanta – Egleston Campus)
  • Nita Louise Seibel, MD (National Cancer Institute)
  • 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

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® Pediatric Treatment Editorial Board. PDQ Ewing Sarcoma and Undifferentiated Small Round Cell Sarcomas of Bone and Soft Tissue Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/bone/hp/ewing-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389480]

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

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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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.

Bone Cancer—Health Professional Version

Bone Cancer—Health Professional Version

Bone Cancer—Patient Version

Bone Cancer—Patient Version

Overview

Bone cancer is rare and includes several types. Some bone cancers, including osteosarcoma and Ewing sarcoma, are seen most often in children and young adults. Explore the links on this page to learn about bone cancer treatment, statistics, research, and clinical trials.

The Primary Bone Cancer fact sheet has additional basic information.

Treatment

PDQ Treatment Information for Patients

More information

Causes & Prevention

NCI does not have PDQ evidence-based information about prevention of bone cancer.

More information

Screening

NCI does not have PDQ evidence-based information about screening for bone cancer.

More information

Statistics

Coping with Cancer

The information in this section is meant to help you cope with the many issues and concerns that occur when you have cancer.

Emotions and Cancer Adjusting to Cancer Support for Caregivers Survivorship Advanced Cancer Managing Cancer Care

Research

ETV6 Protein Could Be an Important Target for Ewing Sarcoma Treatment

Ifosfamide May Be Treatment of Choice for Some People with Ewing Sarcoma, Trial Shows

NCI study provides genetic insights into osteosarcoma in children

Study Identifies Potential Drug Combination for Ewing Sarcoma

View more research

Childhood Ependymoma

Childhood Ependymoma

Ependymoma is a rare type of tumor that starts in the brain or spinal cord. The brain controls all body functions, such as breathing, heart rate, memory and learning, emotion, and senses. The spinal cord is made up of bundles of nerve fibers that carry messages between the brain and the rest of the body. Together, the brain and spinal cord make up the central nervous system (CNS).

Ependymomas start when cells called ependymal cells grow without control. Ependymal cells line the ventricles and passageways in the brain and spinal cord and make cerebrospinal fluid (CSF), which acts as a cushion to protect the brain and spinal cord from injury. Ependymomas can spread when the CSF carries ependymoma cells to other parts of the CNS. Ependymomas rarely spread outside the CNS.

Children and adults can get ependymoma, but it is more common in young children. This type of tumor accounts for about 9% of all childhood brain and spinal cord tumors, affecting about 200 children per year in the United States.

Types of childhood ependymoma

There are different types of ependymomas depending on where the tumor is located. Three main types of ependymoma are seen in children:

  • Posterior fossa (infratentorial) ependymomas form in the lower part of the brain near the middle of the back of the head. In children, most ependymomas arise in this area of the brain and affect the cerebellum and brain stem.
    • The cerebellum is the lower, back part of the brain (near the middle of the back of the head). The cerebellum controls movement, balance, and posture.
    • The brain stem, located in the lowest part of the brain (just above the back of the neck), connects the brain to the spinal cord. The brain stem controls vital functions, such as breathing, heart rate, blood pressure, and the nerves and muscles used in seeing, hearing, walking, talking, and eating.
  • Supratentorial ependymomas form at the top of the head and affect the cerebrum. Ependymoma in this area of the brain is less common in children.
    • The cerebrum is the largest part of the brain, at the top of the head. The cerebrum controls thinking, learning, problem-solving, emotions, speech, reading, writing, and voluntary movement.
  • Spinal cord ependymomas are rare in children. Most spinal cord ependymomas in children are a type called myxopapillary ependymomas, which usually occur in the lower part of the spine.
    • The spinal cord is the column of nerve tissue that runs from the brain stem down the center of the back. Spinal cord nerves carry messages between the brain and the rest of the body, such as a message from the brain to cause muscles to move or a message from the skin to the brain to feel touch.
EnlargeDrawing of the inside of the brain showing the lateral ventricle, third ventricle, fourth ventricle, and the passageways between the ventricles (with cerebrospinal fluid shown in blue). Also shown are the cerebrum, cerebellum, brain stem (pons and medulla), and spinal cord.
Anatomy of the inside of the brain showing the lateral ventricle, third ventricle, fourth ventricle, and the passageways between the ventricles (with cerebrospinal fluid shown in blue). Also shown are the cerebrum, cerebellum, brain stem (pons and medulla), and spinal cord.

Causes and risk factors for childhood ependymoma

Childhood ependymoma is caused by certain changes to the way ependymal cells function, especially how they grow and divide into new cells. The exact cause of these cell changes is unknown. Learn more about how cancer develops at What Is Cancer?

A risk factor is anything that increases the chance of getting a disease. Children with an inherited condition called neurofibromatosis type 2 (NF2) may have an increased risk of developing ependymoma along the optic pathway. Not every child with this risk factor will develop ependymoma. And it will develop in some children who don’t have a known risk factor.

Symptoms of childhood ependymoma

Symptoms of ependymoma depend on the child’s age and where the tumor has formed. It’s important to check with your child’s doctor if your child has any of the symptoms below.

Symptoms of posterior fossa ependymoma in children can include:

  • buildup of spinal fluid in the brain that may cause tiredness, vomiting, eyes that stay looking down, irritability, slowed development, or increased size of the head
  • loss of balance or trouble walking
  • neck pain
  • loss of function of the nerves in the back of the brain

Symptoms of supratentorial ependymomas in children can include:

  • seizures
  • frequent headaches
  • blurry vision
  • nausea and vomiting
  • changes in movement and sensation

Symptoms of spinal cord ependymomas in children can include:

  • neck or back pain
  • neck weakness or stiffness
  • weakness in one or both legs
  • trouble urinating
  • a change in bowel function

These symptoms may be caused by problems other than an ependymoma. The only way to know is to see your child’s doctor.

Tests to diagnose childhood ependymoma

If your child has symptoms that suggest an ependymoma, their doctor will need to find out if these are due to ependymoma or some other problem. The doctor will ask when the symptoms started and how often your child has been having them. They will also ask about your child’s personal and family medical history and do a physical exam, including a neurologic exam. Depending on these results, they may recommend other tests. If your child is diagnosed with an ependymoma, the results of these tests will help you and your child’s doctor plan treatment.

The tests used to diagnose ependymoma in children may include:

Magnetic resonance imaging (MRI) with or without gadolinium

MRI uses a magnet, radio waves, and a computer to make a series of detailed pictures of areas inside the brain and spinal cord. A substance called gadolinium is injected into a vein and travels through the bloodstream. The gadolinium may collect around the cancer cells so they show up brighter in the picture. This procedure is also called nuclear magnetic resonance imaging (NMRI).

EnlargeMagnetic resonance imaging (MRI) scan; drawing shows a child lying on a table that slides into the MRI machine, which takes a series of detailed pictures of areas inside the body.
Magnetic resonance imaging (MRI) scan. The child lies on a table that slides into the MRI machine, which takes a series of detailed pictures of areas inside the body. The positioning of the child on the table depends on the part of the body being imaged.

Biopsy

If the diagnostic tests show there may be a brain tumor, a biopsy can be done by removing part of the skull or making a small hole in the skull and using a needle or surgical device to remove a sample of the brain tissue. Sometimes, when a needle is used, it is guided by a computer to remove the tissue sample. A pathologist views the tissue under a microscope to look for cancer cells and determine the grade of the tumor. If cancer cells are found, the doctor will remove as much tumor as safely possible during the same surgery.

EnlargeDrawing of a craniotomy showing a section of the scalp that has been pulled back to remove a piece of the skull; the dura covering the brain has been opened to expose the brain. The layer of muscle under the scalp is also shown.
Craniotomy. An opening is made in the skull and a piece of the skull is removed to show part of the brain.

The following laboratory tests may be done on the tissue that was removed during the biopsy:

  • Immunohistochemistry 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.
  • Next-generation sequencing uses computers to piece together DNA or RNA fragments in order to sequence a person or other organism’s entire DNA, large segments of DNA or RNA, or the DNA in specific types of cells from a sample of tissue. Next-generation sequencing can also identify changes in certain areas of the genome or in specific genes. There are many different types of next-generation sequencing methods, including whole-genome sequencing, whole-exome sequencing, multigene panel testing, and transcriptome sequencing. Next-generation sequencing may help researchers understand the cause of certain diseases, such as cancer. Also called massively parallel sequencing and NGS.

