Unknown Primary

ON THIS PAGE : You will find out more about the factors that increase the chance of developing cancer of unknown primary (CUP). Use the menu to see other pages.

A risk factor is anything that increases a person’s chance of developing cancer. Although risk factors often influence the development of cancer, most do not directly cause cancer. Some people with several risk factors never develop cancer, while others with no known risk factors do. Knowing your risk factors and talking about them with your doctor may help you make more informed lifestyle and health care choices.

Since CUP can be almost any type of primary cancer, the risk factors for all types of cancer are risk factors for CUP. The following factors may raise a person’s risk of developing CUP:

• Age. The average age of people diagnosed with CUP is 60.

• Tobacco use. This includes cigarette smoking, chewing tobacco, and cigar smoking .

• Sun exposure. Getting too much sun may increase cancer risk. Protect your skin from the sun.

• Exposure to large amounts of radiation.
  

• Exposure to chemicals in some manufacturing industries.
  

• Poor nutrition. Not following a healthy diet may raise the risk of developing cancer.

• Lack of exercise. Not getting regular physical activity may increase the risk of developing cancer.

• Family history. If your family has a history of cancer , then your risk of cancer increases. A family history means more than 1 brother, sister, parent, or grandparent has been diagnosed with a certain or related types of cancer, including breast, ovarian, or colorectal cancers.

The next section in this guide is Symptoms and Signs . It explains what changes or medical problems CUP can cause. Use the menu to choose a different section to read in this guide.

ON THIS PAGE : You will find a list of common tests, procedures, and scans that doctors use to find the cause of a medical problem. Use the menu to see other pages.

By its very nature, cancer of unknown primary (CUP) is found after it has spread to another part of the body from where it started, which is called metastasis. Therefore, doctors use many tests to try to find where in the body the cancer began, called the primary site. Some tests may also determine which treatments may be most effective.

How CUP is diagnosed

This section describes options for diagnosing CUP and trying to find the primary site. Not all tests described here will be used for every person. Your doctor may consider these factors when choosing a diagnostic test:

• The type of cancer suspected

• Your signs and symptoms

• Your age and general health

• The results of earlier medical tests

In addition to a physical examination, the following tests may be used to diagnose CUP.

Biopsy

A biopsy is the removal of a small amount of tissue for examination under a microscope. Other tests can suggest that cancer is present, but only the examination of a biopsy specimen by a pathologist can make a definite diagnosis. A pathologist is a doctor who specializes in interpreting laboratory tests and evaluating cells, tissues, and organs to diagnose disease. Careful evaluation and testing of the tumor tissue removed during a biopsy can sometimes give clues to where the tumor began.

Evaluation by a pathologist

A pathologist diagnoses cancer by looking at the tumor sample collected during a biopsy. The pathologist can sometimes predict the primary site of the tumor based on the appearance of the tumor cells under a microscope or based on the results of special stains, known as immunohistochemical (IHC) stains, that are part of the standard pathologic evaluation. These results, which are often presented in a pathology report , give important information about the cancer and help doctors plan additional testing.

When predicting the location of the primary site is not possible, an additional test called a molecular cancer classifier assay may be considered. For this test, the pathologist uses tumor tissue collected during the biopsy. This new diagnostic test, which uses a technique called gene expression profiling, can accurately predict the site where the tumor began in many people with CUP, even when the actual primary site is not visible on X-rays or scans. The results of this new diagnostic test are often useful in helping choose treatment options. Learn more about gene expression profiling in the Types of Treatment and Latest Research sections of this guide.

Evaluation by an oncologist

Before CUP can be diagnosed, a number of tests need to be performed to search for a primary site. This is called a clinical evaluation, and it is usually done by an oncologist. An oncologist is a doctor who specializes in treating people with cancer.

The following diagnostic tests should be included in the evaluation:

• Medical history. The doctor will ask detailed questions about previous illnesses, surgeries, and medications. Doctors are able to help more if they also know as much information as possible about smoking history, drug use, previous moles or benign (noncancerous) tumors, and any exposure to radiation, asbestos, or other chemicals known to be dangerous. A complete family medical history may also give your doctor important clues, especially if 1 or more siblings, parents, or grandparents have had certain cancers, such as breast, ovarian, or colorectal cancers.

• Physical examination. The doctor will do a thorough physical examination of the entire body, including the lymph nodes, pelvis, breasts, rectum, and genitals.

• Urine and blood tests. These tests can find certain tumor markers and proteins that may help indicate where the cancer began. Tumor markers are substances found at higher-than-normal levels in the blood, urine, or body tissues of some people with cancer. Tumor markers are made either by the tumor or by the body as a result of cancer or other conditions.

  For example, patients who have cancer in their neck lymph nodes and a blood test showing the Epstein-Barr virus (EBV) may have nasopharyngeal cancer . Also, high levels of the proteins human chorionic gonadotropin (HCG) and alpha-fetoprotein (AFP) may mean a young man with poorly differentiated carcinoma has a germ cell tumor .

• X-ray. An x-ray is a way to create a picture of the structures inside of the body using a small amount of radiation.

