Nasopharyngeal cancer is a type of head and neck cancer that starts in the tissues of the nasopharynx.
Being exposed to the Epstein-Barr virus, your ancestry, and where you live can affect the risk of nasopharyngeal cancer.
Signs and symptoms of nasopharyngeal cancer include trouble breathing, speaking, or hearing.
Tests that examine the nose, throat, and nearby organs are used to diagnose and stage nasopharyngeal cancer.
Some people may decide to get a second opinion.
Certain factors affect prognosis (chance of recovery) and treatment options.
Nasopharyngeal cancer is a type of head and neck cancer that starts in the tissues of the nasopharynx.
The pharynx is a hollow tube in the neck about 5 inches long that is made up of three parts:
The nasopharynx is the upper part of the pharynx, located behind the nose. The nostrils are connected to the nasopharynx. Openings on each side of the nasopharynx lead to the ears.
The oropharynx is the middle part, located beneath the nasopharynx.
The hypopharynx is the lowermost part of the pharynx, opening up to both the trachea (windpipe) and esophagus.
When we breathe or swallow, the pharynx acts as a passageway for air to reach the lungs and food to reach the stomach. Nasopharyngeal cancer commonly begins in the squamous cells that line the nasopharynx.
EnlargeAnatomy of the pharynx. The pharynx is a hollow, muscular tube inside the neck that starts behind the nose and opens into the larynx and esophagus. The three parts of the pharynx are the nasopharynx, oropharynx, and hypopharynx.
Being exposed to the Epstein-Barr virus, your ancestry, and where you live can affect the risk of nasopharyngeal cancer.
Nasopharyngeal cancer is caused by certain changes in how nasopharyngeal cells function, especially how they grow and divide into new cells. There are many risk factors for nasopharyngeal cancer, but many do not directly cause cancer. Instead, they increase the chance of DNA damage in cells that may lead to nasopharyngeal cancer. Learn more about how cancer develops at What Is Cancer?
A risk factor is anything that increases a person’s chance of getting a disease. Some risk factors for nasopharyngeal cancer, like tobacco use, can be changed. Risk factors also include things you cannot change, like your family history. Learning about risk factors for nasopharyngeal cancer can help you make choices that might prevent or lower your risk of getting it.
living in or having ancestry in certain parts of Asia, North Africa, and the Arctic
having a family member with nasopharyngeal cancer
using tobacco or breathing in secondhand smoke
frequent and heavy alcohol use
having a diet high in salt-cured fish and meats because these foods may contain cancer-causing chemicals, such as nitrosamine
Nasopharyngeal cancer can occur at any age. In areas where the disease is not common, it is more likely to be diagnosed in people who are older than 50 years. In high-risk areas, younger people are more likely to be affected. Men tend to develop nasopharyngeal cancer more often than women. In rare cases, human papillomavirus (HPV), especially HPV type 16, has been linked to nasopharyngeal cancer. Learn about HPV and Cancer.
Learn more about Tobacco, including help with quitting.
Signs and symptoms of nasopharyngeal cancer include trouble breathing, speaking, or hearing.
The signs and symptoms of nasopharyngeal cancer can vary from person to person. Early signs and symptoms of nasopharyngeal cancer may include:
a lump in the neck
pain, pulsing, or ringing in the ear
trouble hearing
a sore throat
stuffy nose
nosebleeds
Signs and symptoms of advanced nasopharyngeal cancer (nasopharyngeal cancer that has spread to other parts of the body) may include symptoms of early-stage nasopharyngeal cancer and:
These problems may be caused by conditions other than nasopharyngeal cancer. Check with your doctor if you have any of these problems to find out the cause and begin treatment, if needed.
Tests that examine the nose, throat, and nearby organs are used to diagnose and stage nasopharyngeal cancer.
If you have symptoms that suggest nasopharyngeal cancer, your doctor will need to find out if these are due to cancer or another problem. They will ask when the symptoms started and how often you have been having them. They will also ask about your personal and family health history and do a physical exam. Based on these results, the doctor may recommend other tests. If you are diagnosed with nasopharyngeal cancer, the results of these tests will help you and your doctor plan treatment.
The following tests and procedures are used to diagnose and stage nasopharyngeal cancer:
Nasopharyngoscopy with biopsy is a procedure to examine the inside of the nose and back of the throat. The doctor inserts a nasopharyngoscope (a thin, flexible lighted tube) in the nose and advances it to the back of the throat to check for abnormal areas. The nasopharyngoscope may have a tool to remove a sample of cells or tissue (biopsy) so a pathologist can view it under a microscope to check for signs of cancer. Learn about the type of information that can be found in a pathologist’s report about the cells or tissue removed during a biopsy at Pathology Reports.
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).
For the PET scan, a small amount of radioactive glucose (sugar) is injected into a vein. The scanner rotates around the body and makes a picture of where glucose is being used in the body. Because cancer cells often take up more glucose than normal cells, the pictures can be used to find cancer cells in the body.
For the CT scan, a series of detailed x-ray pictures of areas inside the body is taken from different angles. A dye may be injected into a vein or swallowed to help the organs or tissues show up more clearly.
Epstein-Barr virus (EBV) test is a blood test to check for antibodies and DNA markers that are found in the blood of people who have been infected with EBV.
Human papillomavirus (HPV) test is a laboratory test used to check a sample of tissue for certain types of HPV infection. An HPV test is usually done if the EBV test is negative. This is because in rare cases, HPV can cause nasopharyngeal cancer.
A neurological exam uses a series of questions and tests to check brain, spinal cord, and nerve function. The exam checks your mental status, coordination, and ability to walk normally, and how well the muscles, senses, and reflexes work. This may also be called a neuro exam or a neurologic exam.
A hearing test checks your ability to hear soft and loud sounds and low- and high-pitched sounds. Each ear is checked separately. This test is done because nasopharyngeal cancer and its treatment can affect hearing. Hearing tests are usually done before, during, and after treatment.
Blood chemistry study is a laboratory test in which a blood sample is checked to measure the amounts of certain substances released into the blood by organs and tissues in the body. An unusual (higher or lower than normal) amount of a substance can be a sign of disease.
Complete blood count (CBC) is a laboratory test in which a sample of blood is drawn and checked for:
the number of red blood cells, white blood cells, and platelets
the amount of hemoglobin (the substance in the blood that carries oxygen) in the red blood cells
the amount of hematocrit (whole blood that is made up of red blood cells)
EnlargeComplete blood count (CBC). Blood is collected by inserting a needle into a vein and allowing the blood to flow into a tube. The blood sample is sent to the laboratory and the red blood cells, white blood cells, and platelets are counted. The CBC is used to test for, diagnose, and monitor many different conditions.
Some people may decide to get a second opinion.
You may want to get a second opinion to confirm your nasopharyngeal cancer diagnosis and treatment plan. If you seek a second opinion, you will need to get medical test results and reports from the first doctor to share with the second doctor. The second doctor will review the pathology report, slides, and scans. They may agree with the first doctor, suggest changes or another treatment approach, or provide more information about your cancer.
the stage of the cancer, including whether cancer has spread to one or more lymph nodes in the neck
whether there are high levels of EBV antibodies and EBV-DNA markers in the blood before and after treatment
Stages of Nasopharyngeal Cancer
Key Points
Cancer stage describes the extent of cancer in the body.
The following stages are used for nasopharyngeal cancer:
Stage 0 (also called carcinoma in situ of the nasopharynx)
Stage I (also called stage 1) nasopharyngeal cancer
Stage II (also called stage 2) nasopharyngeal cancer
Stage III (also called stage 3) nasopharyngeal cancer
Stage IV (also called stage 4) nasopharyngeal cancer
Nasopharyngeal cancer can recur (come back) after it has been treated.
Cancer stage describes the extent of cancer in 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. Knowing the cancer stage helps plan treatment.
There are several staging systems for cancer that describe the extent of the cancer. Nasopharyngeal cancer staging usually uses the TNM staging system. The cancer may be described by this staging system in your pathology report. Based on the TNM results, a stage (I, II, III, or IV, also written as 1, 2, 3, or 4) is assigned to the cancer. When talking to you about your diagnosis, your doctor may describe the cancer as one of these stages.
EnlargeTumor sizes are often measured in centimeters (cm) or inches. Common food items that can be used to show tumor size in cm include: a pea (1 cm), a peanut (2 cm), a grape (3 cm), a walnut (4 cm), a lime (5 cm or 2 inches), an egg (6 cm), a peach (7 cm), and a grapefruit (10 cm or 4 inches).
Stage II (also called stage 2) nasopharyngeal cancer
In stage II, one of the following is true:
Cancer has spread to one or more lymph nodes on one side of the neck and/or to one or more lymph nodes on one or both sides of the back of the throat. The affected lymph nodes are 6 centimeters or smaller. Cancer is found:
only in the lymph nodes in the neck. The cancer cells in the lymph nodes are infected with Epstein-Barr virus (a virus linked to nasopharyngeal cancer). Cancer was not found in the nasopharynx.
Cancer has spread to the parapharyngeal space and/or nearby muscles. Cancer may have also spread to one or more lymph nodes on one side of the neck and/or to one or more lymph nodes on one or both sides of the back of the throat. The affected lymph nodes are 6 centimeters or smaller.
Stage III (also called stage 3) nasopharyngeal cancer
In stage III, one of the following is true:
Cancer has spread to one or more lymph nodes on both sides of the neck. The affected lymph nodes are 6 centimeters or smaller. Cancer is found:
only in the lymph nodes in the neck. The cancer cells in the lymph nodes are infected with Epstein-Barr virus (a virus linked to nasopharyngeal cancer). Cancer was not found in the nasopharynx.
Cancer has spread to the parapharyngeal space and/or nearby muscles. Cancer has also spread to one or more lymph nodes on both sides of the neck. The affected lymph nodes are 6 centimeters or smaller.
Cancer has spread to the bones at the bottom of the skull, the bones in the neck, jaw muscles, and/or the sinuses around the nose and eyes. Cancer may have also spread to one or more lymph nodes on one or both sides of the neck and/or the back of the throat. The affected lymph nodes are 6 centimeters or smaller.
Stage IV (also called stage 4) nasopharyngeal cancer
Stage IV is divided into stages IVA and IVB.
In stage IVA:
Cancer has spread to the brain, the cranialnerves, the hypopharynx, the salivary gland in the front of the ear, the bone around the eye, and/or the soft tissues of the jaw. Cancer may have also spread to one or more lymph nodes on one or both sides of the neck and/or the back of the throat. The affected lymph nodes are 6 centimeters or smaller; or
Cancer has spread to one or more lymph nodes on one or both sides of the neck. The affected lymph nodes are larger than 6 centimeters and/or are found in the lowest part of the neck.
In stage IVB: Cancer has spread beyond the lymph nodes in the neck to distant lymph nodes, such as those between the lungs, below the collarbone, or in the armpit or groin, or to other parts of the body, such as the lung, bone, or liver.
Stage IV nasopharyngeal cancer is also called metastatic nasopharyngeal cancer. Metastatic cancer happens when cancer cells travel through the lymphatic system or blood and form tumors in other parts of the body. The metastatic tumor is the same type of cancer as the primary tumor. For example, if nasopharyngeal cancer spreads to the lung, the cancer cells in the lung are actually nasopharyngeal cancer cells. The disease is called metastatic nasopharyngeal cancer, not lung cancer. Learn more in Metastatic Cancer: When Cancer Spreads.
Nasopharyngeal cancer can recur (come back) after it has been treated.
Recurrent nasopharyngeal cancer is cancer that has come back after it has been treated. If nasopharyngeal cancer comes back, it may come back in the nasopharynx, lymph nodes, or other parts of the body, such as the lungs, bone, or liver. Tests will help determine where in the body the cancer has returned. The type of treatment that you have for recurrent nasopharyngeal cancer will depend on where it has come back.
There are different types of treatment for people with nasopharyngeal cancer.
People with nasopharyngeal cancer should have their treatment planned by a team of doctors with expertise in treating head and neck cancer.
The following types of treatment are used:
Radiation therapy
Chemotherapy
Surgery
Immunotherapy
Treatment for nasopharyngeal cancer may cause side effects.
New types of treatment are being tested in clinical trials.
Follow-up care may be needed.
There are different types of treatment for people with nasopharyngeal cancer.
Different types of treatments are available for nasopharyngeal cancer. You and your cancer care team will work together to decide your treatment plan, which may include more than one type of treatment. Many factors will be considered, such as the stage of the cancer, your overall health, and your preferences. Your plan will include information about your cancer, the goals of treatment, your treatment options and the possible side effects, and the expected length of treatment.
Talking with your cancer care team before treatment begins about what to expect will be helpful. You’ll want to learn what you need to do before treatment begins, how you’ll feel while going through it, and what kind of help you will need. Learn more at Questions to Ask Your Doctor About Your Treatment.
People with nasopharyngeal cancer should have their treatment planned by a team of doctors with expertise in treating head and neck cancer.
An oncologist, a doctor who specializes in treating people with cancer, oversees treatment for nasopharyngeal cancer. Because the nasopharynx helps in breathing, eating, and talking, you may need help adjusting to the side effects of the cancer and its treatment. The oncologist may refer you to other health care providers who are experts in treating head and neck cancer and also specialize in other areas of medicine. Other specialists may include:
Radiation therapy uses high-energy x-rays or other types of radiation to kill cancer cells or keep them from growing by damaging their DNA. The way radiation therapy is given depends on the type and stage of the cancer. External and internal radiation therapy are used to treat nasopharyngeal cancer.
External radiation therapy uses a machine outside the body to send radiation toward the area of the body with cancer. EnlargeExternal-beam radiation therapy of the head and neck. A machine is used to aim high-energy radiation at the cancer. The machine can rotate around the patient, delivering radiation from many different angles to provide highly conformal treatment. A mesh mask helps keep the patient’s head and neck from moving during treatment. Small ink marks are put on the mask. The ink marks are used to line up the radiation machine in the same position before each treatment.
Certain ways of giving radiation therapy can help keep radiation from damaging nearby healthy tissue. These include:
Intensity-modulated radiation therapy (IMRT): IMRT is a type of 3-dimensional (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. Compared to standard radiation therapy, intensity-modulated radiation therapy may be less likely to cause dry mouth. You will likely have treatment once a day, Monday through Friday, for about 6 to 7 weeks.
Stereotactic radiation therapy: Stereotactic radiation therapy also uses a computer to make detailed images of the tumor. Thin beams of radiation are aimed at the tumor from different angles. High-dose radiation is given in one to five sessions spread over several days. This procedure is also called stereotactic external-beam radiation and stereotaxic radiation therapy.
External radiation therapy to the thyroid or the pituitary gland may change the way the thyroid gland works. A blood test to check the thyroid hormone level in the blood is done before and after therapy to make sure the thyroid gland is working properly. It is also important that a dentist check your teeth, gums, and mouth, and fix any existing problems before radiation therapy begins.
Internal radiation therapy (also called brachytherapy) uses a radioactive substance sealed in needles, seeds, wires, or catheters that are placed directly into or near the cancer. In some cases, it may be used with external radiation therapy to deliver an extra dose of radiation directly to the tumor. Learn more about Brachytherapy to Treat Cancer.
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 for nasopharyngeal cancer is usually systemic, meaning it is taken by mouth or injected into a vein or muscle. When given this way, the drugs enter the bloodstream and can reach cancer cells throughout the body.
Chemotherapy drugs used to treat nasopharyngeal cancer include:
Surgery to remove the tumor is sometimes used for nasopharyngeal cancer that does not respond to radiation therapy. If cancer has spread to the lymph nodes, the doctor may remove lymph nodes and other tissues in the neck.
Immunotherapy is a treatment that uses the patient’s immune system to fight cancer. Substances made by the body or made in a laboratory are used to boost, direct, or restore the body’s natural defenses against cancer.
PD-1 and PD-L1 inhibitor therapy: PD-1 is a protein on the surface of T cells that helps keep the body’s immune responses in check. PD-L1 is a protein found on some types of cancer cells. When PD-1 attaches to PD-L1, it stops the T cell from killing the cancer cell. PD-1 and PD-L1 inhibitors keep PD-1 and PD-L1 proteins from attaching to each other. This allows the T cells to kill cancer cells. Toripalimab is a type of PD-1 inhibitor used to treat metastatic or recurrent nasopharyngeal cancer.
EnlargeImmune checkpoint inhibitor. Checkpoint proteins, such as PD-L1 on tumor cells and PD-1 on T cells, help keep immune responses in check. The binding of PD-L1 to PD-1 keeps T cells from killing tumor cells in the body (left panel). Blocking the binding of PD-L1 to PD-1 with an immune checkpoint inhibitor (anti-PD-L1 or anti-PD-1) allows the T cells to kill tumor cells (right panel).
Immunotherapy uses the body’s immune system to fight cancer. This animation explains one type of immunotherapy that uses immune checkpoint inhibitors to treat cancer.
Side effects from cancer treatment that begin after treatment and continue for months or years are called late effects. Late effects of nasopharyngeal cancer treatment may include:
changes in mood, feelings, thinking, learning, or memory
Some late effects may be treated or controlled. It is important to talk with your doctor about possible late effects caused by some treatments.
New types of treatment are being tested in clinical trials.
For some people, joining a clinical trial may be an option. There are different types of clinical trials for people with cancer. For example, a treatment trial tests new treatments or new ways of using current treatments. Supportive care and palliative care trials look at ways to improve quality of life, especially for those who have side effects from cancer and its treatment.
You can use the clinical trial search to find NCI-supported cancer clinical trials accepting participants. The search allows you to filter trials based on the type of cancer, your age, and where the trials are being done. Clinical trials supported by other organizations can be found on the ClinicalTrials.gov website.
As you go through treatment, you will have follow-up tests or check-ups. Some tests that were done to diagnose or stage the cancer may be repeated to see how well the treatment is working. Decisions about whether to continue, change, or stop treatment may be based on the results of these tests.
Some of the tests will continue to be done from time to time after treatment has ended. The results of these tests can show if your condition has changed or if the cancer has recurred (come back).
After treatment is complete, it is important to have head and neck exams to look for signs that the cancer has come back.
Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.
Treatment of Stage II, III, and IVA Nasopharyngeal Cancer
chemotherapy given with radiation therapy, followed by more chemotherapy
chemotherapy followed by more chemotherapy given with radiation therapy
chemotherapy followed by radiation therapy (under study)
surgery to remove lymph nodes if they still contain cancer cells after initial treatment
chemotherapy
Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.
Treatment of Stage IVB and Recurrent Nasopharyngeal Cancer
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.
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 adult nasopharyngeal cancer. It is meant to inform and help patients, families, and caregivers. It does not give formal guidelines or recommendations for making decisions about health care.
Reviewers and Updates
Editorial Boards write the PDQ cancer information summaries and keep them up to date. These Boards are made up of experts in cancer treatment and other specialties related to cancer. The summaries are reviewed regularly and changes are made when there is new information. The date on each summary (“Updated”) is the date of the most recent change.
The information in this patient summary was taken from the health professional version, which is reviewed regularly and updated as needed, by the PDQ Adult Treatment Editorial Board.
Clinical Trial Information
A clinical trial is a study to answer a scientific question, such as whether one treatment is better than another. Trials are based on past studies and what has been learned in the laboratory. Each trial answers certain scientific questions in order to find new and better ways to help cancer patients. During treatment clinical trials, information is collected about the effects of a new treatment and how well it works. If a clinical trial shows that a new treatment is better than one currently being used, the new treatment may become “standard.” Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.
Clinical trials can be found online at NCI’s website. For more information, call the Cancer Information Service (CIS), NCI’s contact center, at 1-800-4-CANCER (1-800-422-6237).
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The best way to cite this PDQ summary is:
PDQ® Adult Treatment Editorial Board. PDQ Nasopharyngeal Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/head-and-neck/patient/adult/nasopharyngeal-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389409]
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Screening is looking for cancer before a person has any symptoms. This can help find cancer at an early stage. When abnormaltissue or cancer is found early, it may be easier to treat. By the time symptoms appear, cancer may have begun to spread.
Scientists are trying to better understand which people are more likely to get certain types of cancer. They also study the things we do and the things around us to see if they cause cancer. This information helps doctors recommend who should be screened for cancer, which screening tests should be used, and how often the tests should be done.
It is important to remember that your doctor does not necessarily think you have cancer if he or she suggests a screening test. Screening tests are given when you have no cancer symptoms.
If a screening test result is abnormal, you may need to have more tests done to find out if you have cancer. These are called diagnostic tests.
General Information About Oral Cavity and Nasopharyngeal Cancers
Key Points
Oral cavity and nasopharyngeal cancers are diseases in which malignant (cancer) cells form in the mouth and throat.
The number of new cases of oral cavity and nasopharyngeal cancers and the number of deaths from these cancers vary by sex and geographic region.
Different factors increase or decrease the risk of oral cavity and nasopharyngeal cancers.
Oral cavity and nasopharyngeal cancers are diseases in which malignant (cancer) cells form in the mouth and throat.
Oral cavity cancer forms in any of these tissues of the oral cavity:
the lips
the front two thirds of the tongue
the gingiva (gums)
the buccal mucosa (the lining of the inside of the cheeks)
the floor (bottom) of the mouth under the tongue
the hard palate (the front of the roof of the mouth)
the retromolar trigone (the small area behind the wisdom teeth)
EnlargeAnatomy of the oral cavity. The oral cavity includes the lips, hard palate (the bony front portion of the roof of the mouth), soft palate (the muscular back portion of the roof of the mouth), retromolar trigone (the area behind the wisdom teeth), front two-thirds of the tongue, gingiva (gums), buccal mucosa (the inner lining of the lips and cheeks), and floor of the mouth under the tongue.
EnlargeAnatomy of the pharynx. The pharynx is a hollow, muscular tube inside the neck that starts behind the nose and opens into the larynx and esophagus. The three parts of the pharynx are the nasopharynx, oropharynx, and hypopharynx.
Other PDQ summaries containing information related to oral cavity and nasopharyngeal cancers include:
The number of new cases of oral cavity and nasopharyngeal cancers and the number of deaths from these cancers vary by sex and geographic region.
From 2012 to 2021, the number of new cases of oral cavity cancer in the United States increased slightly each year.
Oral cavity cancer is more common in men than in women. Although oral cavity cancer may occur in adults of any age, it occurs most often in those aged 75 to 84 years.
France, Brazil, and parts of Asia have much higher rates of oral cavity cancer than most other countries.
Nasopharyngeal cancer is rare in the United States. Some indigenous populations in Southeast Asia, the Arctic, North Africa, and the Middle East have higher rates of nasopharyngeal cancers.
Different factors increase or decrease the risk of oral cavity and nasopharyngeal cancers.
Anything that increases your chance of getting a disease is called a risk factor. Anything that decreases your chance of getting a disease is called a protective factor.
Being infected with Epstein-Barr virus (EBV) increases the risk of nasopharyngeal cancer.
Other PDQ summaries containing information related to oral cavity and nasopharyngeal cancers include:
Tests are used to screen for different types of cancer when a person does not have symptoms.
There are no standard or routine screening tests for oral cavity and nasopharyngeal cancers.
Screening tests for oral cavity and nasopharyngeal cancers are being studied in clinical trials.
Tests are used to screen for different types of cancer when a person does not have symptoms.
Scientists study screening tests to find those with the fewest harms and most benefits. Cancer screening trials also are meant to show whether early detection (finding cancer before it causes symptoms) helps a person live longer or decreases a person’s chance of dying from the disease. For some types of cancer, the chance of recovery is better if the disease is found and treated at an early stage.
There are no standard or routine screening tests for oral cavity and nasopharyngeal cancers.
A dentist or medical doctor may check the oral cavity during a routine check-up. The exam will include looking for lesions, including areas of leukoplakia (an abnormal white patch of cells) and erythroplakia (an abnormal red patch of cells). Leukoplakia and erythroplakia lesions on the mucous membranes may become cancerous.
If lesions are seen in the mouth, the following procedures may be used to find abnormal tissue that might become oral cavity cancer:
Toluidine blue stain: A procedure in which lesions in the mouth are coated with a blue dye. Areas that stain darker are more likely to be cancer or become cancer.
Fluorescence staining: A procedure in which lesions in the mouth are viewed using a special light. After the patient uses a fluorescent mouth rinse, normal tissue looks different from abnormal tissue when seen under the light.
Exfoliative cytology: A procedure to collect cells from the oral cavity. A piece of cotton, a brush, or a small wooden stick is used to gently scrape cells from the lips, tongue, or mouth. The cells are viewed under a microscope to find out if they are abnormal.
Brush biopsy: The removal of cells using a brush that is designed to collect cells from all layers of a lesion. The cells are viewed under a microscope to find out if they are abnormal.
More than half of oral cancers have already spread to lymph nodes or other areas by the time they are found.
Epstein-Barr virus (EBV) has been linked to nasopharyngeal cancer. Screening for nasopharyngeal cancer using the EBV antibody test or EBV DNA test has been studied. These are laboratory tests used to check the blood for EBV antibodies or EBV DNA. If EBV antibodies or DNA are found in the blood, more tests may be done to check for nasopharyngeal cancer. No studies have shown that screening would decrease the risk of dying from this disease.
Screening tests for oral cavity and nasopharyngeal cancers are being studied in clinical trials.
Risks of Oral Cavity and Nasopharyngeal Cancers Screening
Key Points
Screening tests have risks.
The risks of screening for oral cavity and nasopharyngeal cancers include:
Finding these cancers may not improve health or help a person live longer.
False-negative test results can occur.
False-positive test results can occur.
Screening tests have risks.
Decisions about screening tests can be difficult. Not all screening tests are helpful and most have risks. Before having any screening test, you may want to discuss the test with your doctor. It is important to know the risks of the test and whether it has been proven to reduce the risk of dying from cancer.
The risks of screening for oral cavity and nasopharyngeal cancers include:
Finding these cancers may not improve health or help a person live longer.
Some cancers never cause symptoms or become life-threatening, but if found by a screening test, the cancer may be treated. Finding these cancers is called overdiagnosis. It is not known if treatment of oral cavity cancer or nasopharyngeal cancer would help you live longer than if no treatment were given, and treatments for cancer, such as surgery and radiation therapy, may have serious side effects.
False-negative test results can occur.
Screening test results may appear to be normal even though oral cavity cancer or nasopharyngeal cancer is present. A person who receives a false-negative test result (one that shows there is no cancer when there really is) may delay seeking medical care even if there are symptoms.
False-positive test results can occur.
Screening test results may appear to be abnormal even though no cancer is present. A false-positive test result (one that shows there is cancer when there really isn’t) can cause anxiety and is usually followed by more tests and procedures (such as biopsy), which also have risks.
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 oral cavity and nasopharyngeal cancers screening. 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.
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Clinical Trial Information
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PDQ® Screening and Prevention Editorial Board. PDQ Oral Cavity and Nasopharyngeal Cancers Screening. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/head-and-neck/patient/oral-screening-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389441]
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Tumors of many histologies can occur in the nasopharynx, but only nasopharyngeal carcinomas (also called NPC) are covered in this summary. The American Joint Committee on Cancer nasopharynx staging refers exclusively to the World Health Organization’s (WHO) classification of grades I, II, and III nasopharyngeal carcinoma.
Incidence and Mortality
Less than one person out of 100,000 is diagnosed with nasopharyngeal carcinoma in the world each year, with most cases found in southern China, Southeast Asia, the Arctic, and the Middle East/North Africa. The incidence is higher in males than in females.[1–3] WHO grade I nasopharyngeal carcinoma (keratinizing subtype) accounts for less than 20% of cases in the United States and WHO grades II and III represent the endemic form of nasopharyngeal carcinoma and are found mostly in Asia. Nonkeratinizing subtypes are associated with Epstein-Barr virus (EBV) infection and account for most cases.[4]
Anatomy
The nasopharynx has a cuboidal shape. The lateral walls are formed by the eustachian tube and the fossa of Rosenmuller. The roof, sloping downward from anterior to posterior, is bordered by the pharyngeal hypophysis, pharyngeal tonsil, and pharyngeal bursa with the base of the skull above. Anteriorly, the nasopharynx abuts the posterior choanae and nasal cavity, and the posterior boundary is formed by the muscles of the posterior pharyngeal wall. Inferiorly, the nasopharynx ends at an imaginary horizontal line formed by the upper surface of the soft palate and the posterior pharyngeal wall. Nasopharyngeal carcinoma originates from the epithelial cells that line the nasopharynx.
Risk factors for nasopharyngeal carcinoma include:[4–8]
Risk factors for keratinizing squamous cell carcinoma (WHO grade I):
Heavy alcohol intake.
History of smoking.
Risk factors for nonkeratinizing carcinoma (WHO grades II and III):
Asian race.
EBV exposure.
Family history.
Clinical Features
Signs and symptoms at presentation include:
Headache caused by cranial nerve dysfunction (usually II–VI or IX–XII).
Diplopia.
Facial numbness.
Cervical adenopathy (present in approximately 75% of patients and often bilateral and posterior).
Nasal obstruction.
Epistaxis.
Diminished hearing.
Tinnitus.
Otitis media.
Sore throat.
In patients who present with cervical adenopathy alone, the finding of EBV genomic material in the tissue using polymerase chain reaction (PCR) is strong evidence of a nasopharyngeal primary tumor, and that area should be examined closely.[9]
Diagnostic Evaluation
Diagnostic tests and procedures
Diagnosis is made by biopsy of the nasopharyngeal mass. The following tests and procedures are used in the diagnosis of nasopharyngeal carcinoma:[10]
Careful visual examination by fiberoptic nasal endoscopic examination and/or examination under anesthesia.
Endoscopic biopsy.
Physical examination and health history. Documentation of the size and location of the tumor and cervical lymph nodes is noted.
Evaluation of cranial nerve function including neuro-ophthalmological evaluation and audiological evaluation.
Human papillomavirus (HPV) type 16 blood test if EBV negative.
Any clinical or laboratory finding that suggests distant metastasis may prompt further evaluation of other sites. MRI is often more helpful than CT scans in assessing skull base involvement and in defining the extent of abnormalities detected.[10,12,13]
Circulating cancer-derived EBV DNA
EBV DNA in plasma samples in endemic populations may be useful in screening for early asymptomatic nasopharyngeal carcinoma. Circulating cancer-derived EBV DNA in plasma is an established tumor marker for nasopharyngeal carcinoma, with a sensitivity of 96% and a specificity of 93%.[14–16] The presence of short EBV DNA fragments of fewer than 181 base pairs in the plasma of nasopharyngeal carcinoma patients suggests that EBV DNA molecules are released into the circulation by apoptosis of cancer cells rather than by active viral replication.[17]
Evidence (EBV DNA in plasma for screening and diagnosis of nasopharyngeal carcinoma):
In a study of 20,174 participants in China, EBV DNA in plasma was used to screen for early nasopharyngeal carcinoma.[14]
Initially, 1,112 participants tested positive for EBV DNA in plasma.
Three hundred and nine participants (1.5% of all participants, and 27.8% of those who initially tested positive) had persistently detectable EBV DNA in plasma at baseline and follow-up.
Among the 309 participants, nasopharyngeal carcinoma was confirmed after nasal endoscopic examination, MRI, and biopsy in 34 participants (11.0%).
HPV
Differentiating HPV-related nasopharyngeal carcinoma requires identification of p16 immunohistochemical staining, in situ hybridization, and/or PCR similar to the method for differentiating HPV-related oropharyngeal cancer. Less than 10% of nonkeratinizing nasopharyngeal carcinomas are associated with HPV infection.[18,19]
Prognostic Factors
The following major prognostic factors adversely influence treatment outcome:[20]
WHO grade I.
A higher tumor (T) stage.
The presence of involved cervical lymph nodes (N).
High plasma/serum EBV DNA levels before and after treatment.[21,22]
Follow-up testing for tumor recurrence includes:[24]
Routine periodic examination of the original tumor site and neck.
CT or PET-CT scan.
MRI scan.
Plasma/serum EBV DNA levels.
Patients should be monitored for the following potential late effects of treatment:[25,26]
Xerostomia.
Dental and oral complications.
Hearing loss.
Vision loss.
Dysphagia.
Trismus.
Thyroid and pituitary function.
Cranial neuropathies.
Cognitive impairment.
Although most recurrences occur within 5 years of diagnosis, relapse can be seen at longer intervals. The incidence of second primary malignancies after treatment is lower for nasopharyngeal carcinoma than for other head and neck cancer sites.[27]
Accumulating evidence has demonstrated a high incidence (>30%–40%) of hypothyroidism in patients who have received radiation therapy that delivered external-beam radiation therapy (EBRT) to the entire thyroid gland or to the pituitary gland. Thyroid-function testing of patients should be considered before therapy and as part of posttreatment follow-up.[28,29]
Careful dental and oral hygiene evaluation and therapy is particularly important before initiation of radiation treatment. Intensity-modulated radiation therapy (IMRT) results in a lower incidence of xerostomia and may provide a better quality of life than conventional three-dimensional or two-dimensional radiation therapy (2DRT).[30,31][Level of evidence A3]
Evidence (IMRT vs. 2DRT and incidence of xerostomia):
A randomized prospective study assessed the incidence of xerostomia in patients with early-stage nasopharyngeal carcinoma treated with IMRT (n = 28) or 2DRT (n = 28).[32] Long-term toxicities were graded with the Radiation Therapy Oncology Group (RTOG) criteria.
The incidence of grade 2 xerostomia was 20% for patients who received IMRT and 90% for patients who received 2DRT (P = .001). There was no significant difference between the groups with the xerostomia questionnaire.
Patients who received IMRT had lower scores for dry mouth than patients who received 2DRT.
The overall survival rate was 82% in the IMRT group versus 54% in the 2DRT group.
The relapse-free survival rate was 70% in the IMRT group versus 54% in the 2DRT group.
More late complications were reported among patients in the 2DRT group.
The phase II RTOG-0225 study tested the feasibility of IMRT in a multi-institutional setting.[33]
The rate of grade 2 xerostomia at 1 year from start of IMRT was 13.5%.
The rate of grades 3 and 4 xerostomia was minimal.
Only 2 of 68 patients were reported with grade 3 xerostomia.
Ferlay J, Soerjomataram I, Dikshit R, et al.: Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 136 (5): E359-86, 2015. [PUBMED Abstract]
Chang ET, Adami HO: The enigmatic epidemiology of nasopharyngeal carcinoma. Cancer Epidemiol Biomarkers Prev 15 (10): 1765-77, 2006. [PUBMED Abstract]
Chen YP, Chan ATC, Le QT, et al.: Nasopharyngeal carcinoma. Lancet 394 (10192): 64-80, 2019. [PUBMED Abstract]
Chien YC, Chen JY, Liu MY, et al.: Serologic markers of Epstein-Barr virus infection and nasopharyngeal carcinoma in Taiwanese men. N Engl J Med 345 (26): 1877-82, 2001. [PUBMED Abstract]
Chen L, Gallicchio L, Boyd-Lindsley K, et al.: Alcohol consumption and the risk of nasopharyngeal carcinoma: a systematic review. Nutr Cancer 61 (1): 1-15, 2009. [PUBMED Abstract]
Okekpa SI, S M N Mydin RB, Mangantig E, et al.: Nasopharyngeal Carcinoma (NPC) Risk Factors: A Systematic Review and Meta-Analysis of the Association with Lifestyle, Diets, Socioeconomic and Sociodemographic in Asian Region. Asian Pac J Cancer Prev 20 (11): 3505-3514, 2019. [PUBMED Abstract]
Xie SH, Yu IT, Tse LA, et al.: Tobacco smoking, family history, and the risk of nasopharyngeal carcinoma: a case-referent study in Hong Kong Chinese. Cancer Causes Control 26 (6): 913-21, 2015. [PUBMED Abstract]
Feinmesser R, Miyazaki I, Cheung R, et al.: Diagnosis of nasopharyngeal carcinoma by DNA amplification of tissue obtained by fine-needle aspiration. N Engl J Med 326 (1): 17-21, 1992. [PUBMED Abstract]
Cummings CW, Fredrickson JM, Harker LA, et al.: Otolaryngology – Head and Neck Surgery. Mosby-Year Book, Inc., 1998.
Kim KY, Le QT, Yom SS, et al.: Clinical Utility of Epstein-Barr Virus DNA Testing in the Treatment of Nasopharyngeal Carcinoma Patients. Int J Radiat Oncol Biol Phys 98 (5): 996-1001, 2017. [PUBMED Abstract]
Mendenhall WM, Werning JW, Pfister DG: Treatment of head and neck cancer. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Lippincott Williams & Wilkins, 2011, pp 729-80.
Laramore GE, ed.: Radiation Therapy of Head and Neck Cancer. Springer-Verlag, 1989.
Chan KCA, Woo JKS, King A, et al.: Analysis of Plasma Epstein-Barr Virus DNA to Screen for Nasopharyngeal Cancer. N Engl J Med 377 (6): 513-522, 2017. [PUBMED Abstract]
Lo YM, Chan LY, Lo KW, et al.: Quantitative analysis of cell-free Epstein-Barr virus DNA in plasma of patients with nasopharyngeal carcinoma. Cancer Res 59 (6): 1188-91, 1999. [PUBMED Abstract]
Leung SF, Zee B, Ma BB, et al.: Plasma Epstein-Barr viral deoxyribonucleic acid quantitation complements tumor-node-metastasis staging prognostication in nasopharyngeal carcinoma. J Clin Oncol 24 (34): 5414-8, 2006. [PUBMED Abstract]
Chan KC, Zhang J, Chan AT, et al.: Molecular characterization of circulating EBV DNA in the plasma of nasopharyngeal carcinoma and lymphoma patients. Cancer Res 63 (9): 2028-32, 2003. [PUBMED Abstract]
Huang WB, Chan JYW, Liu DL: Human papillomavirus and World Health Organization type III nasopharyngeal carcinoma: Multicenter study from an endemic area in Southern China. Cancer 124 (3): 530-536, 2018. [PUBMED Abstract]
Robinson M, Suh YE, Paleri V, et al.: Oncogenic human papillomavirus-associated nasopharyngeal carcinoma: an observational study of correlation with ethnicity, histological subtype and outcome in a UK population. Infect Agent Cancer 8 (1): 30, 2013. [PUBMED Abstract]
Sanguineti G, Geara FB, Garden AS, et al.: Carcinoma of the nasopharynx treated by radiotherapy alone: determinants of local and regional control. Int J Radiat Oncol Biol Phys 37 (5): 985-96, 1997. [PUBMED Abstract]
Leung SF, Chan AT, Zee B, et al.: Pretherapy quantitative measurement of circulating Epstein-Barr virus DNA is predictive of posttherapy distant failure in patients with early-stage nasopharyngeal carcinoma of undifferentiated type. Cancer 98 (2): 288-91, 2003. [PUBMED Abstract]
Chan AT, Lo YM, Zee B, et al.: Plasma Epstein-Barr virus DNA and residual disease after radiotherapy for undifferentiated nasopharyngeal carcinoma. J Natl Cancer Inst 94 (21): 1614-9, 2002. [PUBMED Abstract]
Lee CC, Huang TT, Lee MS, et al.: Clinical application of tumor volume in advanced nasopharyngeal carcinoma to predict outcome. Radiat Oncol 5: 20, 2010. [PUBMED Abstract]
Cooper JS, Fu K, Marks J, et al.: Late effects of radiation therapy in the head and neck region. Int J Radiat Oncol Biol Phys 31 (5): 1141-64, 1995. [PUBMED Abstract]
McDowell L, Corry J, Ringash J, et al.: Quality of Life, Toxicity and Unmet Needs in Nasopharyngeal Cancer Survivors. Front Oncol 10: 930, 2020. [PUBMED Abstract]
Fong R, Ward EC, Rumbach AF: Dysphagia after chemo-radiation for nasopharyngeal cancer: A scoping review. World J Otorhinolaryngol Head Neck Surg 6 (1): 10-24, 2020. [PUBMED Abstract]
Cooper JS, Scott C, Marcial V, et al.: The relationship of nasopharyngeal carcinomas and second independent malignancies based on the Radiation Therapy Oncology Group experience. Cancer 67 (6): 1673-7, 1991. [PUBMED Abstract]
Turner SL, Tiver KW, Boyages SC: Thyroid dysfunction following radiotherapy for head and neck cancer. Int J Radiat Oncol Biol Phys 31 (2): 279-83, 1995. [PUBMED Abstract]
Constine LS: What else don’t we know about the late effects of radiation in patients treated for head and neck cancer? Int J Radiat Oncol Biol Phys 31 (2): 427-9, 1995. [PUBMED Abstract]
Pow EH, Kwong DL, McMillan AS, et al.: Xerostomia and quality of life after intensity-modulated radiotherapy vs. conventional radiotherapy for early-stage nasopharyngeal carcinoma: initial report on a randomized controlled clinical trial. Int J Radiat Oncol Biol Phys 66 (4): 981-91, 2006. [PUBMED Abstract]
Kam MK, Leung SF, Zee B, et al.: Prospective randomized study of intensity-modulated radiotherapy on salivary gland function in early-stage nasopharyngeal carcinoma patients. J Clin Oncol 25 (31): 4873-9, 2007. [PUBMED Abstract]
Poon DMC, Kam MKM, Johnson D, et al.: Durability of the parotid-sparing effect of intensity-modulated radiotherapy (IMRT) in early stage nasopharyngeal carcinoma: A 15-year follow-up of a randomized prospective study of IMRT versus two-dimensional radiotherapy. Head Neck 43 (6): 1711-1720, 2021. [PUBMED Abstract]
Lee N, Harris J, Garden AS, et al.: Intensity-modulated radiation therapy with or without chemotherapy for nasopharyngeal carcinoma: radiation therapy oncology group phase II trial 0225. J Clin Oncol 27 (22): 3684-90, 2009. [PUBMED Abstract]
Cellular Classification of Nasopharyngeal Carcinoma
The World Health Organization (WHO) definition of nasopharyngeal carcinoma is a “carcinoma arising in the nasopharyngeal mucosa that shows light microscopic or ultrastructural evidence of squamous differentiation.” The WHO classification for nasopharyngeal carcinoma has evolved over time, and the 2005 classification is the current version.[1–3] The three versions below are all used, and in particular, the undifferentiated carcinomas that carry the worst prognosis and the greatest sensitivity to chemoradiation are generally classified according to the 1978 definitions.[4]
1978 WHO classification:
Squamous cell carcinoma.
Nonkeratinizing squamous cell carcinoma.
Undifferentiated carcinoma (most common subtype).
1991 WHO classification:
Squamous cell carcinoma.
Nonkeratinizing squamous cell carcinoma.
Differentiated nonkeratinizing carcinoma.
Undifferentiated carcinoma.
2005 WHO classification:
Keratinizing squamous cell carcinoma.
Nonkeratinizing carcinoma.
Differentiated nonkeratinizing carcinoma.
Undifferentiated carcinoma.
Basaloid squamous cell carcinoma.
Previous subdivisions of nasopharyngeal carcinoma included lymphoepithelioma, which is now classified as WHO grade III and characterized by lymphoid infiltrate.[5]
References
Thompson LD: Update on nasopharyngeal carcinoma. Head Neck Pathol 1 (1): 81-6, 2007. [PUBMED Abstract]
Wang HY, Chang YL, To KF, et al.: A new prognostic histopathologic classification of nasopharyngeal carcinoma. Chin J Cancer 35: 41, 2016. [PUBMED Abstract]
Stelow EB, Wenig BM: Update From The 4th Edition of the World Health Organization Classification of Head and Neck Tumours: Nasopharynx. Head Neck Pathol 11 (1): 16-22, 2017. [PUBMED Abstract]
Shanmugaratnam K, Chan SH, de-Thé G, et al.: Histopathology of nasopharyngeal carcinoma: correlations with epidemiology, survival rates and other biological characteristics. Cancer 44 (3): 1029-44, 1979. [PUBMED Abstract]
Shanmugaratnam K, Sobin L: Histological Typing of Upper Respiratory Tract Tumours. World Health Organization, 1978. International Histologic Classification of Tumours: No. 19.
Stage Information for Nasopharyngeal Carcinoma
Staging systems used for clinical staging are based on the best possible estimate of the extent of disease before treatment.[1,2]
Assessment of the primary tumor is made on the basis of inspection, palpation, and fiberoptic endoscopic evaluation. The tumor must be confirmed histologically, and any other pathologic data obtained on biopsy may be included. Evaluation of the function of the cranial nerves is important for tumors of the nasopharynx. Nodal drainage areas are examined by careful palpation and radiological evaluation. The retropharyngeal lymph nodes are the first echelon of drainage.[3,4]
Information from the following diagnostic imaging studies may be used in staging:
Magnetic resonance imaging provides additional information to computed tomography (CT) scanning in the evaluation of skull base invasion and intracranial spread.[5]
Positron emission tomography scans combined with CT are helpful in radiation treatment planning for targeted delineation of the primary tumor and aid in the detection of metastatic nodal involvement and metastatic spread, such as that found in lung or skeletal metastases in patients with advanced nasopharyngeal carcinoma.[6]
If the disease relapses, a complete reassessment must be done to select the appropriate additional therapy.
American Joint Committee on Cancer (AJCC) Stage Groupings and TNM Definitions
The AJCC has designated staging by TNM (tumor, node, metastasis) classification to define nasopharyngeal carcinoma.[7]
Table 1. Definition of TNM Stage 0a
Stage
TNM
Description
T = primary tumor; N = regional lymph node; M = distant metastasis.
aReprinted with permission from AJCC: Nasopharynx. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 103–11.
0
Tis, N0, M0
Tis = Carcinoma in situ.
N0 = No regional lymph node metastasis.
M0 = No distant metastasis.
Table 2. Definition of TNM Stage Ia
Stage
TNM
Description
T = primary tumor; N = regional lymph node; M = distant metastasis.
aReprinted with permission from AJCC: Nasopharynx. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 103–11.
I
T1, N0, M0
T1 = Tumor confined to nasopharynx, or extension to oropharynx and/or nasal cavity without parapharyngeal involvement.
N0 = No regional lymph node metastasis.
M0 = No distant metastasis.
Table 3. Definition of TNM Stage IIa
Stage
TNM
Description
T = primary tumor; N = regional lymph node; M = distant metastasis; EBV = Epstein-Barr virus.
aReprinted with permission from AJCC: Nasopharynx. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 103–11.
II
T0, Tis, T1, N1, M0
T0 = No tumor identified, but EBV-positive cervical node(s) involvement.
Tis = Carcinoma in situ.
T1 = Tumor confined to nasopharynx, or extension to oropharynx and/or nasal cavity without parapharyngeal involvement.
N1 = Unilateral metastasis in cervical lymph node(s) and/or unilateral or bilateral metastasis in retropharyngeal lymph node(s), ≤6 cm in greatest dimension, above the caudal border of cricoid cartilage.
M0 = No distant metastasis.
T2, N0, M0
T2 = Tumor with extension to parapharyngeal space, and/or adjacent soft tissue involvement (medial pterygoid, lateral pterygoid, prevertebral muscles).
N0 = No regional lymph node metastasis.
M0 = No distant metastasis.
T2, N1, M0
T2 = Tumor with extension to parapharyngeal space, and/or adjacent soft tissue involvement (medial pterygoid, lateral pterygoid, prevertebral muscles).
N1 = Unilateral metastasis in cervical lymph node(s) and/or unilateral or bilateral metastasis in retropharyngeal lymph node(s), ≤6 cm in greatest dimension, above the caudal border of cricoid cartilage.
M0 = No distant metastasis.
Table 4. Definition of TNM Stage IIIa
Stage
TNM
Description
T = primary tumor; N = regional lymph node; M = distant metastasis; EBV = Epstein-Barr virus.
aReprinted with permission from AJCC: Nasopharynx. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 103–11.
III
T0, Tis, T1, N2, M0
T0 = No tumor identified, but EBV-positive cervical node(s) involvement.
Tis = Carcinoma in situ.
T1 = Tumor confined to nasopharynx, or extension to oropharynx and/or nasal cavity without parapharyngeal involvement.
N2 = Bilateral metastasis in cervical lymph node(s), ≤6 cm in greatest dimension, above the caudal border of cricoid cartilage.