The Molecular Characterization Initiative offers free molecular testing to children, adolescents, and young adults with certain types of newly diagnosed cancer. The program is offered through NCI’s Childhood Cancer Data Initiative. To learn more, visit About the Molecular Characterization Initiative.

Lumbar puncture

Lumbar puncture is a procedure used to collect cerebrospinal fluid (CSF) from the spinal column. This is done by placing a needle between two bones in the spine and into the lining around the spinal cord to remove a sample of CSF. The sample of CSF is checked under a microscope for signs of tumor cells. The sample may also be checked for the amounts of protein and glucose.

EnlargeLumbar puncture; drawing shows a patient lying in a curled position on a table and a spinal needle (a long, thin needle) being inserted into the lower back. Inset shows a close-up of the spinal needle inserted into the cerebrospinal fluid (CSF) in the lower part of the spinal column.
Lumbar puncture. A patient lies in a curled position on a table. After a small area on the lower back is numbed, a spinal needle (a long, thin needle) is inserted into the lower part of the spinal column to remove cerebrospinal fluid (CSF, shown in blue). The fluid may be sent to a laboratory for testing.

Getting a second opinion

You may want to get a second opinion to confirm your child’s 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. This doctor may agree with the first doctor, suggest changes to the treatment plan, or provide more information about your child’s cancer.

To learn more about choosing a doctor and getting a second opinion, see 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 or hospital that can provide a second opinion. For questions you might want to ask at your child’s appointments, see Questions to Ask Your Doctor About Cancer.

Stages and tumor grades of childhood ependymoma

Staging is the process of learning the extent of the cancer in the body and is often used to help plan treatment and make a prognosis. There is no staging system used for childhood ependymoma, but it is given a tumor grade. Tumor grading is based on the World Health Organization (WHO) criteria.

Tumor grade describes how abnormal the cancer cells look under a microscope, how quickly the tumor is likely to grow and spread, and how likely the tumor is to come back after treatment. The WHO criteria also classifies ependymomas by their location in the brain or spinal cord (see the section on Types of childhood ependymoma) and the tumor’s molecular or genetic features.

Low-grade (grade I) cancer cells look more like normal cells than high-grade (grades II and III) cancer cells. Grade I cancer cells also tend to grow and spread more slowly than grade II and III cancer cells.

Childhood ependymoma often comes back after treatment, sometimes as long as 15 years after the initial treatment. The tumor commonly comes back at the original cancer site, although it can also spread to areas near the original site. It is rare for ependymoma to spread to areas far from the original cancer site.

Types of treatment for childhood ependymoma

Who treats children with ependymoma?

A pediatric oncologist, a doctor who specializes in treating children with cancer, oversees treatment for childhood ependymoma. The pediatric oncologist works with other health care providers who are experts in treating children with brain tumors and also specialize in other areas of medicine. Other specialists may include:

There are different types of treatment for children and adolescents with ependymoma. You and your child’s care team will work together to decide treatment. Many factors will be considered, such as where the cancer is located, your child’s age and overall health, and the type and grade of the ependymoma.

Your child’s treatment plan will include information about the cancer, the goals of treatment, treatment options, and the possible side effects. It will be helpful to talk with your child’s care team before treatment begins about what to expect. For help every step of the way, see our booklet, Children with Cancer: A Guide for Parents.

The types of treatment your child might have include:

Surgery

Surgery to remove the tumor and some of the healthy tissue around it is usually the first treatment for childhood ependymoma. Surgery may be done to obtain a biopsy sample to confirm the diagnosis (see Tests to diagnose childhood ependymoma), relieve symptoms caused by the tumor pressing on the brain or spinal cord, and to remove as much of the tumor as possible.

An MRI is often done after the tumor is removed to find out whether any tumor remains. If tumor remains, a second surgery to remove as much of the remaining tumor as possible may be done.

Some children may be given chemotherapy or radiation therapy after surgery to kill any cancer cells that are left. Treatment given after 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. Ependymoma is treated with external beam radiation therapy. This type of therapy uses a machine outside the body to send radiation toward the area of the body with cancer. Radiation therapy may be given alone or with other treatments, such as chemotherapy.

Certain ways of giving external beam radiation therapy can help keep radiation from damaging nearby healthy tissue. These include:

  • Conformal radiation therapy uses a computer to make a 3-dimensional (3-D) picture of the tumor and shapes the radiation beams to fit the tumor.
  • Intensity-modulated radiation therapy (IMRT) is a type of 3-D radiation therapy that uses a computer to make pictures of the size and shape of the tumor. Thin beams of radiation of different intensities (strengths) are aimed at the tumor from many angles.
  • Proton-beam radiation therapy is a type of high-energy radiation therapy. A radiation therapy machine aims streams of protons (tiny, invisible, positively-charged particles) at the cancer cells to kill them.
  • Stereotactic radiosurgery uses a rigid head frame attached to the skull to keep the head still during the radiation treatment. A machine aims a single large dose of radiation directly at the tumor. This procedure does not involve surgery. It is also called stereotaxic radiosurgery, radiosurgery, and radiation surgery.

Younger children who receive radiation therapy to the brain have a higher risk of problems with growth and development than older children. 3-D conformal radiation therapy and proton-beam therapy are being studied in young children to see if it decreases the effects of radiation on growth and development.

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. Chemotherapy either kills the cancer cells or stops them from dividing. Chemotherapy may be given alone or with other types of treatment, such as radiation therapy.

For ependymoma, chemotherapy is injected into a vein. When given this way, the drugs enter the bloodstream to reach cancer cells throughout the body. Chemotherapy that may be used alone or in combination includes:

Other chemotherapy drugs not listed here may also be used.

Learn more at Chemotherapy to Treat Cancer.

Clinical trials

A treatment clinical trial is a research study meant to help improve current treatments or obtain information on new treatments for people with cancer. Because cancer in children is rare, taking part in a clinical trial should be considered.

Find clinical trials for people with ependymoma at Ependymoma Clinical Trials, or 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. Some clinical trials are open only to patients who have not started treatment. Clinical trials supported by other organizations can be found on the ClinicalTrials.gov website.

Learn more at Clinical Trials Information for Patients and Caregivers.

Treatment of childhood ependymoma in the brain or brain stem

Treatment of newly diagnosed childhood ependymoma in the brain or brain stem includes surgery.

After surgery, the plan for further treatment depends on:

  • the ependymoma subtype
  • whether any cancer cells remain after surgery
  • whether the cancer has spread to other parts of the brain or spinal cord
  • your child’s age

When the tumor is completely removed and cancer cells have not spread, treatment may include radiation therapy.

When part of the tumor remains after surgery, but cancer cells have not spread, treatment may include:

  • a second surgery to remove as much of the remaining tumor as possible
  • radiation therapy
  • chemotherapy before radiation therapy

When cancer cells have spread within the brain and spinal cord, treatment may include:

  • radiation therapy to the brain and spinal cord
  • chemotherapy

Treatment for children younger than 1 year of age may include:

Radiation therapy is not given to children until they are older than 1 year.

To learn more about these treatments, see Types of treatment for childhood ependymoma.

Treatment of childhood spinal cord ependymoma

Treatment of newly diagnosed childhood myxopapillary spinal ependymoma (grade 2) is surgery. Sometimes radiation therapy is given after surgery.

Treatment of newly diagnosed childhood nonmyxopapillary spinal ependymoma is surgery. Sometimes radiation therapy is given after surgery for children with grade 2 or grade 3 tumors.

To learn more about these treatments, see Types of treatment for childhood ependymoma.

Treatment of recurrent childhood ependymoma

Treatment of recurrent childhood ependymoma may include:

  • surgery
  • external beam radiation therapy
  • chemotherapy

To learn more about these treatments, see Types of treatment for childhood ependymoma.

