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Unknown Primary - Overview

This section has been reviewed and approved by the Cancer.Net Editorial Board, 03/2014

ON THIS PAGE: You will find some basic information about this disease and the parts of the body it may affect. This is the first page of Cancer.Net’s Guide to Cancer of Unknown Primary. To see other pages, use the menu on the side of your screen. Think of that menu as a roadmap to this full guide.

Overview

Cancer begins when normal cells change and grow uncontrollably, forming a mass called a tumor. A tumor can be cancerous or benign. A cancerous tumor is malignant, meaning it can spread to other parts of the body. A benign tumor means the tumor will not spread.

Cancer is a group of more than 100 different diseases. Most of the time it is fairly easy for doctors to figure out where a cancer began, known as the primary site, and identify any secondary or metastatic site if the cancer has spread. No matter where the cancer spreads, it is still named for the area of the body where it began. For example, breast cancer that has spread to the brain is called metastatic breast cancer, not brain cancer.

For about 2% of people diagnosed with cancer, though, the cancer is found at a secondary site, but routine testing cannot help doctors find where the cancer began. These cancers are called carcinoma of unknown primary site or cancer of unknown primary (CUP). For some people, specialized testing can eventually help identify the primary site; however, sometimes it cannot. This may be because the primary tumor is still very small, the body caused the primary tumor to shrink or disappear, and/or the primary tumor was removed during previous surgery for another condition, such as the removal of a mole on the skin or surgery to remove a woman’s uterus, known as a hysterectomy.

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Unknown Primary - Statistics

This section has been reviewed and approved by the Cancer.Net Editorial Board, 03/2014

ON THIS PAGE: You will find information about how many people learn they have this type of cancer each year and some general survival information. Remember, survival rates depend on several factors. To see other pages, use the menu on the side of your screen.

The exact number of people diagnosed with CUP each year is not known because some cancers start out being classified as unknown primary, only to have the primary cancer found later. However, an estimated 31,430 people will be diagnosed with CUP this year in the United States, which accounts for approximately 2% of all cancers. As new tests that can more accurately determine where a cancer started become available, the number of people diagnosed with CUP will continue to decrease.

People diagnosed with CUP are a diverse group, and prognosis, which is the chance of recovery, varies widely. Often, there are not as many treatments available for people with cancer that has already spread to other parts of the body at diagnosis. However, others have a cancer that can be successfully treated. These differences and survival rates are discussed in the Treatment Options section.

Cancer survival statistics should be interpreted with caution. Estimates are based on data from thousands of people with this type of cancer in the United States each year, but the actual risk for a particular individual may differ. It is not possible to tell a person how long he or she will live with CUP. Learn more about understanding statistics.

Statistics adapted from the American Cancer Society.

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Unknown Primary - Risk Factors

This section has been reviewed and approved by the Cancer.Net Editorial Board, 03/2014

ON THIS PAGE: You will find out more about the factors that increase the chance of developing this type of cancer. To see other pages, use the menu on the side of your screen.

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. However, 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 can raise a person’s risk of developing CUP:

  • Age. The average age of a person diagnosed with CUP is 60.
  • Tobacco use, including cigarette smoking, chewing tobacco, and cigar smoking
  • Sun exposure
  • Exposure to large amounts of radiation
  • Exposure to chemicals in some manufacturing industries
  • Poor nutrition
  • Lack of exercise
  • Family history. If more than one brother, sister, parent, or grandparent has been diagnosed with breast, ovarian, or colorectal cancer, the risk of cancer increases.

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Unknown Primary - Symptoms and Signs

This section has been reviewed and approved by the Cancer.Net Editorial Board, 03/2014

ON THIS PAGE: You will find out more about body changes and other things that can signal a problem that may need medical care. To see other pages, use the menu on the side of your screen.

Because CUP can appear anywhere in the body, the initial symptoms vary. Usually, symptoms are related to the area of the body where the cancer is found, most commonly the liver, lungs, bones, or lymph nodes. These symptoms or signs may include the following. Sometimes, people with CUP do not show any of these symptoms. Or, these symptoms may be caused by a medical condition that is not cancer.