M0 = No distant metastasis.
T2, N2, M0
T2 = Tumor with extension to parapharyngeal space, and/or adjacent soft tissue involvement (medial pterygoid, lateral pterygoid, prevertebral muscles).
N2 = Bilateral metastasis in cervical lymph node(s), ≤6 cm in greatest dimension, above the caudal border of cricoid cartilage.
M0 = No distant metastasis.
T3, N0, M0
T3 = Tumor with infiltration of bony structures at skull base, cervical vertebra, pterygoid structures, and/or paranasal sinuses.
N0 = No regional lymph node metastasis.
M0 = No distant metastasis.
T3, N1, M0
T3 = Tumor with infiltration of bony structures at skull base, cervical vertebra, pterygoid structures, and/or paranasal sinuses.
N1 = Unilateral metastasis in cervical lymph node(s) and/or unilateral or bilateral metastasis in retropharyngeal lymph node(s), ≤6 cm in greatest dimension, above the caudal border of cricoid cartilage.
M0 = No distant metastasis.
T3, N2, M0
T3 = Tumor with infiltration of bony structures at skull base, cervical vertebra, pterygoid structures, and/or paranasal sinuses.
N2 = Bilateral metastasis in cervical lymph node(s), ≤6 cm in greatest dimension, above the caudal border of cricoid cartilage.
M0 = No distant metastasis.
Table 5. Definition of TNM Stages IVA and IVBa
Stage
TNM
Description
T = primary tumor; N = regional lymph node; M = distant metastasis; EBV = Epstein-Barr virus.
aReprinted with permission from AJCC: Nasopharynx. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 103–11.
IVA
T4, N0, M0
T4 = Tumor with intracranial extension, involvement of cranial nerves, hypopharynx, orbit, parotid gland, and/or extensive soft tissue infiltration beyond the lateral surface of the lateral pterygoid muscle.
N0 = No regional lymph node metastasis.
M0 = No distant metastasis.
T4, N1, M0
T4 = Tumor with intracranial extension, involvement of cranial nerves, hypopharynx, orbit, parotid gland, and/or extensive soft tissue infiltration beyond the lateral surface of the lateral pterygoid muscle.
N1 = Unilateral metastasis in cervical lymph node(s) and/or unilateral or bilateral metastasis in retropharyngeal lymph node(s), ≤6 cm in greatest dimension, above the caudal border of cricoid cartilage.
M0 = No distant metastasis.
T4, N2, M0
T4 = Tumor with intracranial extension, involvement of cranial nerves, hypopharynx, orbit, parotid gland, and/or extensive soft tissue infiltration beyond the lateral surface of the lateral pterygoid muscle.
N2 = Bilateral metastasis in cervical lymph node(s), ≤6 cm in greatest dimension, above the caudal border of cricoid cartilage.
M0 = No distant metastasis.
Any T, N3, M0
TX = Primary tumor cannot be assessed.
T0 = No tumor identified, but EBV-positive cervical node(s) involvement.
Tis = Carcinoma in situ.
T1 = Tumor confined to nasopharynx, or extension to oropharynx and/or nasal cavity without parapharyngeal involvement.
T2 = Tumor with extension to parapharyngeal space, and/or adjacent soft tissue involvement (medial pterygoid, lateral pterygoid, prevertebral muscles).
T3 = Tumor with infiltration of bony structures at skull base, cervical vertebra, pterygoid structures, and/or paranasal sinuses.
T4 = Tumor with intracranial extension, involvement of cranial nerves, hypopharynx, orbit, parotid gland, and/or extensive soft tissue infiltration beyond the lateral surface of the lateral pterygoid muscle.
N3 = Unilateral or bilateral metastasis in cervical lymph node(s), >6 cm in greatest dimension, and/or extension below the caudal border of cricoid cartilage.
M0 = No distant metastasis.
IVB
Any T, Any N, M1
Any T = See Stage IVA above.
NX = Regional lymph nodes cannot be assessed.
N0 = No regional lymph node metastasis.
N1 = Unilateral metastasis in cervical lymph node(s) and/or unilateral or bilateral metastasis in retropharyngeal lymph node(s), ≤6 cm in greatest dimension, above the caudal border of cricoid cartilage.
N2 = Bilateral metastasis in cervical lymph node(s), ≤6 cm in greatest dimension, above the caudal border of cricoid cartilage.
N3 = Unilateral or bilateral metastasis in cervical lymph node(s), >6 cm in greatest dimension, and/or extension below the caudal border of cricoid cartilage.
M1 = Distant metastasis.
References
Teo PM, Leung SF, Yu P, et al.: A comparison of Ho’s, International Union Against Cancer, and American Joint Committee stage classifications for nasopharyngeal carcinoma. Cancer 67 (2): 434-9, 1991. [PUBMED Abstract]
Lee AW, Foo W, Law SC, et al.: Staging of nasopharyngeal carcinoma: from Ho’s to the new UICC system. Int J Cancer 84 (2): 179-87, 1999. [PUBMED Abstract]
Mendenhall WM, Werning JW, Pfister DG: Treatment of head and neck cancer. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Lippincott Williams & Wilkins, 2011, pp 729-80.
Laramore GE, ed.: Radiation Therapy of Head and Neck Cancer. Springer-Verlag, 1989.
Liu FY, Chang JT, Wang HM, et al.: [18F]fluorodeoxyglucose positron emission tomography is more sensitive than skeletal scintigraphy for detecting bone metastasis in endemic nasopharyngeal carcinoma at initial staging. J Clin Oncol 24 (4): 599-604, 2006. [PUBMED Abstract]
Nasopharynx. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. Springer; 2017, pp. 103–11.
Treatment Option Overview for Nasopharyngeal Carcinoma
Table 6. Treatment Options for Nasopharyngeal Carcinoma
The DPYD gene encodes an enzyme that catabolizes pyrimidines and fluoropyrimidines, like capecitabine and fluorouracil. An estimated 1% to 2% of the population has germline pathogenic variants in DPYD, which lead to reduced DPD protein function and an accumulation of pyrimidines and fluoropyrimidines in the body.[1,2] Patients with the DPYD*2A variant who receive fluoropyrimidines may experience severe, life-threatening toxicities that are sometimes fatal. Many other DPYD variants have been identified, with a range of clinical effects.[1–3] Fluoropyrimidine avoidance or a dose reduction of 50% may be recommended based on the patient’s DPYD genotype and number of functioning DPYD alleles.[4–6] DPYD genetic testing costs less than $200, but insurance coverage varies due to a lack of national guidelines.[7] In addition, testing may delay therapy by 2 weeks, which would not be advisable in urgent situations. This controversial issue requires further evaluation.[8]
References
Sharma BB, Rai K, Blunt H, et al.: Pathogenic DPYD Variants and Treatment-Related Mortality in Patients Receiving Fluoropyrimidine Chemotherapy: A Systematic Review and Meta-Analysis. Oncologist 26 (12): 1008-1016, 2021. [PUBMED Abstract]
Lam SW, Guchelaar HJ, Boven E: The role of pharmacogenetics in capecitabine efficacy and toxicity. Cancer Treat Rev 50: 9-22, 2016. [PUBMED Abstract]
Shakeel F, Fang F, Kwon JW, et al.: Patients carrying DPYD variant alleles have increased risk of severe toxicity and related treatment modifications during fluoropyrimidine chemotherapy. Pharmacogenomics 22 (3): 145-155, 2021. [PUBMED Abstract]
Amstutz U, Henricks LM, Offer SM, et al.: Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Dihydropyrimidine Dehydrogenase Genotype and Fluoropyrimidine Dosing: 2017 Update. Clin Pharmacol Ther 103 (2): 210-216, 2018. [PUBMED Abstract]
Henricks LM, Lunenburg CATC, de Man FM, et al.: DPYD genotype-guided dose individualisation of fluoropyrimidine therapy in patients with cancer: a prospective safety analysis. Lancet Oncol 19 (11): 1459-1467, 2018. [PUBMED Abstract]
Lau-Min KS, Varughese LA, Nelson MN, et al.: Preemptive pharmacogenetic testing to guide chemotherapy dosing in patients with gastrointestinal malignancies: a qualitative study of barriers to implementation. BMC Cancer 22 (1): 47, 2022. [PUBMED Abstract]
Brooks GA, Tapp S, Daly AT, et al.: Cost-effectiveness of DPYD Genotyping Prior to Fluoropyrimidine-based Adjuvant Chemotherapy for Colon Cancer. Clin Colorectal Cancer 21 (3): e189-e195, 2022. [PUBMED Abstract]
Baker SD, Bates SE, Brooks GA, et al.: DPYD Testing: Time to Put Patient Safety First. J Clin Oncol 41 (15): 2701-2705, 2023. [PUBMED Abstract]
Treatment of Stage I Nasopharyngeal Carcinoma
Treatment Options for Stage I Nasopharyngeal Carcinoma
Treatment options for stage I nasopharyngeal carcinoma include:
High-dose radiation therapy with chemotherapy is the initial treatment of nasopharyngeal carcinoma.[1] High-dose radiation therapy is given to the primary tumor site and prophylactic radiation therapy is given to the bilateral regional lymph nodes in the neck.[2] Radiation therapy dose and field margins are individually tailored to the location and size of the primary tumor and lymph nodes.[3–6]
Most tumors are exclusively treated with external-beam radiation therapy. For some patients, radiation therapy may be boosted with intracavitary or interstitial implants, or by the use of stereotactic radiosurgery when clinical expertise is available and the anatomy is suitable.[7–11]
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
Baujat B, Audry H, Bourhis J, et al.: Chemotherapy in locally advanced nasopharyngeal carcinoma: an individual patient data meta-analysis of eight randomized trials and 1753 patients. Int J Radiat Oncol Biol Phys 64 (1): 47-56, 2006. [PUBMED Abstract]
Xiao WW, Han F, Lu TX, et al.: Treatment outcomes after radiotherapy alone for patients with early-stage nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 74 (4): 1070-6, 2009. [PUBMED Abstract]
Perez CA, Devineni VR, Marcial-Vega V, et al.: Carcinoma of the nasopharynx: factors affecting prognosis. Int J Radiat Oncol Biol Phys 23 (2): 271-80, 1992. [PUBMED Abstract]
Lee AW, Law SC, Foo W, et al.: Nasopharyngeal carcinoma: local control by megavoltage irradiation. Br J Radiol 66 (786): 528-36, 1993. [PUBMED Abstract]
Geara FB, Sanguineti G, Tucker SL, et al.: Carcinoma of the nasopharynx treated by radiotherapy alone: determinants of distant metastasis and survival. Radiother Oncol 43 (1): 53-61, 1997. [PUBMED Abstract]
Sanguineti G, Geara FB, Garden AS, et al.: Carcinoma of the nasopharynx treated by radiotherapy alone: determinants of local and regional control. Int J Radiat Oncol Biol Phys 37 (5): 985-96, 1997. [PUBMED Abstract]
Mendenhall WM, Werning JW, Pfister DG: Treatment of head and neck cancer. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Lippincott Williams & Wilkins, 2011, pp 729-80.
Itami J, Anzai Y, Nemoto K, et al.: Prognostic factors for local control in nasopharyngeal cancer (NPC): analysis by multivariate proportional hazard models. Radiother Oncol 21 (4): 233-9, 1991. [PUBMED Abstract]
Levendag PC, Schmitz PI, Jansen PP, et al.: Fractionated high-dose-rate brachytherapy in primary carcinoma of the nasopharynx. J Clin Oncol 16 (6): 2213-20, 1998. [PUBMED Abstract]
Teo PM, Leung SF, Lee WY, et al.: Intracavitary brachytherapy significantly enhances local control of early T-stage nasopharyngeal carcinoma: the existence of a dose-tumor-control relationship above conventional tumoricidal dose. Int J Radiat Oncol Biol Phys 46 (2): 445-58, 2000. [PUBMED Abstract]
Le QT, Tate D, Koong A, et al.: Improved local control with stereotactic radiosurgical boost in patients with nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 56 (4): 1046-54, 2003. [PUBMED Abstract]
Treatment of Stages II, III, and IV Nonmetastatic Nasopharyngeal Carcinoma
Treatment Options for Stages II, III, and IV Nonmetastatic Nasopharyngeal Carcinoma
Treatment options for stages II, III, and IV nonmetastatic nasopharyngeal carcinoma include:
High-dose radiation therapy with chemotherapy is the initial treatment of nasopharyngeal carcinoma.[2] High-dose radiation therapy is given to the primary tumor site and prophylactic radiation therapy is given to the bilateral regional lymph nodes in the neck.[3] Some studies have reported treatment using altered fractionation radiation therapy.[4,5] Radiation therapy dose and field margins are individually tailored to the location and size of the primary tumor and lymph nodes.[6–9]
Most tumors are exclusively treated with external-beam radiation therapy (EBRT). For some patients, radiation therapy may be boosted with intracavitary or interstitial implants, or by the use of stereotactic radiosurgery when clinical expertise is available and the anatomy is suitable.[10–14]
Evidence (radiation therapy):
A multicenter, noninferiority, phase III trial (NCT02633202) evaluated radiation therapy alone versus chemoradiation therapy for patients with low-risk, stage II, T3, N0, M0 (American Joint Committee on Cancer 7th edition staging) nasopharyngeal carcinoma. The study was performed in endemic China, where almost all cases of nasopharyngeal carcinoma are caused by the Epstein-Barr virus (EBV). In this trial, 341 patients were randomly assigned to receive either intensity-modulated radiation therapy (IMRT) alone (n = 172) or concurrent chemoradiation therapy (IMRT with cisplatin 100 mg/m2 every 3 weeks for three cycles [n = 169]). The primary end point was 3-year failure-free survival (FFS).[15][Level of evidence B1]
The 3-year FFS rate was 90.5% in the IMRT-alone group and 91.9% in the concurrent chemoradiation therapy group (difference, −1.4%; one-sided 95% confidence interval [CI], −7.4% to infinity; P for noninferiority < .001). There were no differences in rates of overall survival (OS), locoregional relapse, or distant metastasis between the two arms.
Patients in the IMRT-alone group experienced significantly lower grades 3 and 4 toxicity, including hematologic and nonhematologic toxicities (nausea, vomiting, anorexia, weight loss, mucositis). The IMRT-alone group had better quality-of-life scores during radiation therapy.
In addition to the trial being conducted in an area where almost all patients with nasopharyngeal carcinoma had cases caused by EBV, all patients had an EBV DNA cut-off of fewer than 4,000 copies/mL to be eligible for entry into the trial. Patients with stage II (T1–2, N1) tumors and nodal disease had to have a nodal size smaller than 3 cm, without extranodal extension, to be eligible for the trial.
This trial shows that radiation therapy alone could be used for limited-stage disease if the EBV titers (which are not usually tested in the United States) show fewer than 4,000 copies/mL. Radiation therapy alone was not previously considered a standard of care, but based on these results, patients with lower-volume disease and a low EBV titer may consider radiation therapy alone.
Chemoradiation therapy
Studies and meta-analyses investigating chemoradiation combinations have been reported.[16][Level of evidence C1]; [2,17–30] Overall, these results report increased survival when chemotherapy is added to radiation therapy.[31]
Evidence (neoadjuvant chemotherapy vs. chemoradiation therapy):
Data from phase III randomized trials support induction chemotherapy with gemcitabine plus cisplatin before concurrent chemoradiation therapy.[30,32–34]
A multicenter, randomized, controlled, phase III trial (NCT01872962) compared gemcitabine and cisplatin induction chemotherapy plus concurrent chemoradiation therapy with concurrent chemoradiation therapy alone. At a median follow-up of 42.7 months, the 3-year recurrence-free survival rate was 85.3% for patients in the induction chemotherapy group and 76.5% for patients in the standard therapy group (stratified hazard ratio [HR] recurrence or death, 0.51; 95% CI, 0.34–0.77; P = .001).[30][Level of evidence B1]
In a multicenter phase III trial, patients were randomly assigned to receive either concurrent chemoradiation therapy alone (standard therapy, n = 238) or gemcitabine and cisplatin induction chemotherapy before concurrent chemoradiation therapy (n = 242). With a median follow-up of 69.8 months, patients in the induction chemotherapy group had a significantly higher 5-year OS rate (87.9%) than those in the standard therapy group (78.8%) (HR, 0.51; 95% CI, 0.34–0.78; P = .001). The risk of late toxicities was comparable (grade 3 or higher toxicity, 11.3% vs. 11.4%).[32][Level of evidence B1]
Evidence (chemoradiation therapy plus adjuvant chemotherapy):
Chemoradiation therapy followed by adjuvant chemotherapy was used in the INT-0099 trial.[16][Level of evidence C1]
Patients with parapharyngeal extension were originally staged as T3 in the INT-0099 study and are now considered T2 in the current staging.
The control rate at 3 years was 91.7% in the radiation therapy group (median follow-up period, 34 months) and 100% in the chemoradiation and adjuvant chemotherapy group (median follow-up period, 44 months) (P =.10). The 3-year disease-free survival (DFS) rate was 91.7% in the radiation therapy group and 96.9% in the chemoradiation and adjuvant chemotherapy group (P =.66).
Evidence (combination chemotherapy plus radiation therapy vs. radiation therapy alone):
Three randomized prospective trials compared combination chemotherapy (i.e., cisplatin, epirubicin, and bleomycin or cisplatin plus fluorouracil [5-FU] infusion) plus radiation therapy with radiation therapy alone.[17][Level of evidence A1]; [35,36][Level of evidence B1]
Although DFS was improved in the chemotherapy group, for both groups, improvement in OS was reported only from the Intergroup trial in which chemotherapy with cisplatin was given concurrently with radiation therapy.[17]
Evidence (chemoradiation therapy using carboplatin vs. cisplatin):
A study of 1,355 patients compared radiation therapy given concurrently with carboplatin or cisplatin that was administered with a 96-hour infusion of 5-FU monthly for three cycles.[37][Level of evidence A1]
The 3-year DFS rate was 63.4% for patients in the cisplatin arm and 60.9% for patients in the carboplatin arm (HR, 0.70; 95% CI, 0.50–0.98; P = .961).
OS rates were 77% for patients in the cisplatin arm and 79% for patients in the carboplatin arm (HR, 0.83; 95% CI, 0.63–1.010; P = .988).
Toxicity to kidneys and red blood cell count was greater in patients in the cisplatin group.
Surgery
Neck dissection may be indicated for patients with persistent or recurrent lymph nodes if the primary tumor site is controlled.[10]
Chemotherapy
Clinical trials for patients with advanced tumors to evaluate the use of chemotherapy before radiation therapy, concurrent with radiation therapy, or as adjuvant therapy after radiation therapy should be considered.[38–41]
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
Wang Q, Xu G, Xia Y, et al.: Comparison of induction chemotherapy plus concurrent chemoradiotherapy and induction chemotherapy plus radiotherapy in locally advanced nasopharyngeal carcinoma. Oral Oncol 111: 104925, 2020. [PUBMED Abstract]
Baujat B, Audry H, Bourhis J, et al.: Chemotherapy in locally advanced nasopharyngeal carcinoma: an individual patient data meta-analysis of eight randomized trials and 1753 patients. Int J Radiat Oncol Biol Phys 64 (1): 47-56, 2006. [PUBMED Abstract]
Xiao WW, Han F, Lu TX, et al.: Treatment outcomes after radiotherapy alone for patients with early-stage nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 74 (4): 1070-6, 2009. [PUBMED Abstract]
Johnson CR, Schmidt-Ullrich RK, Wazer DE: Concomitant boost technique using accelerated superfractionated radiation therapy for advanced squamous cell carcinoma of the head and neck. Cancer 69 (11): 2749-54, 1992. [PUBMED Abstract]
Chen CY, Han F, Zhao C, et al.: Treatment results and late complications of 556 patients with locally advanced nasopharyngeal carcinoma treated with radiotherapy alone. Br J Radiol 82 (978): 452-8, 2009. [PUBMED Abstract]
Perez CA, Devineni VR, Marcial-Vega V, et al.: Carcinoma of the nasopharynx: factors affecting prognosis. Int J Radiat Oncol Biol Phys 23 (2): 271-80, 1992. [PUBMED Abstract]
Lee AW, Law SC, Foo W, et al.: Nasopharyngeal carcinoma: local control by megavoltage irradiation. Br J Radiol 66 (786): 528-36, 1993. [PUBMED Abstract]
Geara FB, Sanguineti G, Tucker SL, et al.: Carcinoma of the nasopharynx treated by radiotherapy alone: determinants of distant metastasis and survival. Radiother Oncol 43 (1): 53-61, 1997. [PUBMED Abstract]
Sanguineti G, Geara FB, Garden AS, et al.: Carcinoma of the nasopharynx treated by radiotherapy alone: determinants of local and regional control. Int J Radiat Oncol Biol Phys 37 (5): 985-96, 1997. [PUBMED Abstract]
Mendenhall WM, Werning JW, Pfister DG: Treatment of head and neck cancer. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Lippincott Williams & Wilkins, 2011, pp 729-80.
Itami J, Anzai Y, Nemoto K, et al.: Prognostic factors for local control in nasopharyngeal cancer (NPC): analysis by multivariate proportional hazard models. Radiother Oncol 21 (4): 233-9, 1991. [PUBMED Abstract]
Levendag PC, Schmitz PI, Jansen PP, et al.: Fractionated high-dose-rate brachytherapy in primary carcinoma of the nasopharynx. J Clin Oncol 16 (6): 2213-20, 1998. [PUBMED Abstract]
Teo PM, Leung SF, Lee WY, et al.: Intracavitary brachytherapy significantly enhances local control of early T-stage nasopharyngeal carcinoma: the existence of a dose-tumor-control relationship above conventional tumoricidal dose. Int J Radiat Oncol Biol Phys 46 (2): 445-58, 2000. [PUBMED Abstract]
Le QT, Tate D, Koong A, et al.: Improved local control with stereotactic radiosurgical boost in patients with nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 56 (4): 1046-54, 2003. [PUBMED Abstract]
Tang LL, Guo R, Zhang N, et al.: Effect of Radiotherapy Alone vs Radiotherapy With Concurrent Chemoradiotherapy on Survival Without Disease Relapse in Patients With Low-risk Nasopharyngeal Carcinoma: A Randomized Clinical Trial. JAMA 328 (8): 728-736, 2022. [PUBMED Abstract]
Cheng SH, Tsai SY, Yen KL, et al.: Concomitant radiotherapy and chemotherapy for early-stage nasopharyngeal carcinoma. J Clin Oncol 18 (10): 2040-5, 2000. [PUBMED Abstract]
Al-Sarraf M, LeBlanc M, Giri PG, et al.: Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized Intergroup study 0099. J Clin Oncol 16 (4): 1310-7, 1998. [PUBMED Abstract]
Teo PM, Chan AT, Lee WY, et al.: Enhancement of local control in locally advanced node-positive nasopharyngeal carcinoma by adjunctive chemotherapy. Int J Radiat Oncol Biol Phys 43 (2): 261-71, 1999. [PUBMED Abstract]
Chan AT, Teo PM, Ngan RK, et al.: Concurrent chemotherapy-radiotherapy compared with radiotherapy alone in locoregionally advanced nasopharyngeal carcinoma: progression-free survival analysis of a phase III randomized trial. J Clin Oncol 20 (8): 2038-44, 2002. [PUBMED Abstract]
Huncharek M, Kupelnick B: Combined chemoradiation versus radiation therapy alone in locally advanced nasopharyngeal carcinoma: results of a meta-analysis of 1,528 patients from six randomized trials. Am J Clin Oncol 25 (3): 219-23, 2002. [PUBMED Abstract]
Lin JC, Jan JS, Hsu CY, et al.: Phase III study of concurrent chemoradiotherapy versus radiotherapy alone for advanced nasopharyngeal carcinoma: positive effect on overall and progression-free survival. J Clin Oncol 21 (4): 631-7, 2003. [PUBMED Abstract]
Chua DT, Ma J, Sham JS, et al.: Long-term survival after cisplatin-based induction chemotherapy and radiotherapy for nasopharyngeal carcinoma: a pooled data analysis of two phase III trials. J Clin Oncol 23 (6): 1118-24, 2005. [PUBMED Abstract]
Wee J, Tan EH, Tai BC, et al.: Randomized trial of radiotherapy versus concurrent chemoradiotherapy followed by adjuvant chemotherapy in patients with American Joint Committee on Cancer/International Union against cancer stage III and IV nasopharyngeal cancer of the endemic variety. J Clin Oncol 23 (27): 6730-8, 2005. [PUBMED Abstract]
Zhang L, Zhao C, Peng PJ, et al.: Phase III study comparing standard radiotherapy with or without weekly oxaliplatin in treatment of locoregionally advanced nasopharyngeal carcinoma: preliminary results. J Clin Oncol 23 (33): 8461-8, 2005. [PUBMED Abstract]
Baujat B, Audry H, Bourhis J, et al.: Chemotherapy as an adjunct to radiotherapy in locally advanced nasopharyngeal carcinoma. Cochrane Database Syst Rev (4): CD004329, 2006. [PUBMED Abstract]
Chen Y, Liu MZ, Liang SB, et al.: Preliminary results of a prospective randomized trial comparing concurrent chemoradiotherapy plus adjuvant chemotherapy with radiotherapy alone in patients with locoregionally advanced nasopharyngeal carcinoma in endemic regions of china. Int J Radiat Oncol Biol Phys 71 (5): 1356-64, 2008. [PUBMED Abstract]
Lee AW, Tung SY, Chua DT, et al.: Randomized trial of radiotherapy plus concurrent-adjuvant chemotherapy vs radiotherapy alone for regionally advanced nasopharyngeal carcinoma. J Natl Cancer Inst 102 (15): 1188-98, 2010. [PUBMED Abstract]
Lee AW, Tung SY, Chan AT, et al.: A randomized trial on addition of concurrent-adjuvant chemotherapy and/or accelerated fractionation for locally-advanced nasopharyngeal carcinoma. Radiother Oncol 98 (1): 15-22, 2011. [PUBMED Abstract]
Lee AW, Tung SY, Ngan RK, et al.: Factors contributing to the efficacy of concurrent-adjuvant chemotherapy for locoregionally advanced nasopharyngeal carcinoma: combined analyses of NPC-9901 and NPC-9902 Trials. Eur J Cancer 47 (5): 656-66, 2011. [PUBMED Abstract]
Zhang Y, Chen L, Hu GQ, et al.: Gemcitabine and Cisplatin Induction Chemotherapy in Nasopharyngeal Carcinoma. N Engl J Med 381 (12): 1124-1135, 2019. [PUBMED Abstract]
Blanchard P, Lee AWM, Carmel A, et al.: Meta-analysis of chemotherapy in nasopharynx carcinoma (MAC-NPC): An update on 26 trials and 7080 patients. Clin Transl Radiat Oncol 32: 59-68, 2022. [PUBMED Abstract]
Zhang Y, Chen L, Hu GQ, et al.: Final Overall Survival Analysis of Gemcitabine and Cisplatin Induction Chemotherapy in Nasopharyngeal Carcinoma: A Multicenter, Randomized Phase III Trial. J Clin Oncol 40 (22): 2420-2425, 2022. [PUBMED Abstract]
Sun Y, Li WF, Chen NY, et al.: Induction chemotherapy plus concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in locoregionally advanced nasopharyngeal carcinoma: a phase 3, multicentre, randomised controlled trial. Lancet Oncol 17 (11): 1509-1520, 2016. [PUBMED Abstract]
Yang Q, Cao SM, Guo L, et al.: Induction chemotherapy followed by concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in locoregionally advanced nasopharyngeal carcinoma: long-term results of a phase III multicentre randomised controlled trial. Eur J Cancer 119: 87-96, 2019. [PUBMED Abstract]
Preliminary results of a randomized trial comparing neoadjuvant chemotherapy (cisplatin, epirubicin, bleomycin) plus radiotherapy vs. radiotherapy alone in stage IV(> or = N2, M0) undifferentiated nasopharyngeal carcinoma: a positive effect on progression-free survival. International Nasopharynx Cancer Study Group. VUMCA I trial. Int J Radiat Oncol Biol Phys 35 (3): 463-9, 1996. [PUBMED Abstract]
Lee AW, Lau WH, Tung SY, et al.: Preliminary results of a randomized study on therapeutic gain by concurrent chemotherapy for regionally-advanced nasopharyngeal carcinoma: NPC-9901 Trial by the Hong Kong Nasopharyngeal Cancer Study Group. J Clin Oncol 23 (28): 6966-75, 2005. [PUBMED Abstract]
Chitapanarux I, Lorvidhaya V, Kamnerdsupaphon P, et al.: Chemoradiation comparing cisplatin versus carboplatin in locally advanced nasopharyngeal cancer: randomised, non-inferiority, open trial. Eur J Cancer 43 (9): 1399-406, 2007. [PUBMED Abstract]
Dimery IW, Peters LJ, Goepfert H, et al.: Effectiveness of combined induction chemotherapy and radiotherapy in advanced nasopharyngeal carcinoma. J Clin Oncol 11 (10): 1919-28, 1993. [PUBMED Abstract]
Chan AT, Teo PM, Leung TW, et al.: A prospective randomized study of chemotherapy adjunctive to definitive radiotherapy in advanced nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 33 (3): 569-77, 1995. [PUBMED Abstract]
Merlano M, Benasso M, Corvò R, et al.: Five-year update of a randomized trial of alternating radiotherapy and chemotherapy compared with radiotherapy alone in treatment of unresectable squamous cell carcinoma of the head and neck. J Natl Cancer Inst 88 (9): 583-9, 1996. [PUBMED Abstract]
Jeremic B, Shibamoto Y, Milicic B, et al.: Hyperfractionated radiation therapy with or without concurrent low-dose daily cisplatin in locally advanced squamous cell carcinoma of the head and neck: a prospective randomized trial. J Clin Oncol 18 (7): 1458-64, 2000. [PUBMED Abstract]
Treatment of Metastatic and Recurrent Nasopharyngeal Carcinoma
Treatment Options for Metastatic and Recurrent Nasopharyngeal Carcinoma
Treatment options for metastatic and recurrent nasopharyngeal carcinoma include:
High-dose radiation therapy with chemotherapy is the initial treatment of patients with nasopharyngeal carcinoma for the primary tumor site and the neck.[1] Selected patients with local recurrence may be retreated with moderate-dose external-beam radiation therapy (EBRT) using intensity-modulated radiation therapy, stereotactic radiation therapy, or intracavitary or interstitial radiation to the site of recurrence.[2–4]; [5][Level of evidence C2]; [6–9][Level of evidence C3] Radiation therapy dose and field margins are individually tailored to the location and size of the primary tumor and lymph nodes.[10–13]
Most tumors are treated with EBRT exclusively. For some patients, radiation therapy may be boosted with intracavitary or interstitial implants or by the use of stereotactic radiosurgery when clinical expertise is available and the anatomy is suitable.[2,14–17]
Surgery
In highly selected patients, surgical resection of locally recurrent lesions may be considered.
Chemotherapy/Immunotherapy
If a patient has metastatic disease or local recurrence that is no longer amenable to surgery or radiation therapy, chemotherapy or immunotherapy may be considered.[18–20]
Evidence (chemotherapy/immunotherapy):
The international, multicenter, randomized, double-blind, phase III JUPITOR-02 study (NCT03581786) was conducted in nasopharyngeal carcinoma–endemic regions, including mainland China, Taiwan, and Singapore. The trial randomly assigned 289 patients to receive either toripalimab, a humanized IgG4K monoclonal antibody against human programmed death 1 (PD-1), (240 mg/m2) or placebo in combination with gemcitabine and cisplatin for up to six cycles. Patients also received maintenance therapy with toripalimab or placebo until disease progression, intolerable toxicity, or completion of 2 years of treatment. The primary end point was progression-free survival (PFS) as assessed by a blinded independent central review. Secondary end points included objective response rate, overall survival (OS), PFS as assessed by an investigator, duration of response, and safety. The median survival follow-up was 36 months.[21]
The median OS was not reached in the toripalimab group (95% confidence interval [CI], 38.7 months–not estimable) and was 33.7 months (95% CI, 27.0–44.2) in the placebo group (hazard ratio [HR], 0.63; 95% CI, 0.45–0.89; P = .0083).[21][Level of evidence A1]
PFS was significantly longer in the toripalimab arm compared with the placebo arm, with a median PFS of 21.4 months in the toripalimab group versus 8.2 months in the placebo group (HR, 0.52; 95% CI, 0.37–0.73).
Grade 3 or higher immune-related adverse events occurred in 9.6% of patients in the toripalimab group. Treatment discontinuation occurred in 11.6% of patients in the toripalimab group and 4.9% of patients in the placebo group.
A multicenter, randomized, open-label, phase III trial included patients with recurrent or metastatic nasopharyngeal carcinoma recruited from 22 hospitals in China. Patients were randomly assigned in a 1:1 ratio to receive either gemcitabine (1 g/m2 intravenously [IV] on days 1 and 8) and cisplatin (80 mg/m2 IV on day 1), or fluorouracil ([5-FU] 4 g/m2 in continuous IV infusion over 96 h) and cisplatin (80 mg/m2 IV on day 1) once every 3 weeks for a maximum of six cycles.[22] Of the 362 patients, 181 were assigned to the gemcitabine-plus-cisplatin group and 181 to the 5-FU-plus-cisplatin group.
The median follow-up time for PFS was 19.4 months (interquartile range [IQR], 12.1–35.6). The median PFS was 7.0 months (range, 4.4–10.9) in the gemcitabine group and 5.6 months (range, 3.0–7.0) in the 5-FU group (HR, 0.55; 95% CI, 0.44–0.68; P < .0001).[22][Level of evidence B1]
There were significant differences in the incidences of the following grade 3 or 4 treatment-related adverse events:
Leukopenia (52 [29%] in the gemcitabine group vs.15 [9%] in the 5-FU group; P < .0001).
Neutropenia (41 [23%] in the gemcitabine group vs. 23 [13%] in the 5-FU group; P = .0251).
Thrombocytopenia (24 [13%] in the gemcitabine group vs. 3 [2%] in the 5-FU group; P = .0007).
Mucosal inflammation (0 in the gemcitabine group vs. 25 [14%] in the 5-FU group; P < .0001).
Serious treatment-related adverse events occurred in seven patients (4%) in the gemcitabine group and ten patients (6%) in the 5-FU group.
Six patients (3%) in the gemcitabine group and 14 patients (8%) in the 5-FU group discontinued treatment because of drug-related adverse events.
No treatment-related deaths occurred in either group.
POLARIS-02 (NCT02915432) was a phase II, open-label, multicenter, single-arm trial in China that enrolled 190 patients with recurrent or metastatic nasopharyngeal carcinoma. Patients received toripalimab (3 mg/kg) once every 2 weeks until disease progression or unacceptable toxicity. Patients had received prior platinum-based chemotherapy or had disease progression within 6 months of completion of platinum-based chemotherapy given as neoadjuvant, adjuvant, or definitive chemoradiation therapy for locally advanced disease. The primary end point was objective response rate. The secondary end points included safety, duration of response, PFS, and OS.[23]
The objective response rate was 20.5%, with a median duration of response of 12.8 months, a median PFS of 1.9 months, and a median OS of 17.4 months.[23][Level of evidence C3]
The U.S. Food and Drug Administration has approved toripalimab with cisplatin and gemcitabine as first-line treatment for patients with metastatic or recurrent locally advanced nasopharyngeal carcinoma. It is also approved as a single agent for adults with recurrent unresectable or metastatic nasopharyngeal carcinoma with disease progression during or after platinum-containing 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
Baujat B, Audry H, Bourhis J, et al.: Chemotherapy in locally advanced nasopharyngeal carcinoma: an individual patient data meta-analysis of eight randomized trials and 1753 patients. Int J Radiat Oncol Biol Phys 64 (1): 47-56, 2006. [PUBMED Abstract]
Mendenhall WM, Werning JW, Pfister DG: Treatment of head and neck cancer. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Lippincott Williams & Wilkins, 2011, pp 729-80.
Vikram B, Strong EW, Shah JP, et al.: Intraoperative radiotherapy in patients with recurrent head and neck cancer. Am J Surg 150 (4): 485-7, 1985. [PUBMED Abstract]
Koutcher L, Lee N, Zelefsky M, et al.: Reirradiation of locally recurrent nasopharynx cancer with external beam radiotherapy with or without brachytherapy. Int J Radiat Oncol Biol Phys 76 (1): 130-7, 2010. [PUBMED Abstract]
Lu JJ, Shakespeare TP, Tan LK, et al.: Adjuvant fractionated high-dose-rate intracavitary brachytherapy after external beam radiotherapy in Tl and T2 nasopharyngeal carcinoma. Head Neck 26 (5): 389-95, 2004. [PUBMED Abstract]
Tate DJ, Adler JR, Chang SD, et al.: Stereotactic radiosurgical boost following radiotherapy in primary nasopharyngeal carcinoma: impact on local control. Int J Radiat Oncol Biol Phys 45 (4): 915-21, 1999. [PUBMED Abstract]
Chua DT, Sham JS, Kwong PW, et al.: Linear accelerator-based stereotactic radiosurgery for limited, locally persistent, and recurrent nasopharyngeal carcinoma: efficacy and complications. Int J Radiat Oncol Biol Phys 56 (1): 177-83, 2003. [PUBMED Abstract]
Pai PC, Chuang CC, Wei KC, et al.: Stereotactic radiosurgery for locally recurrent nasopharyngeal carcinoma. Head Neck 24 (8): 748-53, 2002. [PUBMED Abstract]
Xiao J, Xu G, Miao Y: Fractionated stereotactic radiosurgery for 50 patients with recurrent or residual nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 51 (1): 164-70, 2001. [PUBMED Abstract]
Perez CA, Devineni VR, Marcial-Vega V, et al.: Carcinoma of the nasopharynx: factors affecting prognosis. Int J Radiat Oncol Biol Phys 23 (2): 271-80, 1992. [PUBMED Abstract]
Lee AW, Law SC, Foo W, et al.: Nasopharyngeal carcinoma: local control by megavoltage irradiation. Br J Radiol 66 (786): 528-36, 1993. [PUBMED Abstract]
Geara FB, Sanguineti G, Tucker SL, et al.: Carcinoma of the nasopharynx treated by radiotherapy alone: determinants of distant metastasis and survival. Radiother Oncol 43 (1): 53-61, 1997. [PUBMED Abstract]
Sanguineti G, Geara FB, Garden AS, et al.: Carcinoma of the nasopharynx treated by radiotherapy alone: determinants of local and regional control. Int J Radiat Oncol Biol Phys 37 (5): 985-96, 1997. [PUBMED Abstract]
Itami J, Anzai Y, Nemoto K, et al.: Prognostic factors for local control in nasopharyngeal cancer (NPC): analysis by multivariate proportional hazard models. Radiother Oncol 21 (4): 233-9, 1991. [PUBMED Abstract]
Levendag PC, Schmitz PI, Jansen PP, et al.: Fractionated high-dose-rate brachytherapy in primary carcinoma of the nasopharynx. J Clin Oncol 16 (6): 2213-20, 1998. [PUBMED Abstract]
Teo PM, Leung SF, Lee WY, et al.: Intracavitary brachytherapy significantly enhances local control of early T-stage nasopharyngeal carcinoma: the existence of a dose-tumor-control relationship above conventional tumoricidal dose. Int J Radiat Oncol Biol Phys 46 (2): 445-58, 2000. [PUBMED Abstract]
Le QT, Tate D, Koong A, et al.: Improved local control with stereotactic radiosurgical boost in patients with nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 56 (4): 1046-54, 2003. [PUBMED Abstract]
Al-Sarraf M: Head and neck cancer: chemotherapy concepts. Semin Oncol 15 (1): 70-85, 1988. [PUBMED Abstract]
Jacobs C, Lyman G, Velez-García E, et al.: A phase III randomized study comparing cisplatin and fluorouracil as single agents and in combination for advanced squamous cell carcinoma of the head and neck. J Clin Oncol 10 (2): 257-63, 1992. [PUBMED Abstract]
Foo KF, Tan EH, Leong SS, et al.: Gemcitabine in metastatic nasopharyngeal carcinoma of the undifferentiated type. Ann Oncol 13 (1): 150-6, 2002. [PUBMED Abstract]
Mai HQ, Chen QY, Chen D, et al.: Toripalimab Plus Chemotherapy for Recurrent or Metastatic Nasopharyngeal Carcinoma: The JUPITER-02 Randomized Clinical Trial. JAMA 330 (20): 1961-1970, 2023. [PUBMED Abstract]
Zhang L, Huang Y, Hong S, et al.: Gemcitabine plus cisplatin versus fluorouracil plus cisplatin in recurrent or metastatic nasopharyngeal carcinoma: a multicentre, randomised, open-label, phase 3 trial. Lancet 388 (10054): 1883-1892, 2016. [PUBMED Abstract]
Wang FH, Wei XL, Feng J, et al.: Efficacy, Safety, and Correlative Biomarkers of Toripalimab in Previously Treated Recurrent or Metastatic Nasopharyngeal Carcinoma: A Phase II Clinical Trial (POLARIS-02). J Clin Oncol 39 (7): 704-712, 2021. [PUBMED Abstract]
Latest Updates to This Summary (05/14/2025)
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Editorial changes were made to this summary.
This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.
About This PDQ Summary
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of adult nasopharyngeal carcinoma. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
be discussed at a meeting,
be cited with text, or
replace or update an existing article that is already cited.
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Nasopharyngeal Carcinoma Treatment are:
Andrea Bonetti, MD (Pederzoli Hospital)
Minh Tam Truong, MD (Boston University Medical Center)
Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website’s Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.
Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
Permission to Use This Summary
PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”
The preferred citation for this PDQ summary is:
PDQ® Adult Treatment Editorial Board. PDQ Nasopharyngeal Carcinoma Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/head-and-neck/hp/adult/nasopharyngeal-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389193]
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.
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Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.
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Cancerprevention is action taken to lower the chance of getting cancer. By preventing cancer, the number of new cases of cancer in a group or population is lowered. Hopefully, this will lower the number of deaths caused by cancer.
To prevent new cancers from starting, scientists look at risk factors and protective factors. Anything that increases your chance of developing cancer is called a cancer risk factor; anything that decreases your chance of developing cancer is called a cancer protective factor.
Some risk factors for cancer can be avoided, but many cannot. For example, both smoking and inheriting certain genes are risk factors for some types of cancer, but only smoking can be avoided. Regular exercise and a healthy diet may be protective factors for some types of cancer. Avoiding risk factors and increasing protective factors may lower your risk but it does not mean that you will not get cancer.
Different ways to prevent cancer are being studied, including:
Oral cavity cancer forms in any of these tissues of the oral cavity:
The lips.
The front two thirds of the tongue.
The gingiva (gums).
The buccal mucosa (the lining of the inside of the cheeks).
The floor (bottom) of the mouth under the tongue.
The hard palate (the front, bony part of the roof of the mouth).
The retromolar trigone (the small area behind the wisdom teeth).
EnlargeAnatomy of the oral cavity. The oral cavity includes the lips, hard palate (the bony front portion of the roof of the mouth), soft palate (the muscular back portion of the roof of the mouth), retromolar trigone (the area behind the wisdom teeth), front two-thirds of the tongue, gingiva (gums), buccal mucosa (the inner lining of the lips and cheeks), and floor of the mouth under the tongue.
Pharyngeal cancer forms in any of these tissues of the pharynx (throat):
The nasopharynx (the upper part of the throat behind the nose).
The oropharynx, which includes the following tissues:
The middle part of the throat behind the mouth.
The back one third of the tongue.
The soft palate (the back of the roof of the mouth), including the uvula.
EnlargeAnatomy of the pharynx. The pharynx is a hollow, muscular tube inside the neck that starts behind the nose and opens into the larynx and esophagus. The three parts of the pharynx are the nasopharynx, oropharynx, and hypopharynx.
Laryngeal cancer forms in any of these tissues of the larynx (voice box):
The supraglottis (the area above the vocal cords, including the epiglottis).
The vocal cords (two small bands of muscle within the larynx that vibrate to produce the voice).
The glottis (the middle part of the larynx, including the vocal cords).
The subglottis (the lowest part of the larynx, from just below the vocal cords to the top of the trachea).
EnlargeAnatomy of the larynx. The three parts of the larynx are the supraglottis (including the epiglottis), the glottis (including the vocal cords), and the subglottis.
Oral cavity cancer and oropharyngeal cancer: Men are more than twice as likely as women to have oral cavity cancer or oropharyngeal cancer and die from it.
Hypopharyngeal cancer: Hypopharyngeal cancer is rare. The number of new cases of hypopharyngeal cancer has slightly decreased over the past twenty years. The decrease in new cases is likely because of a decrease in cigarette smoking.
Nasopharyngeal cancer: Nasopharyngeal cancer is rare in the United States. It is more common in parts of Asia, the Arctic region, North Africa, and the Middle East.
Laryngeal cancer: Laryngeal cancer is less common than oral cavity and oropharyngeal cancers. The number of new cases of laryngeal cancer has slightly decreased over the past ten years. The decrease in new cases is likely because of a decrease in cigarette smoking.
Oral Cavity, Oropharyngeal, Hypopharyngeal, and Laryngeal Cancers Prevention
Key Points
Avoiding risk factors and increasing protective factors may help prevent cancer.
The following are risk factors for oral cavity, oropharyngeal, hypopharyngeal, and laryngeal cancers:
Tobacco use
Alcohol use
Tobacco and alcohol use
Betel quid chewing
Personal history of head and neck cancer
The following is a risk factor for oral cavity cancer and oropharyngeal cancer:
Human papillomavirus (HPV) infection
The following is a protective factor for oral cavity, oropharyngeal, hypopharyngeal, and laryngeal cancers:
Quitting smoking
It is not clear whether avoiding certain risk factors will decrease the risk of oral cavity, oropharyngeal, hypopharyngeal, and laryngeal cancers.
Cancer prevention clinical trials are used to study ways to prevent cancer.
New ways to prevent oral cavity, oropharyngeal, hypopharyngeal, and laryngeal cancers are being studied in clinical trials.
Avoiding risk factors and increasing protective factors may help prevent cancer.
Avoiding cancerrisk factors may help prevent certain cancers. Risk factors include smoking, having overweight, and not getting enough exercise. Increasing protective factors such as quitting smoking and exercising may also help prevent some cancers. Talk to your doctor or other health care professional about how you might lower your risk of cancer.
The following are risk factors for oral cavity, oropharyngeal, hypopharyngeal, and laryngeal cancers:
Tobacco use
Using tobacco is the most common cause of oral cavity, oropharyngeal, hypopharyngeal, and laryngeal cancers. The risk of these cancers is about 5 to 10 times higher for current smokers than for people who have never smoked, and is linked to how much and how long the person has smoked.
Using alcohol is also an important risk factor for oral cavity, oropharyngeal, hypopharyngeal, and laryngeal cancers.
The risk of oral cavity, oropharyngeal, hypopharyngeal, and laryngeal cancers increases with the number of alcoholic drinks consumed per day. The risk of these cancers is 2 to 6 times higher in people who have 2 or more alcoholic drinks per day compared with those who don’t drink alcohol.
Tobacco and alcohol use
The risk of oral cavity, oropharyngeal, hypopharyngeal, and laryngeal cancers is higher in people who use both tobacco and alcohol than it is in people who use only tobacco or only alcohol. The risk of oral cavity cancer and oropharyngeal cancer is about 5 to 14 times higher in people who both smoke and drink heavily than it is in people who never smoke cigarettes or consume alcohol.
Betel quid chewing
Chewing betel quid alone or with added tobacco has been shown to increase the risk of oral cavity, oropharyngeal, hypopharyngeal, and laryngeal cancers. Betel quid contains areca nut, which is a cancer-causing substance. The risk of these cancers increases with how long and how often betel quid is chewed. The risk is higher when chewing betel quid with tobacco than when chewing betel quid alone. Betel quid chewing is common in many countries in South Asia and Southeast Asia, including China and India.
Personal history of head and neck cancer
A personal history of head and neck cancer increases the risk of oral cavity, oropharyngeal, hypopharyngeal, and laryngeal cancers.