• Computed tomography (CT or CAT) scan of the chest, abdomen, and pelvis. A CT scan takes pictures of the inside of the body using x-rays taken from different angles. A computer combines these pictures into a detailed, 3-dimensional or 3-D view that shows any abnormalities or tumors. A CT scan can show cancer in the chest, abdomen, or pelvis, and sometimes can lead to the identification of the primary site. A CT scan can also be used to measure the tumor’s size. Sometimes, a special dye called a contrast medium is given before the scan to provide better detail on the image. This dye can be injected into a patient’s vein or given as a pill or liquid to swallow.

• Positron emission tomography (PET) or PET-CT scan. A PET scan is usually combined with a CT scan (see above), called a PET-CT scan . However, you may hear your doctor refer to this procedure just as a PET scan. A PET scan is a way to create pictures of organs and tissues inside the body. A small amount of a radioactive sugar substance is injected into the patient’s body. This sugar substance is taken up by cells that use the most energy. Because cancer tends to use energy actively, it absorbs more of the radioactive substance. However, the amount of radiation in the substance is too low to be harmful. A scanner then detects this substance to produce images of the inside of the body.

  For most patients with CUP, a PET scan is not included in the initial evaluation because it does not improve the ability to locate the primary site when compared to CT scanning alone. However, a PET scan may provide valuable information in specific situations. People with CUP who have 1 area of cancer where local treatment, such as surgery or radiation therapy, is being considered should have a PET scan to make sure that no other parts of the body have cancer. For people with squamous cell carcinoma involving lymph nodes in the neck (see the Subtypes section), a PET-CT scan is often useful in identifying a primary site in the head and neck area.

• Magnetic resonance imaging (MRI). An MRI uses magnetic fields, not x-rays, to produce detailed images of the body. A special dye called a contrast medium is given before the scan to create a clearer picture. This dye can be injected into a patient’s vein or given as a pill or liquid to swallow. In most situations, an MRI scan provides the same type of information as described above for the CT scan. However, in some parts of the body, especially the brain and spinal column, MRI provides more information than CT scans. In addition, women with cancer in the axillary lymph nodes, located under the arm, should have a breast MRI , since this test can sometimes find a small breast cancer that cannot be seen on a mammogram (see below).

• Endoscopy. An endoscopy allows the doctor to see inside the body with a thin, lighted, flexible tube called an endoscope. The person may be sedated as the tube is inserted through the mouth, down the esophagus, and into the stomach and small bowel. Sedation is giving medication to become more relaxed, calm, or sleepy.

  Endoscopy procedures are named according to the part of the body being looked at. For example, a bronchoscopy allows doctors to look inside the bronchial tubes (lungs), and a colonoscopy allows doctors to look inside the colon and rectum.

  Endoscopy is used for patients with CUP to evaluate specific symptoms. For example, patients with squamous cell carcinoma in the neck lymph nodes should always have a complete endoscopy of the nasopharynx, throat, and larynx (voice box) to search for a primary tumor.

• Prostate-specific antigen (PSA) test. Prostate-specific antigen (PSA) is a substance released by prostate tissue. If a PSA test finds higher-than-normal levels of PSA in the blood, it means there is prostate cancer or a noncancerous condition, such as benign prostatic hyperplasia (BPH) or prostatitis (inflammation of the prostate). Men with CUP should have their PSA level measured, since higher-than-normal levels usually identify the prostate as the primary site.

• Mammogram. Women should have a mammogram if they have cancer in the axillary lymph nodes or in other areas that might suggest metastatic breast cancer , such as cancer in the bone, or fluid around the lungs.

If these diagnostic tests find a primary site, then the person will not receive a CUP diagnosis. Their treatment will follow the guidelines for the type of cancer found. If these diagnostic tests do not find a primary site, then the person is diagnosed with CUP. At this point, additional tests are unlikely to find a primary site and treatment for CUP should be considered.

The next section in this guide is Subtypes . It describes the most common CUP tumors that are diagnosed. Use the menu to choose a different section to read in this guide.

ON THIS PAGE : You will learn about the different treatments doctors use for people with cancer of unknown primary (CUP). Use the menu to see other pages.

This section explains the types of treatments, also known as therapies, that are the standard of care for CUP. “Standard of care” means the best treatments known. When making treatment plan decisions, you are encouraged to discuss with your doctor whether clinical trials are an option. A clinical trial is a research study that tests a new approach to treatment. Doctors learn through clinical trials whether a new treatment is safe, effective, and possibly better than the standard treatment. Clinical trials can test a new drug, a new combination of standard treatments, or new doses of standard drugs or other treatments. Clinical trials are an option to for all stages of cancer. Learn more about clinical trials in the About Clinical Trials and Latest Research sections of this guide.

Planning treatment for CUP

In cancer care, different types of doctors often work together to create a patient’s overall treatment plan that combines different types of treatments. This is called a multidisciplinary team . Cancer care teams also include a variety of other health care professionals, including physician assistants, nurse practitioners, oncology nurses, social workers, pharmacists, counselors, dietitians, and others.