  • Long-lasting pain in a specific area of the body
  • Loss of appetite or unexplained weight loss
  • A cough or hoarseness that doesn’t go away
  • Thickening or lump in any part of the body
  • Changes in bowel or bladder habits
  • Unusual bleeding or discharge
  • Recurring fever or night sweats

If you are concerned about one or more of the symptoms or signs on this list, please talk with your doctor. Your doctor will ask how long and how often you’ve been experiencing the symptom(s), in addition to other questions. This is to help find out the cause of the problem, called a diagnosis.

If cancer is diagnosed, a person's signs and symptoms often help the doctor plan effective treatment, even when the primary site cannot be found. Relieving symptoms is also an important part of cancer care and treatment. This may also be called symptom management, palliative care, or supportive care. Be sure to talk with your health care team about symptoms you experience, including any new symptoms or a change in symptoms.

The next section helps explain what tests and scans may be needed to learn more about the cause of the symptoms. Use the menu on the side of your screen to select Diagnosis, or you can select another section, to continue reading this guide.

Unknown Primary - Diagnosis

This section has been reviewed and approved by the Cancer.Net Editorial Board, 03/2014

ON THIS PAGE: You will find a list of the common tests, procedures, and scans that doctors can use to find out what’s wrong and identify the cause of the problem. To see other pages, use the menu on the side of your screen.

By definition, CUP is found after it has spread to another part of the body through a process known as metastasis. Therefore, doctors use many tests to try to find the primary site. Some tests may also determine which treatments may be most effective. For most types of cancer, a biopsy is the only way to make a definitive diagnosis of cancer. Imaging tests are usually used to look for other areas where the cancer has spread. This list describes options for diagnosing CUP and trying to find the original site where it began. Not all tests listed will be used for every person.

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 a biopsy can make a definite diagnosis. The sample removed during the biopsy is analyzed by a pathologist (see below). 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 about where the tumor began.

The type of biopsy performed will depend on the location of the cancer. Learn more about what to expect when having a biopsy in this separate article on Cancer.Net.

Evaluation by a pathologist

A pathologist diagnoses cancer by looking at the sample of the tumor collected during a biopsy. The pathologist can sometimes predict the primary site of the tumor based on the microscopic appearance of the tumor biopsy 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 such a prediction is not possible, an additional test called molecular tumor profiling should be considered. This new diagnostic test can accurately predict the site where the tumor began in most patients with CUP and is frequently useful in directing treatment. More information is provided below.

Evaluation by an oncologist (called clinical evaluation)


Once CUP is diagnosed, an oncologist, which is a doctor who specializes in treating people with cancer, will do more tests to search for the primary site and find out how far the cancer has spread. However, for most patients with CUP, the primary site is not found even after extensive evaluation. For this reason, several diagnostic tests may be done to evaluate specific signs and symptoms, including:

Medical history. The doctor will ask detailed questions about previous illnesses, surgeries, and medications. The doctors can 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 provide your doctor with important clues, especially if one or more siblings, parents, or grandparents have had breast, ovarian, or colorectal cancer.

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 determine 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 the neck lymph nodes and 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 and abdomen. A CT scan helps doctors determine the location of the cancer and where it has spread. A CT scan creates a three-dimensional picture of the inside of the body with an x-ray machine. A computer then combines these images into a detailed, cross-sectional view that shows any abnormalities or tumors. For CUP, a CT scan can show cancer in the abdomen and chest. 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 to swallow.

Positron emission tomography (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. A scanner then detects this substance to produce images of the inside of the body.

PET scans have proven useful for finding a primary site in 20% to 30% of patients with CUP. For this reason, the PET scan is now considered a routine part of the initial evaluation. Even when a primary site is not found, a PET scan sometimes provides information that is useful in planning treatment. For example, for patients who have one area of cancer where local treatment (surgery or radiation therapy) is being considered, a PET scan can make sure that no other parts of the body have cancer. Using PET and CT scans together, called an integrated PET-CT scan, provides more detailed and specific information than either test alone.