The following is a risk factor for oral cavity cancer and oropharyngeal cancer:
Human papillomavirus (HPV) infection
Being infected with certain types of human papillomavirus (HPV), especially HPV-16, increases the risk of oropharyngeal cancers. HPV infection may also increase the risk of some oral cavity cancers. HPV infection is spread mainly through sexual contact.
The risk of oropharyngeal cancer is about 15 times higher in people who have oral HPV-16 infection compared with people who do not have oral HPV-16 infection.
The following is a protective factor for oral cavity, oropharyngeal, hypopharyngeal, and laryngeal cancers:
Quitting smoking
Studies have shown that when people stop smoking cigarettes, their risk of oral cavity, oropharyngeal, hypopharyngeal, and laryngeal cancers decreases by one half (50%) within 5 to 9 years. Within 20 years of quitting, their risk of these cancers is the same as for a person who never smoked cigarettes.
It is not clear whether avoiding certain risk factors will decrease the risk of oral cavity, oropharyngeal, hypopharyngeal, and laryngeal cancers.
Some studies show that when people stop drinking alcohol, their risk of oral cavity and laryngeal cancers decreases within about 20 years.
Getting an HPV vaccination greatly lessens the risk of oral HPV infection. It is not yet known whether getting an HPV vaccination at any age will decrease the risk of oropharyngeal cancer from HPV infection. For information about the use of HPV vaccination to prevent cervical cancer, see Cervical Cancer Causes, Risk Factors, and Prevention.
Cancer prevention clinical trials are used to study ways to prevent cancer.
Cancer preventionclinical trials are used to study ways to lower the risk of certain types of cancer. Some cancer prevention trials are done with healthy people who have not had cancer but who have an increased risk for cancer. Other prevention trials are done with people who have had cancer and are trying to prevent another cancer of the same type or to lower their chance of developing a new type of cancer. Other trials are done with healthy volunteers who are not known to have any risk factors for cancer.
The purpose of some cancer prevention clinical trials is to find out whether actions people take can prevent cancer. These may include eating fruits and vegetables, exercising, quitting smoking, or taking certain medicines, vitamins, minerals, or food supplements.
New ways to prevent oral cavity, oropharyngeal, hypopharyngeal, and laryngeal cancers are being studied in clinical trials.
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 oral cavity, oropharyngeal, hypopharyngeal, and laryngeal cancers prevention. 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 Screening and Prevention 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® Screening and Prevention Editorial Board. PDQ Oral Cavity, Oropharyngeal, Hypopharyngeal, and Laryngeal Cancers Prevention. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/head-and-neck/patient/oral-prevention-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389257]
Images in this summary are used with permission of the author(s), artist, and/or publisher for use in the PDQ summaries only. If you want to use an image from a PDQ summary and you are not using the whole summary, you must get permission from the owner. It cannot be given by the National Cancer Institute. Information about using the images in this summary, along with many other images related to cancer can be found in Visuals Online. Visuals Online is a collection of more than 3,000 scientific images.
Disclaimer
The information in these summaries should not be used to make decisions about insurance reimbursement. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.
Contact Us
More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website’s E-mail Us.
The oral cavity extends from the skin-vermilion junctions of the anterior lips to the junction of the hard and soft palates above and to the line of circumvallate papillae below and is divided into the following specific areas:
Lip.
Anterior two thirds of tongue.
Buccal mucosa.
Floor of mouth.
Lower gingiva.
Retromolar trigone.
Upper gingiva.
Hard palate.
Histopathology
The main routes of lymph node drainage are into the first station nodes (i.e., buccinator, jugulodigastric, submandibular, and submental). Sites close to the midline often drain bilaterally. Second station nodes include the parotid, jugular, and the upper and lower posterior cervical nodes.
Precancerous lesions of the oropharynx include leukoplakia, erythroplakia, and mixed erythroleukoplakia.[1] Leukoplakia, the most common of the three conditions, is defined by the World Health Organization as “a white patch or plaque that cannot be characterized clinically or pathologically as any other disease.”[2] The diagnosis of leukoplakia is one of exclusion; conditions such as candidiasis, lichen planus, leukoedema, and others must be ruled out before a diagnosis of leukoplakia can be made.[1]
The prevalence of leukoplakia in the United States is decreasing as a result of reduced tobacco consumption.[3] Although erythroplakia is not as common as leukoplakia, it is much more likely to be associated with dysplasia or carcinoma.[1,4]
Prognostic Factors
Early cancers (stage I and stage II) of the lip and oral cavity are highly curable by surgery or radiation therapy. The choice of treatment is dictated by the anticipated functional and cosmetic results of treatment and by the availability of a surgeon or radiation oncologist with the required expertise.[5–7] A positive surgical margin or a tumor depth of more than 5 mm significantly increases the risk of local recurrence.[8,9] The risk of occult nodal metastases increases based on depth of invasion of the primary tumor. Depth of invasion holds prognostic significance and was included in tumor staging definitions in the American Joint Committee on Cancer (AJCC) 8th edition staging classification.[10,11] Extranodal extension in a lymph node is a significant adverse prognostic factor and was incorporated into the 8th edition AJCC staging system.[12,13]
Advanced cancers (stage III and stage IV) of the lip and oral cavity represent a wide spectrum of challenges for the surgeon and radiation oncologist. Most patients with stage III or stage IV tumors are candidates for treatment by a combination of surgery and radiation therapy. The exception is patients with small T3 lesions and no regional lymph node and no distant metastases or who have no lymph nodes larger than 2 cm in diameter, for whom treatment by radiation therapy alone or surgery alone might be appropriate.[6] Furthermore, because local recurrence and/or distant metastases are common in this group of patients, clinical trials can be considered. Such trials evaluate the potential role of radiation modifiers or combination chemotherapy combined with surgery and/or radiation therapy.
Survival
Patients with head and neck cancers have an increased chance of developing a second primary tumor of the upper aerodigestive tract.[14,15] A study has shown that daily treatment with moderate doses of isotretinoin for 1 year can significantly reduce the incidence of second tumors. However, no survival advantage has been demonstrated, in part due to recurrence and death from the primary malignancy. An additional trial showed no benefit of retinyl palmitate or retinyl palmitate plus beta-carotene when compared with isotretinoin alone.[16][Level of evidence B1]
The cure rates of cancers of the lip and oral cavity depend on the stage and specific site. Most patients present with early cancers of the lip, which are highly curable by surgery or by radiation therapy with cure rates of 90% to 100%. Small cancers of the retromolar trigone, hard palate, and upper gingiva are highly curable by either radiation therapy or surgery with survival rates of as high as 100%. Local control rates as high as 90% can be achieved with either radiation therapy or surgery in small cancers of the anterior tongue, the floor of the mouth, and buccal mucosa.[17]
Moderately advanced and advanced cancers of the lip also can be controlled effectively by surgery, radiation therapy, or both. The choice of treatment is generally dictated by the anticipated functional and cosmetic results of the treatment. Moderately advanced lesions of the retromolar trigone without evidence of spread to cervical lymph nodes are usually curable and have shown local control rates as high as 90%. Such lesions of the hard palate, upper gingiva, and buccal mucosa have a local control rate of up to 80%. In the absence of clinical evidence of spread to cervical lymph nodes, moderately advanced lesions of the floor of the mouth and anterior tongue are generally curable, with survival rates of as high as 70% and 65%, respectively.[17,18]
References
Neville BW, Day TA: Oral cancer and precancerous lesions. CA Cancer J Clin 52 (4): 195-215, 2002 Jul-Aug. [PUBMED Abstract]
Kramer IR, Lucas RB, Pindborg JJ, et al.: Definition of leukoplakia and related lesions: an aid to studies on oral precancer. Oral Surg Oral Med Oral Pathol 46 (4): 518-39, 1978. [PUBMED Abstract]
Scheifele C, Reichart PA, Dietrich T: Low prevalence of oral leukoplakia in a representative sample of the US population. Oral Oncol 39 (6): 619-25, 2003. [PUBMED Abstract]
Shafer WG, Waldron CA: Erythroplakia of the oral cavity. Cancer 36 (3): 1021-8, 1975. [PUBMED Abstract]
Cummings CW, Fredrickson JM, Harker LA, et al.: Otolaryngology – Head and Neck Surgery. Mosby-Year Book, Inc., 1998.
Harrison LB, Sessions RB, Hong WK, eds.: Head and Neck Cancer: A Multidisciplinary Approach. 3rd ed. Lippincott, William & Wilkins, 2009.
Wang CC, ed.: Radiation Therapy for Head and Neck Neoplasms. 3rd ed. Wiley-Liss, 1997.
Jones KR, Lodge-Rigal RD, Reddick RL, et al.: Prognostic factors in the recurrence of stage I and II squamous cell cancer of the oral cavity. Arch Otolaryngol Head Neck Surg 118 (5): 483-5, 1992. [PUBMED Abstract]
Po Wing Yuen A, Lam KY, Lam LK, et al.: Prognostic factors of clinically stage I and II oral tongue carcinoma-A comparative study of stage, thickness, shape, growth pattern, invasive front malignancy grading, Martinez-Gimeno score, and pathologic features. Head Neck 24 (6): 513-20, 2002. [PUBMED Abstract]
Sparano A, Weinstein G, Chalian A, et al.: Multivariate predictors of occult neck metastasis in early oral tongue cancer. Otolaryngol Head Neck Surg 131 (4): 472-6, 2004. [PUBMED Abstract]
D’Cruz AK, Vaish R, Kapre N, et al.: Elective versus Therapeutic Neck Dissection in Node-Negative Oral Cancer. N Engl J Med 373 (6): 521-9, 2015. [PUBMED Abstract]
Cooper JS, Pajak TF, Forastiere AA, et al.: Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med 350 (19): 1937-44, 2004. [PUBMED Abstract]
Bernier J, Cooper JS, Pajak TF, et al.: Defining risk levels in locally advanced head and neck cancers: a comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (# 9501). Head Neck 27 (10): 843-50, 2005. [PUBMED Abstract]
Day GL, Blot WJ: Second primary tumors in patients with oral cancer. Cancer 70 (1): 14-9, 1992. [PUBMED Abstract]
van der Tol IG, de Visscher JG, Jovanovic A, et al.: Risk of second primary cancer following treatment of squamous cell carcinoma of the lower lip. Oral Oncol 35 (6): 571-4, 1999. [PUBMED Abstract]
Papadimitrakopoulou VA, Lee JJ, William WN, et al.: Randomized trial of 13-cis retinoic acid compared with retinyl palmitate with or without beta-carotene in oral premalignancy. J Clin Oncol 27 (4): 599-604, 2009. [PUBMED Abstract]
Wallner PE, Hanks GE, Kramer S, et al.: Patterns of Care Study. Analysis of outcome survey data-anterior two-thirds of tongue and floor of mouth. Am J Clin Oncol 9 (1): 50-7, 1986. [PUBMED Abstract]
Takagi M, Kayano T, Yamamoto H, et al.: Causes of oral tongue cancer treatment failures. Analysis of autopsy cases. Cancer 69 (5): 1081-7, 1992. [PUBMED Abstract]
Cellular Classification of Lip and Oral Cavity Cancer
Most head and neck cancers are of squamous cell histology and may be preceded by various precancerous lesions. Minor salivary gland tumors are not uncommon in these sites. Specimens removed from the lesions may show the carcinomas to be noninvasive, in which case the term carcinoma in situ is applied. An invasive carcinoma will be well differentiated, moderately well differentiated, poorly differentiated, or undifferentiated.
Tumor grading is recommended using Broder classification (Tumor Grade [G]):
No statistically significant correlation between degree of differentiation and the biological behavior of the cancer exists; however, vascular invasion is a negative prognostic factor.[2]
Because leukoplakia, erythroplakia, and mixed erythroleukoplakia are exclusively clinical terms that have no specific histopathologic connotations,[3] the term leukoplakia should be used solely as a clinically descriptive term to mean that the observer sees a white patch that does not rub off, the significance of which depends on histological findings. Leukoplakia can range from hyperkeratosis to an early invasive carcinoma, or it may represent a fungal infection, lichen planus, or other benign oral disease.
References
Bansberg SF, Olsen KD, Gaffey TA: High-grade carcinoma of the oral cavity. Otolaryngol Head Neck Surg 100 (1): 41-8, 1989. [PUBMED Abstract]
Close LG, Brown PM, Vuitch MF, et al.: Microvascular invasion and survival in cancer of the oral cavity and oropharynx. Arch Otolaryngol Head Neck Surg 115 (11): 1304-9, 1989. [PUBMED Abstract]
Oral cavity and oropharynx. In: Rosai J, ed.: Rosai and Ackerman’s Surgical Pathology. Vol. 1. 10th ed. Mosby Elsevier, 2011, pp. 237-264.
Stage Information for Lip and Oral Cavity Cancer
The staging systems for lip and oral cavity cancer are all clinical staging and are based on the best possible estimate of the extent of disease before treatment. The assessment of the primary tumor is based on inspection and palpation when possible and by both indirect mirror examination and direct endoscopy when necessary. The tumor must be confirmed histologically, and any other pathological data obtained on biopsy may be included. The appropriate nodal drainage areas are examined by careful palpation. Information from diagnostic imaging studies may be used in staging. Magnetic resonance imaging offers an advantage over computed tomographic scans in the detection and localization of head and neck tumors and in the distinction of lymph nodes from blood vessels.[1] If a patient’s disease relapses, complete restaging must be done to select the appropriate additional therapy.[2,3]
American Joint Committee on Cancer (AJCC) Stage Groupings and TNM Definitions
The AJCC has designated staging by TNM (tumor, node, metastasis) classification to define lip and oral cavity cancer. The staging system reflects the whole oral cavity, which includes the mucosa of the lip but not the external (dry) lip.[4] The staging described below is used for patients who have not had a lymph node dissection of the neck.
Table 1. Definition of Primary Tumor (T)a
T Categoryb
T Criteria
DOI = depth of invasion.
aReprinted with permission from AJCC: Oral cavity. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 79–94.
bClinical and pathological DOI are now used in conjunction with size to determine the T category.
cDOI is depth of invasion and not tumor thickness.
dSuperficial erosion of bone/tooth socket (alone) by a gingival primary is not sufficient to classify a tumor as T4.
TX
Primary tumor cannot be assessed.
Tis
Carcinoma in situ.
T1
Tumor ≤2 cm with DOIc ≤5 mm.
T2
Tumor ≤2 cm with DOIc >5 mm or tumor >2 cm and ≤4 cm with DOIc ≤10 mm.
T3
Tumor >2 cm and ≤4 cm with DOIc >10 mm or tumor >4 cm with DOIc ≤10 mm.
T4
Moderately advanced or very advanced local disease.
–T4ad
Moderately advanced local disease. Tumor >4 cm with DOIc >10 mm or tumor invades adjacent structures only (e.g., through cortical bone of the mandible or maxilla or involves the maxillary sinus or skin of the face).
–T4b
Very advanced local disease. Tumor invades masticator space, pterygoid plates, or skull base and/or encases the internal carotid artery.
Table 2. Definition of Regional Lymph Nodes – Pathological (pN)a
N Category
N Criteria
ENE = extranodal extension.
aReprinted with permission from AJCC: Oral cavity. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 79–94.
Note: A designation of U or L may be used for any N category to indicate metastasis above the lower border of the cricoid (U) or below the lower border of the cricoid (L). Similarly, clinical and pathological ENE should be recorded as ENE(–) or ENE(+).
NX
Regional lymph nodes cannot be assessed.
N0
No regional lymph node metastasis.
N1
Metastasis in a single ipsilateral lymph node, ≤3 cm in greatest dimension and ENE(–).
N2
Metastasis in a single ipsilateral lymph node ≤3 cm in greatest dimension and ENE(+) ; or >3 cm but ≤6 cm in greatest dimension and ENE(–); or metastases in multiple ipsilateral lymph nodes, none >6 cm in greatest dimension and ENE(–); or in bilateral or contralateral lymph node(s), none >6 cm in greatest dimension, and ENE(–).
–N2a
Metastasis in a single ipsilateral node ≤3 cm in greatest dimension and ENE(+); or a single ipsilateral node >3 cm but ≤6 cm in greatest dimension and ENE(–).
–N2b
Metastases in multiple ipsilateral nodes, none >6 cm in greatest dimension, and ENE(–).
–N2c
Metastases in bilateral or contralateral lymph nodes, none >6 cm in greatest dimension, and ENE(–).
N3
Metastasis in a lymph node >6 cm in greatest dimension and ENE(–); or metastasis in a single ipsilateral node >3 cm in greatest dimension and ENE(+); or multiple ipsilateral, contralateral, or bilateral nodes, any with ENE(+); or a single contralateral node of any size and ENE(+).
–N3a
Metastasis in a lymph node >6 cm in greatest dimension and ENE(–).
–N3b
Metastasis in a single ipsilateral node >3 cm in greatest dimension and ENE(+); or multiple ipsilateral, contralateral, or bilateral nodes, any with ENE(+); or a single contralateral node of any size and ENE(+).
Table 3. Definition of Distant Metastasis (M)a
M Category
M Criteria
aReprinted with permission from AJCC: Oral cavity. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 79–94.
M0
No distant metastasis.
M1
Distant metastasis.
Table 4. Definition of TNM Stage 0a
Stage
TNM
Description
T = primary tumor; N = regional lymph node; M = metastasis.
aReprinted with permission from AJCC: Oral cavity. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 79–94.
0
Tis, N0, M0
Tis = Carcinoma in situ.
N0 = No regional lymph node metastasis.
M0 = No distant metastasis.
Table 5. Definition of TNM Stage Ia
Stage
TNM
Description
T = primary tumor; N = regional lymph node; M = metastasis; DOI = depth of invasion.
aReprinted with permission from AJCC: Oral cavity. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 79–94.
bDOI is depth of invasion and not tumor thickness.
I
T1, N0, M0
T1 = Tumor ≤2 cm with DOIb ≤5 mm.
N0 = No regional lymph node metastasis.
M0 = No distant metastasis.
Table 6. Definition of TNM Stage IIa
Stage
TNM
Description
T = primary tumor; N = regional lymph node; M = metastasis; DOI = depth of invasion.
aReprinted with permission from AJCC: Oral cavity. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 79–94.
bDOI is depth of invasion and not tumor thickness.
II
T2, N0, M0
T2 = Tumor ≤2 cm with DOIb >5 mm or tumor >2 cm and ≤4 cm with DOIb ≤10 mm.
N0 = No regional lymph node metastasis.
M0 = No distant metastasis.
Table 7. Definitions of TNM Stage IIIa
Stage
TNM
Description
T = primary tumor; N = regional lymph node; M = metastasis; DOI = depth of invasion; ENE = extranodal extension.
aReprinted with permission from AJCC: Oral cavity. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 79–94.
bDOI is depth of invasion and not tumor thickness.
III
T3, N0, M0
T3 = Tumor >2 cm and ≤4 cm with DOIb >10 mm or tumor >4 cm with DOIb ≤10 mm.
N1 = Metastasis in a single ipsilateral lymph node, ≤3 cm in greatest dimension and ENE(–).
M0 = No distant metastasis.
Table 8. Definitions of TNM Stage IVA, IVB, and IVCa
Stage
TNM
Description
T = primary tumor; N = regional lymph node; M = metastasis; DOI = depth of invasion; ENE = extranodal extension.
aReprinted with permission from AJCC: Oral cavity. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 79–94.
bSuperficial erosion of bone/tooth socket (alone) by a gingival primary is not sufficient to classify a tumor as T4.
cDOI is depth of invasion and not tumor thickness.
IVA
T4a, N0, N1, M0
T4ab = Moderately advanced local disease. Tumor >4 cm with DOIc >10 mm or tumor invades adjacent structures only (e.g., through cortical bone of the mandible or maxilla or involves the maxillary sinus or skin of the face).
N0 = No regional lymph node metastasis.
N1 = Metastasis in a single ipsilateral lymph node, ≤3 cm in greatest dimension and ENE(–).
N2 = Metastasis in a single ipsilateral lymph node ≤3 cm in greatest dimension and ENE(+); or >3 cm but ≤6 cm in greatest dimension and ENE(–); or metastases in multiple ipsilateral lymph nodes, none >6 cm in greatest dimension and ENE(–); or in bilateral or contralateral lymph nodes, none >6 cm in greatest dimension, and ENE(–).
N3 = Metastasis in a lymph node >6 cm in greatest dimension and ENE(–); or metastasis in a single ipsilateral node >3 cm in greatest dimension and ENE(+); or multiple ipsilateral, contralateral, or bilateral nodes, any with ENE(+); or in a single contralateral node of any size and ENE(+).
M0 = No distant metastasis.
T4b, Any N, M0
T4b = Very advanced local disease. Tumor invades masticator space, pterygoid plates, or skull base and/or encases the internal carotid artery.
Harrison LB, Sessions RB, Hong WK, eds.: Head and Neck Cancer: A Multidisciplinary Approach. 3rd ed. Lippincott, William & Wilkins, 2009.
Wang CC, ed.: Radiation Therapy for Head and Neck Neoplasms. 3rd ed. Wiley-Liss, 1997.
Oral cavity cancer. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. Springer; 2017, pp. 79–94.
Treatment Option Overview for Lip and Oral Cavity Cancer
The selection of treatment for lip and oral cavity cancer depends on the site and extent of the primary tumor and the status of the lymph nodes. Some options for treatment of this cancer include:[1–5]
Surgery alone.
Radiation therapy alone.
A combination of the surgery and radiation therapy.
For lesions of the oral cavity, surgery must adequately encompass all of the gross as well as the presumed microscopic extent of the disease. If regional nodes are positive, cervical node dissection is usually done in continuity. With modern approaches, the surgeon can successfully ablate large posterior oral cavity tumors and with reconstructive methods can achieve satisfactory functional results. Prosthodontic rehabilitation is important, particularly in early-stage cancers, to assure the best quality of life.
Radiation therapy for lip and oral cavity cancers can be given by external-beam radiation therapy (EBRT) or interstitial implantation alone, but for many sites the use of both modalities produces better control and functional results. Small superficial cancers can be very successfully treated by local implantation using any one of several radioactive sources, by intraoral cone radiation therapy, or by electrons. Larger lesions are frequently managed using EBRT to include the primary site and regional lymph nodes, even if they are not clinically involved. Supplementation with interstitial radiation sources may be necessary to achieve adequate doses to large primary tumors and/or bulky nodal metastases. A review of published clinical results of radical radiation therapy for head and neck cancer suggests a significant loss of local control with prolonged radiation therapy; therefore, lengthened standard treatment schedules should be avoided whenever possible.[6,7]
Early cancers (stage I and stage II) of the lip, floor of the mouth, and retromolar trigone are highly curable by surgery or radiation therapy. The choice of treatment is dictated by the anticipated functional and cosmetic results. Availability of a surgeon or radiation oncologist with the required expertise for the individual patient is also a factor in treatment choice.
Advanced cancers (stage III and stage IV) of the lip, floor of the mouth, and retromolar trigone represent a wide spectrum of challenges for the surgeon and radiation oncologists. Most patients with stage III or stage IV tumors are candidates for treatment with a combination of surgery and radiation therapy. The exceptions are patients with small T3 lesions and no regional lymph nodes, and no distant metastases or patients who have no lymph nodes larger than 2 cm in diameter, for whom treatment by radiation therapy alone or surgery alone might be appropriate. Because local recurrence and/or distant metastases are common in this group of patients, clinical trials that are evaluating the following should be considered:
The potential role of radiation modifiers to improve local control or decrease morbidity.
The role of combinations of chemotherapy with surgery and/or radiation therapy to improve local control and to decrease the frequency of distant metastases.
Early cancers of the buccal mucosa are equally curable by radiation therapy or adequate excision. Patient factors and local expertise influence the choice of treatment. Larger cancers require composite resection with reconstruction of the defect by pedicle flaps.
Early lesions (T1 and T2) of the anterior tongue may be managed by surgery or by radiation therapy alone. Both modalities produce 70% to 85% cure rates in patients with early lesions. Moderate excisions of tongue, even hemiglossectomy, can often result in little speech disability provided the wound closure is such that the tongue is not bound down. However, if the resection is more extensive, problems may include aspiration of liquids and solids, difficulty swallowing, and speech difficulties. Occasionally, patients with tumor of the tongue require almost total glossectomy. Large lesions generally require combined surgical and radiation treatment. The control rates for larger lesions are about 30% to 40%. According to clinical and radiological evidence of involvement, cancers of the lower gingiva that are exophytic and amenable to adequate local excision may be excised to include portions of bone. More advanced lesions require segmental bone resection, hemimandibulectomy, or maxillectomy, depending on the extent of the lesion and its location.
Early lesions of the upper gingiva or hard palate without bone involvement can be treated with equal effectiveness by surgery or radiation therapy alone. Advanced infiltrative and ulcerating lesions should be treated by a combination of radiation therapy and surgery. Most primary cancers of the hard palate are of minor salivary gland origin. Primary squamous cell carcinoma of the hard palate is uncommon, and these tumors generally represent invasion of squamous cell carcinoma arising on the upper gingiva, which is much more common. Management of squamous cell carcinoma of the upper gingiva and hard palate is usually considered together. Surgical treatment of cancer of the hard palate usually requires excision of underlying bone producing an opening into the antrum. This defect can be filled and covered with a dental prosthesis, which is a maneuver that restores satisfactory swallowing and speech.
Patients who smoke while receiving radiation therapy appear to have lower response rates and shorter survival durations than those who do not;[8] therefore, patients should be counseled to stop smoking before beginning radiation therapy. Dental status evaluation should be performed prior to therapy to prevent late sequelae.
Fluorouracil Dosing
The DPYD gene encodes an enzyme that catabolizes pyrimidines and fluoropyrimidines, like capecitabine and fluorouracil. An estimated 1% to 2% of the population has germline pathogenic variants in DPYD, which lead to reduced DPD protein function and an accumulation of pyrimidines and fluoropyrimidines in the body.[9,10] Patients with the DPYD*2A variant who receive fluoropyrimidines may experience severe, life-threatening toxicities that are sometimes fatal. Many other DPYD variants have been identified, with a range of clinical effects.[9–11] Fluoropyrimidine avoidance or a dose reduction of 50% may be recommended based on the patient’s DPYD genotype and number of functioning DPYD alleles.[12–14] DPYD genetic testing costs less than $200, but insurance coverage varies due to a lack of national guidelines.[15] In addition, testing may delay therapy by 2 weeks, which would not be advisable in urgent situations. This controversial issue requires further evaluation.[16]
References
Harrison LB, Sessions RB, Hong WK, eds.: Head and Neck Cancer: A Multidisciplinary Approach. 3rd ed. Lippincott, William & Wilkins, 2009.
Wang CC, ed.: Radiation Therapy for Head and Neck Neoplasms. 3rd ed. Wiley-Liss, 1997.
Myers EN, Suen MD, Myers J, eds.: Cancer of the Head and Neck. 4th ed. Saunders, 2003.
Freund HR: Principles of Head and Neck Surgery. 2nd ed. Appleton-Century-Crofts, 1979.
Lore JM: An Atlas of Head and Neck Surgery. 3rd ed. Saunders, 1988.
Fowler JF, Lindstrom MJ: Loss of local control with prolongation in radiotherapy. Int J Radiat Oncol Biol Phys 23 (2): 457-67, 1992. [PUBMED Abstract]
Langendijk JA, de Jong MA, Leemans ChR, et al.: Postoperative radiotherapy in squamous cell carcinoma of the oral cavity: the importance of the overall treatment time. Int J Radiat Oncol Biol Phys 57 (3): 693-700, 2003. [PUBMED Abstract]
Browman GP, Wong G, Hodson I, et al.: Influence of cigarette smoking on the efficacy of radiation therapy in head and neck cancer. N Engl J Med 328 (3): 159-63, 1993. [PUBMED Abstract]
Sharma BB, Rai K, Blunt H, et al.: Pathogenic DPYD Variants and Treatment-Related Mortality in Patients Receiving Fluoropyrimidine Chemotherapy: A Systematic Review and Meta-Analysis. Oncologist 26 (12): 1008-1016, 2021. [PUBMED Abstract]
Lam SW, Guchelaar HJ, Boven E: The role of pharmacogenetics in capecitabine efficacy and toxicity. Cancer Treat Rev 50: 9-22, 2016. [PUBMED Abstract]
Shakeel F, Fang F, Kwon JW, et al.: Patients carrying DPYD variant alleles have increased risk of severe toxicity and related treatment modifications during fluoropyrimidine chemotherapy. Pharmacogenomics 22 (3): 145-155, 2021. [PUBMED Abstract]
Amstutz U, Henricks LM, Offer SM, et al.: Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Dihydropyrimidine Dehydrogenase Genotype and Fluoropyrimidine Dosing: 2017 Update. Clin Pharmacol Ther 103 (2): 210-216, 2018. [PUBMED Abstract]
Henricks LM, Lunenburg CATC, de Man FM, et al.: DPYD genotype-guided dose individualisation of fluoropyrimidine therapy in patients with cancer: a prospective safety analysis. Lancet Oncol 19 (11): 1459-1467, 2018. [PUBMED Abstract]
Lau-Min KS, Varughese LA, Nelson MN, et al.: Preemptive pharmacogenetic testing to guide chemotherapy dosing in patients with gastrointestinal malignancies: a qualitative study of barriers to implementation. BMC Cancer 22 (1): 47, 2022. [PUBMED Abstract]
Brooks GA, Tapp S, Daly AT, et al.: Cost-effectiveness of DPYD Genotyping Prior to Fluoropyrimidine-based Adjuvant Chemotherapy for Colon Cancer. Clin Colorectal Cancer 21 (3): e189-e195, 2022. [PUBMED Abstract]
Baker SD, Bates SE, Brooks GA, et al.: DPYD Testing: Time to Put Patient Safety First. J Clin Oncol 41 (15): 2701-2705, 2023. [PUBMED Abstract]
Treatment of Stage I Lip and Oral Cavity Cancer
Surgery and/or radiation therapy may be used, depending on the exact site.[1,2]
Treatment Options for Small Lesions of the Lip
Treatment options for stage I small lesions of the lip include:
Surgery.
Radiation therapy.
Surgery and radiation therapy produce similar cure rates, and the method of treatment is dictated by the anticipated cosmetic and functional results.
Treatment Options for Small Anterior Tongue Lesions
Treatment options for stage I small anterior tongue lesions include:
Wide local excision is often used for small lesions that can be resected transorally.
For patients with larger T1 lesions, the following standard treatments are used:
Surgery.
Radiation therapy.
Interstitial implantation alone or with external-beam radiation therapy.
Irradiation of the neck.
Treatment Options for Small Lesions of the Buccal Mucosa
Treatment options for stage I small lesions of the buccal mucosa include:
Surgery alone for patients with lesions smaller than 1 cm in diameter, if the commissure is not involved.
Radiation therapy, including brachytherapy, should be considered to treat lesions smaller than 1 cm in diameter, if the commissure is involved.
Surgical excision with a split-thickness skin graft or radiation therapy is used to treat larger T1 lesions.
Treatment Options for Small Lesions of the Floor of the Mouth
Treatment options for stage I small lesions of the floor of the mouth include:
Surgery for patients with T1 lesions.
Radiation therapy is used to treat T1 lesions.
Excision alone is generally adequate to treat lesions smaller than 0.5 cm if there is a margin of normal mucosa between the lesion and the gingiva.
Surgery is often used if the lesion is attached to the periosteum.
Radiation therapy is often used if the lesion encroaches on the tongue.
Treatment Options for Small Lesions of the Lower Gingiva
Treatment options for stage I small lesions of the lower gingiva include:
Intraoral resection with or without a rim resection of bone and repair with a split-thickness skin graft are used to treat small lesions.
Radiation therapy may be used for small lesions, but results are generally better after surgery alone.
Treatment Options for Small Tumors of the Retromolar Trigone
Treatment options for stage I small tumors of the retromolar trigone include:
Limited resection of the mandible is performed for early lesions without detectable bone invasion.
Radiation therapy may be used initially if limited resection is not feasible, with surgery reserved for radiation failure.
Treatment Options for Small Lesions of the Upper Gingiva and Hard Palate
Treatment options for stage I small lesions of the upper gingiva and hard palate include:
Surgical resection is used to treat most small lesions.
Postoperative radiation therapy may be used if appropriate.
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
Harrison LB, Sessions RB, Hong WK, eds.: Head and Neck Cancer: A Multidisciplinary Approach. 3rd ed. Lippincott, William & Wilkins, 2009.
Surgery and/or radiation therapy may be used, depending on the exact site.[1]
Treatment Options for Small Lesions of the Lip
Treatment options for stage II small lesions of the lip include:
Surgery is used for patients with smaller T2 lesions on the lower lip, if simple closure produces an acceptable cosmetic result.
Radiation therapy, which may include external-beam and/or interstitial techniques, as appropriate, has the advantage of producing a relatively better functional and cosmetic result, with intact skin and muscle innervation, if a reconstructive surgical procedure is required.
Treatment Options for Small Anterior Tongue Lesions
Treatment options for stage II small anterior tongue lesions include:
Radiation therapy is usually selected for patients with T2 lesions that have minimal infiltration to preserve speech and swallowing.[2]
Surgery is reserved for patients for whom radiation treatment failed.[2]
Neck dissection may be considered when primary brachytherapy is used.[2]
Surgery, radiation therapy, or a combination of both are used for deeply infiltrative lesions.
Treatment Options for Small Lesions of the Buccal Mucosa
Treatment options for stage II small lesions of the buccal mucosa include:
Radiation therapy is the usual treatment for patients with small T2 lesions (≤3 cm).
Surgery, radiation therapy, or a combination of these are used, if indicated to treat large T2 lesions (>3 cm). Radiation therapy is often used if the lesion involves the commissure. Surgery is often used, if tumor invades the mandible or maxilla.
Treatment Options for Small Lesions of the Floor of the Mouth
Treatment options for stage II small lesions of the floor of the mouth include:
Surgery is often used for patients with small T2 lesions (≤3 cm) if the lesion is attached to the periosteum.
Radiation therapy is often used to treat patients with small T2 lesions (≤3 cm) if the lesion encroaches on the tongue.
Surgery and radiation therapy are alternative methods of treatment for patients with large T2 lesions (>3 cm), the choice of which depends primarily on the expected extent of disability from surgery.
External-beam radiation therapy with or without interstitial radiation therapy should be considered postoperatively for larger lesions.
Treatment Options for Small Lesions of the Lower Gingiva
Treatment options for stage II small lesions of the lower gingiva include:
Intraoral resection with or without a rim resection of bone and repair with a split-thickness skin graft are used to treat patients with small lesions.
Radiation therapy may be used to treat patients with small lesions, but results are generally better after surgery alone.
Treatment Options for Small Tumors of the Retromolar Trigone
Treatment options for stage II small tumors of the retromolar trigone include:
Limited resection of the mandible is performed to treat patients with early lesions that are without detectable bone invasion.
Radiation therapy may be used initially if limited resection is not feasible.
Surgery is reserved for radiation failure.
Treatment Options for Small Lesions of the Upper Gingiva and Hard Palate
Treatment options for stage II small lesions of the upper gingiva and hard palate include:
Surgical resection with postoperative radiation therapy, as appropriate, is used to treat most lesions. A small study showed that radiation therapy may be used effectively as the sole treatment modality.[3]
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
Harrison LB, Sessions RB, Hong WK, eds.: Head and Neck Cancer: A Multidisciplinary Approach. 3rd ed. Lippincott, William & Wilkins, 2009.
Pernot M, Malissard L, Aletti P, et al.: Iridium-192 brachytherapy in the management of 147 T2N0 oral tongue carcinomas treated with irradiation alone: comparison of two treatment techniques. Radiother Oncol 23 (4): 223-8, 1992. [PUBMED Abstract]
Yorozu A, Sykes AJ, Slevin NJ: Carcinoma of the hard palate treated with radiotherapy: a retrospective review of 31 cases. Oral Oncol 37 (6): 493-7, 2001. [PUBMED Abstract]
Treatment of Stage III Lip and Oral Cavity Cancer
Surgery and/or radiation therapy are used, depending on the exact tumor site.[1,2] Neoadjuvant chemotherapy, as given in clinical trials, has been used to shrink tumors and render them more definitively treatable with either surgery or radiation. Neoadjuvant chemotherapy is given prior to the other modalities, as opposed to standard adjuvant chemotherapy, which is given after or during definitive therapy with radiation or after surgery. Many drug combinations have been used as neoadjuvant chemotherapy.[3–6] However, randomized, prospective trials have yet to demonstrate a benefit in either disease-free survival or overall survival for patients receiving neoadjuvant chemotherapy.[7]
Treatment Options for Moderately Advanced Lesions of the Lip
These lesions, including those involving bone, nerves, and lymph nodes, generally require a combination of surgery and radiation therapy.
Treatment options for stage III advanced lesions of the lip include:
Surgery using a variety of approaches, the choice of which is dependent on the size and location of the lesion and the need for reconstruction.
Radiation therapy using a variety of techniques, including external-beam radiation therapy (EBRT) with or without brachytherapy, the choice of which is dictated by the size and location of the lesion.
Clinical trials for advanced tumors evaluating the use of chemotherapy preoperatively, before radiation therapy, as adjuvant therapy after surgery, or as part of combined modality therapy are appropriate.[3–6,8–10]
Treatment Options for Moderately Advanced (Late T2, Small T3) Lesions of the Anterior Tongue
Treatment options for stage III moderately advanced (late T2, small T3) lesions of the anterior tongue include:
EBRT with or without interstitial implant is used to treat minimally infiltrative lesions.
Surgery with postoperative radiation therapy is used to treat deeply infiltrative lesions.[2]
Treatment Options for Moderately Advanced Lesions of the Buccal Mucosa
Treatment options for stage III advanced lesions of the buccal mucosa include:
Radical surgical resection alone.
Radiation therapy alone.
Surgical resection plus radiation therapy, generally postoperative.
Clinical trials for advanced tumors evaluating the use of chemotherapy preoperatively, before radiation therapy, as adjuvant therapy after surgery, or as part of combined modality therapy are appropriate.[3–6,8–10,12]
Treatment Options for Moderately Advanced Lesions of the Floor of the Mouth
Treatment options for stage III moderately advanced lesions of the floor of the mouth include:
Surgery using rim resection plus neck dissection or partial mandibulectomy with neck dissection, as appropriate.
Radiation therapy using EBRT alone or EBRT plus an interstitial implant.
Clinical trials for advanced tumors evaluating the use of chemotherapy preoperatively, before radiation therapy, as adjuvant therapy after surgery, or as part of combined modality therapy are appropriate.[3–6,8–10,12]
Clinical trials using novel radiation therapy fractionation schemas.[13]
Treatment Options for Moderately Advanced Lesions of the Lower Gingiva
Treatment options for stage III moderately advanced lesions of the lower gingiva include:
Combined radiation therapy and radical resection or radical resection alone are used to treat extensive lesions with moderate bone destruction and/or nodal metastases. Radiation therapy may be administered either preoperatively or postoperatively.
Treatment Options for Moderately Advanced Lesions of the Retromolar Trigone
Treatment options for stage III advanced lesions of the retromolar trigone include:
Surgical composite resection, which may be followed by postoperative radiation therapy.
Clinical trials for advanced tumors evaluating the use of chemotherapy preoperatively, before radiation therapy, as adjuvant therapy after surgery, or as part of combined modality therapy are appropriate.[3–6,8–10,12]
Clinical trials using novel radiation therapy fractionation schemas.[13]
Treatment Options for Moderately Advanced Lesions of the Upper Gingiva
Treatment options for stage III moderately advanced lesions of the upper gingiva include:
Radiation therapy alone is used to treat superficial lesions with extensive involvement of the gingiva, hard palate, or soft palate.
A combination of surgery and radiation therapy is used to treat deeply invasive lesions involving bone.
Treatment Options for Moderately Advanced Lesions of the Hard Palate
Treatment options for stage III moderately advanced lesions of the hard palate include:
Radiation therapy alone is used to treat superficial lesions with extensive involvement of the gingiva, hard palate, or soft palate.
A combination of surgery and radiation therapy or surgery alone is used to treat deeply invasive lesions involving bone.
Treatment Options Under Clinical Evaluation for All Stage III Lip and Oral Cavity Cancers
Chemotherapy has been combined with radiation therapy in patients who have locally advanced disease that is surgically unresectable.[8,10,14,15]
A meta-analysis of 63 randomized prospective trials published between 1965 and 1993 showed an 8% absolute survival advantage in the subset of patients who received concurrent chemotherapy and radiation therapy.[16][Level of evidence B4] Patients who received adjuvant or neoadjuvant chemotherapy had no survival advantage. Cost, quality of life, and morbidity data were not available. No standard regimen existed, and the trials were felt to be too heterogenous to provide definitive recommendations. The results of 18 ongoing trials may further clarify the role of concurrent chemotherapy and radiation therapy in the management of oral cavity cancer.
The best chemotherapy to use and the appropriate way to integrate the two modalities is still unresolved.[17]
Similar approaches in the patient with resectable disease, in whom resection would lead to a major functional deficit, are also being explored in randomized trials but cannot be recommended at this time as standard.
Clinical trials of novel fractionation radiation therapy are under evaluation.[13]
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
Harrison LB, Sessions RB, Hong WK, eds.: Head and Neck Cancer: A Multidisciplinary Approach. 3rd ed. Lippincott, William & Wilkins, 2009.
Franceschi D, Gupta R, Spiro RH, et al.: Improved survival in the treatment of squamous carcinoma of the oral tongue. Am J Surg 166 (4): 360-5, 1993. [PUBMED Abstract]
Ervin TJ, Clark JR, Weichselbaum RR, et al.: An analysis of induction and adjuvant chemotherapy in the multidisciplinary treatment of squamous-cell carcinoma of the head and neck. J Clin Oncol 5 (1): 10-20, 1987. [PUBMED Abstract]
Al-Kourainy K, Kish J, Ensley J, et al.: Achievement of superior survival for histologically negative versus histologically positive clinically complete responders to cisplatin combination in patients with locally advanced head and neck cancer. Cancer 59 (2): 233-8, 1987. [PUBMED Abstract]
Adjuvant chemotherapy for advanced head and neck squamous carcinoma. Final report of the Head and Neck Contracts Program. Cancer 60 (3): 301-11, 1987. [PUBMED Abstract]
Ensley J, Crissman J, Kish J, et al.: The impact of conventional morphologic analysis on response rates and survival in patients with advanced head and neck cancers treated initially with cisplatin-containing combination chemotherapy. Cancer 57 (4): 711-7, 1986. [PUBMED Abstract]
Mazeron JJ, Martin M, Brun B, et al.: Induction chemotherapy in head and neck cancer: results of a phase III trial. Head Neck 14 (2): 85-91, 1992 Mar-Apr. [PUBMED Abstract]
Al-Sarraf M, Pajak TF, Marcial VA, et al.: Concurrent radiotherapy and chemotherapy with cisplatin in inoperable squamous cell carcinoma of the head and neck. An RTOG Study. Cancer 59 (2): 259-65, 1987. [PUBMED Abstract]
Browman GP, Cripps C, Hodson DI, et al.: Placebo-controlled randomized trial of infusional fluorouracil during standard radiotherapy in locally advanced head and neck cancer. J Clin Oncol 12 (12): 2648-53, 1994. [PUBMED Abstract]
Merlano M, Benasso M, Corvò R, et al.: Five-year update of a randomized trial of alternating radiotherapy and chemotherapy compared with radiotherapy alone in treatment of unresectable squamous cell carcinoma of the head and neck. J Natl Cancer Inst 88 (9): 583-9, 1996. [PUBMED Abstract]
Johnson CR, Khandelwal SR, Schmidt-Ullrich RK, et al.: The influence of quantitative tumor volume measurements on local control in advanced head and neck cancer using concomitant boost accelerated superfractionated irradiation. Int J Radiat Oncol Biol Phys 32 (3): 635-41, 1995. [PUBMED Abstract]
Licitra L, Grandi C, Guzzo M, et al.: Primary chemotherapy in resectable oral cavity squamous cell cancer: a randomized controlled trial. J Clin Oncol 21 (2): 327-33, 2003. [PUBMED Abstract]
Stuschke M, Thames HD: Hyperfractionated radiotherapy of human tumors: overview of the randomized clinical trials. Int J Radiat Oncol Biol Phys 37 (2): 259-67, 1997. [PUBMED Abstract]
Bachaud JM, David JM, Boussin G, et al.: Combined postoperative radiotherapy and weekly cisplatin infusion for locally advanced squamous cell carcinoma of the head and neck: preliminary report of a randomized trial. Int J Radiat Oncol Biol Phys 20 (2): 243-6, 1991. [PUBMED Abstract]
Merlano M, Corvo R, Margarino G, et al.: Combined chemotherapy and radiation therapy in advanced inoperable squamous cell carcinoma of the head and neck. The final report of a randomized trial. Cancer 67 (4): 915-21, 1991. [PUBMED Abstract]
Pignon JP, Bourhis J, Domenge C, et al.: Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: three meta-analyses of updated individual data. MACH-NC Collaborative Group. Meta-Analysis of Chemotherapy on Head and Neck Cancer. Lancet 355 (9208): 949-55, 2000. [PUBMED Abstract]
Taylor SG, Murthy AK, Vannetzel JM, et al.: Randomized comparison of neoadjuvant cisplatin and fluorouracil infusion followed by radiation versus concomitant treatment in advanced head and neck cancer. J Clin Oncol 12 (2): 385-95, 1994. [PUBMED Abstract]
Treatment of Stage IV Lip and Oral Cavity Cancer
Randomized prospective trials have yet to demonstrate a benefit in either disease-free survival or overall survival for patients receiving neoadjuvant chemotherapy.[1] The use of isotretinoin daily for 1 year to prevent development of second upper aerodigestive tract primaries is under clinical evaluation.[2]
Treatment Options for Advanced Lesions of the Lip
These lesions, including those involving bone, nerves, and lymph nodes, generally require a combination of surgery and radiation therapy.
Treatment options for stage IV advanced lesions of the lip include:
Surgery using a variety of approaches, the choice of which is dependent on the size and location of the lesion and the need for reconstruction. Treatment of both sides of the neck is indicated for selected patients.
Radiation therapy using a variety of techniques, including external-beam radiation therapy (EBRT) with or without brachytherapy, the choice of which is dictated by the size and location of the lesion.
Treatment Options for Advanced Lesions of the Anterior Tongue
Treatment options for stage IV advanced lesions of the anterior tongue include:
Combined surgery (i.e., total glossectomy, sometimes requiring laryngectomy), possibly followed by postoperative radiation therapy, may be used to treat selected patients.[4]
Palliative radiation therapy may be used to treat patients with very advanced lesions.
Treatment Options for Advanced Lesions of the Buccal Mucosa
Treatment options for stage IV advanced lesions of the buccal mucosa include:
Radical surgical resection alone.
Radiation therapy alone.
Surgical resection plus radiation therapy, which is generally administered postoperatively.
Treatment Options for Advanced Lesions of the Floor of the Mouth
Treatment options for stage IV advanced lesions of the floor of the mouth include:
A combination of surgery and radiation therapy, which is generally administered postoperatively, is often used.
Preoperative radiation therapy is often used for fixed nodes (≥5 cm).
Treatment Options for Advanced Lesions of the Lower Gingiva
Treatment options for stage IV advanced lesions of the lower gingiva include:
Surgery, radiation therapy, or a combination of both are poor controls for advanced tumors with extensive destruction of the mandible and with nodal metastases.
Treatment Options for Advanced Lesions of the Retromolar Trigone
Treatment options for stage IV advanced lesions of the retromolar trigone include:
Surgical composite resection followed by postoperative radiation therapy.
Treatment Options for Advanced Lesions of the Upper Gingiva
Treatment options for stage IV advanced lesions of the upper gingiva include:
Surgery in combination with radiation therapy is generally used to treat lesions that are extensive and infiltrating.
Treatment Options for Advanced Lesions of the Hard Palate
Treatment options for stage IV advanced lesions of the hard palate include:
Surgery in combination with radiation therapy is generally used to treat lesions that are extensive and infiltrating.