To figure out the best treatment plan for CUP, doctors rely on the answers to the following questions:

• Was the primary site found during clinical and imaging testing? If so, treatment should follow guidelines for an advanced (metastatic) tumor of that primary tumor type.

• Did the pathologist identify a primary tumor or a specific tumor type, such as lymphoma or germ cell tumor? If so, treatment should follow guidelines for the specific tumor type.

• If no primary site was found, does this CUP fit into any of the subgroups for which specific treatment is recommended? (See Subtypes .)

• If no primary site was found and this CUP does not fit into any of the specific subgroups, can the site of cancer origin be predicted by molecular testing of the cancer biopsy sample? If so, should treatment be based on the tumor type predicted by the molecular cancer classifier assay, or should it be treated with an empiric (general) chemotherapy program (see below)?

• Are any targeted treatments, as identified by comprehensive molecular profiling of the cancer (see below), likely to be helpful?

How CUP is treated

Because CUP has usually spread to at least 1 place when diagnosed, this type of tumor can rarely be removed by surgery or treated with localized radiation therapy. Therefore, chemotherapy is the most common treatment for CUP. Chemotherapy may be able to completely get rid of some tumors.

Treatment options and recommendations depend on several factors, including the type and stage of cancer, possible side effects, and the patient’s preferences and overall health. Take time to learn about all of your treatment options and be sure to ask questions about things that are unclear. Talk with your doctor about the goals of each treatment and what you can expect while receiving the treatment. These types of talks are called “shared decision-making.” Shared decision-making is when you and your doctors work together to choose treatments that fit the goals of your care. Shared decision-making is particularly important for CUP because there are different treatment options. Learn more about making treatment decisions .

For many patients, a diagnosis of CUP can be very stressful and difficult. You and your family are encouraged to talk about how you feel with doctors, nurses, social workers, or other members of the health care team. It may also be helpful to talk with other patients, such as through a support group or other peer support program.

The common types of cancer treatments for CUP are described below. This section is followed by an outline of treatment for each of the recognized CUP subgroups, listed below. Finally, treatment options are outlined for patients whose clinical features do not fit into any of the recognized subgroups.

• Chemotherapy

• Radiation therapy

• Surgery

• Targeted therapy

• Hormone therapy

• Treatment options for specific CUP subgroups

• Treatment for those not in a CUP subgroup

• Comprehensive molecular profiling

• Physical, emotional, and social effects of cancer

• Remission and the chance of recurrence

• If treatment does not work

Chemotherapy

Chemotherapy is the use of drugs to destroy cancer cells, usually by keeping the cancer cells from growing, dividing, and making more cells.

A chemotherapy regimen, or schedule, usually consists of a specific number of cycles given over a set period of time. A patient may receive 1 drug at a time or a combination of different drugs given at the same time. The chance that chemotherapy will be effective depends on the cancer type and location, the number of metastases involved, and the person's overall health. The medications used to treat cancer are continually being evaluated.

The side effects of chemotherapy depend on the individual as well as the drugs and doses used, but they can include fatigue, risk of infection, nausea and vomiting, hair loss, loss of appetite, and diarrhea. These side effects usually go away after treatment has finished. Learn more about the basics of chemotherapy .

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Radiation therapy

Radiation therapy is the use of high-energy x-rays or other particles to destroy cancer cells. A doctor who specializes in giving radiation therapy to treat cancer is called a radiation oncologist. A radiation therapy regimen, or schedule, usually consists of a specific number of treatments given over a set period of time.

The most common type of radiation treatment is called external-beam radiation therapy, which is radiation given from a machine outside the body. When radiation treatment is given using implants, it is called internal radiation therapy or brachytherapy.

Side effects from radiation therapy may include fatigue, mild skin reactions, upset stomach, and loose bowel movements. Most side effects go away soon after treatment is finished. Learn more about the basics of radiation therapy .

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Surgery

Surgery is the removal of the tumor and some surrounding healthy tissue during an operation. A surgical oncologist is a doctor who specializes in treating cancer using surgery. The extent and location of the surgery depends on where the cancer is found and its size.

Before surgery, talk with your health care team about the possible side effects from the specific surgery you will have. Learn more about the basics of cancer surgery .

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Targeted therapy

Targeted therapy is a treatment using drugs that targets the cancer’s specific genes, proteins, or the tissue environment that contributes to cancer growth and survival. This type of treatment blocks the growth and spread of cancer cells and limits damage to healthy cells.

A number of targeted cancer therapies are approved by the U.S. Food and Drug Administration (FDA) to treat specific types of cancer. Although none of these drugs are currently approved to treat CUP, being able to accurately predict where a CUP started may also help identify a targeted drug that could be beneficial. For example, if a CUP is thought to have started in the lung, it may respond to a targeted therapy currently approved for lung cancer.

Talk with your doctor about possible side effects for a specific medication and how they can be managed. Learn more about the basics of targeted treatments .

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Hormone therapy

The goal of hormone therapy is to alter the activity of hormones in the body, usually by trying to lower their levels or block their actions. Hormone therapy may be given to help stop a tumor from growing or to relieve symptoms caused by the tumor. This type of treatment may be an option for people in specific CUP subgroups (see below).