Magnetic resonance imaging (MRI). An MRI uses magnetic fields, not x-rays, to produce detailed images of the body. MRI can also be used to measure the tumor’s size. 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 to swallow. In some parts of the body, especially the brain and spinal column, MRI provides more information than the CT scan. In addition, women with cancer in the axillary lymph nodes (under the arm) should have a breast MRI scan, since this test can sometimes find a small breast cancer that cannot be seen on a mammogram (x-ray of the breast; see below).

Endoscopy. This test 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.

Similar 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 protein released by prostate tissue. A PSA test detects higher than normal levels of PSA in a man’s blood, which may mean a man has prostate cancer or a noncancerous condition, such as benign prostatic hyperplasia (BPH) or prostatitis (inflammation of the prostate). Men who are experiencing bone pain or have cancer found in their bones will have a PSA test.

Mammography. Women may receive a mammogram, especially if they have cancer in the axillary lymph nodes, cancer found in other areas that might suggest metastatic breast cancer, such as cancer in the bone, or fluid around the lungs.

After diagnostic tests are done, your doctor will review all of the results with you. These results will help determine the type of tumor and guide the development of your individual treatment plan.

The next section helps explain the different types of CUP tumors that may be diagnosed. Use the menu on the side of your screen to select Subtypes, or you can select another section, to continue reading this guide.

Unknown Primary - Subtypes

This section has been reviewed and approved by the Cancer.Net Editorial Board, 03/2014

ON THIS PAGE: You will find descriptions of the most common types of CUP tumors. To see other pages, use the menu on the side of your screen.

Most people with CUP have one of four types of tumors:

Adenocarcinoma. Nearly 60% of people with CUP have adenocarcinoma. Adenocarcinoma may begin in the glandular tissue of most internal organs, including the lungs, stomach, pancreas, colon, ovary, and breast. Because of this, when adenocarcinoma is found at a metastatic site, it is extremely difficult for the pathologist to tell where it began. Additional diagnostic tests on biopsy samples, called IHC stains, usually narrow down the possibilities and can predict the site of origin in about 30% to 40% of patients. A molecular tumor profiling assay that is also performed on the biopsy specimen is able to accurately predict the site of origin in most remaining patients. Learn more about molecular tumor profiling in the Treatment Options and Latest Research sections.

Poorly differentiated carcinoma. Nearly 20% to 30% of people with CUP have poorly differentiated carcinomas. These cancers need to undergo extra testing by the pathologist, since some very treatable cancers may initially be diagnosed as poorly differentiated carcinoma. If testing finds the cancer is lymphoma, germ cell carcinoma, or neuroendocrine carcinoma, effective treatments are often available. Similarly to patients with adenocarcinoma, molecular tumor profiling can usually predict the site of tumor origin and is useful in guiding the choice of therapy (see the Treatment Options section).

Squamous cell carcinoma. Nearly 5% to 10% of people with CUP have squamous cell carcinoma. Effective treatments are available for this type of tumor if it has certain characteristics. For instance, if squamous cell carcinoma is found in the cervical (neck) lymph nodes, the primary site is often in the head and neck area. If it is found in the inguinal (groin) lymph nodes, the primary site may be in the vulva, vagina, cervix, anus, or bladder. A careful search is important, particularly since these cancers can often be treated successfully.

Neuroendocrine carcinoma. Nearly 1% to 5% of people with CUP have neuroendocrine carcinoma. These cancers are being found more often with IHC tests. Some of these tumors are aggressive and fast growing, but combination chemotherapy (see the Treatment Options section) may be effective. Others are very slow growing, and people sometimes live for several years even without treatment.

Information about the tumor’s subtype will help the doctor recommend a treatment plan. The next section helps explain the treatment options for this type of cancer. Use the menu on the side of your screen to select Treatment Options, or you can select another section, to continue reading this guide.

Unknown Primary - Treatment Options

This section has been reviewed and approved by the Cancer.Net Editorial Board, 03/2014

ON THIS PAGE: You will learn about the different ways doctors may treat this type of cancer. To see other pages, use the menu on the side of your screen.