Prognostic factors for childhood ependymoma

If your child has been diagnosed with ependymoma, you likely have questions about how serious the cancer is and your child’s chances of survival. The likely outcome or course of a disease is called prognosis. Your child’s prognosis depends on many factors, including:

  • where the tumor has formed in the central nervous system (CNS)
  • whether there are certain changes in the genes or chromosomes of the cancer cells
  • whether the cancer was completely removed by surgery; the prognosis is better if the cancer can be completely removed
  • the type and grade of ependymoma
  • your child’s age when the tumor was diagnosed
  • whether the cancer has spread to other parts of the brain or spinal cord; the prognosis is better if the cancer has not spread
  • whether the tumor has just been diagnosed or has come back

Prognosis also depends on whether radiation therapy was given, the type and treatment dose, and whether chemotherapy alone was given.

No two people are alike, and responses to treatment can vary greatly. Your child’s cancer care team is in the best position to talk with you about your child’s prognosis.

Side effects and late effects of cancer treatment

Cancer treatments can cause side effects. Which side effects your child might have depends on the type of treatment they receive, the dose, and how their body reacts. Talk with your child’s treatment team about which side effects to look for and ways to manage them.

To learn more about side effects that begin during treatment for cancer, visit Side Effects.

Problems from cancer treatment that begin 6 months or later after treatment and continue for months or years are called late effects. Late effects of treatment for childhood ependymoma may include:

  • physical problems, including problems with:
    • tooth development
    • hearing function
    • bone and muscle growth and development
    • thyroid function
    • blood clots and broken vessels in the brain, leading to stroke
  • changes in mood, feelings, thinking, learning, or memory
  • second cancers (new types of cancer), such as thyroid cancer or brain cancer

Some late effects may be treated or controlled. It is important to talk with your child’s doctors about the effects cancer treatment can have on your child. Learn more about Late Effects of Treatment for Childhood Cancer.

Follow-up care

As your child goes through treatment, they will have follow-up tests or check-ups. Some of the tests that were done to diagnose 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.

Childhood ependymoma may come back as long as 15 years or more after initial treatment. So once your child finishes treatment, they will continue to have certain tests from time to time. The results of these tests can show if your child’s condition has changed or if the cancer has come back.

Your child may receive an MRI of the brain and spinal cord at the following intervals:

  • every 3 to 4 months for the first 2 to 3 years
  • every 6 months at 4 to 5 years after treatment
  • once a year at more than 5 years after treatment

Coping with your child's cancer

When a child has cancer, every member of the family needs support. Taking care of yourself during this difficult time is important. Reach out to your child’s treatment team and to people in your family and community for support. To learn more, see Support for Families: Childhood Cancer and the booklet Children with Cancer: A Guide for Parents.

Related resources

For more childhood cancer information and other general cancer resources, see:

Diffuse Intrinsic Pontine Glioma (DIPG)

Diffuse Intrinsic Pontine Glioma (DIPG)

Diffuse intrinsic pontine glioma (DIPG) is a fast-growing type of brain tumor that starts in the part of the brain stem called the pons. The brain stem is the part of the brain above the back of the neck that is connected to the spinal cord. The pons controls many vital functions such as breathing, heart rate, and blood pressure, and the nerves and muscles used in seeing, hearing, walking, talking, and eating. DIPG is a glioma, meaning it starts in the brain stem’s glial cells. Glial cells support and protect the brain’s nerve cells.

In the United States, about 300 children are diagnosed with DIPG each year. DIPG primarily affects children between the ages of 5 and 10 years but can occur in younger children and teens. DIPG is rare in adults.

EnlargeAnatomy of the brain; the right panel shows the supratentorial area (the upper part of the brain) and the posterior fossa/infratentorial area (the lower back part of the brain). The supratentorial area contains the cerebrum, lateral ventricle and third ventricle (with cerebrospinal fluid shown in blue), choroid plexus, pineal gland, hypothalamus, pituitary gland, and optic nerve. The posterior fossa/infratentorial area contains the cerebellum, tectum, fourth ventricle, and brain stem (midbrain, pons, and medulla). The spinal cord is also shown. The left panel shows the cerebrum, ventricles (fluid-filled spaces), meninges, skull, cerebellum, brain stem (pons and medulla), and spinal cord.
Anatomy of the brain. The supratentorial area (the upper part of the brain) contains the cerebrum, lateral ventricle and third ventricle (with cerebrospinal fluid shown in blue), choroid plexus, pineal gland, hypothalamus, pituitary gland, and optic nerve. The posterior fossa/infratentorial area (the lower back part of the brain) contains the cerebellum, tectum, fourth ventricle, and brain stem (midbrain, pons, and medulla). The skull and meninges protect the brain and spinal cord.

Causes and risk factors for DIPG

DIPG is caused by certain changes to the way glial cells function, especially how they grow and divide into new cells. Often, the exact cause of the cell changes that lead to DIPG is unknown. To learn more about how cancer develops, see What Is Cancer?

A risk factor is anything that increases the chance of getting a disease. There are no known risk factors for DIPG.

Symptoms of DIPG

The symptoms of DIPG depend on:

  • where the tumor forms in the brain
  • the size of the tumor and whether it has spread throughout the brain stem
  • how fast the tumor grows
  • your child’s age and stage of development

DIPG symptoms appear rapidly. It’s important to check with your child’s doctor immediately if your child has:

  • trouble with eye movement (the eye is turned inward)
  • vision problems
  • problems with talking, chewing, and swallowing
  • drooping on one side of the face
  • morning headache or headache that goes away after vomiting
  • nausea and vomiting
  • weakness in the arms or legs
  • loss of balance and trouble walking
  • changes in behavior
  • trouble learning in school

These symptoms may be caused by problems other than DIPG. The only way to know for sure is to see your child’s doctor.

Tests to diagnose DIPG

If your child has symptoms that suggest a DIPG, their doctor will need to find out if these are due to DIPG or some other problem. The doctor will ask when the symptoms started and how often your child has been having them. They will also ask about your child’s personal and family medical history and do a physical exam, including a neurological exam. Depending on these results, they may recommend other tests. If your child is diagnosed with DIPG, the results of these tests will help you and your child’s doctor plan treatment.

The tests and procedures used to diagnose a DIPG may include:

Magnetic resonance imaging (MRI) with or without gadolinium

MRI uses a magnet, radio waves, and a computer to make a series of detailed pictures of areas inside the brain. A substance called gadolinium is injected into 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).

EnlargeMagnetic resonance imaging (MRI) scan; drawing shows a child lying on a table that slides into the MRI machine, which takes a series of detailed pictures of areas inside the body.
Magnetic resonance imaging (MRI) scan. The child lies on a table that slides into the MRI machine, which takes a series of detailed pictures of areas inside the body. The positioning of the child on the table depends on the part of the body being imaged.

Biopsy

Your child’s doctor will discuss whether a biopsy is an option. A biopsy is a procedure in which a surgeon removes a sample of tumor tissue from the pons. A stereotactic biopsy, which involves using an imaging technique to help precisely find and remove the tumor tissue, is usually done. A pathologist will study the biopsy sample and provide the results of their analysis in a pathology report. If the pathologist finds that your child has DIPG, the pathology report will provide information about the cancer that can help guide treatment decisions.

EnlargeDrawing of a craniotomy showing a section of the scalp that has been pulled back to remove a piece of the skull; the dura covering the brain has been opened to expose the brain. The layer of muscle under the scalp is also shown.
Craniotomy. An opening is made in the skull and a piece of the skull is removed to show part of the brain.

Immunohistochemistry

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.

Getting a second opinion

You may want to get a second opinion to confirm your child’s 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 to the treatment plan, or provide more information about your child’s cancer.

To learn more about choosing a doctor and getting a second opinion, see 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 or hospital that can provide a second opinion. For questions you might want to ask at your child’s appointments, see Questions to Ask Your Doctor.

Who treats children with DIPG?

A pediatric oncologist, a doctor who specializes in treating children with cancer, oversees treatment for DIPG. The pediatric oncologist works with other health professionals who are experts in treating children with brain tumors and also specialize in other areas of medicine. Other specialists may include:

Types of treatment for DIPG

There are different types of treatment for children and adolescents with DIPG. You and your child’s care team will work together to decide treatment. Many factors will be considered, such as your child’s overall health and whether the cancer is newly diagnosed or has come back.

Your child’s treatment plan will include information about the cancer, the goals of treatment, treatment options, and the possible side effects. It will be helpful to talk with your child’s cancer care team before treatment begins about what to expect. For help every step of the way, see our booklet, Children with Cancer: A Guide for Parents.