The side effects of hormone therapy depend on the specific type prescribed, so talk with your health care team about potential side effects. Learn more about the basics of hormone therapy .

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Treatment options for specific CUP subgroups

One of the following subgroups may be identified in 35% to 40% of patients during the initial clinical and pathologic evaluation. They each have specific treatment options that are often recommended.

• Women with adenocarcinoma located only in the axillary lymph nodes. Treatment usually follows the guidelines for stage II breast cancer , even if no primary site in the breast can be found. Local treatment includes surgical removal of the breast (mastectomy) or surgical removal of the lymph nodes (axillary node dissection) plus radiation therapy to the breast. Chemotherapy, hormone therapy, and/or HER2-targeted therapy may be recommended after surgery, depending on the number of lymph nodes with cancer as well as the estrogen/progesterone receptor (ER/PR) status, HER2 status, and other molecular features of the tumor.

• Women with peritoneal carcinomatosis, which is adenocarcinoma on the surface of the abdominal cavity. Treatment usually follows the guidelines for stage III ovarian cancer , even for women with healthy ovaries or whose ovaries have been removed. Whenever possible, surgery to remove as much of the cancer as possible, known as debulking surgery, should be performed. Chemotherapy with a taxane/platinum combination, which is used in the treatment of ovarian cancer, is recommended after surgery. CA-125 is often a useful tumor marker blood test for monitoring how well treatment is working. About 20% to 25% of patients in this subgroup live for a long time after receiving treatment.

• Young men with poorly differentiated carcinoma found in the mediastinum (center of the chest between the lungs) or retroperitoneum (back of the abdominal cavity). Some men in this group may have a germ cell tumor, even if the diagnosis cannot be made by the pathologist. High levels of HCG and AFP in the blood strongly suggest a germ cell tumor . People in this subtype usually receive chemotherapy according to the guidelines for the treatment of later-stage testicular cancer . After chemotherapy, surgery to remove any remaining cancer is often needed. This treatment approach is curative in about 30% of men in this group.

• Squamous cell carcinoma in the cervical (neck) lymph nodes. Even if a primary site in the head and neck is not found after a careful search, people with tumors in this subgroup generally receive treatment according to the guidelines for locally advanced head and neck cancer . This usually includes radiation therapy and chemotherapy given at the same time. If small amounts of tumor remain in the cervical lymph nodes after radiation and chemotherapy, surgical removal of lymph nodes may add to the success rate of treatment. About 40% to 60% of people with this diagnosis live a long time after treatment.

• Squamous cell carcinoma in the inguinal (groin) lymph nodes. Treatment generally includes surgical removal of all inguinal lymph nodes or radiation therapy. The doctor may recommend combining chemotherapy with radiation therapy.

• Patients who have only a single metastasis. This group includes a broad range of patients, since the single metastasis (1 tumor) may be found in any part of the body, such as the lymph nodes, brain, lung, or liver. Depending on the location, treatment usually includes either surgical removal of the tumor or radiation therapy. Most people eventually develop metastases in other parts of the body, but this sometimes occurs after a long time without any disease.

• Men with adenocarcinoma metastases only in the bones and/or an elevated PSA level. Treatment for this subtype usually follows the guidelines for the treatment of advanced prostate cancer . Hormone therapy, also called androgen deprivation, often causes long remissions. A remission is the disappearance of the signs and symptoms of CUP.

• Patients with adenocarcinoma in the liver and/or abdomen. For tumors that have only spread in the abdomen, special pathology tests (IHC stains or molecular tumor profiling) sometimes suggest that the cancer started in the colon. These tumors are usually treated according to the guidelines for later-stage colon cancer , even if a primary site cannot be located with a colonoscopy.

• Patients with adenocarcinoma or squamous carcinoma in the chest (mediastinum or lymph nodes). For cancers that have spread in the chest, special pathology tests (IHC or molecular profiling) sometimes suggest that the cancer started in the lungs. These cancers are usually treated according to guidelines for later-stage non-small cell lung cancer , even if the primary site cannot be found in the lungs.

• Patients with pathology findings suggesting kidney cancer. In some people, specific pathologic findings (adenocarcinoma or clear cell histology, specific IHC staining, and/or molecular profiling) suggest that the cancer started in the kidney. People with these findings are usually treated according to guidelines for later-stage kidney cancer , even if no tumors are found in the kidneys.

• Patients with adenocarcinoma or papillary carcinoma and metastases in the cervical (neck) lymph nodes. Though uncommon, people who show these features at diagnosis should be evaluated for thyroid cancer. Elevated serum levels of thyroglobulin or positive IHC staining for thyroglobulin in the cancer biposy is evidence that the cancer started in the thyroid. Treatment should follow guidelines for papillary/follicular thyroid cancer , even if no tumors can be found in the thyroid gland.