This section outlines treatments that are the standard of care (the best proven treatments available) for CUP. When making treatment plan decisions, patients are also encouraged to consider clinical trials as an option. A clinical trial is a research study to test a new approach to treatment to evaluate whether it is safe, effective, and possibly better than the standard treatment. Clinical trials may test such approaches as a new drug, a new combination of standard treatments, or new doses of current therapies. Your doctor can help you review all treatment options. For more information, see the Clinical Trials and Latest Research sections.

Planning treatment

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.

Answers to the following questions are very important for helping doctors plan treatment for CUP:

  • 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? (Subgroups are listed below.)
  • If no primary site was found and this CUP does not fit into any of the specific subgroups, will disease-directed treatment be beneficial? If so, should treatment be based on the tumor type predicted by molecular tumor profiling, or should it be with an empiric (general) chemotherapy program (see below)? The chance that chemotherapy will be effective depends on the location of the tumor, number of tumors involved, and the person's overall health.

Treatment overview

Descriptions of the most common treatment options for CUP are listed below, followed by an outline of treatment by the CUP subgroup or if a subgroup is unknown.

Chemotherapy is the most common treatment for CUP, and it may get rid of some tumors completely. Since CUP has usually spread to more than one place when diagnosed, this type of tumor can rarely be removed surgically or treated with localized radiation therapy. Your care plan may also include treatment for symptoms and side effects, which is an important part of cancer care. Take time to learn about all of your treatment options and be sure to ask questions about things that are unclear. Also, talk about the goals of each treatment with your doctor and what you can expect while receiving the treatment. Learn more about making treatment decisions.

For many patients, a diagnosis of CUP can be very stressful and, at times, difficult to bear. Patients and their families are encouraged to talk about the way they are feeling with doctors, nurses, social workers, or other members of the health care team. It may also be helpful to talk with other patients, including through a support group.

Chemotherapy

Chemotherapy is the use of drugs to destroy cancer cells, usually by stopping the cancer cells’ ability to grow and divide. Chemotherapy is given by a medical oncologist, a doctor who specializes in treating cancer with medication.

Systemic chemotherapy is delivered through the bloodstream to reach cancer cells throughout the body. Common ways to give chemotherapy include an intravenous (IV) tube placed into a vein using a needle or in a pill or capsule that is swallowed (orally). A chemotherapy regimen (schedule) usually consists of a specific number of cycles given over a set period of time. A patient may receive one drug at a time or combinations of different drugs at the same time. The medications used to treat cancer are continually being evaluated.

The side effects of chemotherapy depend on the individual and the dose 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 once treatment has finished.

Learn more about chemotherapy and preparing for treatment. Talking with your doctor is often the best way to learn about the medications you've been prescribed, their purpose, and their potential side effects or interactions with other medications. Learn more about your prescriptions by using searchable drug databases.

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 (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 radiation therapy.

Surgery

Surgery is the removal of the tumor and surrounding 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. Learn more about cancer surgery.

Targeted therapy

Targeted therapy is a treatment 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 while limiting damage to healthy cells.

A number of targeted cancer therapies are approved by the U.S. Food and Drug Administration (FDA) to treat specific cancer types, and most of the new cancer drugs currently being tested are targeted agents. Although none of them are currently approved to treat CUP, the ability to accurately predict where the tumor started in patients diagnosed with CUP may also help identify a targeted drug likely to be of benefit. For example, if a cancer is predicted to have started in the lung, it may respond to one of the targeted therapies 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 targeted treatments.

Hormone therapy

The goal of hormone therapy is to alter the activity of hormones in the body, usually trying to lower their levels or block their actions. Hormone therapy may be given to help stop the 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).

Treatment options for specific subgroups

The following subgroups can often be identified during the initial clinical and pathologic evaluation and have specific treatments that are often recommended.