Treatment Options Under Clinical Evaluation for All Stage IV Lip and Oral Cavity Cancers
Chemotherapy has been combined with radiation therapy in patients who have locally advanced disease that is surgically unresectable.[5–8]
A meta-analysis of 63 randomized prospective trials published between 1965 and 1993 showed an 8% absolute survival advantage in the subset of patients who received concurrent chemotherapy and radiation therapy.[9][Level of evidence B4] Patients who received adjuvant or neoadjuvant chemotherapy had no survival advantage. Cost, quality of life, and morbidity data were not available. No standard regimen existed, and the trials were felt to be too heterogenous to provide definitive recommendations. The results of 18 ongoing trials may further clarify the role of concurrent chemotherapy and radiation therapy in the management of oral cavity cancer.
The best chemotherapy to use and the appropriate way to integrate the two modalities is still unresolved.[10]
Similar approaches in the patient with resectable disease, in whom resection would lead to a major functional deficit, are also being explored in randomized trials but cannot be recommended at this time as standard.
Clinical trials for advanced tumors evaluating the use of chemotherapy preoperatively, before radiation therapy, or as adjuvant therapy after surgery are appropriate.[5,11–18]
Clinical trials of novel fractionation radiation therapy are under evaluation.[19]
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
Mazeron JJ, Martin M, Brun B, et al.: Induction chemotherapy in head and neck cancer: results of a phase III trial. Head Neck 14 (2): 85-91, 1992 Mar-Apr. [PUBMED Abstract]
Hong WK, Lippman SM, Itri LM, et al.: Prevention of second primary tumors with isotretinoin in squamous-cell carcinoma of the head and neck. N Engl J Med 323 (12): 795-801, 1990. [PUBMED Abstract]
Johnson CR, Khandelwal SR, Schmidt-Ullrich RK, et al.: The influence of quantitative tumor volume measurements on local control in advanced head and neck cancer using concomitant boost accelerated superfractionated irradiation. Int J Radiat Oncol Biol Phys 32 (3): 635-41, 1995. [PUBMED Abstract]
Franceschi D, Gupta R, Spiro RH, et al.: Improved survival in the treatment of squamous carcinoma of the oral tongue. Am J Surg 166 (4): 360-5, 1993. [PUBMED Abstract]
Al-Sarraf M, Pajak TF, Marcial VA, et al.: Concurrent radiotherapy and chemotherapy with cisplatin in inoperable squamous cell carcinoma of the head and neck. An RTOG Study. Cancer 59 (2): 259-65, 1987. [PUBMED Abstract]
Bachaud JM, David JM, Boussin G, et al.: Combined postoperative radiotherapy and weekly cisplatin infusion for locally advanced squamous cell carcinoma of the head and neck: preliminary report of a randomized trial. Int J Radiat Oncol Biol Phys 20 (2): 243-6, 1991. [PUBMED Abstract]
Merlano M, Corvo R, Margarino G, et al.: Combined chemotherapy and radiation therapy in advanced inoperable squamous cell carcinoma of the head and neck. The final report of a randomized trial. Cancer 67 (4): 915-21, 1991. [PUBMED Abstract]
Merlano M, Benasso M, Corvò R, et al.: Five-year update of a randomized trial of alternating radiotherapy and chemotherapy compared with radiotherapy alone in treatment of unresectable squamous cell carcinoma of the head and neck. J Natl Cancer Inst 88 (9): 583-9, 1996. [PUBMED Abstract]
Pignon JP, Bourhis J, Domenge C, et al.: Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: three meta-analyses of updated individual data. MACH-NC Collaborative Group. Meta-Analysis of Chemotherapy on Head and Neck Cancer. Lancet 355 (9208): 949-55, 2000. [PUBMED Abstract]
Taylor SG, Murthy AK, Vannetzel JM, et al.: Randomized comparison of neoadjuvant cisplatin and fluorouracil infusion followed by radiation versus concomitant treatment in advanced head and neck cancer. J Clin Oncol 12 (2): 385-95, 1994. [PUBMED Abstract]
Al-Kourainy K, Kish J, Ensley J, et al.: Achievement of superior survival for histologically negative versus histologically positive clinically complete responders to cisplatin combination in patients with locally advanced head and neck cancer. Cancer 59 (2): 233-8, 1987. [PUBMED Abstract]
Adjuvant chemotherapy for advanced head and neck squamous carcinoma. Final report of the Head and Neck Contracts Program. Cancer 60 (3): 301-11, 1987. [PUBMED Abstract]
Toohill RJ, Duncavage JA, Grossmam TW, et al.: The effects of delay in standard treatment due to induction chemotherapy in two randomized prospective studies. Laryngoscope 97 (4): 407-12, 1987. [PUBMED Abstract]
Ensley J, Crissman J, Kish J, et al.: The impact of conventional morphologic analysis on response rates and survival in patients with advanced head and neck cancers treated initially with cisplatin-containing combination chemotherapy. Cancer 57 (4): 711-7, 1986. [PUBMED Abstract]
Fu KK, Phillips TL, Silverberg IJ, et al.: Combined radiotherapy and chemotherapy with bleomycin and methotrexate for advanced inoperable head and neck cancer: update of a Northern California Oncology Group randomized trial. J Clin Oncol 5 (9): 1410-8, 1987. [PUBMED Abstract]
Ryan RF, Krementz ET, Truesdale GL: Salvage of stage IV intraoral squamous cell carcinomas with preoperative 5-fluorouracil. Cancer 57 (4): 699-705, 1986. [PUBMED Abstract]
Ervin TJ, Clark JR, Weichselbaum RR, et al.: An analysis of induction and adjuvant chemotherapy in the multidisciplinary treatment of squamous-cell carcinoma of the head and neck. J Clin Oncol 5 (1): 10-20, 1987. [PUBMED Abstract]
Browman GP, Cripps C, Hodson DI, et al.: Placebo-controlled randomized trial of infusional fluorouracil during standard radiotherapy in locally advanced head and neck cancer. J Clin Oncol 12 (12): 2648-53, 1994. [PUBMED Abstract]
Stuschke M, Thames HD: Hyperfractionated radiotherapy of human tumors: overview of the randomized clinical trials. Int J Radiat Oncol Biol Phys 37 (2): 259-67, 1997. [PUBMED Abstract]
Treatment Options for Management of Lymph Node Metastases
Patients with advanced lesions should have elective lymph node radiation therapy or node dissection. The risk of metastases to lymph nodes is increased by high-grade histology, large lesions, spread to involve the wet mucosa of the lip or the buccal mucosa in patients with recurrent disease, and invasion of muscle (i.e., orbicularis oris).[1]
Treatment options for management of lymph node metastases include:
Radiation therapy alone or neck dissection:
N1 (0–2 cm).
N2b or N3; all nodes smaller than 2 cm. (A combined surgical and radiation therapy approach should also be considered.)
Radiation therapy and neck dissection:
N1 (2–3 cm), N2a, N3.
Surgery followed by radiation therapy, indications for which are as follows:
Multiple positive nodes.
Contralateral subclinical metastases.
Invasion of tumor through the capsule of the lymph node.
N2b or N3 (one or more nodes in each side of the neck, as appropriate, >2 cm).
Radiation therapy prior to surgery:
Large fixed nodes.
References
Harrison LB, Sessions RB, Hong WK, eds.: Head and Neck Cancer: A Multidisciplinary Approach. 3rd ed. Lippincott, William & Wilkins, 2009.
Treatment of Metastatic and Recurrent Lip and Oral Cavity Cancer
For lesions of the lip, anterior tongue, buccal mucosa, floor of the mouth, retromolar trigone, upper gingiva, and hard palate, treatment is dictated by the location and size of the recurrent lesion as well as prior treatment.[1,2]
Treatment Options for Metastatic and Recurrent Lip and Oral Cavity Cancer
Treatment options for metastatic and recurrent lip and oral cavity cancer include:
Surgery is the preferred treatment if radiation therapy was used initially.[3]
Surgery,[3] radiation therapy, or a combination of these treatments may be considered if surgery was used to treat the lesion initially.
Although chemotherapy has been shown to induce responses, no increase in survival has been demonstrated.[13]
Clinical trials evaluating new chemotherapy drugs, chemotherapy and re-irradiation, or hyperthermia should be considered because both surgical salvage after primary radiation therapy and radiation therapy after primary surgery give poor results.[14,15]
Immunotherapy
Pembrolizumab
Pembrolizumab is a monoclonal antibody and an inhibitor of the programmed death-1 (PD-1) pathway. Studies have evaluated pembrolizumab in patients with incurable metastatic or recurrent head and neck squamous cell carcinoma (SCC).
Evidence (pembrolizumab as first-line therapy):
KEYNOTE-048 (NCT02358031) was a nonblinded, randomized, phase III study of participants with untreated locally incurable metastatic or recurrent head and neck SCC that was performed at 200 sites in 37 countries.[6] A total of 882 patients were randomly assigned in a 1:1:1 ratio to receive pembrolizumab alone (n = 301), pembrolizumab plus a platinum and fluorouracil (5-FU) (pembrolizumab with chemotherapy) (n = 281), or cetuximab plus a platinum and 5-FU (cetuximab with chemotherapy) (n = 300). Investigators, patients, and representatives of the sponsor were masked to the programmed death-ligand 1 (PD-L1) combined positive score (CPS) results; PD-L1 positivity was not required for study entry. A total of 754 patients (85%) had a CPS of 1 or higher and 381 patients (43%) had a CPS of 20 or higher.
The primary end points were overall survival (OS) and progression-free survival (PFS). Progression was defined as radiographically confirmed disease progression or death from any cause, whichever came first, in the intention-to-treat population.
At the second interim analysis, pembrolizumab alone showed improved or noninferior OS compared with cetuximab with chemotherapy. The median OS results were reported as follows:[6][Level of evidence A1]
Among the population with a CPS of 20 or higher, the median OS was 14.9 months in patients who received pembrolizumab alone and 10.7 months in patients who received cetuximab with chemotherapy (hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.45–0.83; P = .0007).
Among the population with a CPS of 1 or higher, the median OS was 12.3 months in patients who received pembrolizumab alone and 10.3 months in patients who received cetuximab with chemotherapy (HR, 0.78; 95% CI, 0.64–0.96; P = .0086).
Among the total population, patients who received pembrolizumab alone had noninferior OS (11.6 months) compared with patients who received cetuximab with chemotherapy (10.7 months) (HR, 0.85; 95% CI, 0.71–1.03; P = .0456).
Pembrolizumab with chemotherapy showed improved OS versus cetuximab with chemotherapy. The OS results were reported as follows:
At the second interim analysis, among the total population, the median OS was 13.0 months in patients who received pembrolizumab with chemotherapy and 10.7 months in patients who received cetuximab with chemotherapy (HR, 0.77; 95% CI, 0.63–0.93; P = .0034).
At the final analysis, among the population with a CPS of 20 or higher, the median OS was 14.7 months in patients who received pembrolizumab with chemotherapy and 11.0 months in patients who received cetuximab with chemotherapy (HR, 0.60; 95% CI, 0.45–0.82; P = .0004).
At the final analysis, among the population with a CPS of 1 or higher, the median OS was 13.6 months in patients who received pembrolizumab with chemotherapy and 10.4 months in patients who received cetuximab with chemotherapy (HR, 0.65; 95% CI, 0.53–0.80; P < .0001).
At the second interim analysis, neither pembrolizumab alone nor pembrolizumab with chemotherapy improved PFS.
At the final analysis, grade 3 or higher all-cause adverse events occurred in 164 of 300 patients (55%) in the pembrolizumab-alone group, 235 of 276 patients (85%) who received pembrolizumab with chemotherapy, and 239 of 287 patients (83%) who received cetuximab with chemotherapy.
Adverse events led to death in 25 patients (8%) in the pembrolizumab-alone group, 32 patients (12%) who received pembrolizumab with chemotherapy, and 28 patients (10%) who received cetuximab with chemotherapy.
Pembrolizumab plus a platinum and 5-FU is an appropriate first-line treatment for patients with metastatic or recurrent head and neck SCC. Pembrolizumab monotherapy is an appropriate first-line treatment for patients with PD-L1–positive metastatic or recurrent head and neck SCC. These results were confirmed at a longer median follow-up of 45 months (interquartile range, 41.0–49.2).[7]
Evidence (pembrolizumab after progression on platinum-based treatment):
The phase III KEYNOTE-040 (NCT02252042) trial included patients with incurable metastatic or recurrent head and neck SCC who had received platinum-based treatment within 3 to 6 months.[4] Patients were randomly assigned to the pembrolizumab arm (200 mg every 3 weeks [247 patients]) or to the standard therapy arm of the investigator’s choice (methotrexate, docetaxel, or cetuximab [248 patients]). Patients received treatment until progression or toxicity. The maximum duration of pembrolizumab was 24 months. The primary end point was OS in the intention-to-treat population.
The median OS was 8.4 months in the pembrolizumab arm and 6.9 months in the standard therapy arm (HR, 0.80; 95% CI, 0.65–0.98; nominal P = .0161).[4][Level of evidence A1]
Pembrolizumab was associated with fewer grade 3 or higher adverse events (pembrolizumab, 13% vs. standard therapy, 36%). The most common treatment-related adverse events were hypothyroidism (13%) in the pembrolizumab arm and fatigue (18%) in the standard therapy arm.
In patients who received pembrolizumab, there were four treatment-related deaths resulting from large intestinal perforation, Stevens-Johnson syndrome, and unspecified malignant progression. Two treatment-related deaths in the standard therapy arm resulted from malignant progression and pneumonia.
The PD-L1 CPS was 1 or higher in 79% of the patients in the pembrolizumab arm and 77% of the patients in the standard therapy arm.
Compared with patients treated with standard therapy, a reduced HRdeath was noted for patients who received pembrolizumab and had PD-1 expression on their tumors or in the tumor microenvironment as noted by a PD-L1 CPS of 1 or higher (HR, 0.74; 95% CI, 0.58–0.93; nominal P = .0049) or a PD-L1 tumor proportion score of 50% or higher (HR, 0.53; 95% CI, 0.35–0.81; nominal P = .0014).
Nivolumab
Nivolumab is a fully human immunoglobulin G4 anti–PD-1 monoclonal antibody.
Evidence (nivolumab combined with ipilimumab in patients who have not previously received systemic therapy):
The CheckMate 651 trial (NCT02741570) evaluated first-line nivolumab plus ipilimumab versus EXTREME (cetuximab, cisplatin/carboplatin, and 5-FU for up to six cycles followed by cetuximab maintenance) in patients with recurrent or metastatic head and neck SCC.[9] The primary end points were OS in all randomly assigned patients and patients with a PD-L1 CPS of 20 or higher. Secondary end points included OS in patients with a PD-L1 CPS of 1 or higher and PFS, objective response rate, and duration of response in all randomly assigned patients and patients with a PD-L1 CPS of 20 or higher.
Among all randomly assigned patients, there was no statistically significant difference in OS with nivolumab plus ipilimumab versus EXTREME (median OS, 13.9 vs. 13.5 months; HR, 0.95; 97.9% CI, 0.80–1.13; P = .4951). Among patients with a PD-L1 CPS of 20 or higher, there was also no statistically significant OS difference between the two treatments (median OS, 17.6 vs. 14.6 months; HR, 0.78; 97.51% CI, 0.59–1.03; P = .0469).[9][Level of evidence A1]
In patients with a CPS of 1 or higher, the median OS was 15.7 months for patients who received nivolumab plus ipilimumab versus 13.2 months for patients who received EXTREME (HR, 0.82; 95% CI, 0.69–0.97).
Among patients with a CPS of 20 or higher, the median PFS was 5.4 months for patients who received nivolumab plus ipilimumab and 7.0 months for patients who received EXTREME. The objective response rate was 34.1% for patients who received nivolumab plus ipilimumab and 36.0% for patients who received EXTREME.
Grade 3 or 4 treatment-related adverse events occurred in 28.2% of patients who received nivolumab plus ipilimumab and 70.7% of patients who received EXTREME.
CheckMate 651 did not meet its primary end points of OS in the randomly assigned or CPS of 20 or higher populations.
The absence of a survival benefit for immune checkpoint inhibitors in this trial was an unexpected outcome, given the similarity of nivolumab to pembrolizumab in the studies of patients with cisplatin-refractory disease.[4,5] An editorial accompanying the CheckMate 651 trial analyzed some of the factors that may have contributed to a different result. The editorial suggested that survival in the control group, which was longer than that reported in prior studies, may have been impacted by the greater availability of second-line immunotherapy in the control group (46% in CheckMate 651 compared with 25% in the KEYNOTE-048 trial). The authors also suggested that the coadministration of ipilimumab detracted from the activity of nivolumab, as shown in the CheckMate 714 trial.[8]
CheckMate 714 (NCT02823574), a double-blind phase II trial, evaluated the clinical benefit of first-line nivolumab plus ipilimumab versus nivolumab alone in 425 patients with recurrent or metastatic head and neck SCC.[10] Patients were randomly assigned in a 2:1 ratio to receive either nivolumab (3 mg/kg intravenously [IV] every 2 weeks) plus ipilimumab (1 mg/kg IV every 6 weeks) or nivolumab (3 mg/kg IV every 2 weeks) plus placebo. Treatment continued for up to 2 years or until disease progression, unacceptable toxic effects, or consent withdrawal. The primary end points were objective response rate and duration of response between treatment arms by blinded independent central review in the population with platinum-refractory recurrent or metastatic disease. These were patients who had recurrent disease less than 6 months after completion of platinum-based chemotherapy (adjuvant or neoadjuvant, or as part of multimodal treatment [chemotherapy, surgery, and/or radiation therapy]). Among the 241 patients (56.7%) with platinum-refractory disease, 159 were assigned to receive nivolumab plus ipilimumab and 82 were assigned to receive nivolumab alone. Among the 184 patients (43.3%) with platinum-eligible disease, 123 were assigned to receive nivolumab plus ipilimumab and 61 were assigned to receive nivolumab alone.[10][Level of evidence B3]
At primary database lock, the objective response rate in the population with platinum-refractory disease was 13.2% (95% CI, 8.4%–19.5%) with nivolumab plus ipilimumab and 18.3% (95% CI, 10.6%–28.4%) with nivolumab alone (odds ratio, 0.68; 95.5% CI, 0.33–1.43; P = .29).
The median duration of response was not reached (NR) in the nivolumab-plus-ipilimumab group (95% CI, 11.0 months–NR) and was 11.1 months (95% CI, 4.1–NR) in the nivolumab-alone group. In the population with platinum-eligible disease, the objective response rate was 20.3% (95% CI, 13.6%–28.5%) with nivolumab plus ipilimumab and 29.5% (95% CI, 18.5%–42.6%) with nivolumab alone.
Among the population with platinum-refractory disease, grade 3 or 4 treatment-related adverse events occurred in 25 of 158 patients (15.8%) who received nivolumab plus ipilimumab and in 12 of 82 patients (14.6%) who received nivolumab alone. Among the population with platinum-eligible disease, grade 3 or 4 treatment-related adverse events occurred in 30 of 122 patients (24.6%) who received nivolumab plus ipilimumab and in 8 of 61 patients (13.1%) who received nivolumab alone.
This trial did not meet its primary end point of objective response rate benefit with first-line nivolumab plus ipilimumab versus nivolumab alone in patients with platinum-refractory recurrent or metastatic head and neck SCC.
Evidence (nivolumab after progression on platinum-based treatment):
A phase III open-label trial included 361 patients with recurrent SCC of the head and neck and disease progression within 6 months after platinum-based chemotherapy. Patients were randomly assigned in a 2:1 ratio to receive either nivolumab (at a dose of 3 mg/kg of body weight) every 2 weeks or standard single-agent systemic therapy (methotrexate, docetaxel, or cetuximab). The primary end point was OS.[5]
The median OS was 7.5 months (95% CI, 5.5–9.1) in the nivolumab group versus 5.1 months (95% CI, 4.0–6.0) in the standard therapy group. OS was statistically significantly longer with nivolumab than with standard therapy (HRdeath, 0.70; 97.73% CI, 0.51–0.96; P = .01). The estimated 1-year survival rate was approximately 19% higher in patients who received nivolumab (36.0%) than in those who received standard therapy (16.6%).[5][Level of evidence A1]
There was no statistically significant difference in median PFS between treatment groups. The 6-month PFS rate was 19.7% with nivolumab versus 9.9% with standard therapy.
The response rate was 13.3% in the nivolumab group versus 5.8% in the standard therapy group.
Grade 3 or 4 treatment-related adverse events occurred in 13.1% of the patients in the nivolumab group compared with 35.1% of the patients in the standard therapy group.
Quality-of-life outcomes—including physical, role, and social functioning and pain, sensory, and social contact problems—were stable in the nivolumab group but worse in the standard therapy group. These outcomes were assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ) Core Module (QLQ-C30) and the Head and Neck Module (QLQ-H&N35).
In the subgroup of patients with a PD-L1 expression level of 1% or higher, the HRdeath among patients treated with nivolumab versus standard therapy was 0.55 (95% CI, 0.36–0.83). In the subgroup of patients with a PD-L1 expression level lower than 1%, the HR was 0.89 (95% CI, 0.54–1.45; P = .17 for interaction).
A randomized, phase III, superiority study in India evaluated the dose of immune checkpoint inhibitors in the setting of palliative care for patients with advanced head and neck cancer. Low-dose IV nivolumab (20 mg every 3 weeks) was added to a triple metronomic chemotherapy regimen of oral methotrexate (9 mg/m2 once weekly), celecoxib (200 mg twice daily), and erlotinib (150 mg once daily). Notably, this nivolumab dose is less than 10% of the dose recommended by the U.S. Food and Drug Administration and the European Medicines Agency. A total of 151 patients were randomly assigned to receive either triple metronomic chemotherapy alone (n = 75) or triple metronomic chemotherapy with nivolumab (n = 76). The primary end point was 1-year OS.[11]
The addition of low-dose nivolumab to triple metronomic chemotherapy improved the 1-year OS rate from 16.3% (95% CI, 8.0%–27.4%) to 43.4% (95% CI, 30.8%–55.3%) (HR, 0.545; 95% CI, 0.362–0.820; P = .0036).[11][Level of evidence A1]
The median OS was 6.7 months (95% CI, 5.8–8.1) for patients who received triple metronomic chemotherapy alone and 10.1 months (95% CI, 7.4–12.6) for patients who received triple metronomic chemotherapy with nivolumab (P = .0052).
The rate of grade 3 or higher adverse events was 50% for patients who received triple metronomic chemotherapy alone and 46.1% for patients who received triple metronomic chemotherapy with nivolumab (P = .744).
Although the control arm in this study cannot be considered standard care, lower doses of immunotherapy appeared to have some benefit in this setting.[12]
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
Harrison LB, Sessions RB, Hong WK, eds.: Head and Neck Cancer: A Multidisciplinary Approach. 3rd ed. Lippincott, William & Wilkins, 2009.
Vikram B, Strong EW, Shah JP, et al.: Intraoperative radiotherapy in patients with recurrent head and neck cancer. Am J Surg 150 (4): 485-7, 1985. [PUBMED Abstract]
Wong LY, Wei WI, Lam LK, et al.: Salvage of recurrent head and neck squamous cell carcinoma after primary curative surgery. Head Neck 25 (11): 953-9, 2003. [PUBMED Abstract]
Cohen EEW, Soulières D, Le Tourneau C, et al.: Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): a randomised, open-label, phase 3 study. Lancet 393 (10167): 156-167, 2019. [PUBMED Abstract]
Ferris RL, Blumenschein G, Fayette J, et al.: Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck. N Engl J Med 375 (19): 1856-1867, 2016. [PUBMED Abstract]
Burtness B, Harrington KJ, Greil R, et al.: Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Lancet 394 (10212): 1915-1928, 2019. [PUBMED Abstract]
Harrington KJ, Burtness B, Greil R, et al.: Pembrolizumab With or Without Chemotherapy in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: Updated Results of the Phase III KEYNOTE-048 Study. J Clin Oncol 41 (4): 790-802, 2023. [PUBMED Abstract]
Burtness B: First-Line Nivolumab Plus Ipilimumab in Recurrent/Metastatic Head and Neck Cancer-What Happened? J Clin Oncol 41 (12): 2134-2137, 2023. [PUBMED Abstract]
Haddad RI, Harrington K, Tahara M, et al.: Nivolumab Plus Ipilimumab Versus EXTREME Regimen as First-Line Treatment for Recurrent/Metastatic Squamous Cell Carcinoma of the Head and Neck: The Final Results of CheckMate 651. J Clin Oncol 41 (12): 2166-2180, 2023. [PUBMED Abstract]
Harrington KJ, Ferris RL, Gillison M, et al.: Efficacy and Safety of Nivolumab Plus Ipilimumab vs Nivolumab Alone for Treatment of Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck: The Phase 2 CheckMate 714 Randomized Clinical Trial. JAMA Oncol 9 (6): 779-789, 2023. [PUBMED Abstract]
Patil VM, Noronha V, Menon N, et al.: Low-Dose Immunotherapy in Head and Neck Cancer: A Randomized Study. J Clin Oncol 41 (2): 222-232, 2023. [PUBMED Abstract]
Mitchell AP, Goldstein DA: Cost Savings and Increased Access With Ultra-Low-Dose Immunotherapy. J Clin Oncol 41 (2): 170-172, 2023. [PUBMED Abstract]
Jacobs C, Lyman G, Velez-García E, et al.: A phase III randomized study comparing cisplatin and fluorouracil as single agents and in combination for advanced squamous cell carcinoma of the head and neck. J Clin Oncol 10 (2): 257-63, 1992. [PUBMED Abstract]
Hong WK, Bromer R: Chemotherapy in head and neck cancer. N Engl J Med 308 (2): 75-9, 1983. [PUBMED Abstract]
Vokes EE, Athanasiadis I: Chemotherapy of squamous cell carcinoma of head and neck: the future is now. Ann Oncol 7 (1): 15-29, 1996. [PUBMED Abstract]
Latest Updates to This Summary (05/14/2025)
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Editorial changes were made to this summary.
This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.
About This PDQ Summary
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of adult lip and oral cavity cancer. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
be discussed at a meeting,
be cited with text, or
replace or update an existing article that is already cited.
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Lip and Oral Cavity Cancer Treatment are:
Andrea Bonetti, MD (Pederzoli Hospital)
Minh Tam Truong, MD (Boston University Medical Center)
Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website’s Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.
Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
Permission to Use This Summary
PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”
The preferred citation for this PDQ summary is:
PDQ® Adult Treatment Editorial Board. PDQ Lip and Oral Cavity Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/head-and-neck/hp/adult/lip-mouth-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389262]
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.
Lip and oral cavity cancer is a disease that starts in lips or mouth.
Tobacco and alcohol use can affect the risk of lip and oral cavity cancer.
Signs of lip and oral cavity cancer include a sore or lump on the lips or in the mouth.
Tests that examine the mouth and throat are used to diagnose and stage lip and oral cavity cancer.
Some people decide to get a second opinion.
Certain factors affect prognosis (chance of recovery) and treatment options.
Lip and oral cavity cancer is a disease that starts in lips or mouth.
The oral cavity refers to the mouth. It includes:
the front two thirds of the tongue
the gingiva (gums)
the buccal mucosa (the lining of the inside of the cheeks)
the floor (bottom) of the mouth under the tongue
the hard palate (the roof of the mouth)
the retromolar trigone (the small area behind the wisdom teeth)
EnlargeAnatomy of the oral cavity. The oral cavity includes the lips, hard palate (the bony front portion of the roof of the mouth), soft palate (the muscular back portion of the roof of the mouth), retromolar trigone (the area behind the wisdom teeth), front two-thirds of the tongue, gingiva (gums), buccal mucosa (the inner lining of the lips and cheeks), and floor of the mouth under the tongue.
Most lip and oral cavity cancers start in squamous cells, the thin, flat cells lining the inside of the lips and oral cavity. Cancers that start in squamous cells are called squamous cell carcinomas. Cancer cells may spread into deeper tissue as the cancer grows. Squamous cell carcinoma usually develops in areas of leukoplakia (white patches of cells that do not rub off).
Tobacco and alcohol use can affect the risk of lip and oral cavity cancer.
Lip and oral cavity cancer is caused by certain changes to the way lip and oral cavity cells function, especially how they grow and divide into new cells. There are many risk factors for lip and oral cavity cancer, but many do not directly cause cancer. Instead, they increase the chance of DNA damage in cells that may lead to lip and oral cavity cancer. Learn more about how cancer develops at What Is Cancer?
A risk factor is anything that increases the chance of getting a disease. Some risk factors for lip and oral cavity cancer, such as tobacco and alcohol use, can be changed. However, risk factors also include things people cannot change, like their genetics. Learning about risk factors for lip and oral cavity cancer can help you make changes that might lower your risk of getting it.
Risk factors for lip and oral cavity cancer include:
being exposed to natural sunlight or artificial sunlight (such as from tanning beds) over long periods of time
being male
Learn more about Tobacco, including help with quitting.
Having one or more of these risk factors does not mean that you will get lip and oral cavity cancer. Many people with risk factors never develop lip and oral cavity cancer, while others with no known risk factors do. Talk with your doctor if you think you may be at risk.
Signs of lip and oral cavity cancer include a sore or lump on the lips or in the mouth.
These and other signs and symptoms may be caused by lip and oral cavity cancer or by other conditions. Check with your doctor if you have any of the following:
a sore on the lip or in the mouth that does not heal
a lump or thickening on the lips or gums or in the mouth
a white or red patch on the gums, tongue, or lining of the mouth
bleeding, pain, or numbness in the lip or mouth
change in voice
loose teeth or dentures that no longer fit well
trouble chewing or swallowing or moving the tongue or jaw
swelling of jaw
sore throat or feeling that something is caught in the throat
Lip and oral cavity cancer may not have any symptoms and is sometimes found during a regular dental exam.
Tests that examine the mouth and throat are used to diagnose and stage lip and oral cavity cancer.
If you have symptoms that suggest lip and oral cavity cancer, your doctor will need to find out if these are due to cancer or another problem. They will ask when the symptoms started and how often you have been having them. They will also ask about your personal and family health history and do a physical exam. Based on these results, the doctor may recommend other tests. If you are diagnosed with lip and oral cavity cancer, the results of these tests will help you and your doctor plan treatment.
The following tests and procedures are used to diagnose and stage lip and oral cavity cancer:
Physical exam of the lips and oral cavity is an exam to check the lips and oral cavity for abnormal areas. The medical doctor or dentist will feel the entire inside of the mouth with a gloved finger and examine the oral cavity with a small long-handled mirror and lights. This will include checking the insides of the cheeks and lips; the gums; the roof and floor of the mouth; and the top, bottom, and sides of the tongue. The neck will be felt for swollen lymph nodes. A history of the patient’s health habits and past illnesses and medical and dental treatments will also be taken.
Endoscopy is a procedure to look at organs and tissues inside the body to check for abnormal areas. An endoscope is inserted through an incision (cut) in the skin or opening in the body, such as the mouth. An endoscope is a thin, tube-like instrument with a light and a lens for viewing. It may also have a tool to remove tissue or lymph node samples, which are checked under a microscope for signs of disease.
Biopsy is the removal of cells or tissues so they can be viewed under a microscope by a pathologist. If leukoplakia is found, cells taken from the patches are also checked under the microscope for signs of cancer.
Exfoliative cytology is a procedure to collect cells from the lip or oral cavity. A piece of cotton, a brush, or a small wooden stick is used to gently scrape cells from the lips, tongue, mouth, or throat. The cells are viewed under a microscope to find out if they are abnormal.
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).
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. EnlargeComputed tomography (CT) scan of the head and neck. The patient lies on a table that slides through the CT scanner, which takes x-ray pictures of the inside of the head and neck.
Barium swallow is a series of x-rays of the esophagus and stomach. The patient drinks a liquid that contains barium (a silver-white metallic compound). The liquid coats the esophagus and x-rays are taken. This procedure is also called an upper GI series.
PET scan (positron emission tomography scan) uses a small amount of radioactive sugar (also called glucose) that is injected into a vein. Then a scanner rotates around the body to make detailed, computerized pictures of areas inside the body where the glucose is taken up. Because cancer cells often take up more glucose than normal cells, the pictures can be used to find cancer cells in the body.
Bone scan is a procedure to check 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.
Some people decide to get a second opinion.
You may want to get a second opinion to confirm your cancer diagnosis and treatment plan. If you seek a second opinion, you will need to get medical test results and reports from the first doctor to share with the second doctor. The second doctor will review the pathology report, slides, and scans. They may agree with the first doctor, suggest changes or another treatment approach, or provide more information about your cancer.
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, hospital, or getting a second opinion. For questions you might want to ask at your appointments, see Questions to Ask Your Doctor About Cancer.
Certain factors affect prognosis (chance of recovery) and treatment options.
For patients who smoke, the chance of recovery is better if they stop smoking before beginning radiation therapy.
Treatment options depend on:
the stage of the cancer
the size of the tumor and where it is in the lip or oral cavity
whether the patient’s appearance and ability to talk and eat can stay the same
the patient’s age and general health
Patients who have had lip and oral cavity cancer have an increased risk of developing a second cancer in the head or neck. Frequent and careful follow-up is important. Clinical trials are studying the use of retinoid drugs to reduce the risk of a second head and neck cancer. Information about ongoing clinical trials is available from the NCI website.
Stages of Lip and Oral Cavity Cancer
Key Points
Cancer stage describes the extent of cancer in the body.
The following stages are used for lip and oral cavity cancer:
Stage 0 (carcinoma in situ)
Stage I (also called stage 1) lip and oral cavity cancer
Stage II (also called stage 2) lip and oral cavity cancer
Stage III (also called stage 3) lip and oral cavity cancer
Stage IV (also called stage 4) lip and oral cavity cancer
Lip and oral cavity cancer can recur (come back) after it has been treated.
Cancer stage describes the extent of cancer in 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. Knowing the cancer stage helps plan treatment.
There are several staging systems for cancer that describe the extent of the cancer. Lip and oral cavity cancer staging usually uses the TNM staging system. The cancer may be described by this staging system in your pathology report. Based on the TNM results, a stage (I, II, III, or IV, also written as 1, 2, 3, or 4) is assigned to the cancer. When talking to you about your diagnosis, your doctor may describe the cancer as one of these stages.
The following stages are used for lip and oral cavity cancer:
Stage 0 (carcinoma in situ)
In stage 0, abnormal cells are found in the lining of the lips and oral cavity. These abnormal cells may become cancer and spread into nearby normal tissue. Stage 0 is also called carcinoma in situ.
EnlargeTumor sizes are often measured in centimeters (cm) or inches. Common food items that can be used to show tumor size in cm include: a pea (1 cm), a peanut (2 cm), a grape (3 cm), a walnut (4 cm), a lime (5 cm or 2 inches), an egg (6 cm), a peach (7 cm), and a grapefruit (10 cm or 4 inches).
Stage I (also called stage 1) lip and oral cavity cancer
In stage I, cancer has formed. The tumor is 2 centimeters or smaller and the deepest point of tumor invasion is 5 millimeters or less.
EnlargeTumor sizes are often measured in millimeters (mm) or centimeters. Common items that can be used to show tumor size in mm include: a sharp pencil point (1 mm), a new crayon point (2 mm), a pencil-top eraser (5 mm), a pea (10 mm), a peanut (20 mm), and a lime (50 mm).
Stage II (also called stage 2) lip and oral cavity cancer
In stage II, the tumor:
is 2 centimeters or smaller and the deepest point of tumor invasion is greater than 5 millimeters; or
is larger than 2 centimeters but not larger than 4 centimeters and the deepest point of tumor invasion is 10 millimeters or less.
Stage III (also called stage 3) lip and oral cavity cancer
In stage III, the tumor:
is larger than 2 centimeters but not larger than 4 centimeters and the deepest point of tumor invasion is greater than 10 millimeters; or
is larger than 4 centimeters and the deepest point of tumor invasion is 10 millimeters or less; or
has spread to one lymph node that is 3 centimeters or smaller, on the same side of the neck as the primary tumor.
Stage IV (also called stage 4) lip and oral cavity cancer
Stage IV is divided into stages IVA, IVB, and IVC.
In stage IVA, the tumor:
is larger than 4 centimeters and the deepest point of tumor invasion is greater than 10 millimeters; or has spread to the outer surface of the upper or lower jawbone, into the maxillary sinus, or to the skin of the face. The cancer may have spread to one lymph node that is 3 centimeters or smaller, on the same side of the neck as the primary tumor; or
is any size or cancer has spread to the outer surface of the upper or lower jawbone, into the maxillary sinus, or to the skin of the face. Cancer has spread:
to one lymph node that is 3 centimeters or smaller, on the same side of the neck as the primary tumor, and cancer has spread through the outside covering of the lymph node into nearby connective tissue; or
to one lymph node that is larger than 3 centimeters but not larger than 6 centimeters, on the same side of the neck as the primary tumor; or
to multiple lymph nodes that are not larger than 6 centimeters, on the same side of the neck as the primary tumor; or
to multiple lymph nodes that are not larger than 6 centimeters, on the opposite side of the neck as the primary tumor or on both sides of the neck.
In stage IVB, the tumor:
has spread to one lymph node that is larger than 6 centimeters; or
has spread to one lymph node that is larger than 3 centimeters, on the same side of the neck as the primary tumor, and cancer has spread through the outside covering of the lymph node into nearby connective tissue; or
has spread to one lymph node of any size on the opposite side of the neck as the primary tumor, and cancer has spread through the outside covering of the lymph node into nearby connective tissue; or
has spread to multiple lymph nodes anywhere in the neck, and cancer has spread through the outside covering of any lymph node into nearby connective tissue; or
has spread further into the muscles or bones needed for chewing, or to the part of the sphenoid bone behind the upper jaw, and/or to the carotid artery near the base of the skull. Cancer may have also spread to one or more lymph nodes of any size, anywhere in the neck.
In stage IVC, the tumor:
has spread beyond the lip or oral cavity to other parts of the body, such as the lung, liver, or bone.
Stage IVC lip and oral cavity cancer is also called metastatic lip and oral cavity cancer. Metastatic cancer happens when cancer cells travel through the lymphatic system or blood and form tumors in other parts of the body. The metastatic tumor is the same type of cancer as the primary tumor. For example, if lip and oral cavity cancer spreads to the lung, the cancer cells in the lung are actually lip and oral cavity cancer cells. The disease is called metastatic lip and oral cavity cancer, not lung cancer. Learn more in Metastatic Cancer: When Cancer Spreads.
Lip and oral cavity cancer can recur (come back) after it has been treated.
Recurrent lip and oral cavity cancer is cancer that has come back after it has been treated. If lip and oral cavity cancer comes back, it may come back in the lip, mouth, or other parts of the body. Tests will help determine where in the body the cancer has returned. The type of treatment that you have for recurrent lip and oral cavity cancer will depend on where it has come back.
There are different types of treatment for people with lip and oral cavity cancer.
People with lip and oral cavity cancer should have their treatment planned by a team of doctors who are expert in treating head and neck cancer.
The following types of treatment are used:
Surgery
Radiation therapy
Immunotherapy
New types of treatment are being tested in clinical trials.
Follow-up care may be needed.
There are different types of treatment for people with lip and oral cavity cancer.
Different types of treatments are available for lip and oral cavity cancer. You and your cancer care team will work together to decide your treatment plan, which may include more than one type of treatment. Many factors will be considered, such as the stage of the cancer, your overall health, and your preferences. Your plan will include information about your cancer, the goals of treatment, your treatment options and the possible side effects, and the expected length of treatment.
Talking with your cancer care team before treatment begins about what to expect will be helpful. You’ll want to learn what you need to do before treatment begins, how you’ll feel while going through it, and what kind of help you will need. Learn more at Questions to Ask Your Doctor About Treatment.
People with lip and oral cavity cancer should have their treatment planned by a team of doctors who are expert in treating head and neck cancer.
An oncologist, a doctor who specializes in treating people with cancer, oversees treatment for lip and oral cavity cancer. Because the lips and oral cavity are important for breathing, eating, and talking, you may need special help adjusting to the side effects of the cancer and its treatment. The oncologist may refer you to other health care providers who are experts in treating head and neck cancer and also specialize in other areas of medicine. Other specialists may include:
Surgery (removing the cancer in an operation) is a common treatment for all stages of lip and oral cavity cancer. Surgery may include:
Wide local excision is the removal of the cancer and some of the healthy tissue around it. If cancer has spread into bone, surgery may include removal of the involved bone tissue.
Neck dissection is the removal of lymph nodes and other tissues in the neck. This is done when cancer may have spread from the lip and oral cavity.
Plastic surgery is an operation that restores or improves the appearance of parts of the body. Dental implants, a skin graft, or other plastic surgery may be needed to repair parts of the mouth, throat, or neck after removal of large tumors.
After the doctor removes all the cancer that can be seen at the time of the surgery, some patients may be given chemotherapy or radiation therapy after surgery to kill any cancer cells that are left. Treatment given after the surgery, to lower the risk that the cancer will come back, is called adjuvant therapy.
Radiation therapy uses high-energy x-rays or other types of radiation to kill cancer cells or keep them from growing by damaging their DNA. External and internal radiation therapy are used to treat lip and oral cavity cancer:
External radiation therapy uses a machine outside the body to send radiation toward the area of the body with cancer. EnlargeExternal-beam radiation therapy of the head and neck. A machine is used to aim high-energy radiation at the cancer. The machine can rotate around the patient, delivering radiation from many different angles to provide highly conformal treatment. A mesh mask helps keep the patient’s head and neck from moving during treatment. Small ink marks are put on the mask. The ink marks are used to line up the radiation machine in the same position before each treatment.
Radiation therapy may work better in patients who have stopped smoking before beginning treatment. It is also important for patients to have a dental exam before radiation therapy begins so that existing problems can be treated.
Immunotherapy helps a person’s immune system fight cancer. Your doctor may suggest biomarker tests to help predict your response to certain immunotherapy drugs. Learn more about Biomarker Testing for Cancer Treatment.
Immunotherapy drugs used to treat squamous cell carcinoma of the lip and oral cavity cancer that has come back or spread to other parts of the body include:
New types of treatment are being tested in clinical trials.
For some people, joining a clinical trial may be an option. There are different types of clinical trials for people with cancer. For example, a treatment trial tests new treatments or new ways of using existing 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 that are accepting participants. This search allows you to filter trials based on the type of cancer, your age, and where the trials are being done. Clinical trials supported by other organizations can be found on the ClinicalTrials.gov website.
As you go through treatment, you will have follow-up tests or check-ups. Some tests that were done to diagnose or stage the cancer may be repeated to see how well the treatment is working. Decisions about whether to continue, change, or stop treatment may be based on the results of these tests.
Some of the tests will continue to be done from time to time after treatment has ended. The results of these tests can show if your condition has changed or if the cancer has recurred (come back).
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.
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.
If cancer is in the lower gingiva (gums), treatment may include surgery (wide local excision) with or without radiation therapy. Radiation may be given before or after surgery.
Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.
Treatment of Stage IV Nonmetastatic Lip and Oral Cavity Cancer
Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.
Treatment of Stage IV Metastatic and Recurrent Lip and Oral Cavity Cancer
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.
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 adult lip and oral cavity cancer. It is meant to inform and help patients, families, and caregivers. It does not give formal guidelines or recommendations for making decisions about health care.
Reviewers and Updates
Editorial Boards write the PDQ cancer information summaries and keep them up to date. These Boards are made up of experts in cancer treatment and other specialties related to cancer. The summaries are reviewed regularly and changes are made when there is new information. The date on each summary (“Updated”) is the date of the most recent change.
The information in this patient summary was taken from the health professional version, which is reviewed regularly and updated as needed, by the PDQ Adult Treatment Editorial Board.
Clinical Trial Information
A clinical trial is a study to answer a scientific question, such as whether one treatment is better than another. Trials are based on past studies and what has been learned in the laboratory. Each trial answers certain scientific questions in order to find new and better ways to help cancer patients. During treatment clinical trials, information is collected about the effects of a new treatment and how well it works. If a clinical trial shows that a new treatment is better than one currently being used, the new treatment may become “standard.” Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.
Clinical trials can be found online at NCI’s website. For more information, call the Cancer Information Service (CIS), NCI’s contact center, at 1-800-4-CANCER (1-800-422-6237).
Permission to Use This Summary
PDQ is a registered trademark. The content of PDQ documents can be used freely as text. It cannot be identified as an NCI PDQ cancer information summary unless the whole summary is shown and it is updated regularly. However, a user would be allowed to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks in the following way: [include excerpt from the summary].”
The best way to cite this PDQ summary is:
PDQ® Adult Treatment Editorial Board. PDQ Lip and Oral Cavity Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/head-and-neck/patient/adult/lip-mouth-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389326]
Images in this summary are used with permission of the author(s), artist, and/or publisher for use in the PDQ summaries only. If you want to use an image from a PDQ summary and you are not using the whole summary, you must get permission from the owner. It cannot be given by the National Cancer Institute. Information about using the images in this summary, along with many other images related to cancer can be found in Visuals Online. Visuals Online is a collection of more than 3,000 scientific images.
Disclaimer
The information in these summaries should not be used to make decisions about insurance reimbursement. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.
Contact Us
More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website’s E-mail Us.
Laryngeal cancer is a disease in which malignant (cancer) cells form in the tissues of the larynx.
Use of tobacco products and drinking too much alcohol can affect the risk of laryngeal cancer.
Signs and symptoms of laryngeal cancer include a sore throat and ear pain.
Tests that examine the throat and neck are used to help diagnose and stage laryngeal cancer.
Certain factors affect prognosis (chance of recovery) and treatment options.
Laryngeal cancer is a disease in which malignant (cancer) cells form in the tissues of the larynx.
The larynx is a part of the throat, between the base of the tongue and the trachea. The larynx contains the vocal cords, which vibrate and make sound when air is directed against them. The sound echoes through the pharynx, mouth, and nose to make a person’s voice.
There are three main parts of the larynx:
Supraglottis: The upper part of the larynx above the vocal cords, including the epiglottis.
Glottis: The middle part of the larynx where the vocal cords are located.
Subglottis: The lower part of the larynx between the vocal cords and the trachea (windpipe).
EnlargeLaryngeal cancer forms in the tissues of the larynx (area of the throat that contains the vocal cords). The larynx includes the supraglottis, glottis (vocal cords), and subglottis. The cancer may spread to nearby tissues or to the thyroid, trachea, or esophagus. It may also spread to the lymph nodes in the neck, the carotid artery, the upper part of the spinal column, the chest, and to other parts of the body (not shown).
Use of tobacco products and drinking too much alcohol can affect the risk of laryngeal cancer.
Anything that increases a person’s chance of getting a disease is called a risk factor. Not every person with one or more of these risk factors will develop laryngeal cancer, and it will develop in people who don’t have any known risk factors. Talk with your doctor if you think you may be at risk.
Signs and symptoms of laryngeal cancer include a sore throat and ear pain.
These and other signs and symptoms may be caused by laryngeal cancer or by other conditions. Check with your doctor if you have any of the following:
A sore throat or cough that does not go away.
Trouble or pain when swallowing.
Ear pain.
A lump in the neck or throat.
A change or hoarseness in the voice.
Tests that examine the throat and neck are used to help diagnose and stage laryngeal cancer.
In addition to asking about your personal and family health history, your doctor may perform the following tests and procedures:
Physical exam of the throat and neck: An exam to check the throat and neck for abnormal areas. The doctor will feel the inside of the mouth with a gloved finger and examine the mouth and throat with a small long-handled mirror and light. This will include checking the insides of the cheeks and lips; the gums; the back, roof, and floor of the mouth; the top, bottom, and sides of the tongue; and the throat. The neck will be felt for swollen lymph nodes. A history of the patient’s health habits and past illnesses and medical treatments will also be taken.
Biopsy: The removal of cells or tissues so they can be viewed under a microscope by a pathologist to check for signs of cancer. The sample of tissue may be removed during one of the following procedures:
Laryngoscopy: A procedure in which the doctor checks the larynx (voice box) with a mirror or a laryngoscope to check for abnormal areas. A laryngoscope is a thin, tube-like instrument with a light and a lens for viewing the inside of the throat and voice box. It may also have a tool to remove tissue samples, which are checked under a microscope for signs of cancer.