• Patients with poorly differentiated neuroendocrine tumors. Although the primary site is usually not found, these types of neuroendocrine tumors often respond to chemotherapy with platinum/etoposide (Etopophos). This treatment can effectively shrink the cancer and improve cancer-related symptoms about 60% of the time. About 10% to 15% of people experience a complete remission with chemotherapy, and some live for a long time after treatment.

• Patients with well-differentiated neuroendocrine tumors. Most well-differentiated neuroendocrine tumors, such as neuroendocrine tumors of the GI tract or neuroendocrine tumors of the pancreas , begin in the intestinal tract or pancreas. For cancers with an unknown primary site, the metastases are usually found in the liver. It is usually easy for the pathologist to tell the difference between well-differentiated and poorly differentiated neuroendocrine tumors. This distinction is important because the chemotherapy recommended for poorly differentiated neuroendocrine tumors is usually not effective for well-differentiated tumors. Well-differentiated neuroendocrine tumors usually grow slowly, and patients often live for several years, even without treatment. In general, the treatment follows the guidelines for advanced neuroendocrine tumors arising in the gastrointestinal tract (carcinoid tumors) or pancreas.

All people with CUP are encouraged to talk with their doctor about participating in a clinical trial that is evaluating a new approach to treatment. In addition, talk with your doctor about the possible side effects and goals of each treatment option.

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Treatment for those not in a specific CUP subgroup

About 60 to 65% of all people with CUP do not have the characteristics of any of the specific subgroups described above. Most of the patients in this group have adenocarcinoma or poorly differentiated carcinoma (see Subtypes ). The success of treatment for this group varies widely. Many of these patients have cancer that is resistant to treatment. However, others experience significant benefits from treatment.

The recommendations for treatment are in the process of changing based on ongoing scientific research. Until recently, the standard treatment for CUP focused on an approach called "empiric chemotherapy." Empiric chemotherapy uses a combination of drugs known to work against a variety of cancers.

In the past, many types of cancers were treated in similar ways, so empiric chemotherapy offered the best chance of success in many cases. Only about 5% of patients are cured with empiric chemotherapy, but it can shrink tumors in 35% to 40% of patients. Around 20% to 25% of patients who receive this treatment live for at least 2 years after diagnosis.

Important improvements have been made in the treatment of many types of cancer during the last 15 years. Many of the drugs responsible for these improvements are called targeted therapies (see above). Unlike traditional chemotherapy, targeted drugs work best for cancer with specific tumor features. For example, a drug that targets a mutation specific to lung cancer may not work at all for colon cancer, and vice versa. Another type of drug therapy called immunotherapy is a treatment that stimulates the immune system to attack cancer cells. It works well for some cancer types (e.g. lung, kidney), and less well for others. For these reasons, designing the most effective treatment for a patient with CUP is very difficult if the primary site is unknown.

However, new diagnostic tests can help predict the primary site for people with CUP, even when the primary site cannot be found. These tests are called molecular cancer classifier assays or gene expression profiling. Pathologists perform these new tests on tumor tissue taken during a biopsy. More and more scientific evidence shows that, in most cases, the predictions from these assays are accurate.

Researchers continue to compare treatments directed toward a specific tumor type, as predicted by these tests, and empiric chemotherapy. Some preliminary conclusions from clinical trials that have been completed can guide treatment. If the cancer is predicted to be a treatment-resistant tumor, such as pancreatic cancer or biliary cancer, site-specific treatments and empiric chemotherapy have similar outcomes. If the cancer is predicted to be a treatment-sensitive type (colorectal, breast, ovarian, lung, and other cancers), then site-specific treatment appears better than empiric chemotherapy. As an example, a patient predicted to have a cancer that started in the colon would benefit more from a treatment plan designed for later-stage colon cancer than from empiric chemotherapy. This treatment plan would include chemotherapy, targeted therapies and, in some cases, immunotherapy developed specifically for colon cancer.

Comprehensive molecular profiling

Many of the new drugs being developed to treat cancer are targeted therapies. These drugs work only when the cancer has specific molecular abnormalities, also called mutations or alterations. Many of these drugs are effective regardless of the cancer type, as long as the molecular abnormality is present. Specific molecular alterations in the tumor can also predict the efficacy of immunotherapy. Treatment with drugs based on molecular abnormalities in the cancer, rather than the site of the tumor origin, is called tumor agnostic treatment .

Comprehensive molecular profiling (CMP) is a test performed on cancer tissue from a biopsy to find out whether any molecular abnormalities are present that can be targeted with specific drugs. Treatment with drugs identified in this way has been very successful for other cancer types. Although experience in CUP is still limited, it appears that molecular abnormalities that can be targeted with drugs are present in up to 20% of CUP cases and that the use of appropriate targeted drugs is effective for these patients.

Physical, emotional, and social effects of cancer

Cancer and its treatment cause physical symptoms and side effects, as well as emotional, social, and financial effects. And, a diagnosis of CUP can bring additional challenges with its uncertainty about finding the primary site. Managing all of these effects is called palliative or supportive care. It is an important part of your care that is included along with treatments intended to slow, stop, or eliminate the cancer.