Women with adenocarcinoma located only in the axillary lymph nodes. Treatment should follow guidelines for stage II breast cancer, even if no primary site in the breast can be found. Local treatment should include surgical removal of the breast (mastectomy) or surgical removal of the lymph nodes (axillary node dissection) plus radiation therapy to the breast. After surgery, chemotherapy and/or hormone therapy should also be recommended, depending on the number of lymph nodes with cancer, the estrogen/progesterone receptor (ER/PR) status, the HER2 status, and other features of the tumor.

Women with peritoneal carcinomatosis (adenocarcinoma on the surface of the abdominal cavity). Treatment should follow guidelines for stage III ovarian cancer, even for women with normal 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 for monitoring how well treatment is working. Approximately 20% to 25% of women live for a long time after 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. Initial chemotherapy should follow guidelines for treatment of later-stage testicular cancer. Removal of the remaining tumor after chemotherapy is often needed. About 30% of men in this group have the cancer successfully treated.

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, these patients generally receive treatment according to guidelines for locally advanced head and neck cancer. This usually includes radiation therapy and chemotherapy given at the same time. For some patients with small cervical lymph nodes with cancer, treatment with radiation therapy alone or surgery followed by radiation therapy is enough. About 40% to 60% of patients in this group live a long time after treatment.

Squamous cell carcinoma in the inguinal (groin) lymph nodes. Local treatment should include surgical removal of all inguinal lymph nodes (lymph node dissection) or radiation therapy. Combining chemotherapy at the same time as radiation therapy should also be considered.

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

Men with metastases only in the bones and/or an elevated PSA level. Treatment should follow guidelines for advanced prostate cancer. Treatment with hormone therapy (androgen deprivation) frequently produces long remissions. A remission is the disappearance of the signs and symptoms of CUP.

Patients with adenocarcinoma in the liver and/or abdomen. In some patients where the tumor spread is only in the abdomen, special pathology tests (IHC stains or molecular profiling) suggest that the cancer started in the colon. Patients should receive treatment following guidelines for later-stage colon cancer, even if a primary site cannot be located by a colonoscopy.

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), with or without taxane (docetaxel [Taxotere] or paclitaxel [Taxol]). This treatment can effectively shrink the cancer and improve cancer-related symptoms for about 60% of patients. A smaller percentage of patients in this group, about 10% to 15%, have 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 carcinoid tumors or islet cell tumors, begin in the intestinal tract or pancreas. In patients 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 ineffective against well differentiated tumors. Well differentiated neuroendocrine tumors usually grow slowly, and patients often live for several years even without treatment. Treatment should follow guidelines for advanced carcinoid tumors.

Treatment for those not in a specific CUP subgroup

About 75% of all people with CUP do not have the characteristics of any of the specific subgroups discussed previously. Most of the patients in this group have adenocarcinoma or poorly differentiated carcinoma. The success of treatment for this group of patients varies widely. Many of these patients have cancers that are resistant to treatment; however, others experience significant benefit.  

The recommendations for treatment in this group are in the process of changing based on ongoing scientific findings. Until recently, standard treatment typically included a generalized chemotherapy approach referred to as empiric chemotherapy. This approach uses a combination of drugs traditionally known to work against a variety of cancers. Previously, the treatment of many types of advanced cancers has often been similar to each other, and so this type of approach has offered the best chance of success in many cases. Although only about 5% of patients are cured with this approach, it can shrink tumors in 35% to 40% of patients, and 20% to 25% of patients live for at least two years after diagnosis.

During the last 15 years, important improvements have been made in the treatment of many types of cancer. Many of the drugs responsible for these improvements are called targeted therapies (see above). Unlike many of the traditional chemotherapy drugs, these drugs work best for specific types of cancer with specific tumor features. For example, a drug that targets a tumor abnormality specific to lung cancer may not work at all against colon cancer, and vice versa.  Therefore, it is increasingly difficult to design an empiric/generalized treatment program for patients with CUP that provides the best coverage for various cancer types.

At the same time, new diagnostic tests are now available that can predict the site of tumor origin in patients with CUP, even when the site cannot be found by scans and other clinical evaluation. These new tests, called molecular tumor profiling assays, are performed on tumor tissue taken during the biopsy. Increasing scientific evidence shows the predictions from these assays are accurate in most cases.