Endoscopy: A procedure to look at organs and tissues inside the body, such as the throat, esophagus, and trachea to check for abnormal areas. An endoscope (a thin, lighted tube with a light and a lens for viewing) is inserted through an opening in the body, such as the mouth. A special tool on the endoscope may be used to remove samples of tissue.
CT scan (CAT scan): A procedure that makes a series of detailed pictures of areas inside the body, taken from different angles. The pictures are made by a computer linked to an x-ray machine. A dye may be injected into a vein or swallowed to help the organs or tissues show up more clearly. This procedure is also called computed tomography, computerized tomography, or computerized axial tomography. EnlargeComputed tomography (CT) scan of the head and neck. The patient lies on a table that slides through the CT scanner, which takes x-ray pictures of the inside of the head and neck.
MRI (magnetic resonance imaging): A procedure that 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).
PET scan (positron emission tomography scan): A procedure to find malignanttumor cells in the body. A small amount of radioactiveglucose (sugar) is injected into a vein. The PET scanner rotates around the body and makes a picture of where glucose is being used in the body. Malignant tumor cells show up brighter in the picture because they are more active and take up more glucose than normal cells do.
PET-CT scan: A procedure that 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 with the same machine. The combined scans give more detailed pictures of areas inside the body than either scan gives by itself. A PET-CT scan may be used to help diagnose disease, such as cancer, plan treatment, or find out how well treatment is working.
Bone scan: A procedure to check 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.
Barium swallow: A series of x-rays of the esophagus and stomach. The patient drinks a liquid that contains barium (a silver-white metalliccompound). The liquid coats the esophagus and stomach, and x-rays are taken. This procedure is also called an upper GI series.
Certain factors affect prognosis (chance of recovery) and treatment options.
Smoking tobacco and drinking alcohol decrease the effectiveness of treatment for laryngeal cancer. Patients with laryngeal cancer who continue to smoke and drink are less likely to be cured and more likely to develop a second tumor. After treatment for laryngeal cancer, frequent and careful follow-up is important.
Stages of Laryngeal Cancer
Key Points
After laryngeal cancer has been diagnosed, tests are done to find out if cancer cells have spread within the larynx or to other parts of the body.
There are three ways that cancer spreads in the body.
Cancer may spread from where it began to other parts of the body.
The following stages are used for laryngeal cancer:
Stage 0 (Carcinoma in Situ)
Stage I
Stage II
Stage III
Stage IV
After surgery, the stage of the cancer may change and more treatment may be needed.
Laryngeal cancer can recur (come back) after it has been treated.
After laryngeal cancer has been diagnosed, tests are done to find out if cancer cells have spread within the larynx or to other parts of the body.
The process used to find out if cancer has spread within the larynx 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 of the disease in order to plan treatment. The results of some of the tests used to diagnoselaryngeal cancer are often also used to stage the disease.
There are three ways that cancer spreads in the body.
Tissue. The cancer spreads from where it began by growing into nearby areas.
Lymph system. The cancer spreads from where it began by getting into the lymph system. The cancer travels through the lymph vessels to other parts of the body.
Blood. The cancer spreads from where it began by getting into the blood. The cancer travels through the blood vessels to other parts of the body.
Cancer may spread from where it began to other parts of the body.
When cancer spreads to another part of the body, it is called metastasis. Cancer cells break away from where they began (the primary tumor) and travel through the lymph system or blood.
Lymph system. The cancer gets into the lymph system, travels through the lymph vessels, and forms a tumor (metastatic tumor) in another part of the body.
Blood. The cancer gets into the blood, travels through the blood vessels, and forms a tumor (metastatic tumor) in another part of the body.
The metastatic tumor is the same type of cancer as the primary tumor. For example, if laryngeal cancer spreads to the lung, the cancer cells in the lung are actually laryngeal cancer cells. The disease is metastatic laryngeal cancer, not lung cancer.
Many cancer deaths are caused when cancer moves from the original tumor and spreads to other tissues and organs. This is called metastatic cancer. This animation shows how cancer cells travel from the place in the body where they first formed to other parts of the body.
The following stages are used for laryngeal cancer:
Supraglottis: Cancer is in more than one area of the supraglottis or has spread to the area at the base of the tongue or to tissues near the vocal cords. The vocal cords work normally.
Glottis: Cancer has spread to the supraglottis, subglottis, or both, and/or the vocal cords do not work normally.
Subglottis: Cancer has spread to one or both vocal cords and the vocal cords may not work normally.
EnlargeTumor sizes are often measured in centimeters (cm) or inches. Common food items that can be used to show tumor size in cm include: a pea (1 cm), a peanut (2 cm), a grape (3 cm), a walnut (4 cm), a lime (5 cm or 2 inches), an egg (6 cm), a peach (7 cm), and a grapefruit (10 cm or 4 inches).
In stage III cancer of the supraglottis:
cancer is in the larynx only and the vocal cords do not work, and/or cancer has spread near or through the inner part of the thyroidcartilage. Cancer may have also spread to one lymph node on the same side of the neck as the primary tumor and the lymph node is 3 centimeters or smaller; or
cancer is in one area of the supraglottis and the vocal cords work normally. Cancer has spread to one lymph node on the same side of the neck as the primary tumor and the lymph node is 3 centimeters or smaller; or
cancer is in more than one area of the supraglottis or has spread to the area at the base of the tongue or to tissues near the vocal cords. The vocal cords work normally. Cancer has also spread to one lymph node on the same side of the neck as the primary tumor and the lymph node is 3 centimeters or smaller.
In stage III cancer of the glottis:
cancer is in the larynx only and the vocal cords do not work, and/or cancer has spread near or through the inner part of the thyroid cartilage. Cancer may have also spread to one lymph node on the same side of the neck as the primary tumor and the lymph node is 3 centimeters or smaller; or
cancer is in one or both vocal cords and the vocal cords work normally. Cancer has spread to one lymph node on the same side of the neck as the primary tumor and the lymph node is 3 centimeters or smaller; or
cancer has spread to the supraglottis, subglottis, or both, and/or the vocal cords do not work normally. Cancer has also spread to one lymph node on the same side of the neck as the primary tumor and the lymph node is 3 centimeters or smaller.
In stage III cancer of the subglottis:
cancer is in the larynx only and the vocal cords do not work, and/or cancer has spread near or through the inner part of the thyroid cartilage. Cancer may have also spread to one lymph node on the same side of the neck as the primary tumor and the lymph node is 3 centimeters or smaller; or
cancer is in the subglottis only. Cancer has spread to one lymph node on the same side of the neck as the primary tumor and the lymph node is 3 centimeters or smaller; or
cancer has spread to one or both vocal cords and the vocal cords may not work normally. Cancer has also spread to one lymph node on the same side of the neck as the primary tumor and the lymph node is 3 centimeters or smaller.
Cancer may have spread from the supraglottis, glottis, or subglottis to tissues beyond the larynx, such as the neck, trachea, thyroid, or esophagus. The vocal cords may not work normally. Cancer has spread:
to one lymph node on the same side of the neck as the primary tumor and the lymph node is 3 centimeters or smaller. Cancer has spread through the outside covering of the lymph node; or
to one lymph node on the same side of the neck as the primary tumor and the lymph node is larger than 3 centimeters but not larger than 6 centimeters. Cancer has not spread through the outside covering of the lymph node; or
to more than one lymph node on the same side of the neck as the primary tumor and the lymph nodes are not larger than 6 centimeters. Cancer has not spread through the outside covering of the lymph nodes; or
to lymph nodes on both sides of the neck or on the side of the neck opposite the primary tumor and the lymph nodes are not larger than 6 centimeters. Cancer has not spread through the outside covering of the lymph nodes.
In stage IVB:
Cancer may have spread from the supraglottis, glottis, or subglottis to the space in front of the spine, the area around the carotid artery, or the area between the lungs. The vocal cords may not work normally. Cancer has spread:
to one lymph node that is larger than 6 centimeters. Cancer has not spread through the outside covering of the lymph node; or
to one lymph node on the same side of the neck as the primary tumor and the lymph node is larger than 3 centimeters. Cancer has spread through the outside covering of the lymph node; or
to more than one lymph node anywhere in the neck. Cancer has spread through the outside covering of the lymph nodes; or
to one lymph node of any size on the side of the neck opposite the primary tumor. Cancer has spread through the outside covering of the lymph node;
or
Cancer has spread from the supraglottis, glottis, or subglottis to the space in front of the spine, the area around the carotid artery, or the area between the lungs. Cancer may have also spread to one or more lymph nodes anywhere in the neck and the lymph nodes may be any size.
In stage IVC, cancer has spread to other parts of the body, such as the lungs, liver, or bone.
After surgery, the stage of the cancer may change and more treatment may be needed.
If the cancer is removed by surgery, a pathologist will examine a sample of the cancer tissue under a microscope. Sometimes, the pathologist’s review will result in a change to the stage of the cancer and more treatment after surgery.
Laryngeal cancer can recur (come back) after it has been treated.
The cancer may come back in the larynx or in other parts of the body, such as lungs, liver, or bone. It is most likely to come back in the first 2 to 3 years.
Treatment Option Overview
Key Points
There are different types of treatment for patients with laryngeal cancer.
The following types of treatment are used:
Radiation therapy
Surgery
Chemotherapy
Immunotherapy
New types of treatment are being tested in clinical trials.
Targeted therapy
Radiosensitizers
Treatment for laryngeal cancer may cause side effects.
Patients may want to think about taking part in a clinical trial.
Patients can enter clinical trials before, during, or after starting their cancer treatment.
Follow-up tests may be needed.
There are different types of treatment for patients with laryngeal cancer.
Different types of treatment are available for patients with laryngeal cancer. Some treatments are standard (the currently used treatment), and some are being tested in clinical trials. A treatment clinical trial is a research study meant to help improve current treatments or obtain information on new treatments for patients with cancer. When clinical trials show that a new treatment is better than the standard treatment, the new treatment may become the standard treatment. Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.
The following types of treatment are used:
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. External radiation therapy uses a machine outside the body to send radiation toward the area of the body with cancer.
EnlargeExternal-beam radiation therapy of the head and neck. A machine is used to aim high-energy radiation at the cancer. The machine can rotate around the patient, delivering radiation from many different angles to provide highly conformal treatment. A mesh mask helps keep the patient’s head and neck from moving during treatment. Small ink marks are put on the mask. The ink marks are used to line up the radiation machine in the same position before each treatment.
Radiation therapy may work better in patients who have stopped smoking before beginning treatment. External radiation therapy to the thyroid or the pituitary gland may change the way the thyroid gland works. A blood test to check the thyroid hormone level in the body may be done before and after therapy to make sure the thyroid gland is working properly.
Hyperfractionated radiation therapy may be used to treat laryngeal cancer. Hyperfractionated radiation therapy is radiation treatment in which a smaller than usual total daily dose of radiation is divided into two doses and the treatments are given twice a day. Hyperfractionated radiation therapy is given over the same period of time (days or weeks) as standard radiation therapy. New types of radiation therapy are being studied in the treatment of laryngeal cancer.
Surgery
Surgery (removing the cancer in an operation) is a common treatment for all stages of laryngeal cancer. The following surgical procedures may be used:
Hemilaryngectomy: Surgery to remove half of the larynx (voice box). A hemilaryngectomy saves the voice.
Partial laryngectomy: Surgery to remove part of the larynx (voice box). A partial laryngectomy helps keep the patient’s ability to talk.
Total laryngectomy: Surgery to remove the whole larynx. During this operation, a hole is made in the front of the neck to allow the patient to breathe. This is called a tracheostomy.
Thyroidectomy: The removal of all or part of the thyroid gland.
Laser surgery: A surgical procedure that uses a laser beam (a narrow beam of intense light) as a knife to make bloodless cuts in tissue or to remove a surface lesion such as a tumor in the larynx.
After the doctor removes all the cancer that can be seen at the time of the surgery, some patients may be given chemotherapy or radiation therapy after surgery to kill any cancer cells that are left. Treatment given after the surgery, to lower the risk that the cancer will come back, is called adjuvant therapy.
Chemotherapy
Chemotherapy is a cancer treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping the cells from dividing. When chemotherapy is taken by mouth or injected into a vein or muscle, the drugs enter the bloodstream and can reach cancer cells throughout the body (systemic chemotherapy).
Immunotherapy is a treatment that uses the patient’s immune system to fight cancer. Substances made by the body or made in a laboratory are used to boost, direct, or restore the body’s natural defenses against cancer. This cancer treatment is a type of biologic therapy.
PD-1 and PD-L1 inhibitor therapy: PD-1 is a protein on the surface of T cells that helps keep the body’s immune responses in check. PD-L1 is a protein found on some types of cancer cells. When PD-1 attaches to PD-L1, it stops the T cell from killing the cancer cell. PD-1 and PD-L1 inhibitors keep PD-1 and PD-L1 proteins from attaching to each other. This allows the T cells to kill cancer cells. Nivolumab and pembrolizumab are types of PD-1 inhibitors used to treat metastatic or recurrent laryngeal cancer.
EnlargeImmune checkpoint inhibitor. Checkpoint proteins, such as PD-L1 on tumor cells and PD-1 on T cells, help keep immune responses in check. The binding of PD-L1 to PD-1 keeps T cells from killing tumor cells in the body (left panel). Blocking the binding of PD-L1 to PD-1 with an immune checkpoint inhibitor (anti-PD-L1 or anti-PD-1) allows the T cells to kill tumor cells (right panel).
Immunotherapy uses the body’s immune system to fight cancer. This animation explains one type of immunotherapy that uses immune checkpoint inhibitors to treat cancer.
New types of treatment are being tested in clinical trials.
This summary section describes treatments that are being studied in clinical trials. It may not mention every new treatment being studied. Information about clinical trials is available from the NCI website.
Targeted therapy
Targeted therapy is a type of treatment that uses drugs or other substances to identify and attack specific cancer cells.
Monoclonal antibodies: Monoclonal antibodies are immune system proteins made in the laboratory to treat many diseases, including cancer. As a cancer treatment, these antibodies can attach to a specific target on cancer cells or other cells that may help cancer cells grow. The antibodies are able to then kill the cancer cells, block their growth, or keep them from spreading. Monoclonal antibodies are given by infusion. They may be used alone or to carry drugs, toxins, or radioactive material directly to cancer cells. Cetuximab is being studied in the treatment of laryngeal cancer.
How do monoclonal antibodies work to treat cancer? This video shows how monoclonal antibodies, such as trastuzumab, pembrolizumab, and rituximab, block molecules cancer cells need to grow, flag cancer cells for destruction by the body’s immune system, or deliver harmful substances to cancer cells.
Radiosensitizers
Radiosensitizers are drugs that make tumor cells more sensitive to radiation therapy. Combining radiation therapy with radiosensitizers may kill more tumor cells.
Treatment for laryngeal cancer may cause side effects.
Patients may want to think about taking part in a clinical trial.
For some patients, taking part in a clinical trial may be the best treatment choice. Clinical trials are part of the cancer research process. Clinical trials are done to find out if new cancer treatments are safe and effective or better than the standard treatment.
Many of today’s standard treatments for cancer are based on earlier clinical trials. Patients who take part in a clinical trial may receive the standard treatment or be among the first to receive a new treatment.
Patients who take part in clinical trials also help improve the way cancer will be treated in the future. Even when clinical trials do not lead to effective new treatments, they often answer important questions and help move research forward.
Patients can enter clinical trials before, during, or after starting their cancer treatment.
Some clinical trials only include patients who have not yet received treatment. Other trials test treatments for patients whose cancer has not gotten better. There are also clinical trials that test new ways to stop cancer from recurring (coming back) or reduce the side effects of cancer treatment.
Clinical trials are taking place in many parts of the country. Information about clinical trials supported by NCI can be found on NCI’s clinical trials search webpage. Clinical trials supported by other organizations can be found on the ClinicalTrials.gov website.
Follow-up tests may be needed.
As you go through treatment, you will have follow-up tests or check-ups. Some tests that were done to diagnose or stage the cancer may be repeated to see how well the treatment is working. Decisions about whether to continue, change, or stop treatment may be based on the results of these tests.
Some of the tests will continue to be done from time to time after treatment has ended. The results of these tests can show if your condition has changed or if the cancer has recurred (come back).
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.
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.
Radiation therapy followed by surgery if cancer comes back in the same area.
Radiation therapy alone for patients who cannot be treated with chemotherapy and surgery.
Chemotherapy followed by chemotherapy and radiation therapy given together. Laryngectomy may be done if cancer remains.
A clinical trial of radiation therapy alone compared with radiation and targeted therapy (cetuximab).
A clinical trial of immunotherapy, chemotherapy, radiosensitizers, or radiation therapy.
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.
Chemotherapy followed by chemotherapy and radiation therapy given together. Laryngectomy may be done if cancer remains.
Radiation therapy alone for patients who cannot be treated with chemotherapy and surgery.
Surgery followed by radiation therapy. Chemotherapy may be given with the radiation therapy.
A clinical trial of radiation therapy alone compared with radiation and targeted therapy (cetuximab).
A clinical trial of immunotherapy, chemotherapy, radiosensitizers, or radiation therapy.
If cancer is in the subglottis, treatment may include the following:
Laryngectomy plus total thyroidectomy and removal of lymph nodes in the throat, usually followed by radiation therapy with or without chemotherapy.
Chemotherapy and radiation therapy given together.
A clinical trial of radiation therapy alone compared with radiation and targeted therapy (cetuximab).
A clinical trial of immunotherapy, chemotherapy, radiosensitizers, or radiation therapy.
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 and Recurrent Laryngeal Cancer
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.
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 adult laryngeal cancer. It is meant to inform and help patients, families, and caregivers. It does not give formal guidelines or recommendations for making decisions about health care.
Reviewers and Updates
Editorial Boards write the PDQ cancer information summaries and keep them up to date. These Boards are made up of experts in cancer treatment and other specialties related to cancer. The summaries are reviewed regularly and changes are made when there is new information. The date on each summary (“Updated”) is the date of the most recent change.
The information in this patient summary was taken from the health professional version, which is reviewed regularly and updated as needed, by the PDQ Adult Treatment Editorial Board.
Clinical Trial Information
A clinical trial is a study to answer a scientific question, such as whether one treatment is better than another. Trials are based on past studies and what has been learned in the laboratory. Each trial answers certain scientific questions in order to find new and better ways to help cancer patients. During treatment clinical trials, information is collected about the effects of a new treatment and how well it works. If a clinical trial shows that a new treatment is better than one currently being used, the new treatment may become “standard.” Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.
Clinical trials can be found online at NCI’s website. For more information, call the Cancer Information Service (CIS), NCI’s contact center, at 1-800-4-CANCER (1-800-422-6237).
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The best way to cite this PDQ summary is:
PDQ® Adult Treatment Editorial Board. PDQ Laryngeal Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/head-and-neck/patient/adult/laryngeal-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389298]
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Estimated new cases and deaths from laryngeal cancer in the United States in 2025:[1]
New cases: 13,020.
Deaths: 3,910.
Anatomy
The larynx is divided into the following three anatomical regions:
The supraglottic larynx includes the epiglottis, false vocal cords, ventricles, aryepiglottic folds, and arytenoids.
The glottis includes the true vocal cords and the anterior and posterior commissures.
The subglottic region begins about 1 cm below the true vocal cords and extends to the lower border of the cricoid cartilage or the first tracheal ring.
The supraglottic area is rich in lymphatic drainage. After penetrating the pre-epiglottic space and thyrohyoid membrane, lymphatic drainage is initially to the jugulodigastric and midjugular nodes. About 25% to 50% of patients present with involved lymph nodes. The precise figure depends on the T (tumor) stage. The true vocal cords are devoid of lymphatics. As a result, vocal cord cancer confined to the true cords rarely, if ever, presents with involved lymph nodes. Extension above or below the cords may, however, lead to lymph node involvement. Primary subglottic cancers, which are quite rare, drain through the cricothyroid and cricotracheal membranes to the pretracheal, paratracheal, and inferior jugular nodes, and occasionally to mediastinal nodes.[2]
Risk Factors
There is a clear association among smoking, excess alcohol ingestion, and the development of squamous cell cancers of the upper aerodigestive tract.[3] For smokers, the risk of laryngeal cancer decreases after they stop smoking but remains elevated, even years later, compared with that of nonsmokers.[4] If a patient who has had a single cancer continues to smoke and drink alcoholic beverages, the likelihood of a cure for the initial cancer, by any modality, is diminished, and the risk of second tumor is enhanced. Because of clinical problems related to smoking and alcohol use in this population, many patients die of intercurrent illness rather than the primary cancer.
Clinical Features
Supraglottic cancers typically present with sore throat, painful swallowing, referred ear pain, change in voice quality, or enlarged neck nodes. Early vocal cord cancers are usually detected because of hoarseness. By the time they are detected, cancers arising in the subglottic area commonly involve the vocal cords; thus, symptoms usually relate to contiguous spread.
Prognostic Factors
The most important adverse prognostic factors for laryngeal cancers include increasing T stage and N (regional lymph node) stage. Other prognostic factors may include sex, age, performance status, and a variety of pathological features of the tumor, including grade and depth of invasion.[5]
Prognosis for small laryngeal cancers that have not spread to lymph nodes is very good. Cure rates are 75% to 95% depending on the site, tumor bulk,[6] and degree of infiltration. Although most patients with early lesions can be cured by either radiation therapy or surgery, radiation therapy may be reasonable to preserve the voice, leaving surgery for salvage. Patients with a preradiation hemoglobin level higher than 13 g/dL have higher local control and survival rates than patients who are anemic.[7]
Locally advanced lesions are treated with combined modality treatment involving radiation and chemotherapy with or without surgery. The aim is laryngeal preservation in appropriately selected candidates.[8] Distant metastases are also common, even if the primary tumor is controlled.
Intermediate lesions have intermediate prognoses, depending on the site, T stage, N stage, and performance status. Therapy recommendations for patients with these lesions are based on a variety of complex anatomical, clinical, and social factors, which should be individualized and discussed in multidisciplinary consultation (surgery, radiation therapy, and dental and oral surgery) prior to prescribing therapy.
Follow-Up and Survivorship
Second primary tumors, often in the aerodigestive tract, have been reported in as many as 25% of patients whose initial lesion is controlled. A study has shown that daily treatment of these patients with moderate doses of isotretinoin (i.e., 13-cis-retinoic acid) for 1 year can significantly reduce the incidence of second tumors.[9] No survival advantage has been demonstrated, partially because of recurrence and death from the primary malignancy.
Patients treated for laryngeal cancers are at the highest risk of recurrence in the first 2 to 3 years. Recurrences after 5 years are rare and usually represent new primary malignancies. Close, regular follow-up is crucial to maximize the chance for salvage. Follow-up includes careful clinical examination and repetition of any abnormal staging study, along with attention to any treatment-related toxic effect or complication.
References
American Cancer Society: Cancer Facts and Figures 2025. American Cancer Society, 2025. Available online. Last accessed January 16, 2025.
Spaulding CA, Hahn SS, Constable WC: The effectiveness of treatment of lymph nodes in cancers of the pyriform sinus and supraglottis. Int J Radiat Oncol Biol Phys 13 (7): 963-8, 1987. [PUBMED Abstract]
Spitz MR: Epidemiology and risk factors for head and neck cancer. Semin Oncol 21 (3): 281-8, 1994. [PUBMED Abstract]
Bosetti C, Garavello W, Gallus S, et al.: Effects of smoking cessation on the risk of laryngeal cancer: an overview of published studies. Oral Oncol 42 (9): 866-72, 2006. [PUBMED Abstract]
Yilmaz T, Hoşal S, Gedikoglu G, et al.: Prognostic significance of depth of invasion in cancer of the larynx. Laryngoscope 108 (5): 764-8, 1998. [PUBMED Abstract]
Reddy SP, Mohideen N, Marra S, et al.: Effect of tumor bulk on local control and survival of patients with T1 glottic cancer. Radiother Oncol 47 (2): 161-6, 1998. [PUBMED Abstract]
Fein DA, Lee WR, Hanlon AL, et al.: Pretreatment hemoglobin level influences local control and survival of T1-T2 squamous cell carcinomas of the glottic larynx. J Clin Oncol 13 (8): 2077-83, 1995. [PUBMED Abstract]
Forastiere AA, Zhang Q, Weber RS, et al.: Long-term results of RTOG 91-11: a comparison of three nonsurgical treatment strategies to preserve the larynx in patients with locally advanced larynx cancer. J Clin Oncol 31 (7): 845-52, 2013. [PUBMED Abstract]
Hong WK, Lippman SM, Itri LM, et al.: Prevention of second primary tumors with isotretinoin in squamous-cell carcinoma of the head and neck. N Engl J Med 323 (12): 795-801, 1990. [PUBMED Abstract]
Cellular Classification of Laryngeal Cancer
Most laryngeal cancers are of squamous cell histology. Squamous cell subtypes include keratinizing and nonkeratinizing and well-differentiated to poorly differentiated grade. A variety of nonsquamous cell laryngeal cancers also occur.[1] These are not staged using the American Joint Cancer Committee staging system, and their management, which is not discussed here, can differ from that of squamous cell laryngeal cancers. In situ squamous cell carcinoma of the larynx is usually managed by a conservative surgical procedure such as mucosal stripping or superficial laser excision. Radiation therapy may also be appropriate treatment of selected patients with in situ carcinoma of the glottic larynx.
References
Mendenhall WM, Werning JW, Pfister DG: Treatment of head and neck cancer. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Lippincott Williams & Wilkins, 2011, pp 729-80.
Stage Information for Laryngeal Cancer
The staging system for laryngeal cancer is clinical and based on the best possible estimate of the extent of disease before treatment. The assessment of the primary tumor is based on inspection and palpation, when possible, and by fiberoptic laryngoscopy. Panendoscopy under anesthesia ensures careful clinical examination to determine clinical extent of local disease. The tumor must be confirmed histologically, and any other pathological data obtained on biopsy may be included. Head and neck magnetic resonance imaging, computed tomography, or positron emission tomography-computed tomography should be done before therapy to supplement inspection and palpation.[1] Additional radiographic studies may be included. The appropriate nodal drainage areas in the neck should be examined by careful palpation.
Definitions of TNM
The American Joint Committee on Cancer (AJCC) has designated staging by TNM (tumor, node, metastasis) classification to define laryngeal cancer.[2]
Table 1. Definition of Supraglottis, Glottis, and Subglottis Primary Tumor (T) for Laryngeal Cancera,b
T Category
T Criteria
aReprinted with permission from AJCC: Larynx. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 149–61.
TX
Primary tumor cannot be assessed.
Tis
Carcinoma in situ.
Supraglottis
T1
Tumor limited to one subsite of supraglottis with normal vocal cord mobility.
T2
Tumor invades mucosa of more than one adjacent subsite of supraglottis or glottis or region outside the supraglottis (e.g., mucosa of the base of the tongue, vallecula, medial wall of pyriform sinus) without fixation of the larynx.
T3
Tumor limited to larynx with vocal cord fixation and/or invades any of the following: postcricoid area, pre-epiglottic space, paraglottic space, and/or inner cortex of thyroid cartilage.
T4
Moderately advanced or very advanced.
–T4a
Moderately advanced local disease. Tumor invades through the outer cortex of the thyroid cartilage and/or invades tissues beyond the larynx (e.g., trachea, soft tissues of the neck including deep extrinsic muscle of the tongue, strap muscles, thyroid, or esophagus).
–T4b
Very advanced local disease. Tumor invades prevertebral space, encases carotid artery, or invades mediastinal structures.
Glottis
T1
Tumor limited to the vocal cord(s) (may involve anterior or posterior commissure) with normal mobility.
–T1a
Tumor limited to one vocal cord.
–T1b
Tumor involves both vocal cords.
T2
Tumor extends to supraglottis and/or subglottis, and/or with impaired vocal cord mobility.
T3
Tumor limited to the larynx with vocal cord fixation and/or invasion of paraglottic space and/or inner cortex of the thyroid cartilage.
T4
Moderately advanced or very advanced.
–T4a
Moderately advanced local disease. Tumor invades through the outer cortex of the thyroid cartilage and/or invades tissues beyond the larynx (e.g., trachea, cricoid cartilage, soft tissues of the neck including deep extrinsic muscle of the tongue, strap muscles, thyroid, or esophagus).
–T4b
Very advanced local disease. Tumor invades prevertebral space, encases carotid artery, or invades mediastinal structures.
Subglottis
T1
Tumor limited to the subglottis.
T2
Tumor extends to vocal cord(s) with normal or impaired mobility.
T3
Tumor limited to the larynx with vocal cord fixation and/or invasion of paraglottic space and/or inner cortex of the thyroid cartilage.
T4
Moderately advanced or very advanced.
–T4a
Moderately advanced local disease. Tumor invades cricoid or thyroid cartilage and/or invades tissues beyond the larynx (e.g., trachea, soft tissues of the neck including deep extrinsic muscles of the tongue, strap muscles, thyroid, or esophagus).
–T4b
Very advanced local disease. Tumor invades prevertebral space, encases carotid artery, or invades mediastinal structures.
Table 2. Definition of Clinical (cN) Regional Lymph Nodes (N) for Laryngeal Cancer a,b
N Category
N Criteria
ENE = extranodal extension.
aReprinted with permission from AJCC: Larynx. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 149–61.
bA designation of “U” or “L” may be used for any N category to indicate metastasis above the lower border of the cricoid (U) or below the lower border of the cricoid (L). Similarly, clinical and pathological ENE should be recorded as ENE(–) or ENE(+).
NX
Regional lymph nodes cannot be assessed.
N0
No regional lymph node metastasis.
N1
Metastasis in a single ipsilateral lymph node ≤3 cm in greatest dimension and ENE(–).
N2
Metastasis in a single ipsilateral node, >3 cm but not >6 cm in greatest dimension and ENE(–); or metastases in multiple ipsilateral lymph nodes, none >6 cm in greatest dimension and ENE(–); or metastases in bilateral or contralateral lymph nodes, none >6 cm in greatest dimension and ENE(–).
–N2a
Metastasis in a single ipsilateral node >3 cm but not >6 cm in greatest dimension and ENE(–).
–N2b
Metastases in multiple ipsilateral nodes, none >6 cm in greatest dimension and ENE(–).
–N2c
Metastases in bilateral or contralateral lymph nodes, none >6 cm in greatest dimension and ENE(–).
N3
Metastasis in a lymph node >6 cm in greatest dimension and ENE(–); or metastasis in any lymph nodes(s) with clinically overt ENE(+).
–N3a
Metastasis in a lymph node >6 cm in greatest dimension and ENE(–).
–N3b
Metastasis in any lymph node(s) with clinically overt ENE(+).
Table 3. Definition of Pathological (pN) Regional Lymph Nodes (N) for Laryngeal Cancera,b
N Category
N Criteria
ENE = extranodal extension.
aReprinted with permission from AJCC: Larynx. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 149–61.
bA designation of “U” or “L” may be used for any N category to indicate metastasis above the lower border of the cricoid (U) or below the lower border of the cricoid (L). Similarly, clinical and pathological ENE should be recorded as ENE(–) or ENE(+).
NX
Regional lymph nodes cannot be assessed.
N0
No regional lymph node metastasis.
N1
Metastasis in a single ipsilateral lymph node ≤3 cm in greatest dimension and ENE(–).
N2
Metastasis in a single ipsilateral lymph node, ≤3 cm in greatest dimension and ENE(+); or metastasis in a single ipsilateral lymph node, >3 cm but not >6 cm in greatest dimension and ENE(–); or metastases in multiple ipsilateral lymph nodes, none >6 cm in greatest dimension and ENE(–); or metastases in bilateral or contralateral lymph nodes, none >6 cm in greatest dimension and ENE(–).
–N2a
Metastasis in a single ipsilateral node ≤3 cm in greatest dimension and ENE(+); or metastasis in a single ipsilateral node >3 cm but not >6 cm in greatest dimension and ENE.
–N2b
Metastases in multiple ipsilateral nodes, none >6 cm in greatest dimension and ENE(–).
–N2c
Metastases in bilateral or contralateral lymph node(s), none >6 cm in greatest dimension and ENE(–).
N3
Metastasis in a lymph node >6 cm in greatest dimension and ENE(–); or metastasis in a single ipsilateral node >3 cm in greatest dimension and ENE(+); or metastases in multiple ipsilateral, contralateral, or bilateral lymph nodes and any with ENE(+); or a single contralateral node of any size and ENE(+).
–N3a
Metastasis in a lymph node, >6 cm in greatest dimension and ENE(–).
–N3b
Metastasis in a single ipsilateral node >3 cm in greatest dimension and ENE(+); or metastases in multiple ipsilateral, contralateral, or bilateral nodes and any with ENE(+); or a single contralateral node of any size and ENE(+).
Table 4. Definition of Distant Metastasis (M) for Laryngeal Cancera
M Category
M Criteria
aReprinted with permission from AJCC: Larynx. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 149–61.
M0
No distant metastasis.
M1
Distant metastasis.
AJCC Prognostic Stage Groups
Table 5. Definition of TNM Stage 0a
Stage
TNM
Description
T = primary tumor; N = regional lymph node; M = metastasis.
aReprinted with permission from AJCC: Larynx. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 149–61.
0
Tis, N0, M0
Tis = Carcinoma in situ.
N0 (cN and pN) = No regional lymph node metastasis.
M0 = No distant metastasis.
Table 6. Definition of TNM Stage Ia
Stage
TNM
Description
T = primary tumor; N = regional lymph node; M = metastasis; cN = clinical N; pN = pathological N.
aReprinted with permission from AJCC: Larynx. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 149–61.
I
T1, N0, M0
Supraglottis
T1 = Tumor limited to one subsite of supraglottis with normal vocal cord mobility.
Glottis
T1 = Tumor limited to the vocal cord(s) (may involve anterior or posterior commissure) with normal mobility.
–T1a = Tumor limited to one vocal cord.
–T1b = Tumor involves both vocal cords.
Subglottis
T1 = Tumor limited to the subglottis.
N0 (cN and pN) = No regional lymph node metastasis.
M0 = No distant metastasis.
Table 7. Definition of TNM Stage IIa
Stage
TNM
Description
T = primary tumor; N = regional lymph node; M = metastasis; cN = clinical N; pN = pathological N.
aReprinted with permission from AJCC: Larynx. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 149–61.
II
T2, N0, M0
Supraglottis
T2 = Tumor invades mucosa of more than one adjacent subsite of supraglottis or glottis or region outside the supraglottis (e.g., mucosa of the base of the tongue, vallecula, medial wall of pyriform sinus) without fixation of the larynx.
Glottis
T2 = Tumor extends to supraglottis and/or subglottis, and/or with impaired vocal cord mobility.
Subglottis
T2 = Tumor extends to vocal cord(s) with normal or impaired mobility.
N0 (cN and pN) = No regional lymph node metastasis.
M0 = No distant metastasis.
Table 8. Definition of TNM Stage IIIa
Stage
TNM
Description
T = primary tumor; N = regional lymph node; M = metastasis; cN = clinical N; ENE = extranodal extension; pN = pathological N.
aReprinted with permission from AJCC: Larynx. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 149–61.
III
T3, N0, M0
Supraglottis
T3 = Tumor limited to larynx with vocal cord fixation and/or invades any of the following: postcricoid area, pre-epiglottic space, paraglottic space, and/or inner cortex of thyroid cartilage.
Glottis
T3 = Tumor limited to the larynx with vocal cord fixation and/or invasion of paraglottic space and/or inner cortex of the thyroid cartilage.
Subglottis
T3 = Tumor limited to larynx with vocal cord fixation and/or invasion of paraglottic space and/or inner cortex of the thyroid cartilage.
N0 (cN or pN) = No regional lymph node metastasis.
M0 = No distant metastasis.
T1, T2, T3, N1, M0
Supraglottis
T1 = Tumor limited to one subsite of supraglottis with normal vocal cord mobility.
T2 = Tumor invades mucosa of more than one adjacent subsite of supraglottis or glottis or region outside the supraglottis (e.g., mucosa of the base of the tongue, vallecula, medial wall of pyriform sinus) without fixation of the larynx.
T3 = Tumor limited to larynx with vocal cord fixation and/or invades any of the following: postcricoid area, pre-epiglottic space, paraglottic space, and/or inner cortex of thyroid cartilage.
Glottis
T1 = Tumor limited to the vocal cord(s) (may involve anterior or posterior commissure) with normal mobility.
T1a = Tumor limited to one vocal cord.
T1b = Tumor involves both vocal cords.
T2 = Tumor extends to supraglottis and/or subglottis, and/or with impaired vocal cord mobility.
T3 = Tumor limited to the larynx with vocal cord fixation and/or invasion of paraglottic space and/or inner cortex of the thyroid cartilage.
Subglottis
T1 = Tumor limited to the subglottis.
T2 = Tumor extends to vocal cord(s) with normal or impaired mobility.
T3 = Tumor limited to the larynx with vocal cord fixation and/or invasion of paraglottic space and/or inner cortex of the thyroid cartilage.
N1 (cN or pN) = Metastasis in a single ipsilateral node, ≤3 cm in greatest dimension and ENE (–).
M0 = No distant metastasis.
Table 9. Definition of TNM Stage IVA, IVB, and IVCa
Stage
TNM
Description
T = primary tumor; N = regional lymph node; M = metastasis; cN = clinical N; ENE = extranodal extension; pN = pathological N.
aReprinted with permission from AJCC: Larynx. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 149–61.
IVA
T4a, N0, N1, M0
Supraglottis
–T4a = Moderately advanced local disease. Tumor invades through the outer cortex of the thyroid cartilage and/or invades tissues beyond the larynx (e.g., trachea, soft tissues of the neck including deep extrinsic muscle of the tongue, strap muscles, thyroid, or esophagus).
Glottis
–T4a = Moderately advanced local disease. Tumor invades through the outer cortex of the thyroid cartilage and/or invades tissues beyond the larynx (e.g., trachea, cricoid cartilage, soft tissues of the neck including deep extrinsic muscle of the tongue, strap muscles, thyroid, or esophagus).
Subglottis
–T4a = Moderately advanced local disease. Tumor invades cricoid or thyroid cartilage and/or invades tissues beyond the larynx (e.g., trachea, soft tissues of the neck including deep extrinsic muscles of the tongue, strap muscles, thyroid, or esophagus).
N0 (cN and pN) = Metastasis in a single ipsilateral node, ≤3 cm in greatest dimension and ENE (–).
N1 (cN and pN) = Metastasis in a single ipsilateral node, ≤3 cm in greatest dimension and ENE (–).
M0 = No distant metastasis.
T1, T2, T3, T4a, N2, M0
Supraglottis
T1 = Tumor limited to one subsite of supraglottis with normal vocal cord mobility.
T2 = Tumor invades mucosa of more than one adjacent subsite of supraglottis or glottis or region outside the supraglottis (e.g., mucosa of the base of the tongue, vallecula, medial wall of pyriform sinus) without fixation of the larynx.
T3 = Tumor limited to larynx with vocal cord fixation and/or invades any of the following: postcricoid area, pre-epiglottic space, paraglottic space, and/or inner cortex of thyroid cartilage.
–T4a = Moderately advanced local disease. Tumor invades through the outer cortex of the thyroid cartilage and/or invades tissues beyond the larynx (e.g., trachea, soft tissues of the neck including deep extrinsic muscle of the tongue, strap muscles, thyroid, or esophagus).
Glottis
T1 = Tumor limited to the vocal cord(s) (may involve anterior or posterior commissure) with normal mobility.
–T1a = Tumor limited to one vocal cord.
–T1b = Tumor involves both vocal cords.
T2 = Tumor extends to supraglottis and/or subglottis, and/or with impaired vocal cord mobility.
T3 = Tumor limited to the larynx with vocal cord fixation and/or invasion of paraglottic space and/or inner cortex of the thyroid cartilage.
–T4a = Moderately advanced local disease. Tumor invades through the outer cortex of the thyroid cartilage and/or invades tissues beyond the larynx (e.g., trachea, cricoid cartilage, soft tissues of the neck including deep extrinsic muscle of the tongue, strap muscles, thyroid, or esophagus).
Subglottis
T1 = Tumor limited to the subglottis.
T2 = Tumor extends to vocal cord(s) with normal or impaired mobility.
T3 = Tumor limited to the larynx with vocal cord fixation and/or invasion of paraglottic space and/or inner cortex of the thyroid cartilage.
–T4a = Moderately advanced local disease. Tumor invades through the outer cortex of the thyroid cartilage and/or invades tissues beyond the larynx (e.g., trachea, cricoid cartilage, soft tissues of the neck including deep extrinsic muscle of the tongue, strap muscles, thyroid, or esophagus).
cN2 = Metastasis in a single ipsilateral node >3 cm but not >6 cm in greatest dimension and ENE(–); or metastases in multiple ipsilateral lymph nodes, none >6 cm in greatest dimension and ENE(–); or metastases in bilateral or contralateral lymph nodes, none >6 cm in greatest dimension and ENE(–).
‒cN2a = Metastasis in a single ipsilateral node, larger than 3 cm but not larger than 6 cm in greatest dimension and ENE(–).
‒cN2b = Metastases in multiple ipsilateral nodes, none larger than 6 cm in greatest dimension and ENE(–).
‒cN2c = Metastasis in bilateral of contralateral lymph nodes, none larger than 6 cm in greatest dimension and ENE(–).
pN2 = Metastasis in a single ipsilateral lymph node, ≤3 cm in greatest dimension and ENE(+); or metastasis in a single ipsilateral lymph node >3 cm but not >6 cm in greatest dimension and ENE(–); or metastases in multiple ipsilateral lymph nodes, none >6 cm in greatest dimension and ENE(–); or metastases in bilateral or contralateral lymph nodes, none >6 cm in greatest dimension and ENE(–).
‒pN2a = Metastasis in a single ipsilateral or contralateral node, 3 cm or smaller in greatest dimension and ENE(+); or metastasis in a single ipsilateral node, larger than 3 cm but not larger than 6 cm in greatest dimension and ENE(–).
‒pN2b = Metastases in multiple ipsilateral nodes, none larger than 6 cm in greatest dimension and ENE(–).
‒pN2c = Metastasis in bilateral or contralateral lymph nodes, none larger than 6 cm in greatest dimension and ENE(–).
cN3 = Metastasis in a lymph node >6 cm in greatest dimension and ENE(–); or metastasis in any lymph node(s) with clinically overt ENE(+).
–cN3a = Metastasis in a lymph node >6 cm in greatest dimension and ENE(–).
–cN3b = Metastasis in any lymph node(s) with clinically overt ENE(+).
pN3 = Metastasis in a lymph node >6 cm in greatest dimension and ENE(–); or metastasis in a single ipsilateral node >3 cm in greatest dimension and ENE(+); or metastases in multiple ipsilateral, contralateral, or bilateral lymph nodes and any with ENE(+).
–pN3a = Metastasis in a lymph mode >6 cm in greatest dimension and ENE(–).
–pN3b = Metastasis in a single ipsilateral node >3 cm in greatest dimension and ENE(+); or metastases in multiple ipsilateral, contralateral, or bilateral lymph nodes and any with ENE(+).
M0 = No distant metastasis.
T4b, Any N, M0
Supraglottis
–T4b = Very advanced local disease. Tumor invades prevertebral space, encases carotid artery or invades mediastinal structures.
Glottis
–T4b = Very advanced local disease. Tumor invades prevertebral space, encases carotid artery, or invades mediastinal structures.
Subglottis
–T4b = Very advanced local disease. Tumor invades prevertebral space, encases carotid artery, or invades mediastinal structures.
Thabet HM, Sessions DG, Gado MH, et al.: Comparison of clinical evaluation and computed tomographic diagnostic accuracy for tumors of the larynx and hypopharynx. Laryngoscope 106 (5 Pt 1): 589-94, 1996. [PUBMED Abstract]
Surgery and radiation therapy have been the standard treatments for laryngeal cancer. However, outcome data from randomized trials are limited. Studies have attempted to evaluate the use of surgery or radiation but have been underpowered.[1] Selection of primary surgery versus radiation therapy–based treatment should be made in a multidisciplinary setting with consideration of disease stage, comorbidities, and functional status, including voice and swallowing outcomes and lung capacity.
Small superficial cancers without laryngeal fixation or lymph node involvement are successfully treated by radiation therapy or surgery alone, including laser excision surgery. Radiation therapy may be selected to preserve the voice and to reserve surgery for salvaging failures. The radiation field and dose are determined by the location and size of the primary tumor. A variety of curative surgical procedures are also recommended for laryngeal cancers, some of which preserve vocal function. An appropriate surgical procedure must be considered for each patient, given the anatomical problem, performance status, and clinical expertise of the treatment team. Advanced laryngeal cancers are often treated by combining radiation with concurrent chemotherapy for larynx preservation and total laryngectomy for bulky T4 disease or salvage.[2–4]
Evaluation of treatment outcome can be reported in various ways: locoregional control, disease-free survival, determinate survival, and overall survival (OS) at 2 to 5 years. Preservation of voice is an important parameter to evaluate. Outcome should be reported after initial surgery, initial radiation, planned combined treatment, or surgical salvage of radiation failures. Primary source material should be consulted to review these differences.
A review of published clinical results of definitive radiation therapy for head and neck cancer suggests a significant loss of local control when radiation therapy was prolonged. Extending standard treatment schedules should be avoided whenever possible.[5,6]
Radiation therapy has not been directly compared with endolaryngeal surgery (with or without laser) for the treatment of patients with early-stage laryngeal cancer. The evidence is insufficient to show a clear difference in local control or OS for these two treatment options. Retrospective data suggest that, compared with surgery, radiation therapy might cause less perturbation of voice quality without a significant difference in patient perception.[7]
Concurrent Chemoradiation Therapy
Concurrent chemoradiation therapy is a standard treatment option for patients with locally advanced (stage III and stage IV) laryngeal cancer.
Evidence (concurrent chemoradiation therapy):
A meta-analysis of 93 randomized prospective head and neck cancer trials published between 1965 and 2000 showed the following:[8][Level of evidence B4]
The subset of patients receiving chemotherapy and radiation therapy had a 4.5% absolute survival advantage.
Patients who received concurrent chemotherapy had a greater survival benefit than those who received neoadjuvant chemotherapy.
In a randomized trial of patients with locally advanced head and neck cancer, curative-intent radiation therapy alone (213 patients) was compared with radiation therapy plus weekly cetuximab (211 patients).[9] The initial dose of cetuximab was 400 mg/m2 of body-surface area 1 week before radiation therapy was started, followed by a weekly dose of 250 mg/m2 of body-surface area for the duration of the radiation therapy. This study allowed altered-fractionation regimens to be used in both arms.[9,10][Level of evidence A1]
At a median follow-up of 54 months, patients treated with cetuximab and radiation therapy demonstrated significantly higher progression-free survival (PFS) (hazard ratio [HR] for disease progression or death, 0.70; P = .006).
Patients in the cetuximab arm experienced higher rates of acneiform rash and infusion reactions, although the incidence of other grade 3 or higher toxicities, including mucositis, did not differ significantly between the two groups.
Neoadjuvant Chemotherapy Followed by Concurrent Chemoradiation Therapy
In a meta-analysis of five randomized trials, a total of 1,022 patients with locally advanced head and neck squamous cell cancer were randomly assigned to receive either neoadjuvant chemotherapy with TPF (docetaxel, cisplatin, and fluorouracil [5-FU]) followed by concurrent chemoradiation therapy or concurrent chemoradiation therapy alone. The analysis failed to show an OS (HR, 1.01; 95% confidence limits [CLs], 0.84–1.21; P = .92) or PFS (HR, 0.91; 95% CLs, 0.75–1.1; P = .32) advantage for neoadjuvant chemotherapy using the TPF regimen over concurrent chemoradiation therapy alone.[11][Level of evidence A1]
Evidence (neoadjuvant chemotherapy followed by concurrent chemoradiation therapy):
The Department of Veterans Affairs (VA) Laryngeal Cancer Study Group directly compared chemotherapy followed by radiation therapy versus up-front surgery with postoperative radiation therapy. A total of 332 patients were randomly assigned to either three cycles of chemotherapy (cisplatin and 5-FU) and radiation therapy or surgery and radiation therapy.[12]
After two cycles of chemotherapy, the clinical tumor response was complete in 31% of the patients, and there was a partial response in 54% of the patients. Survival was similar in both arms; however, larynx preservation was possible in 64% of the patients in the chemotherapy-followed-by-radiation therapy arm.