Palliative care focuses on improving how you feel during treatment by managing symptoms and supporting patients and their families with other, non-medical needs. Any person, regardless of age or type and stage of cancer, may receive this type of care. And it often works best when it is started right after a cancer diagnosis. People who receive palliative care along with treatment for the cancer often have less severe symptoms, better quality of life, and report that they are more satisfied with treatment.

Palliative treatments vary widely and often include medication, nutritional changes, relaxation techniques, emotional and spiritual support, and other therapies. You may also receive palliative treatments similar to those meant to get rid of the cancer, such as chemotherapy, surgery, or radiation therapy.

Before treatment begins, talk with your doctor about the goals of each treatment in the recommended treatment plan. You should also talk about the possible side effects of the specific treatment plan and palliative care options. Many patients also benefit from talking with a social worker and participating in support groups. Ask your doctor about these resources, too.

During treatment, your health care team may ask you to answer questions about your symptoms and side effects and to describe each problem. Be sure to tell the health care team if you are experiencing a problem. This helps the health care team treat any symptoms and side effects as quickly as possible. It can also help prevent more serious problems in the future.

Learn more about the importance of tracking side effects in another part of this guide. Learn more about palliative care in a separate section of this website.

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Remission and the chance of recurrence

A remission is when cancer cannot be detected in the body and there are no symptoms. This may also be called having “no evidence of disease” or NED. For patients with CUP who receive chemotherapy and experience remission, treatment is usually stopped after 4 to 6 months.

A remission may be temporary or permanent. This uncertainty causes many people to worry that the cancer will come back. While many remissions are permanent, it is important to talk with your doctor about the possibility of the cancer returning. Understanding your risk of recurrence and the treatment options may help you feel more prepared if the cancer does return. Learn more about coping with the fear of recurrence .

If the cancer returns after chemotherapy or other treatment, it is called recurrent cancer. It may come back in the same place or in other areas of the body. If a recurrence happens, a new cycle of testing will begin again to learn as much as possible about it. After this testing is done, you and your doctor will talk about the treatment options.

Chemotherapy will usually be recommended, either with the same drugs you received before or with a new combination. If your first treatment was based on the tumor type predicted by gene expression profiling, second-line treatment will likely continue to follow the standard treatment for that tumor type. Your doctor may suggest clinical trials that are studying new ways to treat recurrent CUP. Whichever treatment plan you choose, palliative care will be important for relieving symptoms and side effects.

People with recurrent cancer often experience emotions such as disbelief or fear. You are encouraged to talk with your health care team about these feelings and ask about support services to help you cope. Learn more about dealing with cancer recurrence .

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If treatment does not work

Recovery from cancer is not always possible. If the cancer cannot be cured or controlled, the disease may be called advanced or terminal.

This diagnosis is stressful, and for some people, advanced cancer is difficult to discuss. However, it is important to have open and honest conversations with your health care team to express your feelings, preferences, and concerns. The health care team has special skills, experience, and knowledge to support patients and their families and is there to help. Making sure a person is physically comfortable, free from pain, and emotionally supported is extremely important.

People who have advanced cancer and who are expected to live less than 6 months may want to consider hospice care. Hospice care is designed to provide the best possible quality of life for people who are near the end of life. You and your family are encouraged to talk with the health care team about hospice care options, which include hospice care at home, a special hospice center, or other health care locations. Nursing care and special equipment can make staying at home a workable option for many families. Learn more about advanced cancer care planning .

After the death of a loved one, many people need support to help them cope with the loss. Learn more about grief and loss .

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The next section in this guide is About Clinical Trials . It offers more information about research studies that are focused on finding better ways to care for people with cancer. Use the menu to choose a different section to read in this guide.

ON THIS PAGE : You will read about the scientific research being done to learn more about this type of cancer and how to treat it. Use the menu to see other pages.

Doctors are working to learn more about cancer of unknown primary (CUP), ways to prevent cancer, how to best treat CUP, and how to provide the best care to people diagnosed with this disease. The following areas of research may include new options for patients through clinical trials. Always talk with your doctor about the best diagnostic and treatment options for you.

• Using tumor genetics to diagnose the primary site. Different tissues within the body make different proteins, depending on which genes are active. This is called gene expression. For example, genes expressed by healthy lung cells are different than genes expressed by healthy colon cells. When cancer develops somewhere in the body, it usually has the same pattern of gene expression as the place where the cancer started. A tumor sample from a biopsy can be analyzed to figure out which genes are being expressed. This can usually predict where the cancer began.

  As explained in the Types of Treatment section, site-treatment based on gene expression profiling prediction is being used instead of empiric chemotherapy as the standard treatment for people with CUP who do not fit into a specific subgroup. Ongoing clinical trials continue to look at the outcomes of site-specific treatment using gene expression profiling.

• Targeted therapy. As explained in the Types of Treatment section, targeted therapy directs treatment at specific genes and proteins that are involved in the growth and survival of cancer cells. Learn more about the basics of targeted treatments .