Types of treatment your child might have include:

Radiation therapy

Radiation therapy uses high-energy x-rays or other types of radiation to kill cancer cells or keep them from growing. DIPG is treated with external-beam radiation therapy. This type of radiation therapy uses a machine outside the body to send radiation toward the area of the body with cancer.

Several months after radiation therapy to the brain, imaging tests may show changes to the brain tissue. These changes may be caused by the radiation therapy or may mean the tumor is growing. It is important to be sure the tumor is growing before any more treatment is given.

To learn more, see 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. Chemotherapy either kills the cancer cells or stops them from dividing.

To treat a DIPG in infants, chemotherapy is taken by mouth or injected into a vein. When given this way, the drugs enter the bloodstream and can reach cancer cells throughout the body. Chemotherapy drugs that cross the blood-brain barrier and reach tumor cells in the brain are used.

Because radiation therapy to the brain can affect growth and brain development in young children, chemotherapy may be given to delay or reduce the need for radiation therapy.

To learn more, see Chemotherapy to Treat Cancer.

Surgery to place a shunt

Sometimes children with a DIPG have increased fluid around the brain or spinal cord. They may need surgery to place a shunt (long, thin tube) in a ventricle (fluid-filled space) of the brain and thread it under the skin to another part of the body, usually the abdomen. The shunt carries extra fluid away from the brain so it may be absorbed elsewhere in the body. This decreases the fluid and pressure on the brain or spinal cord.

EnlargeDrawing shows extra cerebrospinal fluid (CSF) flowing through a shunt (a long, thin tube) from a ventricle (fluid-filled space) in the brain into the abdomen. The shunt goes from the ventricle, under the skin in the neck and chest, and into the abdomen. Also shown is a shunt valve that controls the flow of CSF.
A cerebrospinal fluid (CSF) shunt (a long, thin tube) carries extra CSF away from the brain so it may be absorbed elsewhere in the body. The shunt is placed in a ventricle (fluid-filled space) in the brain and threaded under the skin to another part of the body, usually the abdomen. The shunt has a valve that controls the flow of CSF.

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. Because cancer in children is rare, taking part in a clinical trial should be considered.

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. Some clinical trials are open only to patients who have not started treatment. Clinical trials supported by other organizations can be found on the ClinicalTrials.gov website.

To learn more, see Clinical Trials Information for Patients and Caregivers.

Treatment of DIPG

Palliative care is an important part of your child’s treatment plan throughout their cancer journey. It includes physical, psychological, social, and spiritual support for your child and family. The goal of palliative care is to help control symptoms and give your child the best quality of life possible.

Treatment of newly diagnosed childhood DIPG may include:

  • external-beam radiation therapy
  • chemotherapy (to treat infants)

Treatment of DIPG that is progressive (getting worse) or has come back after treatment may include radiation therapy, if the cancer responded when first treated with radiation therapy.

Prognosis and prognostic factors for DIPG

If your child has been diagnosed with DIPG, you likely have questions about your child’s chances of survival. The likely outcome or course of a disease is called prognosis.

Doctors consider these and other factors when making a prognosis for DIPG:

  • where the tumor is found in the brain and if it has spread within the brain stem
  • your child’s age at diagnosis
  • how long your child has had symptoms prior to diagnosis
  • whether the tumor has a certain change to H3 K27m

DIPG is a challenging cancer to treat because of its location in the brain, how fast it progresses, and the way it spreads into healthy tissue. Unfortunately, most children with DIPG do not live longer than 2 years after diagnosis. Your child’s cancer care team is in the best position to talk with you about your child’s prognosis.

Follow-up care

As your child goes through treatment, they will have follow-up tests or check-ups. Some of the tests that were done to diagnose 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 child’s condition has changed or if the cancer has come back. If the results of imaging tests done after treatment for DIPG show a mass in the brain, a biopsy may be done to find out if it is made up of dead tumor cells or if new cancer cells are growing.

Coping with your child's cancer

When your child has cancer, every member of the family needs support. Taking care of yourself during this time is important. Talk with your child’s treatment team and people in your family and community for support with coping with the emotional and physical stress that comes with a cancer diagnosis. To learn more, see Support for Families When a Child Has Cancer and the booklet Children with Cancer: A Guide for Parents.

Related resources

For more childhood cancer information and other general cancer resources, see:

Childhood Glioma (Including Astrocytoma)

Childhood Glioma (Including Astrocytoma)

Gliomas are a group of tumors that arise from glial cells in the central nervous system (brain and spinal cord). Glial cells support and protect the brain’s nerve cells (also called neurons). They hold nerve cells in place, bring food and oxygen to nerve cells, and help protect nerve cells from disease, such as infection. Gliomas can form in any area of the CNS and can be low grade or high grade.

Other types of tumors can form in glial cells and nerve cells. Neuronal tumors are rare tumors made up of nerve cells. Glioneuronal tumors are a mix of nerve cells and glial cells. Neuronal and glioneuronal tumors are rare, low-grade tumors and are treated the same as gliomas.

Although cancer is rare in children, brain tumors are the second most common type of childhood cancer, after leukemia.

Gliomas are most common in these parts of the CNS:

  • Cerebrum, the largest part of the brain, at the top of the head. The cerebrum controls thinking, learning, problem-solving, speech, emotions, reading, writing, and voluntary movement.
  • Cerebellum, the lower, back part of the brain (near the middle of the back of the head). The cerebellum controls voluntary movement, balance, and posture.
  • Brain stem, the part of the brain that is connected to the spinal cord. The brain stem is in the lowest part of the brain (just above the back of the neck). It controls breathing, heart rate, and the nerves and muscles used in seeing, hearing, walking, talking, and eating.
  • Hypothalamus, the area in the middle of the base of the brain. It controls body temperature, hunger, and thirst.
  • Visual pathway, the group of nerves that connect the eye with the brain.
  • Spinal cord, the column of nerve tissue that runs from the brain stem down the center of the back. It is covered by three thin layers of tissue called membranes. The spinal cord and membranes are surrounded by the vertebrae (back bones). Spinal cord nerves carry messages between the brain and the rest of the body, such as a message from the brain to cause muscles to move or a message from the skin to the brain to feel touch.
EnlargeAnatomy of the brain; the right panel shows the supratentorial area (the upper part of the brain) and the posterior fossa/infratentorial area (the lower back part of the brain). The supratentorial area contains the cerebrum, lateral ventricle and third ventricle (with cerebrospinal fluid shown in blue), choroid plexus, pineal gland, hypothalamus, pituitary gland, and optic nerve. The posterior fossa/infratentorial area contains the cerebellum, tectum, fourth ventricle, and brain stem (midbrain, pons, and medulla). The spinal cord is also shown. The left panel shows the cerebrum, ventricles (fluid-filled spaces), meninges, skull, cerebellum, brain stem (pons and medulla), and spinal cord.
Anatomy of the brain. The supratentorial area (the upper part of the brain) contains the cerebrum, lateral ventricle and third ventricle (with cerebrospinal fluid shown in blue), choroid plexus, pineal gland, hypothalamus, pituitary gland, and optic nerve. The posterior fossa/infratentorial area (the lower back part of the brain) contains the cerebellum, tectum, fourth ventricle, and brain stem (midbrain, pons, and medulla). The skull and meninges protect the brain and spinal cord.

Types of glioma, neuronal, and glioneuronal tumors

Astrocytoma is the most common type of glioma diagnosed in children. It starts in a type of star-shaped glial cell called an astrocyte. Astrocytomas can form anywhere in the central nervous system.

Optic pathway glioma is a type of low-grade (slow-growing) glioma that can grow in children with a genetic condition called neurofibromatosis type 1 (NF1).

There are many types of astrocytomas, other gliomas, neuronal tumors, and glioneuronal tumors including:

  • diffuse pediatric-type high-grade glioma
  • infant-type hemispheric glioma
  • diffuse low-grade glioma
  • diffuse astrocytoma
  • pilocytic astrocytoma
  • high-grade astrocytoma with piloid features
  • pleomorphic xanthoastrocytoma
  • subependymal giant cell astrocytoma
  • ganglioglioma
  • desmoplastic infantile ganglioglioma/desmoplastic infantile astrocytoma
  • dysembryoplastic neuroepithelial tumor

Diffuse intrinsic pontine glioma (DIPG) is a type of high-grade glioma that forms in the brain stem and most often occurs in children. To learn more, see Diffuse Intrinsic Pontine Glioma.