The VA study was followed by a randomized study, RTOG 9111 (NCT00002496), in which the laryngeal preservation arm of the VA study was compared with the concurrent chemoradiation therapy and radiation therapy-alone arms. The primary end point was laryngectomy-free survival.[4] RTOG 9111 evaluated 547 patients with locally advanced laryngeal cancer who were enrolled between August 1992 and May 2000, with a median follow-up for surviving patients of 10.8 years (range, 0.07–17 years). Three regimens were compared, including neoadjuvant chemotherapy plus radiation therapy, concurrent chemoradiation therapy, and radiation therapy alone.
Both chemotherapy regimens improved laryngectomy-free survival compared with radiation therapy alone (neoadjuvant chemotherapy vs. radiation therapy alone, HR, 0.75; 95% confidence interval [CI], 0.59–0.95; P = .02; concurrent chemotherapy vs. radiation therapy alone, HR, 0.78; 95% CI, 0.78–0.98; P = .03).
Concurrent radiation therapy plus cisplatin resulted in a statistically significantly higher percentage of patients with an intact larynx at 10 years (67.5% for patients who had neoadjuvant chemotherapy; 81.7% for patients who had concurrent chemotherapy; and 63.8% for patients who received radiation therapy alone); 80% of laryngectomies were performed during the first 2 years (84 laryngectomies during year 1 and 35 laryngectomies during year 2).
Concurrent cisplatin with radiation therapy resulted in a 41% reduction in risk of locoregional failure compared with radiation therapy alone (HR, 0.59; 95% CI, 0.43–0.82; P = .0015) and a 34% reduction in risk compared with neoadjuvant chemotherapy (HR, 0.66; 95% CI, 0.48–0.92; P = .004). Both chemotherapy regimens had a lower incidence of distant metastases, although this did not reach statistical significance compared with radiation therapy alone.
The 10-year cumulative rates of late toxicity (grades 3–5) were 30.6% for neoadjuvant chemotherapy, 33.3% for concurrent chemotherapy, and 38% for radiation therapy alone, and were not significantly different between the arms.
OS was not significantly different between the groups, although there was possibly a worse outcome in the concurrent groups compared with the neoadjuvant chemotherapy group (HR, 1.25; 95% CI, 0.98–1.61; P = .08). The OS rates were 58% (5 year) and 39% (10 year) for neoadjuvant chemotherapy, 55% (5 year) and 28% (10 year) for concurrent chemoradiation therapy, and 54% (5 year) and 32% (10 year) for radiation therapy alone.
The number of deaths not attributed to larynx cancer or treatment were higher with concurrent chemotherapy (30.8% vs. 20.8% with neoadjuvant chemotherapy and 16.9% with radiation alone), because after approximately 4.5 years, the survival curves began to separate and favor neoadjuvant chemotherapy, although the difference was not statistically significant.
Fluorouracil dosing
The DPYD gene encodes an enzyme that catabolizes pyrimidines and fluoropyrimidines, like capecitabine and fluorouracil. An estimated 1% to 2% of the population has germline pathogenic variants in DPYD, which lead to reduced DPD protein function and an accumulation of pyrimidines and fluoropyrimidines in the body.[13,14] Patients with the DPYD*2A variant who receive fluoropyrimidines may experience severe, life-threatening toxicities that are sometimes fatal. Many other DPYD variants have been identified, with a range of clinical effects.[13–15] Fluoropyrimidine avoidance or a dose reduction of 50% may be recommended based on the patient’s DPYD genotype and number of functioning DPYD alleles.[16–18] DPYD genetic testing costs less than $200, but insurance coverage varies due to a lack of national guidelines.[19] In addition, testing may delay therapy by 2 weeks, which would not be advisable in urgent situations. This controversial issue requires further evaluation.[20]
Altered Fractionation Versus Standard Fractionation Radiation Therapy
Radiation therapy alone with altered fractionation may be used for patients with locally advanced laryngeal cancer who are not candidates for chemotherapy. Altered fractionation radiation therapy yields a higher locoregional control rate compared with standard fractionated radiation therapy for patients with stage III and stage IV head and neck cancer.
Evidence (altered fractionation vs. standard fractionation radiation therapy):
Standard fractionation (SFX) to 70 Gy in 35 daily fractions for 7 weeks.
Hyperfractionation (HFX) to 81.6 Gy in 68 twice-daily fractions for 7 weeks.
Accelerated fractionation split course (AFX-S) to 67.2 Gy in 42 fractions for 6 weeks with a 2-week rest after 38.4 Gy.
Accelerated concurrent boost fractionation (AFX-C) to 72 Gy in 42 fractions for 6 weeks.
In a long-term analysis, the three investigational arms were compared with SFX.
Only the HFX arm showed superior locoregional control and survival at 5 years compared with the SFX arm (HR, 0.79; 95% CI, 0.62–1.00; P = .05).
AFX-C was associated with increased late toxicity compared with SFX.
The following results were shown in a meta-analysis of 15 randomized trials with a total of 6,515 patients and a median follow-up of 6 years involving the assessment of HFX or AFX-S for patients with stage III and stage IV oropharyngeal cancer:[23][Level of evidence A1]
There was a significant survival benefit with altered-fractionated radiation therapy and a 3.4% absolute benefit at 5 years (HR, 0.92; 95% CI, 0.86–0.97; P = .003).
Altered-fractionation radiation therapy improves locoregional control, with greater benefit shown in younger patients.
HFX demonstrated a greater survival benefit (8% at 5 years) than did AFX-S (2% with accelerated fractionation without total dose-reduction and 1.7% with total dose-reduction at 5 years; P = .02).
An additional late effect from radiation therapy is hypothyroidism, which occurs in 30% to 40% of patients who have received external-beam radiation therapy to the entire thyroid gland. Thyroid function testing of patients is a consideration before therapy and as part of posttreatment follow-up.[24,25]
Prospective data from two randomized controlled trials reported the incidence of hypothyroidism.[26]
At a median follow-up of 41 months, 55.1% of the patients developed hypothyroidism (39.3% subclinical, 15.7% biochemical).
Patients who underwent intensity-modulated radiation therapy (IMRT) had higher subclinical hypothyroidism (51.1% vs. 27.3%; P = .021), peaking around 1 year after radiation therapy.
Younger age, hypopharynx/larynx primary, node positivity, higher dose/fraction (IMRT arm), and D100 were statistically significant factors for developing hypothyroidism.[26][Level of evidence A3]
For patients with well-lateralized oropharyngeal cancer, such as a T1 or T2 tonsil primary tumor with limited extension into the palate or tongue base and limited ipsilateral lymph node involvement without extracapsular extension, elective treatment to the ipsilateral lymph nodes results in only minimal risk of spread to the contralateral neck.[27] For T3 and T4 tumors that are midline or approach the midline, bilateral nodal treatment is a consideration. In addition to the cervical lymph node chain, retropharyngeal lymph nodes can also be encompassed in the elective nodal treatment.
Surgery Followed by Postoperative Radiation Therapy (PORT) With or Without Chemotherapy for Patients With Locally Advanced Disease
New surgical techniques for resection and reconstruction that provide access and functional preservation have extended the surgical options for patients with stage III or stage IV laryngeal cancer. Specific surgical procedures and their modifications are not described here because of the wide variety of surgical approaches, the variety of opinions about the role of modified neck dissections, and the multiple reconstructive techniques that may give the same results. This group of patients is managed by head and neck surgeons who are skilled in the multiple procedures available and are actively and frequently involved in the care of these patients.
Depending on pathological findings after primary surgery, PORT with or without chemotherapy is used in the adjuvant setting for the following histological findings:
T4 disease.
Perineural invasion.
Lymphovascular invasion.
Positive margins or margins less than 5 mm.
Extracapsular extension of a lymph node.
Two or more involved lymph nodes.
The addition of chemotherapy to PORT for laryngeal cancer squamous cell carcinoma demonstrates a locoregional control and OS benefit compared with radiation therapy alone in patients who have high-risk pathological risk factors, extracapsular extension of a lymph node, or positive margins, based on a pooled analysis of the EORTC-22931 [NCT00002555] and RTOG-9501 [NCT00002670] studies.[28–31][Level of evidence A1]
For patients with intermediate pathological risk factors, the addition of cisplatin chemotherapy given concurrently with PORT is unclear. Intermediate pathological risk factors include:
T3 and T4 disease (or stage III and stage IV disease).
Perineural infiltration.
Vascular embolisms.
Clinically enlarged level IV–V lymph nodes secondary to tumors arising in the oral cavity or oropharynx.
Two or more histopathologically involved lymph nodes without extracapsular extension.
Close margins less than 5 mm.
The addition of cetuximab with radiation therapy in the postoperative setting for these intermediate pathological risk factors is being tested in a randomized trial (RTOG-0920 [NCT00956007]).
The incidence of lymph node metastases in patients with stage I glottic cancer ranges from 0% to 2%; for more advanced disease, such as stage II, 10%; and for stage III glottic, 15%. Thus, there is no need to treat glottic cancer cervical lymph nodes electively in patients with stage I tumors and small stage II tumors. Elective neck radiation is a consideration for T3 or T4 glottic tumors or T1 to T4 supraglottic tumors.[32]
For patients with cancer of the subglottis, combined modality therapy is generally preferred for the uncommon small lesions (i.e., stage I or stage II); however, radiation therapy alone may be used.
Patients who smoke during radiation therapy appear to have lower response rates and shorter survival durations than those who do not.[33] Such patients should be counseled on smoking cessation before beginning radiation therapy.
References
Iyer NG, Tan DS, Tan VK, et al.: Randomized trial comparing surgery and adjuvant radiotherapy versus concurrent chemoradiotherapy in patients with advanced, nonmetastatic squamous cell carcinoma of the head and neck: 10-year update and subset analysis. Cancer 121 (10): 1599-607, 2015. [PUBMED Abstract]
Silver CE, Ferlito A: Surgery for Cancer of the Larynx and Related Structures. 2nd ed. Saunders, 1996.
Mendenhall WM, Werning JW, Pfister DG: Treatment of head and neck cancer. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Lippincott Williams & Wilkins, 2011, pp 729-80.
Forastiere AA, Zhang Q, Weber RS, et al.: Long-term results of RTOG 91-11: a comparison of three nonsurgical treatment strategies to preserve the larynx in patients with locally advanced larynx cancer. J Clin Oncol 31 (7): 845-52, 2013. [PUBMED Abstract]
Fowler JF, Lindstrom MJ: Loss of local control with prolongation in radiotherapy. Int J Radiat Oncol Biol Phys 23 (2): 457-67, 1992. [PUBMED Abstract]
Hansen O, Overgaard J, Hansen HS, et al.: Importance of overall treatment time for the outcome of radiotherapy of advanced head and neck carcinoma: dependency on tumor differentiation. Radiother Oncol 43 (1): 47-51, 1997. [PUBMED Abstract]
Yoo J, Lacchetti C, Hammond JA, et al.: Role of endolaryngeal surgery (with or without laser) compared with radiotherapy in the management of early (T1) glottic cancer: a clinical practice guideline. Curr Oncol 20 (2): e132-5, 2013. [PUBMED Abstract]
Pignon JP, le Maître A, Maillard E, et al.: Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients. Radiother Oncol 92 (1): 4-14, 2009. [PUBMED Abstract]
Bonner JA, Harari PM, Giralt J, et al.: Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 354 (6): 567-78, 2006. [PUBMED Abstract]
Curran D, Giralt J, Harari PM, et al.: Quality of life in head and neck cancer patients after treatment with high-dose radiotherapy alone or in combination with cetuximab. J Clin Oncol 25 (16): 2191-7, 2007. [PUBMED Abstract]
Budach W, Bölke E, Kammers K, et al.: Induction chemotherapy followed by concurrent radio-chemotherapy versus concurrent radio-chemotherapy alone as treatment of locally advanced squamous cell carcinoma of the head and neck (HNSCC): A meta-analysis of randomized trials. Radiother Oncol 118 (2): 238-43, 2016. [PUBMED Abstract]
Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. The Department of Veterans Affairs Laryngeal Cancer Study Group. N Engl J Med 324 (24): 1685-90, 1991. [PUBMED Abstract]
Sharma BB, Rai K, Blunt H, et al.: Pathogenic DPYD Variants and Treatment-Related Mortality in Patients Receiving Fluoropyrimidine Chemotherapy: A Systematic Review and Meta-Analysis. Oncologist 26 (12): 1008-1016, 2021. [PUBMED Abstract]
Lam SW, Guchelaar HJ, Boven E: The role of pharmacogenetics in capecitabine efficacy and toxicity. Cancer Treat Rev 50: 9-22, 2016. [PUBMED Abstract]
Shakeel F, Fang F, Kwon JW, et al.: Patients carrying DPYD variant alleles have increased risk of severe toxicity and related treatment modifications during fluoropyrimidine chemotherapy. Pharmacogenomics 22 (3): 145-155, 2021. [PUBMED Abstract]
Amstutz U, Henricks LM, Offer SM, et al.: Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Dihydropyrimidine Dehydrogenase Genotype and Fluoropyrimidine Dosing: 2017 Update. Clin Pharmacol Ther 103 (2): 210-216, 2018. [PUBMED Abstract]
Henricks LM, Lunenburg CATC, de Man FM, et al.: DPYD genotype-guided dose individualisation of fluoropyrimidine therapy in patients with cancer: a prospective safety analysis. Lancet Oncol 19 (11): 1459-1467, 2018. [PUBMED Abstract]
Lau-Min KS, Varughese LA, Nelson MN, et al.: Preemptive pharmacogenetic testing to guide chemotherapy dosing in patients with gastrointestinal malignancies: a qualitative study of barriers to implementation. BMC Cancer 22 (1): 47, 2022. [PUBMED Abstract]
Brooks GA, Tapp S, Daly AT, et al.: Cost-effectiveness of DPYD Genotyping Prior to Fluoropyrimidine-based Adjuvant Chemotherapy for Colon Cancer. Clin Colorectal Cancer 21 (3): e189-e195, 2022. [PUBMED Abstract]
Baker SD, Bates SE, Brooks GA, et al.: DPYD Testing: Time to Put Patient Safety First. J Clin Oncol 41 (15): 2701-2705, 2023. [PUBMED Abstract]
Fu KK, Pajak TF, Trotti A, et al.: A Radiation Therapy Oncology Group (RTOG) phase III randomized study to compare hyperfractionation and two variants of accelerated fractionation to standard fractionation radiotherapy for head and neck squamous cell carcinomas: first report of RTOG 9003. Int J Radiat Oncol Biol Phys 48 (1): 7-16, 2000. [PUBMED Abstract]
Beitler JJ, Zhang Q, Fu KK, et al.: Final results of local-regional control and late toxicity of RTOG 9003: a randomized trial of altered fractionation radiation for locally advanced head and neck cancer. Int J Radiat Oncol Biol Phys 89 (1): 13-20, 2014. [PUBMED Abstract]
Baujat B, Bourhis J, Blanchard P, et al.: Hyperfractionated or accelerated radiotherapy for head and neck cancer. Cochrane Database Syst Rev (12): CD002026, 2010. [PUBMED Abstract]
Turner SL, Tiver KW, Boyages SC: Thyroid dysfunction following radiotherapy for head and neck cancer. Int J Radiat Oncol Biol Phys 31 (2): 279-83, 1995. [PUBMED Abstract]
Constine LS: What else don’t we know about the late effects of radiation in patients treated for head and neck cancer? Int J Radiat Oncol Biol Phys 31 (2): 427-9, 1995. [PUBMED Abstract]
Murthy V, Narang K, Ghosh-Laskar S, et al.: Hypothyroidism after 3-dimensional conformal radiotherapy and intensity-modulated radiotherapy for head and neck cancers: prospective data from 2 randomized controlled trials. Head Neck 36 (11): 1573-80, 2014. [PUBMED Abstract]
O’Sullivan B, Warde P, Grice B, et al.: The benefits and pitfalls of ipsilateral radiotherapy in carcinoma of the tonsillar region. Int J Radiat Oncol Biol Phys 51 (2): 332-43, 2001. [PUBMED Abstract]
Cooper JS, Pajak TF, Forastiere AA, et al.: Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med 350 (19): 1937-44, 2004. [PUBMED Abstract]
Bernier J, Domenge C, Ozsahin M, et al.: Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med 350 (19): 1945-52, 2004. [PUBMED Abstract]
Bernier J, Cooper JS, Pajak TF, et al.: Defining risk levels in locally advanced head and neck cancers: a comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (# 9501). Head Neck 27 (10): 843-50, 2005. [PUBMED Abstract]
Cooper JS, Zhang Q, Pajak TF, et al.: Long-term follow-up of the RTOG 9501/intergroup phase III trial: postoperative concurrent radiation therapy and chemotherapy in high-risk squamous cell carcinoma of the head and neck. Int J Radiat Oncol Biol Phys 84 (5): 1198-205, 2012. [PUBMED Abstract]
Spaulding CA, Hahn SS, Constable WC: The effectiveness of treatment of lymph nodes in cancers of the pyriform sinus and supraglottis. Int J Radiat Oncol Biol Phys 13 (7): 963-8, 1987. [PUBMED Abstract]
Browman GP, Wong G, Hodson I, et al.: Influence of cigarette smoking on the efficacy of radiation therapy in head and neck cancer. N Engl J Med 328 (3): 159-63, 1993. [PUBMED Abstract]
Treatment of Stage I Laryngeal Cancer
Supraglottis
Treatment options for stage I cancer of the supraglottis include:
Supraglottic laryngectomy. Total laryngectomy may be reserved for patients unable to tolerate potential respiratory complications of surgery or the supraglottic laryngectomy.
Glottis
Treatment options for stage I cancer of the glottis include:
Selection of treatment should include an evaluation of voice function and quality after treatment. Endoscopic CO2 laser resections may also achieve similar results in terms of local control and function [8] compared with radiation therapy, although no randomized studies have been performed.[9]
Evidence (transoral CO2 laser excision vs. EBRT):
A meta-analysis examined oncologic control in 22 consecutive case series.
No clear differences were demonstrated between transoral CO2 laser excision and EBRT in terms of local control (odds ratio [OR], 0.81; 95% confidence interval [CI], 0.51–1.3) and laryngectomy-free survival (OR, 0.84; 95% CI, 0.42–1.66).
There was a trend for improved posttreatment voice quality with radiation therapy. Transoral CO2 laser–excision surgery dominates radiation therapy from a cost-utility standpoint.[5][Level of evidence B4]
Conventional radiation therapy versus hypofractionated radiation therapy
Conventional and hypofractionated radiation therapy regimens have been studied regarding radiation-dose fractionation for patients with early-stage larynx cancer.
Evidence (conventional radiation therapy vs. hypofractionated radiation therapy):
In a randomized study of patients with early-stage larynx cancer, patients were assigned to standard fractionation in 2 Gy daily fractions or a hypofractionated regimen of 2.25 Gy daily; 82 patients were allocated to a conventional fractionation (CONV) arm (66 Gy/33 fractions for T1 and 70 Gy/35 fractions for T2), with 74 patients to the hypofractionation (HYPO) arm (63 Gy/28 fractions for T1 and 67.5 Gy/30 fractions for T2).[10] The study was underpowered and closed early because of a lack of accrual, although no statistically significant differences were seen between treatment arms in terms of local progression-free survival (PFS).
With a median follow-up of 67 months (range, 2–122 months), the 5-year local PFS rate was 77.8% for the CONV arm and 88.5% for the HYPO arm (hazard ratio [HR], 1.55; P = .213).
No significant difference was observed in the toxicity profile between the two arms.
In a subgroup exploratory analysis for T1a disease, the 5-year local PFS rate trended positively in the HYPO arm (76.7% vs. 93.0%; HR, 3.65; P = .056).[10][Level of evidence B1]
Earlier single-institution reports support hypofractionated regimens using 2.25 Gy per fraction for early T1 and T2 larynx cancer with high local control rates.[11][Level of evidence C3]
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
Mittal B, Rao DV, Marks JE, et al.: Role of radiation in the management of early vocal cord carcinoma. Int J Radiat Oncol Biol Phys 9 (7): 997-1002, 1983. [PUBMED Abstract]
Wang CC: Factors influencing the success of radiation therapy for T2 and T3 glottic carcinomas. Importance of cord mobility and sex. Am J Clin Oncol 9 (6): 517-20, 1986. [PUBMED Abstract]
Mendenhall WM, Amdur RJ, Morris CG, et al.: T1-T2N0 squamous cell carcinoma of the glottic larynx treated with radiation therapy. J Clin Oncol 19 (20): 4029-36, 2001. [PUBMED Abstract]
Foote RL, Olsen KD, Kunselman SJ, et al.: Early-stage squamous cell carcinoma of the glottic larynx managed with radiation therapy. Mayo Clin Proc 67 (7): 629-36, 1992. [PUBMED Abstract]
Higgins KM: What treatment for early-stage glottic carcinoma among adult patients: CO2 endolaryngeal laser excision versus standard fractionated external beam radiation is superior in terms of cost utility? Laryngoscope 121 (1): 116-34, 2011. [PUBMED Abstract]
Steiner W: Results of curative laser microsurgery of laryngeal carcinomas. Am J Otolaryngol 14 (2): 116-21, 1993 Mar-Apr. [PUBMED Abstract]
Olsen KD, Thomas JV, DeSanto LW, et al.: Indications and results of cordectomy for early glottic carcinoma. Otolaryngol Head Neck Surg 108 (3): 277-82, 1993. [PUBMED Abstract]
Agrawal A, Moon J, Davis RK, et al.: Transoral carbon dioxide laser supraglottic laryngectomy and irradiation in stage I, II, and III squamous cell carcinoma of the supraglottic larynx: report of Southwest Oncology Group Phase 2 Trial S9709. Arch Otolaryngol Head Neck Surg 133 (10): 1044-50, 2007. [PUBMED Abstract]
Dey P, Arnold D, Wight R, et al.: Radiotherapy versus open surgery versus endolaryngeal surgery (with or without laser) for early laryngeal squamous cell cancer. Cochrane Database Syst Rev (2): CD002027, 2002. [PUBMED Abstract]
Fein DA, Mendenhall WM, Parsons JT, et al.: T1-T2 squamous cell carcinoma of the glottic larynx treated with radiotherapy: a multivariate analysis of variables potentially influencing local control. Int J Radiat Oncol Biol Phys 25 (4): 605-11, 1993. [PUBMED Abstract]
Moon SH, Cho KH, Chung EJ, et al.: A prospective randomized trial comparing hypofractionation with conventional fractionation radiotherapy for T1-2 glottic squamous cell carcinomas: results of a Korean Radiation Oncology Group (KROG-0201) study. Radiother Oncol 110 (1): 98-103, 2014. [PUBMED Abstract]
Treatment of Stage II Laryngeal Cancer
Supraglottis
Treatment options for stage II cancer of the supraglottis include:
External-beam radiation therapy alone for the smaller lesions encompassing the primary disease and regional elective nodes.[1]
Supraglottic laryngectomy with bilateral neck dissections, depending on location of the lesion, clinical status of the patient, and expertise of the treatment team. Careful selection must be made to ensure adequate pulmonary and swallowing function postoperatively.
Postoperative radiation therapy (PORT) is indicated for positive or close surgical margins or other adverse pathological risk factors.
Radiation therapy should be preferred because of the good results, preservation of the voice, and the possibility of surgical salvage in patients whose disease recurs locally.
Glottis
Treatment options for stage II cancer of the glottis include:
Partial or hemilaryngectomy or total laryngectomy, depending on anatomical considerations. Under certain circumstances, laser microsurgery may be appropriate.[6]
Subglottis
Treatment options for stage II cancer of the subglottis include:
Lesions can be treated successfully by radiation therapy alone with preservation of normal voice.[1]
Surgery is reserved for failure of radiation therapy or for patients in whom follow-up is likely to be difficult.
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
Mendenhall WM, Werning JW, Pfister DG: Treatment of head and neck cancer. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Lippincott Williams & Wilkins, 2011, pp 729-80.
Mittal B, Marks JE, Ogura JH: Transglottic carcinoma. Cancer 53 (1): 151-61, 1984. [PUBMED Abstract]
Medini E, Medini I, Lee CK, et al.: Curative radiotherapy for stage II-III squamous cell carcinoma of the glottic larynx. Am J Clin Oncol 21 (3): 302-5, 1998. [PUBMED Abstract]
Mendenhall WM, Amdur RJ, Morris CG, et al.: T1-T2N0 squamous cell carcinoma of the glottic larynx treated with radiation therapy. J Clin Oncol 19 (20): 4029-36, 2001. [PUBMED Abstract]
Higgins KM: What treatment for early-stage glottic carcinoma among adult patients: CO2 endolaryngeal laser excision versus standard fractionated external beam radiation is superior in terms of cost utility? Laryngoscope 121 (1): 116-34, 2011. [PUBMED Abstract]
Steiner W: Results of curative laser microsurgery of laryngeal carcinomas. Am J Otolaryngol 14 (2): 116-21, 1993 Mar-Apr. [PUBMED Abstract]
Treatment of Stage III Laryngeal Cancer
Supraglottis
Treatment options for stage III cancer of the supraglottis include:
Definitive radiation therapy alone with altered fractionation in patients who are not candidates for concurrent chemotherapy and surgery (total laryngectomy) for salvage of radiation failures.[7]
Surgery with or without postoperative radiation therapy (PORT).[8]
Glottis
Treatment options for stage III cancer of the glottis include:
Definitive radiation therapy alone with altered fractionation in patients who are not candidates for concurrent chemotherapy and surgery (total laryngectomy) for salvage of radiation failures.[7]
Treatment options for stage III cancer of the subglottis include:
Laryngectomy plus isolated thyroidectomy and tracheoesophageal node dissection usually followed by PORT.[10]
Treatment by radiation therapy alone is indicated for patients who are not candidates for surgery. Patients should be closely followed, and surgical salvage should be planned for recurrences that are local or in the neck.
Definitive radiation therapy alone with altered fractionation in patients who are not candidates for concurrent chemotherapy and surgery (total laryngectomy) for salvage of radiation failures.[6,7]
Role of Neck Dissection in the Post-Radiation Therapy Setting
A prospective randomized trial included 564 patients with head and neck cancer and N2 or N3 disease. Patients were assigned to undergo planned neck dissection or surveillance with positron emission tomography–computed tomography (PET-CT). With a median follow-up of 36 months, PET-CT resulted in fewer neck dissections compared with the surgical arm (54 vs. 221), with a 2-year survival rate of 84.9% versus 81.5%, respectively. The hazard ratio (HR)death slightly favored PET-CT–guided surveillance and indicated noninferiority (upper boundary, 95% confidence interval for HR, <1.50; P = .004).[11][Level of evidence A1]
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
Forastiere AA, Zhang Q, Weber RS, et al.: Long-term results of RTOG 91-11: a comparison of three nonsurgical treatment strategies to preserve the larynx in patients with locally advanced larynx cancer. J Clin Oncol 31 (7): 845-52, 2013. [PUBMED Abstract]
Spaulding MB, Fischer SG, Wolf GT: Tumor response, toxicity, and survival after neoadjuvant organ-preserving chemotherapy for advanced laryngeal carcinoma. The Department of Veterans Affairs Cooperative Laryngeal Cancer Study Group. J Clin Oncol 12 (8): 1592-9, 1994. [PUBMED Abstract]
Adelstein DJ, Saxton JP, Lavertu P, et al.: A phase III randomized trial comparing concurrent chemotherapy and radiotherapy with radiotherapy alone in resectable stage III and IV squamous cell head and neck cancer: preliminary results. Head Neck 19 (7): 567-75, 1997. [PUBMED Abstract]
Jeremic B, Shibamoto Y, Milicic B, et al.: Hyperfractionated radiation therapy with or without concurrent low-dose daily cisplatin in locally advanced squamous cell carcinoma of the head and neck: a prospective randomized trial. J Clin Oncol 18 (7): 1458-64, 2000. [PUBMED Abstract]
Bernier J, Domenge C, Ozsahin M, et al.: Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med 350 (19): 1945-52, 2004. [PUBMED Abstract]
Lefebvre JL, Pointreau Y, Rolland F, et al.: Induction chemotherapy followed by either chemoradiotherapy or bioradiotherapy for larynx preservation: the TREMPLIN randomized phase II study. J Clin Oncol 31 (7): 853-9, 2013. [PUBMED Abstract]
MacKenzie RG, Franssen E, Balogh JM, et al.: Comparing treatment outcomes of radiotherapy and surgery in locally advanced carcinoma of the larynx: a comparison limited to patients eligible for surgery. Int J Radiat Oncol Biol Phys 47 (1): 65-71, 2000. [PUBMED Abstract]
Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. The Department of Veterans Affairs Laryngeal Cancer Study Group. N Engl J Med 324 (24): 1685-90, 1991. [PUBMED Abstract]
Adelstein DJ, Lavertu P, Saxton JP, et al.: Mature results of a phase III randomized trial comparing concurrent chemoradiotherapy with radiation therapy alone in patients with stage III and IV squamous cell carcinoma of the head and neck. Cancer 88 (4): 876-83, 2000. [PUBMED Abstract]
Mendenhall WM, Werning JW, Pfister DG: Treatment of head and neck cancer. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Lippincott Williams & Wilkins, 2011, pp 729-80.
Mehanna H, Wong WL, McConkey CC, et al.: PET-CT Surveillance versus Neck Dissection in Advanced Head and Neck Cancer. N Engl J Med 374 (15): 1444-54, 2016. [PUBMED Abstract]
Treatment of Stage IV Laryngeal Cancer
Supraglottis
Treatment options for stage IV cancer of the supraglottis include:
Concurrent chemoradiation therapy can be considered for patients who would require total laryngectomy for control of disease, including those with nonbulky T4a disease.[1]
Definitive radiation therapy alone in patients who are not candidates for concurrent chemotherapy and surgery (total laryngectomy) for salvage of radiation failures.[7]
Treatment options for stage IV cancer of the glottis include:
Concurrent chemoradiation therapy can be considered for patients who would require total laryngectomy for control of disease, including those with nonbulky T4a disease.[1]
Definitive radiation therapy alone in patients who are not candidates for concurrent chemotherapy and surgery (total laryngectomy) for salvage of radiation failures.[7]
Treatment options for stage IV cancer of the subglottis include:
Laryngectomy plus total thyroidectomy and bilateral tracheoesophageal node dissection usually followed by PORT with or without concurrent chemotherapy based on pathological risk factors.[10]
Concurrent chemoradiation therapy can be considered for patients who would require total laryngectomy for control of disease, including those with nonbulky T4a disease.[1]
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
Forastiere AA, Zhang Q, Weber RS, et al.: Long-term results of RTOG 91-11: a comparison of three nonsurgical treatment strategies to preserve the larynx in patients with locally advanced larynx cancer. J Clin Oncol 31 (7): 845-52, 2013. [PUBMED Abstract]
Spaulding MB, Fischer SG, Wolf GT: Tumor response, toxicity, and survival after neoadjuvant organ-preserving chemotherapy for advanced laryngeal carcinoma. The Department of Veterans Affairs Cooperative Laryngeal Cancer Study Group. J Clin Oncol 12 (8): 1592-9, 1994. [PUBMED Abstract]
Adelstein DJ, Saxton JP, Lavertu P, et al.: A phase III randomized trial comparing concurrent chemotherapy and radiotherapy with radiotherapy alone in resectable stage III and IV squamous cell head and neck cancer: preliminary results. Head Neck 19 (7): 567-75, 1997. [PUBMED Abstract]
Jeremic B, Shibamoto Y, Milicic B, et al.: Hyperfractionated radiation therapy with or without concurrent low-dose daily cisplatin in locally advanced squamous cell carcinoma of the head and neck: a prospective randomized trial. J Clin Oncol 18 (7): 1458-64, 2000. [PUBMED Abstract]
Bernier J, Domenge C, Ozsahin M, et al.: Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med 350 (19): 1945-52, 2004. [PUBMED Abstract]
Lefebvre JL, Pointreau Y, Rolland F, et al.: Induction chemotherapy followed by either chemoradiotherapy or bioradiotherapy for larynx preservation: the TREMPLIN randomized phase II study. J Clin Oncol 31 (7): 853-9, 2013. [PUBMED Abstract]
MacKenzie RG, Franssen E, Balogh JM, et al.: Comparing treatment outcomes of radiotherapy and surgery in locally advanced carcinoma of the larynx: a comparison limited to patients eligible for surgery. Int J Radiat Oncol Biol Phys 47 (1): 65-71, 2000. [PUBMED Abstract]
Bernier J, Cooper JS: Chemoradiation after surgery for high-risk head and neck cancer patients: how strong is the evidence? Oncologist 10 (3): 215-24, 2005. [PUBMED Abstract]
Adelstein DJ, Lavertu P, Saxton JP, et al.: Mature results of a phase III randomized trial comparing concurrent chemoradiotherapy with radiation therapy alone in patients with stage III and IV squamous cell carcinoma of the head and neck. Cancer 88 (4): 876-83, 2000. [PUBMED Abstract]
Mendenhall WM, Werning JW, Pfister DG: Treatment of head and neck cancer. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Lippincott Williams & Wilkins, 2011, pp 729-80.
Treatment of Metastatic and Recurrent Laryngeal Cancer
Treatment Options for Metastatic and Recurrent Laryngeal Cancer
Treatment options for metastatic and recurrent laryngeal cancer include:
Surgery [1] and/or radiation therapy. Salvage is possible for failures of surgery alone or of radiation therapy alone, and further surgery [1] and/or radiation therapy should be attempted, as indicated. Selected patients may be candidates for partial laryngectomy after high-dose radiation therapy has failed.[2]
Radiation therapy. Re-irradiation for laryngeal salvage following radiation therapy failure has resulted in long-term survival in a small number of patients; it may be considered for small recurrences after radiation therapy, especially in patients who refuse or are not candidates for laryngectomy.[3]
Platinum-based chemotherapy is often used as first-line treatment for patients with recurrent or metastatic squamous cell carcinoma (SCC) of the head and neck. A response of variable duration may be achieved after systemic chemotherapy.[4]
Evidence (chemotherapy):
In a phase III randomized trial of 442 patients with untreated metastatic or recurrent SCC of the head and neck, adding cetuximab to platinum plus fluorouracil (5-FU) compared with platinum plus 5-FU alone improved overall survival (OS), with a median survival of 10.1 months versus 7.4 months (hazard ratio [HR]death, 0.80; 95% confidence interval [CI], 0.64–0.99; P = .04).[5]
Quality of life was not adversely affected by adding cetuximab to this platinum-based regimen.[6]
Tumor EGFR gene copy number was not found to be a predictive biomarker for the efficacy of cetuximab plus platinum and 5-FU as first-line therapy for patients with recurrent or metastatic SCC of the head and neck.[7][Level of evidence A1]
A phase III, open-label, randomized trial demonstrated improvements in progression-free survival (PFS) for patients who received afatinib compared with patients who received methotrexate.[8]
After a median follow-up of 6.7 months, the median PFS was 2.6 months (95% CI, 2.0–2.7) for the afatinib group and 1.7 months (95% CI, 1.5–2.4) for the methotrexate group (HR, 0.80; 95% CI, 0.65–0.98; P = .030).
The most frequent grade 3 or grade 4 drug-related adverse events for patients treated with afatinib or methotrexate included:
Rash or acne (10% for afatinib vs. 0% for methotrexate).
Diarrhea (9% for afatinib vs. 2% for methotrexate).
Stomatitis (6% for afatinib vs. 8% for methotrexate).
Fatigue (6% for afatinib vs. 3% for methotrexate).
Neutropenia (<1% for afatinib vs. 7% for methotrexate).
Overall serious adverse events occurred in 14% of patients treated with afatinib and 11% of patients treated with methotrexate.
Immunotherapy
Immunotherapy (inhibitor of the programmed death-ligand 1 [PD-L1] pathway) can be used after platinum-based failure in patients with metastatic or locally recurrent disease.[9,10]
Pembrolizumab
Pembrolizumab is a monoclonal antibody and an inhibitor of the programmed death-1 (PD-1) pathway. Studies have evaluated pembrolizumab in patients with incurable metastatic or recurrent head and neck squamous cell carcinoma (SCC).
Evidence (pembrolizumab as first-line therapy):
KEYNOTE-048 (NCT02358031) was a nonblinded, randomized, phase III study of participants with untreated locally incurable metastatic or recurrent head and neck SCC that was performed at 200 sites in 37 countries.[11] A total of 882 patients were randomly assigned in a 1:1:1 ratio to receive pembrolizumab alone (n = 301), pembrolizumab plus a platinum and fluorouracil (5-FU) (pembrolizumab with chemotherapy) (n = 281), or cetuximab plus a platinum and 5-FU (cetuximab with chemotherapy) (n = 300). Investigators, patients, and representatives of the sponsor were masked to the programmed death-ligand 1 (PD-L1) combined positive score (CPS) results; PD-L1 positivity was not required for study entry. A total of 754 patients (85%) had a CPS of 1 or higher and 381 patients (43%) had a CPS of 20 or higher.
The primary end points were overall survival (OS) and progression-free survival (PFS). Progression was defined as radiographically confirmed disease progression or death from any cause, whichever came first, in the intention-to-treat population.
At the second interim analysis, pembrolizumab alone showed improved or noninferior OS compared with cetuximab with chemotherapy. The median OS results were reported as follows:[11][Level of evidence A1]
Among the population with a CPS of 20 or higher, the median OS was 14.9 months in patients who received pembrolizumab alone and 10.7 months in patients who received cetuximab with chemotherapy (hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.45–0.83; P = .0007).
Among the population with a CPS of 1 or higher, the median OS was 12.3 months in patients who received pembrolizumab alone and 10.3 months in patients who received cetuximab with chemotherapy (HR, 0.78; 95% CI, 0.64–0.96; P = .0086).
Among the total population, patients who received pembrolizumab alone had noninferior OS (11.6 months) compared with patients who received cetuximab with chemotherapy (10.7 months) (HR, 0.85; 95% CI, 0.71–1.03; P = .0456).
Pembrolizumab with chemotherapy showed improved OS versus cetuximab with chemotherapy. The OS results were reported as follows:
At the second interim analysis, among the total population, the median OS was 13.0 months in patients who received pembrolizumab with chemotherapy and 10.7 months in patients who received cetuximab with chemotherapy (HR, 0.77; 95% CI, 0.63–0.93; P = .0034).
At the final analysis, among the population with a CPS of 20 or higher, the median OS was 14.7 months in patients who received pembrolizumab with chemotherapy and 11.0 months in patients who received cetuximab with chemotherapy (HR, 0.60; 95% CI, 0.45–0.82; P = .0004).
At the final analysis, among the population with a CPS of 1 or higher, the median OS was 13.6 months in patients who received pembrolizumab with chemotherapy and 10.4 months in patients who received cetuximab with chemotherapy (HR, 0.65; 95% CI, 0.53–0.80; P < .0001).
At the second interim analysis, neither pembrolizumab alone nor pembrolizumab with chemotherapy improved PFS.
At the final analysis, grade 3 or higher all-cause adverse events occurred in 164 of 300 patients (55%) in the pembrolizumab-alone group, 235 of 276 patients (85%) who received pembrolizumab with chemotherapy, and 239 of 287 patients (83%) who received cetuximab with chemotherapy.
Adverse events led to death in 25 patients (8%) in the pembrolizumab-alone group, 32 patients (12%) who received pembrolizumab with chemotherapy, and 28 patients (10%) who received cetuximab with chemotherapy.
Pembrolizumab plus a platinum and 5-FU is an appropriate first-line treatment for patients with metastatic or recurrent head and neck SCC. Pembrolizumab monotherapy is an appropriate first-line treatment for patients with PD-L1–positive metastatic or recurrent head and neck SCC. These results were confirmed at a longer median follow-up of 45 months (interquartile range, 41.0–49.2).[12]
Evidence (pembrolizumab after progression on platinum-based treatment):
The phase III KEYNOTE-040 (NCT02252042) trial included patients with incurable metastatic or recurrent head and neck SCC who had received platinum-based treatment within 3 to 6 months.[9] Patients were randomly assigned to the pembrolizumab arm (200 mg every 3 weeks [247 patients]) or to the standard therapy arm of the investigator’s choice (methotrexate, docetaxel, or cetuximab [248 patients]). Patients received treatment until progression or toxicity. The maximum duration of pembrolizumab was 24 months. The primary end point was OS in the intention-to-treat population.
The median OS was 8.4 months in the pembrolizumab arm and 6.9 months in the standard therapy arm (HR, 0.80; 95% CI, 0.65–0.98; nominal P = .0161).[9][Level of evidence A1]
Pembrolizumab was associated with fewer grade 3 or higher adverse events (pembrolizumab, 13% vs. standard therapy, 36%). The most common treatment-related adverse events were hypothyroidism (13%) in the pembrolizumab arm and fatigue (18%) in the standard therapy arm.
In patients who received pembrolizumab, there were four treatment-related deaths resulting from large intestinal perforation, Stevens-Johnson syndrome, and unspecified malignant progression. Two treatment-related deaths in the standard therapy arm resulted from malignant progression and pneumonia.
The PD-L1 CPS was 1 or higher in 79% of the patients in the pembrolizumab arm and 77% of the patients in the standard therapy arm.
Compared with patients treated with standard therapy, a reduced HRdeath was noted for patients who received pembrolizumab and had PD-1 expression on their tumors or in the tumor microenvironment as noted by a PD-L1 CPS of 1 or higher (HR, 0.74; 95% CI, 0.58–0.93; nominal P = .0049) or a PD-L1 tumor proportion score of 50% or higher (HR, 0.53; 95% CI, 0.35–0.81; nominal P = .0014).
Nivolumab
Nivolumab is a fully human immunoglobulin G4 anti–PD-1 monoclonal antibody.
Evidence (nivolumab combined with ipilimumab in patients who have not previously received systemic therapy):
The CheckMate 651 trial (NCT02741570) evaluated first-line nivolumab plus ipilimumab versus EXTREME (cetuximab, cisplatin/carboplatin, and 5-FU for up to six cycles followed by cetuximab maintenance) in patients with recurrent or metastatic head and neck SCC.[13] The primary end points were OS in all randomly assigned patients and patients with a PD-L1 CPS of 20 or higher. Secondary end points included OS in patients with a PD-L1 CPS of 1 or higher and PFS, objective response rate, and duration of response in all randomly assigned patients and patients with a PD-L1 CPS of 20 or higher.
Among all randomly assigned patients, there was no statistically significant difference in OS with nivolumab plus ipilimumab versus EXTREME (median OS, 13.9 vs. 13.5 months; HR, 0.95; 97.9% CI, 0.80–1.13; P = .4951). Among patients with a PD-L1 CPS of 20 or higher, there was also no statistically significant OS difference between the two treatments (median OS, 17.6 vs. 14.6 months; HR, 0.78; 97.51% CI, 0.59–1.03; P = .0469).[13][Level of evidence A1]
In patients with a CPS of 1 or higher, the median OS was 15.7 months for patients who received nivolumab plus ipilimumab versus 13.2 months for patients who received EXTREME (HR, 0.82; 95% CI, 0.69–0.97).
Among patients with a CPS of 20 or higher, the median PFS was 5.4 months for patients who received nivolumab plus ipilimumab and 7.0 months for patients who received EXTREME. The objective response rate was 34.1% for patients who received nivolumab plus ipilimumab and 36.0% for patients who received EXTREME.
Grade 3 or 4 treatment-related adverse events occurred in 28.2% of patients who received nivolumab plus ipilimumab and 70.7% of patients who received EXTREME.
CheckMate 651 did not meet its primary end points of OS in the randomly assigned or CPS of 20 or higher populations.
The absence of a survival benefit for immune checkpoint inhibitors in this trial was an unexpected outcome, given the similarity of nivolumab to pembrolizumab in the studies of patients with cisplatin-refractory disease.[9,10] An editorial accompanying the CheckMate 651 trial analyzed some of the factors that may have contributed to a different result. The editorial suggested that survival in the control group, which was longer than that reported in prior studies, may have been impacted by the greater availability of second-line immunotherapy in the control group (46% in CheckMate 651 compared with 25% in the KEYNOTE-048 trial). The authors also suggested that the coadministration of ipilimumab detracted from the activity of nivolumab, as shown in the CheckMate 714 trial.[14]
CheckMate 714 (NCT02823574), a double-blind phase II trial, evaluated the clinical benefit of first-line nivolumab plus ipilimumab versus nivolumab alone in 425 patients with recurrent or metastatic head and neck SCC.[15] Patients were randomly assigned in a 2:1 ratio to receive either nivolumab (3 mg/kg intravenously [IV] every 2 weeks) plus ipilimumab (1 mg/kg IV every 6 weeks) or nivolumab (3 mg/kg IV every 2 weeks) plus placebo. Treatment continued for up to 2 years or until disease progression, unacceptable toxic effects, or consent withdrawal. The primary end points were objective response rate and duration of response between treatment arms by blinded independent central review in the population with platinum-refractory recurrent or metastatic disease. These were patients who had recurrent disease less than 6 months after completion of platinum-based chemotherapy (adjuvant or neoadjuvant, or as part of multimodal treatment [chemotherapy, surgery, and/or radiation therapy]). Among the 241 patients (56.7%) with platinum-refractory disease, 159 were assigned to receive nivolumab plus ipilimumab and 82 were assigned to receive nivolumab alone. Among the 184 patients (43.3%) with platinum-eligible disease, 123 were assigned to receive nivolumab plus ipilimumab and 61 were assigned to receive nivolumab alone.[15][Level of evidence B3]
At primary database lock, the objective response rate in the population with platinum-refractory disease was 13.2% (95% CI, 8.4%–19.5%) with nivolumab plus ipilimumab and 18.3% (95% CI, 10.6%–28.4%) with nivolumab alone (odds ratio, 0.68; 95.5% CI, 0.33–1.43; P = .29).
The median duration of response was not reached (NR) in the nivolumab-plus-ipilimumab group (95% CI, 11.0 months–NR) and was 11.1 months (95% CI, 4.1–NR) in the nivolumab-alone group. In the population with platinum-eligible disease, the objective response rate was 20.3% (95% CI, 13.6%–28.5%) with nivolumab plus ipilimumab and 29.5% (95% CI, 18.5%–42.6%) with nivolumab alone.
Among the population with platinum-refractory disease, grade 3 or 4 treatment-related adverse events occurred in 25 of 158 patients (15.8%) who received nivolumab plus ipilimumab and in 12 of 82 patients (14.6%) who received nivolumab alone. Among the population with platinum-eligible disease, grade 3 or 4 treatment-related adverse events occurred in 30 of 122 patients (24.6%) who received nivolumab plus ipilimumab and in 8 of 61 patients (13.1%) who received nivolumab alone.
This trial did not meet its primary end point of objective response rate benefit with first-line nivolumab plus ipilimumab versus nivolumab alone in patients with platinum-refractory recurrent or metastatic head and neck SCC.
Evidence (nivolumab after progression on platinum-based treatment):
A phase III open-label trial included 361 patients with recurrent SCC of the head and neck and disease progression within 6 months after platinum-based chemotherapy. Patients were randomly assigned in a 2:1 ratio to receive either nivolumab (at a dose of 3 mg/kg of body weight) every 2 weeks or standard single-agent systemic therapy (methotrexate, docetaxel, or cetuximab). The primary end point was OS.[10]
The median OS was 7.5 months (95% CI, 5.5–9.1) in the nivolumab group versus 5.1 months (95% CI, 4.0–6.0) in the standard therapy group. OS was statistically significantly longer with nivolumab than with standard therapy (HRdeath, 0.70; 97.73% CI, 0.51–0.96; P = .01). The estimated 1-year survival rate was approximately 19% higher in patients who received nivolumab (36.0%) than in those who received standard therapy (16.6%).[10][Level of evidence A1]
There was no statistically significant difference in median PFS between treatment groups. The 6-month PFS rate was 19.7% with nivolumab versus 9.9% with standard therapy.