  Several targeted therapies are approved by the FDA for specific cancers. Examples include HER2 targeted therapy for HER2-positive breast cancer, BRAF inhibitors for BRAF -mutated melanoma, and EGFR inhibitors for EGFR -mutated non-small cell lung cancer. However, no targeted therapies are currently approved to treat CUP specifically, and the targeted drugs approved for other cancers have not been tested for CUP.

  Since CUP covers many tumor types, it is likely that some of these cancers have molecular abnormalities that have been successfully targeted in other cancer types. Until recently, testing for potential molecular targets (such as HER2, BRAF , and EGFR ) had not been performed in CUP. With the availability of comprehensive molecular profiling, recent studies have found that the incidence of potentially treatable molecular abnormalities (using targeted treatments already approved for other cancers) is approximately 25% in CUP.

  The efficacy of targeted treatment aimed at these detected molecular abnormalities has not yet been adequately tested in patients with CUP. However, a few such patients treated outside of clinical trials (with clinically available drugs) have had excellent responses. In ongoing clinical trials, people with CUP whose tumors have specific molecular abnormalities are being treated with drugs targeted against that abnormality. These clinical trials provide a major opportunity to identify additional effective treatment options for specific patient groups.

• Immunotherapy . Immunotherapy helps the immune system fight cancer. During the last several years, many new immunotherapy drugs have been developed. For example, treatments that target PD-1 and PD-L1 pathways have become standard parts of treatment for several common cancers, including lung, kidney, bladder, head and neck, and certain breast and colon cancers.
  
  Since people with CUP can have cancer that started in any of these locations, researchers think that some people with CUP could also benefit from immunotherapy. In addition to cancer type, several other predictors of responsiveness to immunotherapy have been identified, including high tumor PD-1 or PD-L1 expression, high microsatellite instability (MSI-H), or high tumor mutational burden (TMB) All of these abnormalities have been detected in CUP, and can be detected with comprehensive molecular profiling. Clinical trials are ongoing to understand the results of immunotherapy treatment in people with CUP. Learn more about the basics of immunotherapy .

• New types of treatment. Many new drugs are being tested for the first time in studies called phase I clinical trials . Usually, these clinical trials are not specifically for CUP, but accept patients of all types of cancer who have already received all standard treatments. The goals of these studies are to identify the side effects and best doses for these new drugs, as well as to learn if they could be effective against cancer.

• Palliative care/supportive care. Clinical trials are underway to find better ways of reducing symptoms and side effects of current cancer treatments to improve comfort and quality of life for patients.

Looking for More About the Latest Research?

If you would like more information about the latest areas of research in CUP, explore these related items that take you outside of this guide:

• To find clinical trials specific to your diagnosis, talk with your doctor or search online clinical trial databases .

• Visit the website of Conquer Cancer, the ASCO Foundation , to find out how to help support cancer research. Please note that this link takes you to a different ASCO website.

The next section in this guide is Coping with Treatment . It offers some guidance on how to cope with the physical, emotional, social, and financial changes that cancer and its treatment can bring. Use the menu to choose a different section to read in this guide.

ON THIS PAGE : You will read about your medical care after cancer treatment is finished and why this follow-up care is important. Use the menu to see other pages.

Care for people diagnosed with cancer does not end when active treatment has finished. Your health care team will continue to check that the cancer has not come back, manage any side effects, and monitor your overall health. This is called follow-up care.

Your follow-up care may include regular physical examinations, medical tests, or both. Doctors want to keep track of your recovery in the months and years ahead. Patients diagnosed with cancer of unknown primary (CUP) are a diverse group of people and recommended treatment plans vary, so the possible short-term and long-term effects of treatment are different. In addition, recommended follow-up and long-term prognosis varies from person to person. The recommendations in this section are directed primarily at people who are in remission after successful treatment.

In general, close follow-up care is recommended during the first year after treatment for CUP ends, with physical examinations and routine laboratory tests every 2 months and appropriate x-rays and scans every 3 to 4 months. After the first year, follow-up care will continue based on a personalized schedule.

Cancer rehabilitation may be recommended, and this could mean any of a wide range of services, such as physical therapy, occupational therapy, career counseling, pain management, nutritional planning, and/or emotional counseling. The goal of rehabilitation is to help people regain control over many aspects of their lives and remain as independent and productive as possible. Learn more about cancer rehabilitation .

Learn more about the importance of follow-up care .

Watching for recurrence

One goal of follow-up care is to check for a recurrence, which means that the cancer has come back. Cancer recurs because small areas of cancer cells may remain undetected in the body. Over time, these cells may increase in number until they show up on test results or cause signs or symptoms.

During follow-up care, a doctor familiar with your medical history can give you personalized information about your risk of recurrence. Your doctor will ask specific questions about your health. Some people may have blood tests or imaging tests done as part of regular follow-up care, but testing recommendations depend on several factors including the subgroup or subtype of CUP first diagnosed and the types of treatment given.

The anticipation before having a follow-up test or waiting for test results can add stress to you or a family member. This is sometimes called “scanxiety.” Learn more about how to cope with this type of stress .

People who were treated for CUP should tell their doctor about any new symptoms right away. Talk with your doctor during your follow-up care appointments about specific symptoms to watch for.