Ependymoma is another type of tumor that can form from glial cells, but these tumors are not treated the same as gliomas. To learn more, see Childhood Ependymoma.

Causes and risk factors for childhood glioma (including astrocytoma)

Gliomas are caused by certain changes to the way glial cells function, especially how they grow and divide into new cells. Often, the exact cause of cell changes that lead to glioma is unknown. To learn more about how cancer develops, see What Is Cancer?

A risk factor is anything that increases the chance of getting a disease. Not every child with a risk factor will develop a glioma, and it will develop in some children who don’t have a known risk factor. Inherited genetic disorders that may be risk factors for glioma include:

Talk with your child’s doctor if you think your child may be at risk of a glioma.

Symptoms of childhood glioma (including astrocytoma)

The symptoms of childhood gliomas depend on the following factors:

  • where the tumor forms in the brain or spinal cord
  • the size of the tumor
  • how fast the tumor grows
  • your child’s age and development

Some tumors do not cause symptoms while other tumors cause symptoms based on their location in the central nervous system. It’s important to check with your child’s doctor if your child has any symptoms below:

  • morning headache or headache that goes away after vomiting
  • nausea and vomiting
  • vision, hearing, and speech problems
  • loss of balance and trouble walking
  • worsening handwriting or slow speech
  • weakness or change in feeling on one side of the body
  • unusual sleepiness
  • more or less energy than usual
  • change in personality or behavior
  • seizures
  • weight loss or weight gain for no known reason
  • increase in the size of the head (in infants)

These symptoms may be caused by conditions other than childhood gliomas. The only way to know is to see your child’s doctor.

Tests to diagnose childhood glioma (including astrocytoma)

If your child has symptoms that suggest a central nervous system tumor such as glioma, the doctor will need to find out if they are due to cancer or another condition. The doctor will ask you when the symptoms started and how often your child has been having them. They will also ask about your child’s personal and family medical history and do a physical exam, including a neurologic exam. Depending on these results, they may recommend tests to find out if your child has a central nervous system tumor.

The following tests may be used to diagnose a glioma, neuronal tumor, or glioneuronal tumor. The results will also help you and your child’s doctor plan treatment.

Magnetic resonance imaging (MRI) with or without gadolinium

MRI uses a magnet, radio waves, and a computer to make a series of detailed pictures of the brain and spinal cord. Sometimes a substance called gadolinium is injected into 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). Magnetic resonance spectroscopy (MRS) may be done during the same MRI scan to look at the chemical makeup of the brain tissue.

EnlargeMagnetic resonance imaging (MRI) scan; drawing shows a child lying on a table that slides into the MRI machine, which takes a series of detailed pictures of areas inside the body.
Magnetic resonance imaging (MRI) scan. The child lies on a table that slides into the MRI machine, which takes a series of detailed pictures of areas inside the body. The positioning of the child on the table depends on the part of the body being imaged.

Immunohistochemistry

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. An MIB-1 test is a type of immunohistochemistry that checks tumor tissue for an antigen called MIB-1. This may show how fast a tumor is growing.

Molecular testing

A molecular test checks for certain genes, proteins, or other molecules in a sample of tissue, blood, or bone marrow. Molecular tests also check for certain changes in a gene or chromosome that may cause or affect the chance of developing a brain tumor. A molecular test may be used to help plan treatment, find out how well treatment is working, or make a prognosis.

The Molecular Characterization Initiative offers free molecular testing to children, adolescents, and young adults with certain types of newly diagnosed cancer. The program is offered through NCI’s Childhood Cancer Data Initiative. To learn more, visit About the Molecular Characterization Initiative.

Surgery to diagnose and possibly remove the glioma

Your child might have surgery to diagnose or to remove all or part of the glioma. During the surgery, the surgeon removes a part of the skull, which gives an opening to remove the tumor. Sometimes scans are done during the procedure to help the surgeon locate the tumor and remove it. A pathologist will study the tumor under a microscope. If cancer cells are found, the surgeon may remove as much tumor as safely possible during the same surgery. The piece of skull is usually put back in place after the procedure.

EnlargeDrawing of a craniotomy showing a section of the scalp that has been pulled back to remove a piece of the skull; the dura covering the brain has been opened to expose the brain. The layer of muscle under the scalp is also shown.
Craniotomy. An opening is made in the skull and a piece of the skull is removed to show part of the brain.

Sometimes tumors form in a place that makes them hard to remove. If removing the tumor may cause severe physical, emotional, or learning problems, a biopsy is done and more treatment is given after the biopsy.

Children who have a rare genetic condition called neurofibromatosis type 1 may be at risk of a low-grade glioma called optic pathway glioma that forms in the area of the brain that controls vision. These children may not need a biopsy to diagnose the tumor. Surgery to remove the tumor may not be needed if the tumor does not grow and symptoms do not occur.

Getting a second opinion

You may want to get a second opinion to confirm your child’s 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 approach, or provide more information about your child’s cancer.

To learn more about choosing a doctor and getting a second opinion, see 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 or hospital that can provide a second opinion. For questions you might want to ask at your appointments, see Questions to Ask Your Doctor about Cancer.

Stages and tumor grades of childhood glioma (including astrocytoma)

Staging is the process of learning the extent of cancer in the body and is often used to help plan treatment and make a prognosis. There is no staging system used for childhood glioma, but it is given a tumor grade. Tumor grading is based on World Health Organization (WHO) criteria.

Tumor grade describes how abnormal the cancer cells look under a microscope, how quickly the tumor is likely to grow and spread within the central nervous system, and how likely the tumor is to come back after treatment.

There are four grades of gliomas, but they are most often grouped into low grade (grades I or II) or high grade (grades III or IV):

  • Low-grade gliomas grow slowly and do not spread within the brain and spinal cord. But as they grow, they press on nearby healthy areas of the brain, affecting brain function. Most low-grade gliomas are treatable.
  • High-grade gliomas are fast growing and often spread within the brain and spinal cord, which makes them harder to treat.

Childhood gliomas usually do not spread to other parts of the body.

Recurrent glioma

When a glioma comes back after it has been treated it is called a recurrent glioma. A glioma may come back in the same place as the first tumor or in other areas of the brain or spinal cord. Tests will be done to help determine if and where the cancer has returned. The type of treatment that your child will have for recurrent glioma will depend on where it came back.

Sometimes a low-grade glioma can come back as a high-grade glioma. High-grade gliomas often come back within 3 years either in the place where the cancer first formed or somewhere else in the brain or spinal cord.

Progressive childhood glioma is cancer that continues to grow, spread, or get worse. Progressive disease can be a sign that the cancer no longer responds to treatment.

Types of treatment for childhood glioma (including astrocytoma)

There are different types of treatment for children and adolescents with glioma. You and your child’s cancer care team will work together to decide treatment. Many factors will be considered, such as your child’s overall health, the tumor grade, and whether the cancer is newly diagnosed or has come back.

A pediatric oncologist, a doctor who specializes in treating children with cancer, will oversee treatment. The pediatric oncologist works with other health care providers who are experts in treating children with brain tumors and who specialize in certain areas of medicine. Other specialists may include:

Your child’s treatment plan will include information about the cancer, the goals of treatment, treatment options, and the possible side effects. It will be helpful to talk with your child’s cancer care team before treatment begins about what to expect. For help every step of the way, see our downloadable booklet, Children with Cancer: A Guide for Parents.

Surgery

Surgery is used to diagnose and treat childhood gliomas, as discussed in the Tests to diagnose childhood glioma (including astrocytoma) section of this summary. After surgery, an MRI (magnetic resonance imaging) is done to see if any cancer cells remain. If cancer cells are found, further treatment depends on:

  • where the remaining cancer cells are
  • the grade of the tumor
  • your child’s age

After the doctor removes all the cancer that can be seen at the time of the surgery, some children may be given chemotherapy or radiation therapy 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.

Sometimes children with a glioma have increased fluid around the brain or spinal cord. They may need surgery to place a shunt (long, thin tube) in a ventricle (fluid-filled space) of the brain and thread it under the skin to another part of the body, usually the abdomen. The shunt carries extra fluid away from the brain so it may be absorbed elsewhere in the body. This decreases the fluid and pressure on the brain or spinal cord. This process is called a CSF shunt.