The response rate was 13.3% in the nivolumab group versus 5.8% in the standard therapy group.
Grade 3 or 4 treatment-related adverse events occurred in 13.1% of the patients in the nivolumab group compared with 35.1% of the patients in the standard therapy group.
Quality-of-life outcomes—including physical, role, and social functioning and pain, sensory, and social contact problems—were stable in the nivolumab group but worse in the standard therapy group. These outcomes were assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ) Core Module (QLQ-C30) and the Head and Neck Module (QLQ-H&N35).
In the subgroup of patients with a PD-L1 expression level of 1% or higher, the HRdeath among patients treated with nivolumab versus standard therapy was 0.55 (95% CI, 0.36–0.83). In the subgroup of patients with a PD-L1 expression level lower than 1%, the HR was 0.89 (95% CI, 0.54–1.45; P = .17 for interaction).
A randomized, phase III, superiority study in India evaluated the dose of immune checkpoint inhibitors in the setting of palliative care for patients with advanced head and neck cancer. Low-dose IV nivolumab (20 mg every 3 weeks) was added to a triple metronomic chemotherapy regimen of oral methotrexate (9 mg/m2 once weekly), celecoxib (200 mg twice daily), and erlotinib (150 mg once daily). Notably, this nivolumab dose is less than 10% of the dose recommended by the U.S. Food and Drug Administration and the European Medicines Agency. A total of 151 patients were randomly assigned to receive either triple metronomic chemotherapy alone (n = 75) or triple metronomic chemotherapy with nivolumab (n = 76). The primary end point was 1-year OS.[16]
The addition of low-dose nivolumab to triple metronomic chemotherapy improved the 1-year OS rate from 16.3% (95% CI, 8.0%–27.4%) to 43.4% (95% CI, 30.8%–55.3%) (HR, 0.545; 95% CI, 0.362–0.820; P = .0036).[16][Level of evidence A1]
The median OS was 6.7 months (95% CI, 5.8–8.1) for patients who received triple metronomic chemotherapy alone and 10.1 months (95% CI, 7.4–12.6) for patients who received triple metronomic chemotherapy with nivolumab (P = .0052).
The rate of grade 3 or higher adverse events was 50% for patients who received triple metronomic chemotherapy alone and 46.1% for patients who received triple metronomic chemotherapy with nivolumab (P = .744).
Although the control arm in this study cannot be considered standard care, lower doses of immunotherapy appeared to have some benefit in this setting.[17]
Salvage after previous combined total laryngectomy and radiation therapy is poor.
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
Wong LY, Wei WI, Lam LK, et al.: Salvage of recurrent head and neck squamous cell carcinoma after primary curative surgery. Head Neck 25 (11): 953-9, 2003. [PUBMED Abstract]
Paleri V, Thomas L, Basavaiah N, et al.: Oncologic outcomes of open conservation laryngectomy for radiorecurrent laryngeal carcinoma: a systematic review and meta-analysis of English-language literature. Cancer 117 (12): 2668-76, 2011. [PUBMED Abstract]
Wang CC, McIntyre J: Re-irradiation of laryngeal carcinoma–techniques and results. Int J Radiat Oncol Biol Phys 26 (5): 783-5, 1993. [PUBMED Abstract]
Al-Sarraf M: Head and neck cancer: chemotherapy concepts. Semin Oncol 15 (1): 70-85, 1988. [PUBMED Abstract]
Vermorken JB, Mesia R, Rivera F, et al.: Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 359 (11): 1116-27, 2008. [PUBMED Abstract]
Mesía R, Rivera F, Kawecki A, et al.: Quality of life of patients receiving platinum-based chemotherapy plus cetuximab first line for recurrent and/or metastatic squamous cell carcinoma of the head and neck. Ann Oncol 21 (10): 1967-73, 2010. [PUBMED Abstract]
Licitra L, Mesia R, Rivera F, et al.: Evaluation of EGFR gene copy number as a predictive biomarker for the efficacy of cetuximab in combination with chemotherapy in the first-line treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck: EXTREME study. Ann Oncol 22 (5): 1078-87, 2011. [PUBMED Abstract]
Machiels JP, Haddad RI, Fayette J, et al.: Afatinib versus methotrexate as second-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck progressing on or after platinum-based therapy (LUX-Head & Neck 1): an open-label, randomised phase 3 trial. Lancet Oncol 16 (5): 583-94, 2015. [PUBMED Abstract]
Cohen EEW, Soulières D, Le Tourneau C, et al.: Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): a randomised, open-label, phase 3 study. Lancet 393 (10167): 156-167, 2019. [PUBMED Abstract]
Ferris RL, Blumenschein G, Fayette J, et al.: Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck. N Engl J Med 375 (19): 1856-1867, 2016. [PUBMED Abstract]
Burtness B, Harrington KJ, Greil R, et al.: Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Lancet 394 (10212): 1915-1928, 2019. [PUBMED Abstract]
Harrington KJ, Burtness B, Greil R, et al.: Pembrolizumab With or Without Chemotherapy in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: Updated Results of the Phase III KEYNOTE-048 Study. J Clin Oncol 41 (4): 790-802, 2023. [PUBMED Abstract]
Haddad RI, Harrington K, Tahara M, et al.: Nivolumab Plus Ipilimumab Versus EXTREME Regimen as First-Line Treatment for Recurrent/Metastatic Squamous Cell Carcinoma of the Head and Neck: The Final Results of CheckMate 651. J Clin Oncol 41 (12): 2166-2180, 2023. [PUBMED Abstract]
Burtness B: First-Line Nivolumab Plus Ipilimumab in Recurrent/Metastatic Head and Neck Cancer-What Happened? J Clin Oncol 41 (12): 2134-2137, 2023. [PUBMED Abstract]
Harrington KJ, Ferris RL, Gillison M, et al.: Efficacy and Safety of Nivolumab Plus Ipilimumab vs Nivolumab Alone for Treatment of Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck: The Phase 2 CheckMate 714 Randomized Clinical Trial. JAMA Oncol 9 (6): 779-789, 2023. [PUBMED Abstract]
Patil VM, Noronha V, Menon N, et al.: Low-Dose Immunotherapy in Head and Neck Cancer: A Randomized Study. J Clin Oncol 41 (2): 222-232, 2023. [PUBMED Abstract]
Mitchell AP, Goldstein DA: Cost Savings and Increased Access With Ultra-Low-Dose Immunotherapy. J Clin Oncol 41 (2): 170-172, 2023. [PUBMED Abstract]
Latest Updates to This Summary (05/14/2025)
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Editorial changes were made to this summary.
This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.
About This PDQ Summary
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of adult laryngeal cancer. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
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be cited with text, or
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Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Laryngeal Cancer Treatment are:
Andrea Bonetti, MD (Pederzoli Hospital)
Minh Tam Truong, MD (Boston University Medical Center)
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.
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PDQ® Adult Treatment Editorial Board. PDQ Laryngeal Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/head-and-neck/hp/adult/laryngeal-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389189]
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Hypopharyngeal cancer is a disease in which malignant (cancer) cells form in the tissues of the hypopharynx.
Use of tobacco products and heavy drinking can affect the risk of developing hypopharyngeal cancer.
Signs and symptoms of hypopharyngeal cancer include a sore throat and ear pain.
Tests that examine the throat and neck are used to help diagnose hypopharyngeal cancer and find out whether the cancer has spread.
Certain factors affect prognosis (chance of recovery) and treatment options.
Hypopharyngeal cancer is a disease in which malignant (cancer) cells form in the tissues of the hypopharynx.
The hypopharynx is the bottom part of the pharynx. The pharynx is a hollow tube about 5 inches long that starts behind the nose, goes down the neck, and ends at the top of the trachea (windpipe) and esophagus (the tube that goes from the throat to the stomach). Air and food pass through the pharynx on the way to the trachea or the esophagus.
EnlargeHypopharyngeal cancer forms in the tissues of the hypopharynx (the bottom part of the throat). It may spread to nearby tissues or to cartilage around the thyroid or trachea, the bone under the tongue (hyoid bone), the thyroid, the trachea, the larynx, or the esophagus. It may also spread to the lymph nodes in the neck, the carotid artery, the tissues around the upper part of the spinal column, the lining of the chest cavity, and to other parts of the body (not shown).
Most hypopharyngeal cancers form in squamous cells, the thin, flat cells lining the inside of the hypopharynx. The hypopharynx has 3 different areas. Cancer may be found in 1 or more of these areas.
Use of tobacco products and heavy drinking can affect the risk of developing hypopharyngeal cancer.
Anything that increases your risk of getting a disease is called a risk factor. Having a risk factor does not mean that you will get cancer; not having risk factors doesn’t mean that you will not get cancer. Talk with your doctor if you think you may be at risk. Risk factors include:
Tests that examine the throat and neck are used to help diagnose hypopharyngeal cancer and find out whether the cancer has spread.
The following tests and procedures may be used:
Physical exam and health history: An exam of the body to check general signs of health, including checking for signs of disease, such as lumps or anything else that seems unusual. A history of the patient’s health habits and past illnesses and treatments will also be taken.
Physical exam of the throat: An exam in which the doctor feels for swollen lymph nodes in the neck and looks down the throat with a small, long-handled mirror to check for abnormal areas.
Neurological exam: A series of questions and tests to check the brain, spinal cord, and nerve function. The exam checks a person’s mental status, coordination, and ability to walk normally, and how well the muscles, senses, and reflexes work. This may also be called a neuro exam or a neurologic exam.
CT scan (CAT scan): A procedure that makes a series of detailed pictures of areas inside the body, such as the head, neck, chest, and lymph nodes, taken from different angles. The pictures are made by a computer linked to an x-ray machine. A dye may be injected into a vein or swallowed to help the organs or tissues show up more clearly. This procedure is also called computed tomography, computerized tomography, or computerized axial tomography. EnlargeComputed tomography (CT) scan of the head and neck. The patient lies on a table that slides through the CT scanner, which takes x-ray pictures of the inside of the head and neck.
PET scan (positron emission tomography scan): A procedure to find malignanttumor cells in the body. A small amount of radioactive glucose (sugar) is injected into a vein. The PET scanner rotates around the body and makes a picture of where glucose is being used in the body. Malignant tumor cells show up brighter in the picture because they are more active and take up more glucose than normal cells do. A PET scan and CT scan may be done at the same time. This is called a PET-CT. EnlargePET (positron emission tomography) scan. The patient lies on a table that slides through the PET machine. The head rest and white strap help the patient lie still. A small amount of radioactive glucose (sugar) is injected into the patient’s vein, and a scanner makes a picture of where the glucose is being used in the body. Cancer cells show up brighter in the picture because they take up more glucose than normal cells do.
MRI (magnetic resonance imaging): A procedure that uses a magnet, radio waves, and a computer to make a series of detailed pictures of areas inside the body, such as the head, neck, chest, and lymph nodes. This procedure is also called nuclear magnetic resonance imaging (NMRI).
Endoscopy: A procedure used to look at areas in the throat that cannot be seen with a mirror during the physical exam of the throat. An endoscope (a thin, lighted tube) is inserted through the nose or mouth to check the throat for anything that seems unusual. Tissue samples may be taken for biopsy.
Biopsy: The removal of cells or tissues so they can be viewed under a microscope to check for signs of cancer.
Bone scan: A procedure to check 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.
Barium esophagogram: An x-ray of the esophagus. The patient drinks a liquid that contains barium (a silver-white metalliccompound). The liquid coats the esophagus and x-rays are taken.
Esophagoscopy: A procedure to look inside the esophagus to check for abnormal areas. An esophagoscope (a thin, lighted tube) is inserted through the mouth or nose and down the throat into the esophagus. Tissue samples may be taken for biopsy.
Bronchoscopy: A procedure to look inside the trachea and large airways in the lung for abnormal areas. A bronchoscope (a thin, lighted tube) is inserted through the nose or mouth into the trachea and lungs. Tissue samples may be taken for biopsy.
Certain factors affect prognosis (chance of recovery) and treatment options.
The stage of the cancer (whether it affects part of the hypopharynx, involves the whole hypopharynx, or has spread to other places in the body). Hypopharyngeal cancer is usually detected in later stages because early signs and symptoms rarely occur.
Keeping the patient’s ability to talk, eat, and breathe as normal as possible.
The patient’s general health.
Patients who have had hypopharyngeal cancer are at an increased risk of developing a second cancer in the head or neck. Frequent and careful follow-up is important.
Stages of Hypopharyngeal Cancer
Key Points
After hypopharyngeal cancer has been diagnosed, tests are done to find out if cancer cells have spread within the hypopharynx or to other parts of the body.
There are three ways that cancer spreads in the body.
Cancer may spread from where it began to other parts of the body.
The following stages are used for hypopharyngeal cancer:
Stage 0 (carcinoma in situ)
Stage I
Stage II
Stage III
Stage IV
After surgery, the stage of the cancer may change and more treatment may be needed.
Hypopharyngeal cancer can recur (come back) after it has been treated.
After hypopharyngeal cancer has been diagnosed, tests are done to find out if cancer cells have spread within the hypopharynx or to other parts of the body.
The process used to find out if cancer has spread within the hypopharynx 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 of the disease in order to plan treatment. The results of some of the tests and procedures used to diagnosehypopharyngeal cancer are often also used to stage the disease.
There are three ways that cancer spreads in the body.
Tissue. The cancer spreads from where it began by growing into nearby areas.
Lymph system. The cancer spreads from where it began by getting into the lymph system. The cancer travels through the lymph vessels to other parts of the body.
Blood. The cancer spreads from where it began by getting into the blood. The cancer travels through the blood vessels to other parts of the body.
Cancer may spread from where it began to other parts of the body.
When cancer spreads to another part of the body, it is called metastasis. Cancer cells break away from where they began (the primary tumor) and travel through the lymph system or blood.
Lymph system. The cancer gets into the lymph system, travels through the lymph vessels, and forms a tumor (metastatic tumor) in another part of the body.
Blood. The cancer gets into the blood, travels through the blood vessels, and forms a tumor (metastatic tumor) in another part of the body.
The metastatic tumor is the same type of cancer as the primary tumor. For example, if hypopharyngeal cancer spreads to the lung, the cancer cells in the lung are actually hypopharyngeal cancer cells. The disease is metastatic hypopharyngeal cancer, not lung cancer.
Many cancer deaths are caused when cancer moves from the original tumor and spreads to other tissues and organs. This is called metastatic cancer. This animation shows how cancer cells travel from the place in the body where they first formed to other parts of the body.
The following stages are used for hypopharyngeal cancer:
The staging described below is only used for patients who have not had lymph nodes in the neck removed and checked for signs of cancer.
EnlargeTumor sizes are often measured in centimeters (cm) or inches. Common food items that can be used to show tumor size in cm include: a pea (1 cm), a peanut (2 cm), a grape (3 cm), a walnut (4 cm), a lime (5 cm or 2 inches), an egg (6 cm), a peach (7 cm), and a grapefruit (10 cm or 4 inches).
is larger than 4 centimeters or has spread to the larynx (voice box) or the mucosa (inner lining) of the esophagus. Cancer may have spread to one lymph node on the same side of the neck as the tumor. The affected lymph node is 3 centimeters or smaller; or
has spread to one lymph node on the same side of the neck as the tumor. The affected lymph node is 3 centimeters or smaller. Cancer is also found:
in only one area of the hypopharynx and/or the tumor is 2 centimeters or smaller; or
in more than one area of the hypopharynx or in a nearby area, or the tumor is larger than 2 centimeters but not larger than 4 centimeters and has not spread to the larynx.
Stage IV
Stage IV is divided into stages IVA, IVB, and IVC as follows:
is found in the hypopharynx and may have spread to the thyroid cartilage, the bone above the thyroid cartilage, the thyroid gland, the cartilage around the trachea, the esophagus, or the nearby muscles and fatty tissue in the neck. Cancer has spread to one of the following:
one lymph node on the same side of the neck as the tumor. The affected lymph node is larger than 3 centimeters but not larger than 6 centimeters; or
more than one lymph node anywhere in the neck. The affected lymph nodes are 6 centimeters or smaller.
may be any size and cancer may have spread to the thyroid cartilage, the bone above the thyroid cartilage, the thyroid gland, the cartilage around the trachea, the esophagus, or the nearby muscles and fatty tissue in the neck. Cancer has spread to a lymph node that is larger than 6 centimeters or has spread through the outside covering of a lymph node into nearby connective tissue; or
has spread to the connective tissue covering the muscles that support the spinal column, the area around the carotid artery, or the area between the lungs. Cancer may have also spread to lymph nodes in the neck.
In stage IVC, cancer has spread to other parts of the body, such as the lung, liver, or bone.
After surgery, the stage of the cancer may change and more treatment may be needed.
If the cancer is removed by surgery, a pathologist will examine a sample of the cancer tissue under a microscope. Sometimes, the pathologist’s review results in a change to the stage of the cancer and more treatment is needed after surgery.
Hypopharyngeal cancer can recur (come back) after it has been treated.
The cancer may come back in the hypopharynx or in other parts of the body.
Treatment Option Overview
Key Points
There are different types of treatment for patients with hypopharyngeal cancer.
The following types of treatment are used:
Surgery
Radiation therapy
Chemotherapy
Immunotherapy
New types of treatment are being tested in clinical trials.
Treatment for hypopharyngeal cancer may cause side effects.
Patients may want to think about taking part in a clinical trial.
Patients can enter clinical trials before, during, or after starting their cancer treatment.
Follow-up care may be needed.
There are different types of treatment for patients with hypopharyngeal cancer.
Different types of treatment are available for patients with hypopharyngeal cancer. Some treatments are standard (the currently used treatment), and some are being tested in clinical trials. A treatment clinical trial is a research study meant to help improve current treatments or obtain information on new treatments for patients with cancer. When clinical trials show that a new treatment is better than the standard treatment, the new treatment may become the standard treatment. Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.
The following types of treatment are used:
Surgery
Surgery (removing the cancer in an operation) is a common treatment for all stages of hypopharyngeal cancer. The following surgical procedures may be used:
Laryngopharyngectomy: Surgery to remove the larynx (voice box) and part of the pharynx (throat).
Partial laryngopharyngectomy: Surgery to remove part of the larynx and part of the pharynx. A partial laryngopharyngectomy prevents loss of the voice.
After the doctor removes all the cancer that can be seen at the time of the surgery, some patients may be given chemotherapy or radiation therapy after surgery to kill any cancer cells that are left. Treatment given after the surgery, to lower the risk that the cancer will come back, is called adjuvant therapy.
Radiation therapy
Radiation therapy is a cancer treatment that uses high-energy x-rays or other types of radiation to kill cancer cells or keep them from growing. External radiation therapy uses a machine outside the body to send radiation toward the area of the body with cancer.
EnlargeExternal-beam radiation therapy of the head and neck. A machine is used to aim high-energy radiation at the cancer. The machine can rotate around the patient, delivering radiation from many different angles to provide highly conformal treatment. A mesh mask helps keep the patient’s head and neck from moving during treatment. Small ink marks are put on the mask. The ink marks are used to line up the radiation machine in the same position before each treatment.
Radiation therapy may work better in patients who have stopped smoking before beginning treatment. External radiation therapy to the thyroid or the pituitary gland may change the way the thyroid gland works. A blood test to check the thyroid hormone level in the body may be done before and after therapy to make sure the thyroid gland is working properly.
Chemotherapy
Chemotherapy is a cancer treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping the cells from dividing. When chemotherapy is taken by mouth or injected into a vein or muscle, the drugs enter the bloodstream and can reach cancer cells throughout the body (systemic chemotherapy).
Chemotherapy may be used to shrink the tumor before surgery or radiation therapy. This is called neoadjuvant chemotherapy.
Immunotherapy is a treatment that uses a person’s immune system to fight cancer. Your doctor may suggest biomarker tests to help predict your response to certain immunotherapy drugs. Learn more about Biomarker Testing for Cancer Treatment.
Patients may want to think about taking part in a clinical trial.
For some patients, taking part in a clinical trial may be the best treatment choice. Clinical trials are part of the cancer research process. Clinical trials are done to find out if new cancer treatments are safe and effective or better than the standard treatment.
Many of today’s standard treatments for cancer are based on earlier clinical trials. Patients who take part in a clinical trial may receive the standard treatment or be among the first to receive a new treatment.
Patients who take part in clinical trials also help improve the way cancer will be treated in the future. Even when clinical trials do not lead to effective new treatments, they often answer important questions and help move research forward.
Patients can enter clinical trials before, during, or after starting their cancer treatment.
Some clinical trials only include patients who have not yet received treatment. Other trials test treatments for patients whose cancer has not gotten better. There are also clinical trials that test new ways to stop cancer from recurring (coming back) or reduce the side effects of cancer treatment.
Clinical trials are taking place in many parts of the country. Information about clinical trials supported by NCI can be found on NCI’s clinical trials search webpage. Clinical trials supported by other organizations can be found on the ClinicalTrials.gov website.
Follow-up care may be needed.
As you go through treatment, you will have follow-up tests or check-ups. Some tests that were done to diagnose or stage the cancer may be repeated to see how well the treatment is working. Decisions about whether to continue, change, or stop treatment may be based on the results of these tests.
Some of the tests will continue to be done from time to time after treatment has ended. The results of these tests can show if your condition has changed or if the cancer has recurred (come back).
For hypopharyngeal cancer, follow-up to check for recurrence should include careful head and neck exams once a month in the first year after treatment ends, every 2 months in the second year, every 3 months in the third year, and every 6 months thereafter.
Partial laryngopharyngectomy with or without high-dose radiation therapy to the lymph nodes on both sides of the neck.
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.
A clinical trial of chemotherapy followed by radiation therapy or surgery.
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.
Chemotherapy given during or after radiation therapy or after surgery.
A clinical trial of chemotherapy followed by surgery and/or radiation therapy.
A clinical trial of surgery followed by chemotherapy given at the same time as radiation therapy.
A clinical trial of chemotherapy given at the same time as radiation therapy.
Treatment and follow-up of stage III hypopharyngeal cancer is complex and is ideally overseen by a team of specialists with experience and expertise in treating this type of cancer. If all or part of the hypopharynx is removed, the patient may need plastic surgery and other special help with breathing, eating, and talking.
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.
A clinical trial of surgery followed by chemotherapy given at the same time as radiation therapy.
Surgical treatment and follow-up of stage IV hypopharyngeal cancer is complex and is ideally overseen by a team of specialists with experience and expertise in treating this type of cancer. If all or part of the hypopharynx is removed, the patient may need plastic surgery and other special help with breathing, eating, and talking.
Chemotherapy given at the same time as radiation therapy.
A clinical trial of radiation therapy with chemotherapy.
Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.
Treatment of Recurrent and Metastatic Hypopharyngeal Cancer
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.
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 hypopharyngeal cancer. It is meant to inform and help patients, families, and caregivers. It does not give formal guidelines or recommendations for making decisions about health care.
Reviewers and Updates
Editorial Boards write the PDQ cancer information summaries and keep them up to date. These Boards are made up of experts in cancer treatment and other specialties related to cancer. The summaries are reviewed regularly and changes are made when there is new information. The date on each summary (“Updated”) is the date of the most recent change.
The information in this patient summary was taken from the health professional version, which is reviewed regularly and updated as needed, by the PDQ Adult Treatment Editorial Board.
Clinical Trial Information
A clinical trial is a study to answer a scientific question, such as whether one treatment is better than another. Trials are based on past studies and what has been learned in the laboratory. Each trial answers certain scientific questions in order to find new and better ways to help cancer patients. During treatment clinical trials, information is collected about the effects of a new treatment and how well it works. If a clinical trial shows that a new treatment is better than one currently being used, the new treatment may become “standard.” Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.
Clinical trials can be found online at NCI’s website. For more information, call the Cancer Information Service (CIS), NCI’s contact center, at 1-800-4-CANCER (1-800-422-6237).
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The best way to cite this PDQ summary is:
PDQ® Adult Treatment Editorial Board. PDQ Hypopharyngeal Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/head-and-neck/patient/adult/hypopharyngeal-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389254]
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Cancer of the hypopharynx is uncommon; approximately 2,500 new cases are diagnosed in the United States each year.[1] The peak incidence of this cancer occurs in people aged 50 to 60 years.[2] Excessive alcohol and tobacco use are the primary risk factors for hypopharyngeal cancer.[3,4] In the United States, hypopharyngeal cancers are more common in men than in women.[5] In Europe and Asia, high incidences of pharyngeal cancers, namely, oropharyngeal and hypopharyngeal, have been found among men in France, in the counties of Bas-Rhin and Herault; Switzerland, in the section of Vaud; Spain, in the Basque Country region; Slovakia; Slovenia; and India, in the cities of Bombay and Madras.[6] This cancer is extremely rare in children.[7]
Upper hypopharyngeal cancers appear to be associated more with heavy drinking and smoking, whereas the lower hypopharyngeal, or postcricoid, cancers are more often associated with nutritional deficiencies.[1,8] Although earlier reports from northern Europe, particularly from Sweden, indicated a link between Plummer-Vinson syndrome, which consisted of sideropenic anemia and epithelial changes of the aerodigestive tract, and other nutritional deficiencies in women, current cases of hypopharyngeal cancer among women are more likely to be associated with excessive use of alcohol and tobacco, rather than with deficiency diseases.[2,9–11]
Anatomy
Anatomically, the hypopharynx extends from the plane of the hyoid bone above to the plane of the inferior border of the cricoid cartilage below. The hypopharynx is composed of the following three parts and does not include the larynx:
The pyriform sinus.
The postcricoid area.
The posterior pharyngeal wall.
Clinical Features
The lymphatic drainage from the pharynx is into the jugulodigastric, jugulo-omohyoid, upper and middle deep cervical, and retropharyngeal nodes. In the United States and Canada, 65% to 85% of hypopharyngeal carcinomas involve the pyriform sinuses, 10% to 20% involve the posterior pharyngeal wall, and 5% to 15% involve the postcricoid area.[12] Pyriform sinus and postcricoid carcinomas are typically flat plaques with raised edges and superficial ulceration. In contrast, posterior hypopharyngeal wall tumors tend to be exophytic and are often large (i.e., 80% >5 cm) at presentation.[13] Hypopharyngeal carcinomas tend to spread within the mucosa, beneath intact epithelium, and are prone to skip metastasis and to resurface at various locations remote from the primary site.[1,13] Because of this fact and the abundant lymphatic network of the region, a localized hypopharyngeal tumor is the exception.[1]
Almost all hypopharyngeal cancers are mucosal squamous cell carcinomas (SCCs).[1] Multiple primary tumors are not uncommon. Approximately 25% of patients in a retrospective study of 150 cases were found to have second primary tumors.[14] Field cancerization may be responsible, in part, for the multiple, synchronous, primary malignant neoplasms that occur in patients with hypopharyngeal cancer.[1,14–16] The concept of field cancerization, originally described in 1953, proposes that tumors develop in a multifocal fashion within a field of tissue that has been chronically exposed to carcinogens.[17]
Clinically, cancers of the hypopharynx tend to be aggressive and demonstrate a natural history that is characterized by diffuse local spread, early metastasis, and a relatively high rate of distant spread. More than 50% of patients with hypopharyngeal cancer have clinically positive cervical nodes at the time of presentation. In 50% of these individuals, a neck mass is the presenting symptom.[2,18,19] In a retrospective study of 78 cases of hypopharyngeal cancer, other symptoms in addition to a neck mass (25.6%) included dysphagia (46.1%), odynophagia (44.8%), voice change (16.3%), and otalgia (14.2%).[2] A voice change resulting from pyriform sinus or postcricoid lesions is a late symptom that usually indicates invasion into the larynx or the recurrent laryngeal nerve.[1]
In a large retrospective study of patients with SCC of the larynx and hypopharynx, 87% of patients with pyriform sinus SCC were found to have stage III or stage IV disease; 82% of patients with SCC of the posterior pharyngeal wall were found to have stage III or stage IV disease.[20] As many as 17% of hypopharyngeal SCCs may be associated with distant metastases when clinically diagnosed.[20] This is quite different from the rate of distant metastasis detected at autopsy, which has been reported to be as high as 60%.[21] A relatively high incidence of delayed regional (i.e., 2 or more years after completion of primary therapy) and distant metastatic disease in hypopharyngeal SCC is related to the advanced stage of the disease at diagnosis. Almost 33% of pyriform sinus tumors may be associated with delayed regional metastases.[20]
The treatment of hypopharyngeal cancer is controversial, in part because of its low incidence and the inherent difficulty in conducting adequately powered, prospective, randomized clinical studies.[22] Therefore, it is difficult to define the ideal therapy for a specific site or stage of hypopharyngeal cancer. In general, both surgery and radiation therapy are the mainstays of most curative efforts. In recent years, chemotherapy has been added to the treatment strategies for selected advanced presentations of hypopharyngeal cancer.[23] In pyriform sinus cancer, neoadjuvant chemotherapy followed by radiation therapy may achieve larynx preservation without jeopardizing survival.[24]
Prognosis and Survival
Chronic pulmonary and hepatic diseases related to the excessive use of tobacco and alcohol are found in patients with hypopharyngeal cancer. Recognition of these comorbidities is essential when planning appropriate treatment.[1] The primary prognostic factors for hypopharyngeal SCC include:[1,25,26]
Stage.
Age.
Performance status.
Factors that contribute to an overall poor prognosis with hypopharyngeal SCC include:
Presentation at a late stage.
Multisite involvement within the hypopharynx.
Unrestricted soft-tissue tumor growth.
An extensive regional lymphatic network conducive to metastases.
Restricted surgical options for complete resection.
In many patients, a poor prognosis is related to poor overall health.[13] The most common cause of failure of treatment of the primary tumor is local and/or regional recurrence. Most treatment failures occur within the first 2 years following definitive therapy. The burden of lymph node metastases may yield information of prognostic value. In a retrospective study, a total volume of metastatic disease of more than 100 cm3 indicated a particularly poor prognosis.[25]
Risk Factors
In addition to the risk of delayed regional metastases, the risk of developing a second primary tumor in patients with tumors of the upper aerodigestive tract has been estimated to be 4% to 7% per year.[20,26–28] Because of these risks, surveillance of patients with hypopharyngeal cancer should be lifelong.
Histopathology
SCC of the hypopharynx has not been associated with any specific chromosomal or genetic abnormalities;[13] however, loss of chromosome 18 was observed in 57% of hypopharyngeal tumors in one study.[29] Several other studies have emphasized the importance of chromosome 11q13 amplification, which may be related to the presence of nodal metastases, greater local aggressiveness, and a higher incidence of tumor recurrence.[30–33]
References
Mendenhall WM, Werning JW, Pfister DG: Treatment of head and neck cancer. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Lippincott Williams & Wilkins, 2011, pp 729-80.
Uzcudun AE, Bravo Fernández P, Sánchez JJ, et al.: Clinical features of pharyngeal cancer: a retrospective study of 258 consecutive patients. J Laryngol Otol 115 (2): 112-8, 2001. [PUBMED Abstract]
Blot WJ, McLaughlin JK, Winn DM, et al.: Smoking and drinking in relation to oral and pharyngeal cancer. Cancer Res 48 (11): 3282-7, 1988. [PUBMED Abstract]
Day GL, Blot WJ, Shore RE, et al.: Second cancers following oral and pharyngeal cancers: role of tobacco and alcohol. J Natl Cancer Inst 86 (2): 131-7, 1994. [PUBMED Abstract]
Canto MT, Devesa SS: Oral cavity and pharynx cancer incidence rates in the United States, 1975-1998. Oral Oncol 38 (6): 610-7, 2002. [PUBMED Abstract]
Franceschi S, Bidoli E, Herrero R, et al.: Comparison of cancers of the oral cavity and pharynx worldwide: etiological clues. Oral Oncol 36 (1): 106-15, 2000. [PUBMED Abstract]
Siddiqui F, Sarin R, Agarwal JP, et al.: Squamous carcinoma of the larynx and hypopharynx in children: a distinct clinical entity? Med Pediatr Oncol 40 (5): 322-4, 2003. [PUBMED Abstract]
WYNDER EL, HULTBERG S, JACOBSSON F, et al.: Environmental factors in cancer of the upper alimentary tract; a Swedish study with special reference to Plummer-Vinson (Paterson-Kelly) syndrome. Cancer 10 (3): 470-87, 1957 May-Jun. [PUBMED Abstract]
Ahlbom HE: Simple achlorhydric anaemia, Plummer-Vinson syndrome, and carcinoma of the mouth, pharynx, and oesophagus in women: observations at Radiumhemmet, Stockholm. Br Med J 2 (3945): 331-3, 1936. [PUBMED Abstract]
Larsson LG, Sandström A, Westling P: Relationship of Plummer-Vinson disease to cancer of the upper alimentary tract in Sweden. Cancer Res 35 (11 Pt. 2): 3308-16, 1975. [PUBMED Abstract]
Amos A: Women and smoking. Br Med Bull 52 (1): 74-89, 1996. [PUBMED Abstract]
Barnes L, Johnson JT: Pathologic and clinical considerations in the evaluation of major head and neck specimens resected for cancer. Part I. Pathol Annu 21 Pt 1: 173-250, 1986. [PUBMED Abstract]
Helliwell TR: acp Best Practice No 169. Evidence based pathology: squamous carcinoma of the hypopharynx. J Clin Pathol 56 (2): 81-5, 2003. [PUBMED Abstract]
Raghavan U, Quraishi S, Bradley PJ: Multiple primary tumors in patients diagnosed with hypopharyngeal cancer. Otolaryngol Head Neck Surg 128 (3): 419-25, 2003. [PUBMED Abstract]
Tabor MP, Brakenhoff RH, van Houten VM, et al.: Persistence of genetically altered fields in head and neck cancer patients: biological and clinical implications. Clin Cancer Res 7 (6): 1523-32, 2001. [PUBMED Abstract]
Braakhuis BJ, Tabor MP, Kummer JA, et al.: A genetic explanation of Slaughter’s concept of field cancerization: evidence and clinical implications. Cancer Res 63 (8): 1727-30, 2003. [PUBMED Abstract]
Slaughter DP, Southwick HW, Smejkal W: Field cancerization in oral stratified squamous epithelium: clinical implications of multicentric origin. Cancer 6 (5): 963-8, 1953. [PUBMED Abstract]
Horwitz SD, Caldarelli DD, Hendrickson FR: Treatment of carcinoma of the hypopharynx. Head Neck Surg 2 (2): 107-11, 1979 Nov-Dec. [PUBMED Abstract]
Keane TJ: Carcinoma of the hypopharynx. J Otolaryngol 11 (4): 227-31, 1982. [PUBMED Abstract]
Spector JG, Sessions DG, Haughey BH, et al.: Delayed regional metastases, distant metastases, and second primary malignancies in squamous cell carcinomas of the larynx and hypopharynx. Laryngoscope 111 (6): 1079-87, 2001. [PUBMED Abstract]
Kotwall C, Sako K, Razack MS, et al.: Metastatic patterns in squamous cell cancer of the head and neck. Am J Surg 154 (4): 439-42, 1987. [PUBMED Abstract]
Godballe C, Jørgensen K, Hansen O, et al.: Hypopharyngeal cancer: results of treatment based on radiation therapy and salvage surgery. Laryngoscope 112 (5): 834-8, 2002. [PUBMED Abstract]
Lefebvre JL, Andry G, Chevalier D, et al.: Laryngeal preservation with induction chemotherapy for hypopharyngeal squamous cell carcinoma: 10-year results of EORTC trial 24891. Ann Oncol 23 (10): 2708-14, 2012. [PUBMED Abstract]
Jakobsen J, Hansen O, Jørgensen KE, et al.: Lymph node metastases from laryngeal and pharyngeal carcinomas–calculation of burden of metastasis and its impact on prognosis. Acta Oncol 37 (5): 489-93, 1998. [PUBMED Abstract]
Khuri FR, Lippman SM, Spitz MR, et al.: Molecular epidemiology and retinoid chemoprevention of head and neck cancer. J Natl Cancer Inst 89 (3): 199-211, 1997. [PUBMED Abstract]
Pfister DG, Shaha AR, Harrison LB: The role of chemotherapy in the curative treatment of head and neck cancer. Surg Oncol Clin N Am 6 (4): 749-68, 1997. [PUBMED Abstract]
León X, Quer M, Diez S, et al.: Second neoplasm in patients with head and neck cancer. Head Neck 21 (3): 204-10, 1999. [PUBMED Abstract]
Poetsch M, Kleist B, Lorenz G, et al.: Different numerical chromosomal aberrations detected by FISH in oropharyngeal, hypopharyngeal and laryngeal squamous cell carcinoma. Histopathology 34 (3): 234-40, 1999. [PUBMED Abstract]
Meredith SD, Levine PA, Burns JA, et al.: Chromosome 11q13 amplification in head and neck squamous cell carcinoma. Association with poor prognosis. Arch Otolaryngol Head Neck Surg 121 (7): 790-4, 1995. [PUBMED Abstract]
Muller D, Millon R, Velten M, et al.: Amplification of 11q13 DNA markers in head and neck squamous cell carcinomas: correlation with clinical outcome. Eur J Cancer 33 (13): 2203-10, 1997. [PUBMED Abstract]
Rodrigo JP, García LA, Ramos S, et al.: EMS1 gene amplification correlates with poor prognosis in squamous cell carcinomas of the head and neck. Clin Cancer Res 6 (8): 3177-82, 2000. [PUBMED Abstract]
Rodrigo JP, González MV, Lazo PS, et al.: Genetic alterations in squamous cell carcinomas of the hypopharynx with correlations to clinicopathological features. Oral Oncol 38 (4): 357-63, 2002. [PUBMED Abstract]
Cellular Classification of Hypopharyngeal Cancer
Almost all hypopharyngeal cancers are epithelial in origin, predominantly squamous cell (i.e., epidermoid) carcinomas (SCCs), and may be preceded by various precancerous lesions.[1,2] Rare types of hypopharyngeal carcinomas include:
Nonepithelial tumors, including lymphomas, sarcomas, and melanomas, require separate consideration and are not included in the staging and treatment options discussed in this summary.[1,3–8]
Invasive SCCs are usually moderately or poorly differentiated and invariably stain positively for keratin.[1] In situ carcinoma is often seen adjacent to invasive SCC.[1,9]
The term, leukoplakia, should be used only as a clinically descriptive term meaning that the observer sees a white patch that does not rub off, the significance of which depends on the histological findings.[10] Based on this description, leukoplakia can range from hyperkeratosis to an actual early invasive carcinoma or may represent only a fungal infection, lichen planus, or other benign oral disease.
Mendenhall WM, Werning JW, Pfister DG: Treatment of head and neck cancer. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Lippincott Williams & Wilkins, 2011, pp 729-80.
Ibrahim NB, Briggs JC, Corbishley CM: Extrapulmonary oat cell carcinoma. Cancer 54 (8): 1645-61, 1984. [PUBMED Abstract]
Stanley RJ, Weiland LH, DeSanto LW, et al.: Lymphoepithelioma (undifferentiated carcinoma) of the laryngohypopharynx. Laryngoscope 95 (9 Pt 1): 1077-81, 1985. [PUBMED Abstract]
McKay MJ, Bilous AM: Basaloid-squamous carcinoma of the hypopharynx. Cancer 63 (12): 2528-31, 1989. [PUBMED Abstract]
Frank DK, Cheron F, Cho H, et al.: Nonnasopharyngeal lymphoepitheliomas (undifferentiated carcinomas) of the upper aerodigestive tract. Ann Otol Rhinol Laryngol 104 (4 Pt 1): 305-10, 1995. [PUBMED Abstract]
Olsen KD, Lewis JE, Suman VJ: Spindle cell carcinoma of the larynx and hypopharynx. Otolaryngol Head Neck Surg 116 (1): 47-52, 1997. [PUBMED Abstract]
Lengyel E, Gilde K, Remenár E, et al.: Malignant mucosal melanoma of the head and neck. Pathol Oncol Res 9 (1): 7-12, 2003. [PUBMED Abstract]
Helliwell TR: acp Best Practice No 169. Evidence based pathology: squamous carcinoma of the hypopharynx. J Clin Pathol 56 (2): 81-5, 2003. [PUBMED Abstract]
Neville BW, Day TA: Oral cancer and precancerous lesions. CA Cancer J Clin 52 (4): 195-215, 2002 Jul-Aug. [PUBMED Abstract]
Stage Information for Hypopharyngeal Cancer
The staging systems are all clinical staging and are based on the best possible estimate of the extent of disease before treatment. The assessment of the primary tumor is based on inspection and palpation, when possible, and by both indirect mirror examination and direct endoscopy. The tumor must be confirmed histologically, and any other pathological data obtained from a biopsy may be included. Additional radiographic studies may be included. As an adjunct to clinical examination, computed tomography and/or magnetic resonance imaging are needed for an accurate staging of laryngeal and hypopharyngeal carcinomas because both cross-sectional imaging modalities are known to reliably evaluate deep tumor infiltration.[1–3] The appropriate nodal drainage areas are examined by careful palpation. If a patient relapses, complete restaging must be done to select the appropriate additional therapy.
American Joint Committee on Cancer (AJCC) Stage Groupings and TNM Definitions
The AJCC has designated staging by TNM (tumor, node, metastasis) classification to define hypopharyngeal cancer.[4]
Table 1. Definitions of Primary Tumor (T) for Hypopharyngeal Cancera
T Category
T Criteria
aReprinted with permission from AJCC: Oropharynx (p16-) and Hypopharynx. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 123–35.
bCentral compartment soft tissue includes prelaryngeal strap muscles and subcutaneous fat.
TX
Primary tumor cannot be assessed.
Tis
Carcinoma in situ.
T1
Tumor limited to one subsite of hypopharynx and/or ≤2 cm in greatest dimension.
T2
Tumor invades more than one subsite of hypopharynx or an adjacent site, or measures >2 cm but ≤4 cm in greatest dimension without fixation of hemilarynx.
T3
Tumor >4 cm in greatest dimension or with fixation of hemilarynx or extension to esophageal mucosa.
T4
Moderately advanced and very advanced local disease.
‒T4a
Moderately advanced local disease. Tumor invades thyroid/cricoid cartilage, hyoid bone, thyroid gland, esophageal muscle, or central compartment soft tissue.b
‒T4b
Very advanced local disease. Tumor invades prevertebral fascia, encases carotid artery, or involves mediastinal structures.
Table 2. Definitions of Regional Lymph Nodes (N) for Hypopharyngeal Cancera
N Category
Clinical N (cN) Criteria
Pathological N (pN) Criteria
ENE = extranodal extension.
aReprinted with permission from AJCC: Oropharynx (p16-) and Hypopharynx. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 123–35.
Note: A designation of U or L may be used for any N category to indicate metastasis above the lower border of the cricoid (U) or below the lower border of the cricoid (L). Similarly, clinical and pathological ENE should be recorded as ENE(‒) or ENE(+).
NX
Regional lymph nodes cannot be assessed.
Regional lymph nodes cannot be assessed.
N0
No regional lymph node metastasis.
No regional lymph node metastasis.
N1
Metastasis in a single ipsilateral lymph node, ≤3 cm in greatest dimension and ENE(‒).
Metastasis in a single ipsilateral lymph node, ≤3 cm in greatest dimension and ENE(‒).
N2
Metastasis in a single ipsilateral node >3 cm but ≤6 cm in greatest dimension and ENE(‒); or metastases in multiple ipsilateral lymph nodes, none >6 cm in greatest dimension and ENE(‒); or in bilateral or contralateral lymph nodes, none >6 cm in greatest dimension and ENE(‒).
Metastasis in a single ipsilateral lymph node, ≤3 cm in greatest dimension and ENE(+); or >3 cm but ≤6 cm in greatest dimension and ENE(‒); or metastases in multiple ipsilateral lymph nodes, none >6 cm in greatest dimension and ENE(‒); or in bilateral or contralateral lymph nodes, none >6 cm in greatest dimension and ENE(‒).
‒N2a
Metastasis in a single ipsilateral node >3 cm but ≤6 cm in greatest dimension and ENE(‒).
Metastasis in single ipsilateral node ≤3 cm in greatest dimension and ENE(+); or a single ipsilateral node >3 cm but ≤6 cm in greatest dimension and ENE(‒).
‒N2b
Metastases in multiple ipsilateral nodes, none >6 cm in greatest dimension and ENE(‒).
Metastases in multiple ipsilateral nodes, none >6 cm in greatest dimension and ENE(‒).
‒N2c
Metastases in bilateral or contralateral lymph nodes, none >6 cm in greatest dimension and ENE(‒).
Metastases in bilateral or contralateral lymph nodes, none >6 cm in greatest dimension and ENE(‒).
N3
Metastasis in a lymph node >6 cm in greatest dimension and ENE(‒); or metastasis in any node(s) and clinically overt ENE(+).
Metastasis in a lymph node >6 cm in greatest dimension and ENE(‒); or metastasis in a single ipsilateral node >3 cm in greatest dimension and ENE(+); or multiple ipsilateral, contralateral, or bilateral nodes, any with ENE(+); or a single contralateral node of any size and ENE(+).
‒N3a
Metastasis in a lymph node >6 cm in greatest dimension and ENE(‒).
Metastasis in a lymph node >6 cm in greatest dimension and ENE(‒).
‒N3b
Metastasis in any node(s) and clinically overt ENE(+).
Metastasis in a single ipsilateral node >3 cm in greatest dimension and ENE(+); or multiple ipsilateral, contralateral, or bilateral nodes, any with ENE(+); or a single contralateral node of any size and ENE(+).
Table 3. Definitions of Distant Metastasis (M)a
M Category
M Criteria
aReprinted with permission from AJCC: Oropharynx (p16-) and Hypopharynx. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 123–35.
M0
No distant metastasis.
M1
Distant metastasis.
Table 4. Definition of TNM Stage 0a
Stage
TNM
Description
T = primary tumor; N = regional lymph node; M = distant metastasis.
aReprinted with permission from AJCC: Oropharynx (p16-) and Hypopharynx. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 123–35.
0
Tis, N0, M0
Tis = Carcinoma in situ.
N0 = No regional lymph node metastasis.
M0 = No distant metastasis.
Table 5. Definition of TNM Stage Ia
Stage
TNM
Description
T = primary tumor; N = regional lymph node; M = distant metastasis.
aReprinted with permission from AJCC: Oropharynx (p16-) and Hypopharynx. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 123–35.
I
T1, N0, M0
T1 = Tumor limited to one subsite of hypopharynx and/or ≤2 cm in greatest dimension.
N0 = No regional lymph node metastasis.
M0 = No distant metastasis.
Table 6. Definition of TNM Stage IIa
Stage
TNM
Description
T = primary tumor; N = regional lymph node; M = distant metastasis.
aReprinted with permission from AJCC: Oropharynx (p16-) and Hypopharynx. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 123–35.
II
T2, N0, M0
T2 = Tumor invades more than one subsite of hypopharynx or an adjacent site, or measures >2 cm but ≤4 cm in greatest dimension without fixation of hemilarynx.
N0 = No regional lymph node metastasis.
M0 = No distant metastasis.
Table 7. Definitions of TNM Stage IIIa
Stage
TNM
Description
T = primary tumor; N = regional lymph node; M = distant metastasis; ENE = extranodal extension.
aReprinted with permission from AJCC: Oropharynx (p16-) and Hypopharynx. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 123–35.
III
T3, N0, M0
T3 = Tumor >4 cm in greatest dimension or with fixation of hemilarynx or extension to esophageal mucosa.
N1 = Metastasis in a single ipsilateral lymph node, ≤3 cm in greatest dimension and ENE(‒).
M0 = No distant metastasis.