Managing long-term and late side effects

Most people expect to have side effects when receiving treatment. However, it is often surprising to survivors that some side effects may linger beyond the treatment period. These are called long-term side effects. Other side effects called late effects may develop months or even years after treatment has ended. Long-term and late effects can include both physical and emotional changes.

For patients in specific subgroups (see the Types of Treatment section) who received treatment based on guidelines for various cancers of a known primary site, the side effects and post-treatment recommendations are similar to those of that specific cancer. Please refer to that specific cancer type section for more information. If you had a treatment known to cause specific late effects, you may have certain physical examinations, scans, or blood tests to help diagnose and manage them.

For people who receive chemotherapy, most of the treatment-related side effects, such as low blood counts, fatigue, weakness, and joint aches, go away within 4 to 6 weeks after treatment ends. However, other possible side effects like peripheral neuropathy, which is numbness, tingling, or pain in the hands and feet, improve slowly and may take 6 to 12 months to go away.

Talk with your doctor about your risk of developing such side effects based on the subtype of CUP, your individual treatment plan, and your overall health.

Keeping personal health records

You and your doctor should work together to develop a personalized follow-up care plan. Be sure to discuss any concerns you have about your future physical or emotional health. ASCO offers forms to help keep track of the cancer treatment you received and develop a survivorship care plan when treatment is completed.

This is also a good time to talk with your doctor about who will lead your follow-up care. Some survivors continue to see their oncologist, while others transition back to the general care of their primary care doctor or another health care professional. This decision depends on several factors, including the details of the CUP diagnosis, side effects, health insurance rules, and your personal preferences.

If a doctor who was not directly involved in your cancer care will lead your follow-up care, be sure to share your cancer treatment summary and survivorship care plan forms with them, and with all future health care providers. Details about your cancer treatment are very valuable to the health care professionals who will care for you throughout your lifetime.

The next section in this guide is Survivorship . It describes how to cope with challenges in everyday life after a cancer diagnosis. Use the menu to choose a different section to read in this guide.

ON THIS PAGE : You will find some questions to ask your doctor or another member of the health care team to help you better understand your diagnosis, treatment plan, and overall care. Use the menu to see other pages.

Talking often with the health care team is important to make informed decisions about your health care. These suggested questions are a starting point to help you learn more about your cancer care and treatment. You are also encouraged to ask additional questions that are important to you. You may want to print this list and bring it to your next appointment, or download Cancer.Net’s free mobile app for a digital list and other interactive tools to manage your care. It may also be helpful to ask a family member or friend to come with you to appointments to help take notes.

Questions to ask after the initial evaluation

• Where exactly is the tumor?

• How large is the tumor?

• What are the results of the biopsy?

• Can you explain my pathology report (laboratory test results) to me?

• Have specialized tests been done by the pathologist to help find the primary site?

• Would a molecular cancer classifier assay of my biopsy sample help predict a primary site?

• Would comprehensive molecular profiling help to identify potentially useful targeted therapy?

• Will I need to have another biopsy to provide the pathologist with the best possible specimen for examination?

• What tests or scans are available to help identify a primary site?

• Should I get a second opinion?

Questions to ask about choosing a treatment and managing side effects

• Have specialized, pathologic studies of my tumor predicted where my cancer started? If so, will my treatment follow the guidelines for the predicted cancer type?

• Can my tumor be treated with targeted therapy?

• What are all my treatment options?

• What clinical trials are available for me? Where are they located, and how do I find out more about them?

• What treatment plan do you recommend? Why?

• What is the goal of each treatment? Is it to eliminate the cancer, help me feel better, or both?

• What is my prognosis?

• Who will be part of my health care team, and what does each member do?

• Who will be leading my overall treatment?

• What are the possible side effects of each treatment, both in the short term and the long term?

• How will this treatment affect my daily life? Will I be able to work, exercise, or perform my usual activities?

• Could this treatment affect my sex life? If so, how and for how long?

• Could this treatment affect my ability to become pregnant or have children? If so, should I talk with a fertility specialist before cancer treatment begins?

• If I’m worried about managing the costs of cancer care, who can help me?

• What support services are available to me? To my family?

• If I have questions or problems, who should I call?

Questions to ask about specific treatments

• What type of treatment is recommended?

• What is the goal of this treatment?

• How long will it take to give this treatment?

• Will I receive this treatment at a hospital or clinic? Or will I take it at home?

• What side effects can I expect during treatment?

• Who should I contact about any side effects I experience? And how soon?

• What are the possible long-term or late effects of having this treatment?

• What can be done to prevent or relieve the side effects?

Questions to ask about planning follow-up care

• What is the chance that the cancer will come back? Should I watch for specific signs or symptoms?

• What long-term side effects or late effects are possible based on the treatment I received?

• What follow-up tests will I need, and how often those tests be needed?

• How do I get a treatment summary and survivorship care plan to keep in my personal records?

• Who will be leading my follow-up care?

• What survivorship support services are available to me? To my family?

The next section in this guide is Additional Resources . It offers more resources on this website that may be helpful to you. Use the menu to choose a different section to read in this guide.