EnlargeDrawing shows extra cerebrospinal fluid (CSF) flowing through a shunt (a long, thin tube) from a ventricle (fluid-filled space) in the brain into the abdomen. The shunt goes from the ventricle, under the skin in the neck and chest, and into the abdomen. Also shown is a shunt valve that controls the flow of CSF.
A cerebrospinal fluid (CSF) shunt (a long, thin tube) carries extra CSF away from the brain so it may be absorbed elsewhere in the body. The shunt is placed in a ventricle (fluid-filled space) in the brain and threaded under the skin to another part of the body, usually the abdomen. The shunt has a valve that controls the flow of CSF.

Observation

Observation is closely monitoring a person’s condition without giving any treatment or additional treatment until signs or symptoms appear or change. Observation may be used:

  • if your child has no symptoms, such as children with neurofibromatosis type 1 (NF1)
  • if your child’s tumor is small and is found when a different health problem is being diagnosed or treated
  • after the tumor is removed by surgery until signs or symptoms appear or change

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. Chemotherapy may be given alone or with other types of treatment, such as radiation therapy.

To treat a glioma, chemotherapy is taken by mouth or injected into a vein. When given this way, the drugs enter the bloodstream and can reach cancer cells throughout the body. Chemotherapy that may be used includes:

Combinations of these drugs may be used. Other chemotherapy drugs not listed here may also be used.

Learn more about Chemotherapy to Treat Cancer.

Radiation therapy

Radiation therapy uses high-energy x-rays or other types of radiation to kill cancer cells or keep them from growing. Glioma may be treated with external beam radiation therapy. This type of treatment uses a machine outside the body to send radiation toward the area of the body with cancer. Radiation therapy may be given alone or with other treatments, such as chemotherapy.

Certain ways of giving external beam radiation therapy can help keep radiation from damaging nearby healthy tissue. These types of radiation therapy include:

  • Conformal radiation therapy uses a computer to make a 3-dimensional (3-D) picture of the tumor and shapes the radiation beams to fit the tumor. This allows a high dose of radiation to reach the tumor and causes less damage to nearby healthy tissue.
  • Intensity-modulated radiation therapy (IMRT) uses a computer to make 3-D pictures of the size and shape of the tumor. Thin beams of radiation of different intensities (strengths) are aimed at the tumor from many angles.
  • Stereotactic radiation therapy uses a machine that aims radiation directly at the tumor causing less damage to nearby healthy tissue. The total dose of radiation is divided into several smaller doses given over several days. A rigid head frame is attached to the skull to keep the head still during the radiation treatment. This procedure is also called stereotactic radiosurgery and stereotaxic radiation therapy.
  • Proton beam radiation therapy is a type of high-energy, external radiation therapy that uses streams of protons (tiny particles with a positive charge) to kill tumor cells. This type of treatment can lower the amount of radiation damage to healthy tissue near a tumor.

The way radiation therapy is given depends on the type of tumor and where the tumor formed in the brain or spinal cord.

Radiation therapy to the brain can affect growth and development, especially in young children. For children younger than 3 years, chemotherapy may be given instead, to delay or reduce the need for radiation therapy. Radiation therapy may also be delayed for patients with NF1 because they may be at increased risk for a second cancer.

To learn more, see External Beam Radiation Therapy for Cancer and Radiation Therapy Side Effects.

Targeted therapy

Targeted therapy uses drugs or other substances to block the action of specific enzymes, proteins, or other molecules involved in the growth and spread of cancer cells.

Targeted therapies that may be used or are being studied to treat glioma include:

Learn more about Targeted Therapy to Treat Cancer.

Clinical trials

A treatment clinical trial is a research study meant to help improve current treatments or obtain information on new treatments for people with cancer. Because cancer in children is rare, taking part in a clinical trial should be considered.

Use our clinical trials 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. Some clinical trials are open only to patients who have not started treatment. Clinical trials supported by other organizations can be found on the ClinicalTrials.gov website.

To learn more, see Clinical Trials Information for Patients and Caregivers.

Immunotherapy

Immunotherapy helps a person’s immune system fight cancer.

The following treatments are being studied to treat glioma:

Learn more about how immunotherapy works against cancer, how it is given, and possible side effects, and more in Immunotherapy to Treat Cancer.

Treatment of newly diagnosed childhood low-grade glioma, astrocytoma, neuronal, and glioneuronal tumors

Children with neurofibromatosis type 1 and a central nervous system tumor, children with an optic pathway glioma, or children who had a tumor found when getting a scan for another health problem may be observed (closely watched). These children may not receive treatment until signs or symptoms appear or change or the tumor grows.

Children with tuberous sclerosis may develop low-grade tumors in the brain called subependymal giant cell astrocytoma (SEGAs). Targeted therapy with everolimus or sirolimus may be used instead of surgery, to shrink the tumors.

Children diagnosed with low-grade glioma are treated based on where the tumor is located. The first treatment is usually surgery. An MRI is done after surgery to see if any tumor remains. If the tumor was completely removed by surgery, more treatment may not be needed and the child is closely observed.

If there is tumor remaining after surgery, treatment may include:

To learn more about these treatments, see Types of treatment for childhood glioma (including astrocytoma).

Treatment of progressive or recurrent childhood low-grade glioma, astrocytoma, neuronal, or glioneuronal tumors

Childhood glioma, astrocytoma, glioneuronal, and neuronal tumors can be progressive or recurrent. They most often come back in the same area but can spread to other areas in the brain. Before more cancer treatment is given, imaging tests, biopsy, or surgery are done to find out if there is cancer, how much there is, and the grade.

Treatment of progressive or recurrent childhood low-grade glioma, astrocytoma, glioneuronal, and neuronal tumors may include:

  • a second surgery to remove the tumor
  • radiation therapy (including conformal radiation therapy), if radiation therapy was not used when the tumor was first diagnosed
  • chemotherapy, if the tumor progressed or recurred where it cannot be removed by surgery
  • targeted therapy (bevacizumab) with or without chemotherapy
  • targeted therapy (everolimus or sirolimus)
  • targeted therapy (dabrafenib and trametinib)

To learn more about these treatments, see Types of treatment for childhood glioma (including astrocytoma).

Treatment of childhood high-grade gliomas

Treatment of newly diagnosed childhood high-grade glioma may include:

  • surgery to remove the tumor
  • radiation therapy with or without chemotherapy
  • a clinical trial of targeted therapy with a combination of dabrafenib and trametinib after radiation therapy to treat newly diagnosed high-grade glioma that has mutations in the BRAF gene
  • a clinical trial of immunotherapy

To learn more about these treatments, see Types of treatment for childhood glioma (including astrocytoma).

Treatment of recurrent childhood high-grade gliomas

Treatment of recurrent childhood high-grade glioma may include:

  • second surgery depending on tumor type, location, and length of time between treatment and recurrence
  • radiation therapy
  • targeted therapy (dabrafenib and trametinib)
  • a clinical trial of targeted therapy
  • a clinical trial of immunotherapy

To learn more about these treatments, see Types of treatment for childhood glioma (including astrocytoma).

Prognosis and prognostic factors for childhood glioma (including astrocytoma)

If your child has been diagnosed with a glioma, you likely have questions about how serious the cancer is and your child’s chances of survival. The likely outcome or course of a disease is called prognosis.

The prognosis depends on many factors, including:

  • whether the tumor is a low-grade or high-grade glioma
  • where the tumor has formed in the central nervous system and if it has spread within the central nervous system or to other parts of the body
  • how fast the tumor is growing
  • your child’s age
  • whether cancer cells remain after surgery
  • whether there are changes in certain genes such as BRAF
  • whether your child has NF1 or tuberous sclerosis
  • whether your child has diencephalic syndrome, a condition which slows physical growth
  • whether the glioma has just been diagnosed or has come back after treatment

Children with a low-grade glioma, astrocytoma, neuronal tumor, or glioneuronal tumor have a relatively favorable prognosis if the tumor can be removed by surgery.