Table 8. Definitions of TNM Stage IVa
Stage
TNM
Description
T = primary tumor; N = regional lymph node; M = distant metastasis; ENE = extranodal extension.
aReprinted with permission from AJCC: Oropharynx (p16-) and Hypopharynx. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp 123–35.
bCentral compartment soft tissue includes prelaryngeal strap muscles and subcutaneous fat.
IVA
T4a, N0, N1, M0
T4a = Moderately advanced local disease. Tumor invades thyroid/cricoid cartilage, hyoid bone, thyroid gland, esophageal muscle, or central compartment soft tissue.b
N0 = No regional lymph node metastasis.
N1 = Metastasis in a single ipsilateral lymph node, ≤3 cm in greatest dimension and ENE(‒).
Thabet HM, Sessions DG, Gado MH, et al.: Comparison of clinical evaluation and computed tomographic diagnostic accuracy for tumors of the larynx and hypopharynx. Laryngoscope 106 (5 Pt 1): 589-94, 1996. [PUBMED Abstract]
Becker M: Larynx and hypopharynx. Radiol Clin North Am 36 (5): 891-920, vi, 1998. [PUBMED Abstract]
Keberle M, Kenn W, Hahn D: Current concepts in imaging of laryngeal and hypopharyngeal cancer. Eur Radiol 12 (7): 1672-83, 2002. [PUBMED Abstract]
Oropharynx (p16-) and Hypopharynx. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. Springer; 2017, pp. 123-35.
Treatment Option Overview for Hypopharyngeal Cancer
Hypopharyngeal cancer usually does not cause symptoms until late in the course of the disease. Coupled with the high incidence of early metastasis, survival rates for carcinoma of the hypopharynx are perhaps the lowest of all cancer sites in the head and neck.
No single therapeutic regimen offers a superior survival advantage over other regimens. Although the literature highlights various therapeutic options, few reports present any valid comparative studies. The ultimate therapeutic choice will depend on a careful review of each individual case, paying attention to the staging of the neoplasm, the patient’s general physical condition and emotional status, the experience of the treating team, and the available treatment facilities.[1,2]
Treatment Overview
Except for very early stage (T1) cancers of this region, treatment has primarily been surgery, usually followed with postoperative radiation therapy (PORT). Some early stage (T1 and T2), low-volume, exophytic pyriform sinus carcinomas have been successfully treated with radiation therapy alone.[3–5] Single-modality therapy of advanced-stage hypopharyngeal cancer, with either surgery or radiation therapy, has resulted in consistently poor survival.[6–8]
Combined-modality treatment should be considered for patients with stage III or stage IV disease.[4,6,9,10] When used with surgery, radiation therapy is typically administered postoperatively. In selected advanced cases, alternative strategies using neoadjuvant chemotherapy and radiation therapy may increase the chance for local control as much as resection and PORT.[4]
A review of published clinical results of radical radiation therapy for head and neck cancer suggests a significant loss of local control when radiation therapy was prolonged; therefore, lengthening of standard treatment schedules should be avoided whenever possible.[11,12]
Chronic pulmonary and hepatic diseases related to excessive tobacco and alcohol use are common in patients with head and neck cancer; recognition of these comorbidities is essential when planning appropriate treatment.[6] Patients who smoke during radiation therapy appear to have lower response rates and shorter survival durations than those who do not.[13] Consequently, patients should be counseled to stop smoking before beginning radiation therapy. Evidence has demonstrated a high incidence (i.e., >30%–40%) of hypothyroidism in patients who have received external-beam radiation therapy to the entire thyroid gland or to the pituitary gland. Thyroid function testing of patients should be considered before therapy and as part of posttreatment follow-up.[14,15]
Fluorouracil Dosing
The DPYD gene encodes an enzyme that catabolizes pyrimidines and fluoropyrimidines, like capecitabine and fluorouracil. An estimated 1% to 2% of the population has germline pathogenic variants in DPYD, which lead to reduced DPD protein function and an accumulation of pyrimidines and fluoropyrimidines in the body.[16,17] Patients with the DPYD*2A variant who receive fluoropyrimidines may experience severe, life-threatening toxicities that are sometimes fatal. Many other DPYD variants have been identified, with a range of clinical effects.[16–18] Fluoropyrimidine avoidance or a dose reduction of 50% may be recommended based on the patient’s DPYD genotype and number of functioning DPYD alleles.[19–21] DPYD genetic testing costs less than $200, but insurance coverage varies due to a lack of national guidelines.[22] In addition, testing may delay therapy by 2 weeks, which would not be advisable in urgent situations. This controversial issue requires further evaluation.[23]
References
Thawley SE, Panje WR, Batsakis JG, et al., eds.: Comprehensive Management of Head and Neck Tumors. 2nd ed. WB Saunders, 1999.
Murthy AK, Galinsky D, Hendrickson FR: Hypopharynx. In: Laramore GE, ed.: Radiation Therapy of Head and Neck Cancer. Springer-Verlag, 1989, pp 107-24.
Pameijer FA, Mancuso AA, Mendenhall WM, et al.: Evaluation of pretreatment computed tomography as a predictor of local control in T1/T2 pyriform sinus carcinoma treated with definitive radiotherapy. Head Neck 20 (2): 159-68, 1998. [PUBMED Abstract]
Mendenhall WM, Parsons JT, Stringer SP, et al.: Radiotherapy alone or combined with neck dissection for T1-T2 carcinoma of the pyriform sinus: an alternative to conservation surgery. Int J Radiat Oncol Biol Phys 27 (5): 1017-27, 1993. [PUBMED Abstract]
Mendenhall WM, Werning JW, Pfister DG: Treatment of head and neck cancer. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Lippincott Williams & Wilkins, 2011, pp 729-80.
Godballe C, Jørgensen K, Hansen O, et al.: Hypopharyngeal cancer: results of treatment based on radiation therapy and salvage surgery. Laryngoscope 112 (5): 834-8, 2002. [PUBMED Abstract]
Spector JG, Sessions DG, Emami B, et al.: Squamous cell carcinoma of the pyriform sinus: a nonrandomized comparison of therapeutic modalities and long-term results. Laryngoscope 105 (4 Pt 1): 397-406, 1995. [PUBMED Abstract]
Jones AS, Stell PM: Squamous carcinoma of the posterior pharyngeal wall. Clin Otolaryngol 16 (5): 462-5, 1991. [PUBMED Abstract]
Fowler JF, Lindstrom MJ: Loss of local control with prolongation in radiotherapy. Int J Radiat Oncol Biol Phys 23 (2): 457-67, 1992. [PUBMED Abstract]
Hansen O, Overgaard J, Hansen HS, et al.: Importance of overall treatment time for the outcome of radiotherapy of advanced head and neck carcinoma: dependency on tumor differentiation. Radiother Oncol 43 (1): 47-51, 1997. [PUBMED Abstract]
Browman GP, Wong G, Hodson I, et al.: Influence of cigarette smoking on the efficacy of radiation therapy in head and neck cancer. N Engl J Med 328 (3): 159-63, 1993. [PUBMED Abstract]
Turner SL, Tiver KW, Boyages SC: Thyroid dysfunction following radiotherapy for head and neck cancer. Int J Radiat Oncol Biol Phys 31 (2): 279-83, 1995. [PUBMED Abstract]
Constine LS: What else don’t we know about the late effects of radiation in patients treated for head and neck cancer? Int J Radiat Oncol Biol Phys 31 (2): 427-9, 1995. [PUBMED Abstract]
Sharma BB, Rai K, Blunt H, et al.: Pathogenic DPYD Variants and Treatment-Related Mortality in Patients Receiving Fluoropyrimidine Chemotherapy: A Systematic Review and Meta-Analysis. Oncologist 26 (12): 1008-1016, 2021. [PUBMED Abstract]
Lam SW, Guchelaar HJ, Boven E: The role of pharmacogenetics in capecitabine efficacy and toxicity. Cancer Treat Rev 50: 9-22, 2016. [PUBMED Abstract]
Shakeel F, Fang F, Kwon JW, et al.: Patients carrying DPYD variant alleles have increased risk of severe toxicity and related treatment modifications during fluoropyrimidine chemotherapy. Pharmacogenomics 22 (3): 145-155, 2021. [PUBMED Abstract]
Amstutz U, Henricks LM, Offer SM, et al.: Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Dihydropyrimidine Dehydrogenase Genotype and Fluoropyrimidine Dosing: 2017 Update. Clin Pharmacol Ther 103 (2): 210-216, 2018. [PUBMED Abstract]
Henricks LM, Lunenburg CATC, de Man FM, et al.: DPYD genotype-guided dose individualisation of fluoropyrimidine therapy in patients with cancer: a prospective safety analysis. Lancet Oncol 19 (11): 1459-1467, 2018. [PUBMED Abstract]
Lau-Min KS, Varughese LA, Nelson MN, et al.: Preemptive pharmacogenetic testing to guide chemotherapy dosing in patients with gastrointestinal malignancies: a qualitative study of barriers to implementation. BMC Cancer 22 (1): 47, 2022. [PUBMED Abstract]
Brooks GA, Tapp S, Daly AT, et al.: Cost-effectiveness of DPYD Genotyping Prior to Fluoropyrimidine-based Adjuvant Chemotherapy for Colon Cancer. Clin Colorectal Cancer 21 (3): e189-e195, 2022. [PUBMED Abstract]
Baker SD, Bates SE, Brooks GA, et al.: DPYD Testing: Time to Put Patient Safety First. J Clin Oncol 41 (15): 2701-2705, 2023. [PUBMED Abstract]
Treatment of Stage I Hypopharyngeal Cancer
Treatment Options for Stage I Hypopharyngeal Cancer
Except for the very early T1 cancers of this region, treatment has been primarily surgery, usually followed with postoperative radiation therapy. Because these tumors are clinically silent until they reach advanced stages, it is very unusual to diagnose them at the T1 N0 stage. In most available retrospective reviews, T1 N0 cases represent only 1% to 2% of all patients seen. In the case of exophytic T1 N0 lesions, radiation therapy alone may be considered.[1,2]
Treatment options for stage I hypopharyngeal cancer include:
Laryngopharyngectomy and neck dissection has been the most frequently used therapy for hypopharyngeal cancers.
In very selected cases of pyriform sinus cancers, that is, those arising in the upper lateral wall, a partial laryngopharyngectomy may be successfully used to preserve vocal function. All groups who use radiation therapy advocate high-dose treatment to the primary site and to both sides of the neck to include the retropharyngeal and lateral cervical nodes.[1]
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
Mendenhall WM, Parsons JT, Devine JW, et al.: Squamous cell carcinoma of the pyriform sinus treated with surgery and/or radiotherapy. Head Neck Surg 10 (2): 88-92, 1987 Nov-Dec. [PUBMED Abstract]
Murthy AK, Galinsky D, Hendrickson FR: Hypopharynx. In: Laramore GE, ed.: Radiation Therapy of Head and Neck Cancer. Springer-Verlag, 1989, pp 107-24.
Treatment of Stage II Hypopharyngeal Cancer
Treatment Options for Stage II Hypopharyngeal Cancer
Treatment has been primarily surgery, which is usually followed with postoperative radiation therapy (PORT). Because these tumors are clinically silent until they reach advanced stages, it is very unusual to diagnose these tumors at the T2 N0 stage.
Treatment options for stage II hypopharyngeal cancer include:
Laryngopharyngectomy and neck dissection has been the most frequently used therapy for hypopharyngeal cancers.
In very selected cases of pyriform sinus cancers, that is, those arising in the upper medial wall, a partial laryngopharyngectomy may be successfully used to preserve vocal function. In T2 cases, PORT has been given in combination with surgery in an effort to improve the local control rates of surgery alone. There are advocates of preoperative radiation therapy, but all groups giving radiation therapy advocate high-dose treatment to the primary site and to both sides of the neck to include the retropharyngeal and lateral cervical nodes.[1,2]
Neoadjuvant chemotherapy is commonly used to treat patients who present with advanced disease to improve locoregional control or survival, despite the lack of data from randomized, prospective trials.[3]
The use of neoadjuvant chemotherapy to increase organ preservation has also been advocated. In a prospective randomized trial (GORTEC-TREMPLIN trial [NCT00169247]), the European Organisation for the Research and Treatment of Cancer compared surgery plus PORT with neoadjuvant chemotherapy (i.e., cisplatin plus fluorouracil) followed by radiation therapy in responding patients. Local and regional failures were similar in both groups. Although median survival was 25 months in the immediate surgery arm of the study and 44 months in the induction chemotherapy arm (P = .006), 5-year disease-free and overall survival were the same. A functional larynx was preserved in 42% of patients at 3 years and 35% at 5 years in patients who received induction chemotherapy. These data have not been confirmed by other phase III trials but suggest that larynx preservation may be feasible without jeopardizing survival.[4][Level of evidence A1 and A3]
Most neoadjuvant chemotherapy clinical trials have included patients with stage II hypopharyngeal carcinoma because of the low survival rates for this population.[5]
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
Mendenhall WM, Parsons JT, Devine JW, et al.: Squamous cell carcinoma of the pyriform sinus treated with surgery and/or radiotherapy. Head Neck Surg 10 (2): 88-92, 1987 Nov-Dec. [PUBMED Abstract]
Murthy AK, Galinsky D, Hendrickson FR: Hypopharynx. In: Laramore GE, ed.: Radiation Therapy of Head and Neck Cancer. Springer-Verlag, 1989, pp 107-24.
Harari PM: Why has induction chemotherapy for advanced head and neck cancer become a United States community standard of practice? J Clin Oncol 15 (5): 2050-5, 1997. [PUBMED Abstract]
Lefebvre JL, Andry G, Chevalier D, et al.: Laryngeal preservation with induction chemotherapy for hypopharyngeal squamous cell carcinoma: 10-year results of EORTC trial 24891. Ann Oncol 23 (10): 2708-14, 2012. [PUBMED Abstract]
Meoz-Mendez RT, Fletcher GH, Guillamondegui OM, et al.: Analysis of the results of irradiation in the treatment of squamous cell carcinomas of the pharyngeal walls. Int J Radiat Oncol Biol Phys 4 (7-8): 579-85, 1978 Jul-Aug. [PUBMED Abstract]
Treatment of Stage III Hypopharyngeal Cancer
Treatment Options for Stage III Hypopharyngeal Cancer
The management of patients with stage III hypopharyngeal cancer is complex and requires multidisciplinary input to establish the optimal treatment regimen. New surgical techniques and reconstructions (using the gastric pull-up operation or free jejunal transfers) have greatly reduced the morbidity associated with resection of these tumors and have almost eliminated the need for multistage reconstructions. This has greatly aided the combined treatment regimens because these patients have a high likelihood of beginning postoperative radiation therapy (PORT) within 3 to 4 weeks following resection.
Details of surgical procedures and modifications of radiation fields or dosage schedules are not specifically designated here because of legitimate variations in techniques that, according to various retrospective data, give similar survival results in different treatment centers. This group of patients should be managed by surgeons and radiation oncologists who are skilled in the multiple procedures and techniques available, and who are actively and frequently involved in the care of these patients.
Treatment options for stage III hypopharyngeal cancer include:
The combination of surgery and radiation, most often postoperative as seen in a follow-up study of preoperative versus PORT (RTOG-7303), has become the usual form of therapy for this group of patients in the United States.[1–3]
Neoadjuvant chemotherapy is commonly used to treat patients who present with advanced disease to improve locoregional control or survival, despite the lack of data from randomized prospective trials.[4]
The use of neoadjuvant chemotherapy to increase organ preservation has also been advocated. In a prospective randomized trial (GORTEC-TREMPLIN [NCT00169247]), the European Organisation for the Treatment and Research of Cancer compared surgery plus PORT with induction chemotherapy (i.e., cisplatin plus fluorouracil [5-FU]) followed by radiation in responding patients.[5] Local and regional failures were similar in both groups. Although median survival was 25 months in the immediate surgery arm of the study and 44 months in the induction chemotherapy arm (P = .006), 5-year disease-free survival (DFS) and overall survival (OS) were the same. A functional larynx was preserved in 42% of patients at 3 years and 35% at 5 years in patients who received induction chemotherapy.[5][Level of evidence A1 and A3]
In contrast to this, another randomized prospective trial has demonstrated a statistically significant survival advantage for patients undergoing chemotherapy (i.e., cisplatin plus 5-FU) followed by laryngopharyngectomy and PORT when compared with chemotherapy and radiation therapy.[6][Level of evidence A1 and A3] Although organ preservation was not discussed in this study, chemotherapy in combination with radiation therapy without surgery should not be considered standard treatment.
Patients with stage III hypopharyngeal cancer should consider combined postoperative, adjuvant radiation therapy and chemotherapy.
In a prospective randomized trial, postoperative adjuvant radiation therapy alone was compared with postoperative adjuvant radiation therapy plus concurrent chemotherapy. Both the OS (P < .01) and the DFS (P < .02) were better in the group of patients receiving radiation therapy plus concurrent chemotherapy.[7][Level of evidence A1] In another study, primary site preservation was improved, though OS was not improved when chemotherapy was administered concomitantly with radiation therapy.[8,9]
Chemotherapy combined with radiation therapy for patients with locally advanced disease (under clinical evaluation).[10–12]
Concurrent chemotherapy is a standard treatment option for patients with locally advanced (stage III and stage IV) hypopharyngeal cancer. A meta-analysis of 93 randomized prospective head and neck cancer trials published between 1965 and 2000 showed a 4.5% absolute survival advantage in the subset of patients who received chemotherapy and radiation therapy.[13][Level of evidence B4] Patients who received concurrent chemotherapy had a greater survival benefit than those who received induction chemotherapy.
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
Arriagada R, Eschwege F, Cachin Y, et al.: The value of combining radiotherapy with surgery in the treatment of hypopharyngeal and laryngeal cancers. Cancer 51 (10): 1819-25, 1983. [PUBMED Abstract]
Mendenhall WM, Parsons JT, Devine JW, et al.: Squamous cell carcinoma of the pyriform sinus treated with surgery and/or radiotherapy. Head Neck Surg 10 (2): 88-92, 1987 Nov-Dec. [PUBMED Abstract]
Tupchong L, Scott CB, Blitzer PH, et al.: Randomized study of preoperative versus postoperative radiation therapy in advanced head and neck carcinoma: long-term follow-up of RTOG study 73-03. Int J Radiat Oncol Biol Phys 20 (1): 21-8, 1991. [PUBMED Abstract]
Harari PM: Why has induction chemotherapy for advanced head and neck cancer become a United States community standard of practice? J Clin Oncol 15 (5): 2050-5, 1997. [PUBMED Abstract]
Lefebvre JL, Andry G, Chevalier D, et al.: Laryngeal preservation with induction chemotherapy for hypopharyngeal squamous cell carcinoma: 10-year results of EORTC trial 24891. Ann Oncol 23 (10): 2708-14, 2012. [PUBMED Abstract]
Beauvillain C, Mahé M, Bourdin S, et al.: Final results of a randomized trial comparing chemotherapy plus radiotherapy with chemotherapy plus surgery plus radiotherapy in locally advanced resectable hypopharyngeal carcinomas. Laryngoscope 107 (5): 648-53, 1997. [PUBMED Abstract]
Bachaud JM, Cohen-Jonathan E, Alzieu C, et al.: Combined postoperative radiotherapy and weekly cisplatin infusion for locally advanced head and neck carcinoma: final report of a randomized trial. Int J Radiat Oncol Biol Phys 36 (5): 999-1004, 1996. [PUBMED Abstract]
Adelstein DJ, Lavertu P, Saxton JP, et al.: Mature results of a phase III randomized trial comparing concurrent chemoradiotherapy with radiation therapy alone in patients with stage III and IV squamous cell carcinoma of the head and neck. Cancer 88 (4): 876-83, 2000. [PUBMED Abstract]
Bernier J, Domenge C, Ozsahin M, et al.: Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med 350 (19): 1945-52, 2004. [PUBMED Abstract]
Browman GP, Cripps C, Hodson DI, et al.: Placebo-controlled randomized trial of infusional fluorouracil during standard radiotherapy in locally advanced head and neck cancer. J Clin Oncol 12 (12): 2648-53, 1994. [PUBMED Abstract]
Merlano M, Benasso M, Corvò R, et al.: Five-year update of a randomized trial of alternating radiotherapy and chemotherapy compared with radiotherapy alone in treatment of unresectable squamous cell carcinoma of the head and neck. J Natl Cancer Inst 88 (9): 583-9, 1996. [PUBMED Abstract]
Jeremic B, Shibamoto Y, Milicic B, et al.: Hyperfractionated radiation therapy with or without concurrent low-dose daily cisplatin in locally advanced squamous cell carcinoma of the head and neck: a prospective randomized trial. J Clin Oncol 18 (7): 1458-64, 2000. [PUBMED Abstract]
Pignon JP, le Maître A, Maillard E, et al.: Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients. Radiother Oncol 92 (1): 4-14, 2009. [PUBMED Abstract]
Treatment of Stage IV Hypopharyngeal Cancer
Treatment Options for Resectable Stage IV Hypopharyngeal Cancer
The management of patients with resectable hypopharyngeal cancer is complex and requires multidisciplinary input to establish the optimal treatment regimen. New surgical techniques and reconstructions using the gastric pull-up operation or free jejunal transfers have greatly reduced the morbidity associated with resection of these tumors and have almost eliminated the need for multistage reconstructions. This has greatly aided the combined treatment regimens because these patients have a high likelihood of beginning postoperative radiation therapy within 3 to 4 weeks following resection.
Details of surgical procedures and modifications of radiation fields or dosage schedules are not specifically designated here because of legitimate variations in techniques that, according to various retrospective data, give similar survival results in different treatment centers. This group of patients should be managed by surgeons and radiation oncologists who are skilled in the multiple procedures and techniques available, and who are actively and frequently involved in the care of these patients.
Treatment options for resectable stage IV hypopharyngeal cancer include:
The combination of surgery and radiation, most often postoperative as seen in a follow-up study of preoperative versus postoperative radiation therapy (PORT) (RTOG-7303), has become the usual form of therapy for this group of patients in the United States.[1,2]
Neoadjuvant chemotherapy is commonly used to treat patients presenting with advanced disease to improve locoregional control or survival, despite the lack of data from randomized prospective trials.[3]
The use of neoadjuvant chemotherapy to increase organ preservation has also been advocated. In a prospective randomized trial (GORTEC-TREMPLIN [NCT00169247]), the European Organisation for the Research and Treatment of Cancer compared surgery plus PORT with induction chemotherapy (i.e., cisplatin plus fluorouracil [5-FU]) followed by radiation in responding patients.[4] Local and regional failures were similar in both groups. Although median survival was 25 months in the immediate surgery arm of the study and 44 months in the induction chemotherapy arm (P = .006), 5-year disease-free survival (DFS) and overall survival (OS) were the same. A functional larynx was preserved in 42% of patients at 3 years and 35% at 5 years in patients who received induction chemotherapy.[4][Level of evidence A1 and A3]
In contrast to this, another randomized prospective trial has demonstrated a statistically significant survival advantage for patients undergoing chemotherapy (i.e., cisplatin plus 5-FU) followed by laryngopharyngectomy and PORT when compared with chemotherapy and radiation therapy.[5][Level of evidence A1 and A3] Although organ preservation was not discussed, chemotherapy in combination with radiation therapy without surgery should not be considered standard treatment.
Patients with stage IV hypopharyngeal cancer should consider combined postoperative, adjuvant radiation therapy and chemotherapy.
In a prospective randomized trial, postoperative adjuvant radiation therapy alone was compared with postoperative adjuvant radiation therapy plus concurrent chemotherapy. Both the OS (P < .01) and the DFS (P < .02) were better in the group of patients who received radiation therapy plus concurrent chemotherapy.[6][Level of evidence A1] In another study, primary site preservation was improved, though OS was not improved when chemotherapy was given concomitantly with radiation therapy.[7,8]
Treatment Options for Unresectable Stage IV Hypopharyngeal Cancer
Treatment options for unresectable stage IV hypopharyngeal cancer include:
Radiation therapy.
Chemotherapy has been combined with radiation therapy in patients who have locally advanced disease.[9–11] In a randomized trial, the 3-year projected OS rate was 37% (P = .14) for patients with stage III or stage IV inoperable disease receiving single daily fractionated radiation with concurrent cisplatin.[11][Level of evidence A1]
Radiation therapy clinical trials evaluating hyperfractionation schedules may be considered with chemotherapy (under clinical evaluation).[12–17]
Concurrent chemotherapy is a standard treatment option for patients with locally advanced (stage III and stage IV) hypopharyngeal cancer. A meta-analysis of 93 randomized prospective head and neck cancer trials published between 1965 and 2000 showed a 4.5% absolute survival advantage in the subset of patients who received chemotherapy and radiation therapy.[18][Level of evidence B4] Patients who received concurrent chemotherapy had a greater survival benefit than those who received induction chemotherapy.
Posttreatment follow-up for unresectable stage IV hypopharyngeal cancer
These patients should have a careful head and neck examination, looking for recurrence monthly for the first posttreatment year, every 2 months for the second year, every 3 months the third year, and every 6 months thereafter.
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
Arriagada R, Eschwege F, Cachin Y, et al.: The value of combining radiotherapy with surgery in the treatment of hypopharyngeal and laryngeal cancers. Cancer 51 (10): 1819-25, 1983. [PUBMED Abstract]
Tupchong L, Scott CB, Blitzer PH, et al.: Randomized study of preoperative versus postoperative radiation therapy in advanced head and neck carcinoma: long-term follow-up of RTOG study 73-03. Int J Radiat Oncol Biol Phys 20 (1): 21-8, 1991. [PUBMED Abstract]
Harari PM: Why has induction chemotherapy for advanced head and neck cancer become a United States community standard of practice? J Clin Oncol 15 (5): 2050-5, 1997. [PUBMED Abstract]
Lefebvre JL, Andry G, Chevalier D, et al.: Laryngeal preservation with induction chemotherapy for hypopharyngeal squamous cell carcinoma: 10-year results of EORTC trial 24891. Ann Oncol 23 (10): 2708-14, 2012. [PUBMED Abstract]
Beauvillain C, Mahé M, Bourdin S, et al.: Final results of a randomized trial comparing chemotherapy plus radiotherapy with chemotherapy plus surgery plus radiotherapy in locally advanced resectable hypopharyngeal carcinomas. Laryngoscope 107 (5): 648-53, 1997. [PUBMED Abstract]
Bachaud JM, Cohen-Jonathan E, Alzieu C, et al.: Combined postoperative radiotherapy and weekly cisplatin infusion for locally advanced head and neck carcinoma: final report of a randomized trial. Int J Radiat Oncol Biol Phys 36 (5): 999-1004, 1996. [PUBMED Abstract]
Adelstein DJ, Lavertu P, Saxton JP, et al.: Mature results of a phase III randomized trial comparing concurrent chemoradiotherapy with radiation therapy alone in patients with stage III and IV squamous cell carcinoma of the head and neck. Cancer 88 (4): 876-83, 2000. [PUBMED Abstract]
Bernier J, Domenge C, Ozsahin M, et al.: Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med 350 (19): 1945-52, 2004. [PUBMED Abstract]
Al-Sarraf M, Pajak TF, Marcial VA, et al.: Concurrent radiotherapy and chemotherapy with cisplatin in inoperable squamous cell carcinoma of the head and neck. An RTOG Study. Cancer 59 (2): 259-65, 1987. [PUBMED Abstract]
Merlano M, Benasso M, Corvò R, et al.: Five-year update of a randomized trial of alternating radiotherapy and chemotherapy compared with radiotherapy alone in treatment of unresectable squamous cell carcinoma of the head and neck. J Natl Cancer Inst 88 (9): 583-9, 1996. [PUBMED Abstract]
Adelstein DJ, Li Y, Adams GL, et al.: An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer. J Clin Oncol 21 (1): 92-8, 2003. [PUBMED Abstract]
Weissler MC, Melin S, Sailer SL, et al.: Simultaneous chemoradiation in the treatment of advanced head and neck cancer. Arch Otolaryngol Head Neck Surg 118 (8): 806-10, 1992. [PUBMED Abstract]
Jeremic B, Shibamoto Y, Milicic B, et al.: Hyperfractionated radiation therapy with or without concurrent low-dose daily cisplatin in locally advanced squamous cell carcinoma of the head and neck: a prospective randomized trial. J Clin Oncol 18 (7): 1458-64, 2000. [PUBMED Abstract]
Staar S, Rudat V, Stuetzer H, et al.: Intensified hyperfractionated accelerated radiotherapy limits the additional benefit of simultaneous chemotherapy–results of a multicentric randomized German trial in advanced head-and-neck cancer. Int J Radiat Oncol Biol Phys 50 (5): 1161-71, 2001. [PUBMED Abstract]
Wendt TG, Grabenbauer GG, Rödel CM, et al.: Simultaneous radiochemotherapy versus radiotherapy alone in advanced head and neck cancer: a randomized multicenter study. J Clin Oncol 16 (4): 1318-24, 1998. [PUBMED Abstract]
Brizel DM, Albers ME, Fisher SR, et al.: Hyperfractionated irradiation with or without concurrent chemotherapy for locally advanced head and neck cancer. N Engl J Med 338 (25): 1798-804, 1998. [PUBMED Abstract]
Semrau R, Mueller RP, Stuetzer H, et al.: Efficacy of intensified hyperfractionated and accelerated radiotherapy and concurrent chemotherapy with carboplatin and 5-fluorouracil: updated results of a randomized multicentric trial in advanced head-and-neck cancer. Int J Radiat Oncol Biol Phys 64 (5): 1308-16, 2006. [PUBMED Abstract]
Pignon JP, le Maître A, Maillard E, et al.: Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients. Radiother Oncol 92 (1): 4-14, 2009. [PUBMED Abstract]
Treatment of Metastatic and Recurrent Hypopharyngeal Cancer
Treatment Options for Metastatic and Recurrent Hypopharyngeal Cancer
Treatment options for metastatic and recurrent hypopharyngeal cancer include:
Surgical resection if radiation therapy fails and if technically feasible.[1]
Radiation therapy, if not previously used in curative doses that preclude further treatment, if surgery fails.
Surgical salvage, if technically feasible, when surgery fails.
Clinical trials evaluating the use of chemotherapy should be considered.[12]
Immunotherapy
Pembrolizumab
Pembrolizumab is a monoclonal antibody and an inhibitor of the programmed death-1 (PD-1) pathway. Studies have evaluated pembrolizumab in patients with incurable metastatic or recurrent head and neck squamous cell carcinoma (SCC).
Evidence (pembrolizumab as first-line therapy):
KEYNOTE-048 (NCT02358031) was a nonblinded, randomized, phase III study of participants with untreated locally incurable metastatic or recurrent head and neck SCC that was performed at 200 sites in 37 countries.[3] A total of 882 patients were randomly assigned in a 1:1:1 ratio to receive pembrolizumab alone (n = 301), pembrolizumab plus a platinum and fluorouracil (5-FU) (pembrolizumab with chemotherapy) (n = 281), or cetuximab plus a platinum and 5-FU (cetuximab with chemotherapy) (n = 300). Investigators, patients, and representatives of the sponsor were masked to the programmed death-ligand 1 (PD-L1) combined positive score (CPS) results; PD-L1 positivity was not required for study entry. A total of 754 patients (85%) had a CPS of 1 or higher and 381 patients (43%) had a CPS of 20 or higher.
The primary end points were overall survival (OS) and progression-free survival (PFS). Progression was defined as radiographically confirmed disease progression or death from any cause, whichever came first, in the intention-to-treat population.
At the second interim analysis, pembrolizumab alone showed improved or noninferior OS compared with cetuximab with chemotherapy. The median OS results were reported as follows:[3][Level of evidence A1]
Among the population with a CPS of 20 or higher, the median OS was 14.9 months in patients who received pembrolizumab alone and 10.7 months in patients who received cetuximab with chemotherapy (hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.45–0.83; P = .0007).
Among the population with a CPS of 1 or higher, the median OS was 12.3 months in patients who received pembrolizumab alone and 10.3 months in patients who received cetuximab with chemotherapy (HR, 0.78; 95% CI, 0.64–0.96; P = .0086).
Among the total population, patients who received pembrolizumab alone had noninferior OS (11.6 months) compared with patients who received cetuximab with chemotherapy (10.7 months) (HR, 0.85; 95% CI, 0.71–1.03; P = .0456).
Pembrolizumab with chemotherapy showed improved OS versus cetuximab with chemotherapy. The OS results were reported as follows:
At the second interim analysis, among the total population, the median OS was 13.0 months in patients who received pembrolizumab with chemotherapy and 10.7 months in patients who received cetuximab with chemotherapy (HR, 0.77; 95% CI, 0.63–0.93; P = .0034).
At the final analysis, among the population with a CPS of 20 or higher, the median OS was 14.7 months in patients who received pembrolizumab with chemotherapy and 11.0 months in patients who received cetuximab with chemotherapy (HR, 0.60; 95% CI, 0.45–0.82; P = .0004).
At the final analysis, among the population with a CPS of 1 or higher, the median OS was 13.6 months in patients who received pembrolizumab with chemotherapy and 10.4 months in patients who received cetuximab with chemotherapy (HR, 0.65; 95% CI, 0.53–0.80; P < .0001).
At the second interim analysis, neither pembrolizumab alone nor pembrolizumab with chemotherapy improved PFS.
At the final analysis, grade 3 or higher all-cause adverse events occurred in 164 of 300 patients (55%) in the pembrolizumab-alone group, 235 of 276 patients (85%) who received pembrolizumab with chemotherapy, and 239 of 287 patients (83%) who received cetuximab with chemotherapy.
Adverse events led to death in 25 patients (8%) in the pembrolizumab-alone group, 32 patients (12%) who received pembrolizumab with chemotherapy, and 28 patients (10%) who received cetuximab with chemotherapy.
Pembrolizumab plus a platinum and 5-FU is an appropriate first-line treatment for patients with metastatic or recurrent head and neck SCC. Pembrolizumab monotherapy is an appropriate first-line treatment for patients with PD-L1–positive metastatic or recurrent head and neck SCC. These results were confirmed at a longer median follow-up of 45 months (interquartile range, 41.0–49.2).[9]
Evidence (pembrolizumab after progression on platinum-based treatment):
The phase III KEYNOTE-040 (NCT02252042) trial included patients with incurable metastatic or recurrent head and neck SCC who had received platinum-based treatment within 3 to 6 months.[4] Patients were randomly assigned to the pembrolizumab arm (200 mg every 3 weeks [247 patients]) or to the standard therapy arm of the investigator’s choice (methotrexate, docetaxel, or cetuximab [248 patients]). Patients received treatment until progression or toxicity. The maximum duration of pembrolizumab was 24 months. The primary end point was OS in the intention-to-treat population.
The median OS was 8.4 months in the pembrolizumab arm and 6.9 months in the standard therapy arm (HR, 0.80; 95% CI, 0.65–0.98; nominal P = .0161).[4][Level of evidence A1]
Pembrolizumab was associated with fewer grade 3 or higher adverse events (pembrolizumab, 13% vs. standard therapy, 36%). The most common treatment-related adverse events were hypothyroidism (13%) in the pembrolizumab arm and fatigue (18%) in the standard therapy arm.
In patients who received pembrolizumab, there were four treatment-related deaths resulting from large intestinal perforation, Stevens-Johnson syndrome, and unspecified malignant progression. Two treatment-related deaths in the standard therapy arm resulted from malignant progression and pneumonia.
The PD-L1 CPS was 1 or higher in 79% of the patients in the pembrolizumab arm and 77% of the patients in the standard therapy arm.
Compared with patients treated with standard therapy, a reduced HRdeath was noted for patients who received pembrolizumab and had PD-1 expression on their tumors or in the tumor microenvironment as noted by a PD-L1 CPS of 1 or higher (HR, 0.74; 95% CI, 0.58–0.93; nominal P = .0049) or a PD-L1 tumor proportion score of 50% or higher (HR, 0.53; 95% CI, 0.35–0.81; nominal P = .0014).
Nivolumab
Nivolumab is a fully human immunoglobulin G4 anti–PD-1 monoclonal antibody.
Evidence (nivolumab combined with ipilimumab in patients who have not previously received systemic therapy):
The CheckMate 651 trial (NCT02741570) evaluated first-line nivolumab plus ipilimumab versus EXTREME (cetuximab, cisplatin/carboplatin, and 5-FU for up to six cycles followed by cetuximab maintenance) in patients with recurrent or metastatic head and neck SCC.[5] The primary end points were OS in all randomly assigned patients and patients with a PD-L1 CPS of 20 or higher. Secondary end points included OS in patients with a PD-L1 CPS of 1 or higher and PFS, objective response rate, and duration of response in all randomly assigned patients and patients with a PD-L1 CPS of 20 or higher.
Among all randomly assigned patients, there was no statistically significant difference in OS with nivolumab plus ipilimumab versus EXTREME (median OS, 13.9 vs. 13.5 months; HR, 0.95; 97.9% CI, 0.80–1.13; P = .4951). Among patients with a PD-L1 CPS of 20 or higher, there was also no statistically significant OS difference between the two treatments (median OS, 17.6 vs. 14.6 months; HR, 0.78; 97.51% CI, 0.59–1.03; P = .0469).[5][Level of evidence A1]
In patients with a CPS of 1 or higher, the median OS was 15.7 months for patients who received nivolumab plus ipilimumab versus 13.2 months for patients who received EXTREME (HR, 0.82; 95% CI, 0.69–0.97).
Among patients with a CPS of 20 or higher, the median PFS was 5.4 months for patients who received nivolumab plus ipilimumab and 7.0 months for patients who received EXTREME. The objective response rate was 34.1% for patients who received nivolumab plus ipilimumab and 36.0% for patients who received EXTREME.
Grade 3 or 4 treatment-related adverse events occurred in 28.2% of patients who received nivolumab plus ipilimumab and 70.7% of patients who received EXTREME.
CheckMate 651 did not meet its primary end points of OS in the randomly assigned or CPS of 20 or higher populations.
The absence of a survival benefit for immune checkpoint inhibitors in this trial was an unexpected outcome, given the similarity of nivolumab to pembrolizumab in the studies of patients with cisplatin-refractory disease.[4,7] An editorial accompanying the CheckMate 651 trial analyzed some of the factors that may have contributed to a different result. The editorial suggested that survival in the control group, which was longer than that reported in prior studies, may have been impacted by the greater availability of second-line immunotherapy in the control group (46% in CheckMate 651 compared with 25% in the KEYNOTE-048 trial). The authors also suggested that the coadministration of ipilimumab detracted from the activity of nivolumab, as shown in the CheckMate 714 trial.[10]
CheckMate 714 (NCT02823574), a double-blind phase II trial, evaluated the clinical benefit of first-line nivolumab plus ipilimumab versus nivolumab alone in 425 patients with recurrent or metastatic head and neck SCC.[6] Patients were randomly assigned in a 2:1 ratio to receive either nivolumab (3 mg/kg intravenously [IV] every 2 weeks) plus ipilimumab (1 mg/kg IV every 6 weeks) or nivolumab (3 mg/kg IV every 2 weeks) plus placebo. Treatment continued for up to 2 years or until disease progression, unacceptable toxic effects, or consent withdrawal. The primary end points were objective response rate and duration of response between treatment arms by blinded independent central review in the population with platinum-refractory recurrent or metastatic disease. These were patients who had recurrent disease less than 6 months after completion of platinum-based chemotherapy (adjuvant or neoadjuvant, or as part of multimodal treatment [chemotherapy, surgery, and/or radiation therapy]). Among the 241 patients (56.7%) with platinum-refractory disease, 159 were assigned to receive nivolumab plus ipilimumab and 82 were assigned to receive nivolumab alone. Among the 184 patients (43.3%) with platinum-eligible disease, 123 were assigned to receive nivolumab plus ipilimumab and 61 were assigned to receive nivolumab alone.[6][Level of evidence B3]
At primary database lock, the objective response rate in the population with platinum-refractory disease was 13.2% (95% CI, 8.4%–19.5%) with nivolumab plus ipilimumab and 18.3% (95% CI, 10.6%–28.4%) with nivolumab alone (odds ratio, 0.68; 95.5% CI, 0.33–1.43; P = .29).
The median duration of response was not reached (NR) in the nivolumab-plus-ipilimumab group (95% CI, 11.0 months–NR) and was 11.1 months (95% CI, 4.1–NR) in the nivolumab-alone group. In the population with platinum-eligible disease, the objective response rate was 20.3% (95% CI, 13.6%–28.5%) with nivolumab plus ipilimumab and 29.5% (95% CI, 18.5%–42.6%) with nivolumab alone.
Among the population with platinum-refractory disease, grade 3 or 4 treatment-related adverse events occurred in 25 of 158 patients (15.8%) who received nivolumab plus ipilimumab and in 12 of 82 patients (14.6%) who received nivolumab alone. Among the population with platinum-eligible disease, grade 3 or 4 treatment-related adverse events occurred in 30 of 122 patients (24.6%) who received nivolumab plus ipilimumab and in 8 of 61 patients (13.1%) who received nivolumab alone.
This trial did not meet its primary end point of objective response rate benefit with first-line nivolumab plus ipilimumab versus nivolumab alone in patients with platinum-refractory recurrent or metastatic head and neck SCC.
Evidence (nivolumab after progression on platinum-based treatment):
A phase III open-label trial included 361 patients with recurrent SCC of the head and neck and disease progression within 6 months after platinum-based chemotherapy. Patients were randomly assigned in a 2:1 ratio to receive either nivolumab (at a dose of 3 mg/kg of body weight) every 2 weeks or standard single-agent systemic therapy (methotrexate, docetaxel, or cetuximab). The primary end point was OS.[7]
The median OS was 7.5 months (95% CI, 5.5–9.1) in the nivolumab group versus 5.1 months (95% CI, 4.0–6.0) in the standard therapy group. OS was statistically significantly longer with nivolumab than with standard therapy (HRdeath, 0.70; 97.73% CI, 0.51–0.96; P = .01). The estimated 1-year survival rate was approximately 19% higher in patients who received nivolumab (36.0%) than in those who received standard therapy (16.6%).[7][Level of evidence A1]
There was no statistically significant difference in median PFS between treatment groups. The 6-month PFS rate was 19.7% with nivolumab versus 9.9% with standard therapy.
The response rate was 13.3% in the nivolumab group versus 5.8% in the standard therapy group.
Grade 3 or 4 treatment-related adverse events occurred in 13.1% of the patients in the nivolumab group compared with 35.1% of the patients in the standard therapy group.
Quality-of-life outcomes—including physical, role, and social functioning and pain, sensory, and social contact problems—were stable in the nivolumab group but worse in the standard therapy group. These outcomes were assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ) Core Module (QLQ-C30) and the Head and Neck Module (QLQ-H&N35).
In the subgroup of patients with a PD-L1 expression level of 1% or higher, the HRdeath among patients treated with nivolumab versus standard therapy was 0.55 (95% CI, 0.36–0.83). In the subgroup of patients with a PD-L1 expression level lower than 1%, the HR was 0.89 (95% CI, 0.54–1.45; P = .17 for interaction).
A randomized, phase III, superiority study in India evaluated the dose of immune checkpoint inhibitors in the setting of palliative care for patients with advanced head and neck cancer. Low-dose IV nivolumab (20 mg every 3 weeks) was added to a triple metronomic chemotherapy regimen of oral methotrexate (9 mg/m2 once weekly), celecoxib (200 mg twice daily), and erlotinib (150 mg once daily). Notably, this nivolumab dose is less than 10% of the dose recommended by the U.S. Food and Drug Administration and the European Medicines Agency. A total of 151 patients were randomly assigned to receive either triple metronomic chemotherapy alone (n = 75) or triple metronomic chemotherapy with nivolumab (n = 76). The primary end point was 1-year OS.[8]
The addition of low-dose nivolumab to triple metronomic chemotherapy improved the 1-year OS rate from 16.3% (95% CI, 8.0%–27.4%) to 43.4% (95% CI, 30.8%–55.3%) (HR, 0.545; 95% CI, 0.362–0.820; P = .0036).[8][Level of evidence A1]
The median OS was 6.7 months (95% CI, 5.8–8.1) for patients who received triple metronomic chemotherapy alone and 10.1 months (95% CI, 7.4–12.6) for patients who received triple metronomic chemotherapy with nivolumab (P = .0052).
The rate of grade 3 or higher adverse events was 50% for patients who received triple metronomic chemotherapy alone and 46.1% for patients who received triple metronomic chemotherapy with nivolumab (P = .744).
Although the control arm in this study cannot be considered standard care, lower doses of immunotherapy appeared to have some benefit in this setting.[11]
Posttreatment follow-up for metastatic and recurrent hypopharyngeal cancer
These patients should have a careful head and neck examination, looking for recurrence monthly for the first posttreatment year, every 2 months for the second year, every 3 months the third year, and every 6 months thereafter.
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
Wong LY, Wei WI, Lam LK, et al.: Salvage of recurrent head and neck squamous cell carcinoma after primary curative surgery. Head Neck 25 (11): 953-9, 2003. [PUBMED Abstract]
Adelstein DJ, Tan EH, Lavertu P: Treatment of head and neck cancer: the role of chemotherapy. Crit Rev Oncol Hematol 24 (2): 97-116, 1996. [PUBMED Abstract]
Burtness B, Harrington KJ, Greil R, et al.: Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Lancet 394 (10212): 1915-1928, 2019. [PUBMED Abstract]
Cohen EEW, Soulières D, Le Tourneau C, et al.: Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): a randomised, open-label, phase 3 study. Lancet 393 (10167): 156-167, 2019. [PUBMED Abstract]
Haddad RI, Harrington K, Tahara M, et al.: Nivolumab Plus Ipilimumab Versus EXTREME Regimen as First-Line Treatment for Recurrent/Metastatic Squamous Cell Carcinoma of the Head and Neck: The Final Results of CheckMate 651. J Clin Oncol 41 (12): 2166-2180, 2023. [PUBMED Abstract]
Harrington KJ, Ferris RL, Gillison M, et al.: Efficacy and Safety of Nivolumab Plus Ipilimumab vs Nivolumab Alone for Treatment of Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck: The Phase 2 CheckMate 714 Randomized Clinical Trial. JAMA Oncol 9 (6): 779-789, 2023. [PUBMED Abstract]
Ferris RL, Blumenschein G, Fayette J, et al.: Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck. N Engl J Med 375 (19): 1856-1867, 2016. [PUBMED Abstract]
Patil VM, Noronha V, Menon N, et al.: Low-Dose Immunotherapy in Head and Neck Cancer: A Randomized Study. J Clin Oncol 41 (2): 222-232, 2023. [PUBMED Abstract]
Harrington KJ, Burtness B, Greil R, et al.: Pembrolizumab With or Without Chemotherapy in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: Updated Results of the Phase III KEYNOTE-048 Study. J Clin Oncol 41 (4): 790-802, 2023. [PUBMED Abstract]
Burtness B: First-Line Nivolumab Plus Ipilimumab in Recurrent/Metastatic Head and Neck Cancer-What Happened? J Clin Oncol 41 (12): 2134-2137, 2023. [PUBMED Abstract]
Mitchell AP, Goldstein DA: Cost Savings and Increased Access With Ultra-Low-Dose Immunotherapy. J Clin Oncol 41 (2): 170-172, 2023. [PUBMED Abstract]
Jacobs C, Lyman G, Velez-García E, et al.: A phase III randomized study comparing cisplatin and fluorouracil as single agents and in combination for advanced squamous cell carcinoma of the head and neck. J Clin Oncol 10 (2): 257-63, 1992. [PUBMED Abstract]
Latest Updates to This Summary (05/14/2025)
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Editorial changes were made to this summary.
This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.
About This PDQ Summary
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of adult hypopharyngeal cancer. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
be discussed at a meeting,
be cited with text, or
replace or update an existing article that is already cited.
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Hypopharyngeal Cancer Treatment are:
Andrea Bonetti, MD (Pederzoli Hospital)
Minh Tam Truong, MD (Boston University Medical Center)
Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website’s Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.
Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
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PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”
The preferred citation for this PDQ summary is:
PDQ® Adult Treatment Editorial Board. PDQ Hypopharyngeal Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/head-and-neck/hp/adult/hypopharyngeal-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389199]
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Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.
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