Children with a high-grade glioma have a poor prognosis. Some children diagnosed with a high-grade glioma, particularly infants younger than 1 year, may have tumors with certain fusion genes. Infants with a high-grade glioma whose tumors show these genetic changes may have a better prognosis than older children with a high-grade glioma.

For glioma that has come back after treatment, prognosis and treatment depend on how much time passed between the time treatment ended and the time the glioma came back.

No two people are alike, and responses to treatment can vary greatly. Your child’s cancer care team is in the best position to talk with you about your child’s prognosis.

Side effects from the tumor and treatment

The signs or symptoms caused by the tumor may begin before diagnosis and continue for months or years. It is important to talk with your child’s doctors about signs or symptoms caused by the tumor that may continue after treatment.

To learn more about side effects that begin during treatment for cancer, visit Side Effects.

Problems from cancer treatment that begin 6 months or later after treatment and continue for months or years are called late effects. Late effects of cancer treatment may include:

  • physical problems that affect:
    • vision, including blindness
    • blood vessels
    • hormone levels
  • changes in mood, feelings, thinking, learning, or memory
  • second cancers (new types of cancer)

Some late effects may be treated or controlled. It is important to talk with your child’s doctors about the effects cancer treatment can have on your child. To learn more, see Late Effects of Treatment for Childhood Cancer.

Follow-up care

As your child goes through treatment, they will have follow-up tests or checkups. Some of the tests that were done to diagnose the cancer will be repeated in order 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.

Regular MRIs will continue to be done after treatment has ended. The results of the MRI can show if your child’s condition has changed or if the glioma has come back. If the results of the MRI show a mass in the brain, a biopsy may be done to find out if it is made up of dead tumor cells or if new cancer cells are growing.

Children who received radiation therapy to treat an optic pathway glioma are at risk of developing vision changes. These changes are most likely to occur within 2 years after radiation therapy. The effect of tumor growth and treatment on the child’s vision will be closely followed during and after treatment.

Coping with your child's cancer

When your child has cancer, every member of the family needs support. Taking care of yourself during this time is important. Reach out to your child’s treatment team and to people in your family and community for support. To learn more, see Support for Families When a Child Has Cancer and Children with Cancer: A Guide for Parents.

Related resources

For more childhood cancer information and other general cancer resources, see:

Brain and Spinal Cord Tumor Research Results and Study Updates

Brain and Spinal Cord Tumor Research Results and Study Updates

See Advances in Brain and Spinal Cord Tumor Research for an overview of recent findings and progress, plus ongoing projects supported by NCI.

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    In a small clinical trial, an experimental CAR T-cell therapy that targets the protein GD2 on cancer cells shrank tumors—for 2 years or more in several cases—in children and young adults with diffuse midline glioma, an aggressive brain and spinal cord cancer.

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    Posted:

    Recent results from several small clinical trials have suggested it may be possible to develop an effective immunotherapy for glioblastoma. Among them are findings from a four-patient trial testing a unique type of mRNA cancer vaccine.

  • Tovorafenib Approved for Some Children with Low-Grade Glioma

    Posted:

    FDA has granted an accelerated approval to tovorafenib (Ojemda) for kids and teens who have low-grade glioma with changes in the BRAF gene. In a small clinical trial, the drug shrank or completely eliminated tumors in nearly 70% of patients.

  • Genetic Signature May Help Tailor Treatment for Meningioma

    Posted:

    The activity of 34 genes can accurately predict the aggressiveness of meningiomas, a new study shows. This gene expression signature may help oncologists select the best treatments for people with this common type of brain cancer than they can with current methods.

  • Engaging People with Low-Grade Glioma in Cancer Research

    Posted:

    An NCI-supported study called OPTIMUM, part of the Cancer Moonshot, was launched to improve the care of people with brain tumors called low-grade glioma in part by bringing them into glioma-related research.

  • Targeted Drug Combo May Change Care for Rare Brain Tumor Craniopharyngioma

    Posted:

    Treating craniopharyngioma often requires surgery, radiation therapy, or both. But results of a study suggest that, for many, combining the targeted therapies vemurafenib (Zelboraf) and cobimetinib (Cotellic) may substantially delay, or even eliminate, the need for these treatments.

  • Vorasidenib Treatment Shows Promise for Some Low-Grade Gliomas

    Posted:

    In a large clinical trial, vorasidenib slowed the growth of low-grade gliomas that had mutations in the IDH1 or IDH2 genes. Vorasidenib is the first targeted drug developed specifically to treat brain tumors.

  • How Some Brain Tumors Hijack the Mind to Grow

    Posted:

    Researchers have found that the aggressive brain cancer glioblastoma can co-opt the formation of new synapses to fuel its own growth. This neural redirection also appears to play a role in the devastating cognitive decline seen in many people with glioblastoma.

  • Vulnerability in Brain Tumors May Open Door to New Treatments

    Posted:

    Two companion studies have found different forms of some brain tumors, diffuse midline glioma and IDH-mutant glioma, become dependent for their survival on the production of chemicals called pyrimidines. Clinical trials are planned to test a drug that blocks pyrimidine synthesis in patients with gliomas.

  • For Some Kids with Brain Cancer, Targeted Therapy Is Better than Chemo

    Posted:

    The combination of dabrafenib (Tafinlar) and trametinib (Mekinist) shrank more brain tumors, kept the tumors at bay for longer, and caused fewer side effects than chemotherapy, trial results showed. The children all had glioma with a BRAF V600 mutation that could not be surgically removed or came back after surgery.

  • New Way to Classify Meningioma Brain Tumors Suggests Potential Treatments

    Posted:

    Two separate but complementary studies have identified a new way to classify meningioma, the most common type of brain tumor. The grouping system may help predict whether a patient’s tumor will grow back after treatment and identify new treatments.

  • Experimental Medulloblastoma Treatment Gets a Boost with Nanoparticles

    Posted:

    A nanoparticle coating may help cancer drugs reach medulloblastoma tumors in the brain and make the treatment less toxic. Mice treated with nanoparticles containing palbociclib (Ibrance) and sapanisertib lived substantially longer than those treated with either drug alone.

  • Test Detects Early Signs of Remaining Cancer in Kids Treated for Medulloblastoma

    Posted:

    A new test could potentially be used to identify children treated for medulloblastoma who are at high risk of their cancer returning. The test detects evidence of remaining cancer in DNA shed from medulloblastoma tumor cells into cerebrospinal fluid.

  • For Kids with Medulloblastoma, Trial Suggests Radiation Can Be Tailored

    Posted:

    Standard radiation for medulloblastoma can cause long-term damage to a child’s developing brain. A new clinical trial suggests that the volume and dose of radiation could be safely tailored based on genetic features in the patient’s tumor.

  • Steroids May Limit the Effectiveness of Immunotherapy for Brain Cancer

    Posted:

    In people with glioblastoma and other brain cancers, steroids appear to limit the effectiveness of immunotherapy drugs, a new study shows. The findings should influence how steroids are used to manage brain tumor symptoms, researchers said.

  • Liquid Biopsy Detects Brain Cancer and Early-Stage Kidney Cancer

    Posted:

    Results from two studies show that a liquid biopsy that analyzes DNA in blood accurately detected kidney cancer at early and more advanced stages and identified and classified different types of brain tumors.

  • Artificial Intelligence Expedites Brain Tumor Diagnosis during Surgery

    Posted:

    A method that combines artificial intelligence with an advanced imaging technology can accurately diagnose brain tumors in fewer than 3 minutes during surgery, a new study shows. The approach can also accurately distinguish tumor from healthy tissue.

  • Brain Cancer Cells Hijack Gene “On Switches” to Drive Tumor Growth

    Posted:

    Glioblastoma cells sneak many copies of a key oncogene into circular pieces of DNA. In a new NCI-funded study, scientists found that the cells also slip several different genetic “on switches” into these DNA circles, helping to fuel the cancer’s growth.

  • Glioblastoma Study Highlights Sex Differences in Brain Cancer

    Posted:

    Men and women with glioblastoma appear to respond differently to standard treatment. A new study identifies biological factors that might contribute to this sex difference.

  • Blood Test Shows Promise for Detecting Genetic Changes in Brain Tumors

    Posted:

    A liquid biopsy blood test can detect DNA from brain tumors called diffuse midline gliomas, researchers have found. This minimally invasive test could be used to identify and follow molecular changes in children with these highly lethal brain tumors.

  • Can Immunotherapy Succeed in Glioblastoma?

    Posted:

    Despite continued efforts to develop new therapies for glioblastoma, none have been able to improve how long patients live appreciably. Despite some setbacks, researchers are hopeful that immunotherapy might be able to succeed where other therapies have not.

Advances in Brain and Spinal Cord Tumor Research

Advances in Brain and Spinal Cord Tumor Research

A meningioma in brain tissue seen in a slice from a magnetic resonance imaging (MRI) procedure.

MRI of a meningioma in the brain.

Credit: NCI-CONNECT Staff

NCI-supported researchers are working to improve our understanding of how to treat tumors that arise in the brain or the spinal cord (together known as the central nervous system, or CNS). Such tumors can be either benign or malignant. But the tissues of the nervous system are so important and so vulnerable that even some benign tumors may need urgent treatment.

Tumors that begin in the brain or spinal cord account for less than 2% of all cancers diagnosed each year in the United States. And there are over 130 different types. This diversity and the rarity of some types pose unique challenges to developing new treatments.

Often, tumors found in the brain have started somewhere else in the body and then spread to the brain. These are called metastatic brain tumors (or brain metastases). The research highlighted on this page addresses primary brain tumors (tumors that start in the tissue of the brain), not metastatic brain tumors. It also includes research into primary spinal cord tumors.

The research on this page includes clinical advances that may soon translate into improved care and research findings from recent studies.

Research in the Diagnosis of Brain and Spinal Cord Tumors 

Many types of brain and spinal cord tumors look similar when the cells are examined under the microscope. Even with trained pathologists examining tissue samples, up to 10% of people with a brain or spinal cord tumor receive the wrong diagnosis at first. This can potentially affect outcomes, because tumors that look similar at the cellular level may require very different treatments.

NCI-supported researchers are studying ways to improve the diagnosis of brain and spinal cord tumors. For example:

If you have received a diagnosis of a rare brain or spinal cord tumor and are seeking a second opinion, the NCI-CONNECT program offers free consultations, as well as advice for patients’ cancer care teams at home.

Research in Treatments for Brain and Spinal Cord Tumors in Adults 

Treatments for brain and spinal cord tumors can damage normal cells as well as tumor cells in the brain and spinal cord, so they may come with serious side effects. And many brain tumors come back (recur) soon after treatment.

Researchers are testing ways to improve the treatment of brain and spinal cord tumors, including targeted therapies, improving radiation response, and immunotherapies.

Targeted Therapy for Brain and Spinal Cord Tumors

Targeted therapies use drugs or other substances to attack specific types of cancer cells with less harm to normal cells. Researchers are developing treatments that target the specific changes that drive the growth of brain and spinal cord tumors.

Scientists are also trying to understand other biological factors that influence brain tumor development and its response to treatment. For example, studies have found that glioblastoma in women tends to respond better to standard treatments. Such work may uncover further avenues for treatment personalization.

Testing targeted therapies for brain and spinal cord tumors can be challenging, because clinical trials will be limited to fewer patients with already rare cancers. Examples of NCI-led initiatives to overcome this challenge and foster collaboration across cancer centers include the NCI-led Brain Tumor Trials Collaborative and NCI-CONNECT clinical trial network. (See more in the NCI-Supported Research Programs section below.)

Improving the Response to Radiation 

The amount and shape of the tissue that gets treated with radiation is tailored to each tumor’s size and location. However, the dose (or amount) of radiation used is usually the same for everyone with a specific tumor type. 

  • Researchers want to find ways to figure out whether a tumor’s response to radiation can be predicted before treatment. That would make it possible for people with tumors that are unlikely to shrink after standard doses of radiation to instead join clinical trials that are testing other strategies, such as higher radiation doses. Scientists are also studying whether machine learning, also called artificial intelligence or AI, can predict radiation response based on data from MRI scans of brain tumors.
  • Scientists are also trying to develop substances called radiation sensitizers to improve killing of cancer cells. Dozens of small clinical trials across the country are studying radiation sensitizers in glioblastoma. For example, a trial led by NCI researchers is looking at whether the drug selinexor (Xpovio), when combined with chemotherapy and radiation, can improve survival.

Immunotherapy

For some blood cancers and solid tumors, immunotherapy drugs have provided huge gains in survival for some people. But to date, immunotherapy has not worked well for brain tumors. Issues may include:

  • The blood–brain barrier. This network of blood vessels and tissue that helps protect the brain also prevents some drugs and types of immune cells from reaching tumors. 
  • The widespread use of anti-inflammatory drugs called corticosteroids to manage the symptoms of brain tumors. These drugs may limit the availability of the immune system to fight cancer. For example,

However, some people with brain or spinal cord tumors given immunotherapy in clinical trials have had their tumors shrink or disappear. Researchers want to know if these responses could be predicted, both to spare people unnecessary treatment and to develop new strategies to make resistant tumors respond to immunotherapies. 

Research in Survivorship and Quality of Life for People with Brain or Spinal Cord Tumors

Because both brain and spinal cord tumors and their treatments can be debilitating, researchers are looking for new ways to improve quality of life for people with these tumors.

Research in the Treatment of Brain and Spinal Cord Tumors in Children

Tumors of the brain and spinal cord in children are relatively rare. But about 4,000 children and adolescents nationwide receive a diagnosis of a brain or spinal cord tumor every year, making them the second most common cancer type in this age group after leukemia.

Treatment has improved for young patients with these tumors over the last several decades. Although some brain and spinal cord tumors can’t be cured, almost three-quarters of children and adolescents treated for one will be alive 5 years after diagnosis. 

However, effective treatments can harm children’s developing nervous systems. Current research in childhood brain and spinal cord tumors focuses on understanding the underlying causes of these cancers, developing new treatments, and reducing the toxic effects of effective therapies. For example,

  • One study found that some children with medulloblastoma, a type of brain cancer, can safely get less radiation therapy without reducing their long-term survival. The effectiveness of this approach depended on the genetic alterations found in children’s tumors. A follow-up study is looking more closely at reducing the intensity of treatment in children with medulloblastoma caused by changes in a gene called WNT. 
  • Some children with a type of brain tumor called low-grade glioma have certain changes in a gene called BRAF in their cancer cells.
  • A targeted drug called selumetinib (Koselugo) is approved for treating nerve tumors in children with a rare condition called neurofibromatosis type 1 (NF1) . A small study found that it could also shrink a type of brain tumor called low-grade glioma in some children with NF1 whose tumors have certain BRAF changes. NCI researchers have launched a clinical trial of the drug in children with and without NF1 who have low-grade glioma with these BRAF changes.
  • A rare type of brain tumor called diffuse midline glioma, which occurs more commonly in children than adults, currently has no cure. An NCI-supported clinical trial is testing CAR T cells, a type of immunotherapy, that target cells with a mutation found in some of these tumors. The treatment has been found to shrink tumors and reduce neurologic symptoms caused by the tumor in some children.
  • Other studies are using information about mutations in children’s brain tumors to test new treatments in those who may benefit the most. One such study, the Pediatric MATCH study, is testing new targeted therapies in children with solid tumors—including those in the brain or spinal cord—that have not responded to standard treatments. In the study, children are assigned to an experimental treatment based on the genetic changes found in their tumors rather than on their type of cancer or cancer site.

Additional clinical trials for children with brain and spinal cord tumors are being performed by the NCI-supported Children’s Oncology Group and Pediatric Brain Tumor Consortium.

NCI-Supported Research Programs

Many NCI-supported researchers working at the National Institutes of Health (NIH) campus, as well as across the United States and throughout the world, are seeking ways to address tumors of the brain and spinal cord more effectively. Some research is basic, exploring questions such as the biological underpinnings of cancer. And some is more clinical, seeking to translate this basic information into improving patient outcomes. The programs listed below are a small sampling of NCI’s related research efforts.

Clinical Trials

NCI funds and oversees both early- and late-phase clinical trials to develop new treatments and improve patient care. Use our clinical trials search form to find trials to treat glioblastoma, glioma, medulloblastoma, and other types of brain and spinal cord tumors.

Brain and Spinal Cord Tumor Research Results

The following are some of our latest news articles on brain and spinal cord tumor research.

View the full list of brain cancer research results and study updates.