Although scientific evidence is not complete, it now appears that treatment based on the results of molecular profiling offers advantages over empiric chemotherapy. For example, a patient predicted to have a site of tumor origin in the colon would receive greater benefit from treatment specifically for later-stage colon cancer, which includes targeted agents developed specifically for colon cancer, than from a generalized chemotherapy regimen traditionally used for CUP. Currently, all of the information from clinical trials consistently shows better treatment outcomes with treatment guided by molecular profiling prediction than with empiric chemotherapy.

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

Getting care for symptoms and side effects

Cancer and its treatment often cause side effects. In addition to treatment to slow, stop, or eliminate the cancer, an important part of cancer care is relieving a person’s symptoms and side effects. This approach is called palliative or supportive care, and it includes supporting the patient with his or her physical, emotional, and social needs.

Palliative care can help a person at any stage of illness. People often receive treatment for the cancer and treatment to ease side effects at the same time. Even for patients whose tumors do not respond to chemotherapy, treatments are available to reduce symptoms. In fact, patients who receive both often have less severe symptoms, better quality of life, and report they are more satisfied with treatment.

Palliative treatments vary widely and often include medication, nutritional changes, relaxation techniques, and other therapies. You may also receive palliative treatments similar to those meant to eliminate the cancer, such as chemotherapy, surgery, and radiation therapy. Talk with your doctor about the goals of each treatment in your treatment plan.

Before treatment begins, talk with your health care team about the possible side effects of your specific treatment plan and supportive care options. And during and after treatment, be sure to tell your doctor or another health care team member if you are experiencing a problem so it is addressed as quickly as possible. Learn more about palliative care.

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 “no evidence of disease” or NED.  For patients who receive chemotherapy and experience remission, treatment is usually stopped after four to six months.

A remission can be temporary or permanent. This uncertainty leads to many survivors feeling worried or anxious that the cancer will come back. While many remissions are permanent, it’s important to talk with your doctor about the possibility of the cancer returning. Understanding the 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 does return after the original treatment, it is called recurrent cancer. It may come back in the same place or in other areas of the body. When this occurs, a cycle of testing will begin again to learn as much as possible about the recurrence. After testing is done, you and your doctor will talk about your 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 molecular tumor profiling, second-line treatment will likely continue to follow the standard treatment for that tumor type. Your doctor may also suggest clinical trials that are studying new ways to treat this type of recurrent cancer.

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

If treatment fails

Recovery from cancer is not always possible. If treatment is not successful, the disease may be called advanced or terminal cancer.

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

Patients who have advanced cancer and who are expected to live less than six months may want to consider a type of palliative care called 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 think about where you would be most comfortable: at home, in the hospital, or in a hospice environment. Nursing care and special equipment can make staying at home a workable alternative 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.

The next section helps explain clinical trials, which are research studies. Use the menu on the side of your screen to select About Clinical Trials, or you can select another section, to continue reading this guide.

Unknown Primary - About Clinical Trials

This section has been reviewed and approved by the Cancer.Net Editorial Board, 03/2014

ON THIS PAGE: You will learn more about clinical trials, which are the main way that new medical approaches are tested to see how well they work. To see other pages, use the menu on the side of your screen.

Doctors and scientists are always looking for better ways to treat patients with CUP. To make scientific advances, doctors create research studies involving volunteers, called clinical trials.

Many clinical trials are focused on new treatments, evaluating whether a new treatment is safe, effective, and possibly better than the current (standard) treatment. In patients with CUP, most clinical trials evaluate new drugs or different combinations of existing drugs. In addition, new diagnostic tests are currently being studied to identify the primary site, allowing more specific treatment. Patients who participate in clinical trials are often among the first to receive new treatments before they are widely available. However, there is no guarantee that the new treatment will be safe, effective, or better than a standard treatment.  

There are also clinical trials that study new ways to ease symptoms and side effects during treatment and manage the late effects that may occur after treatment. Talk with your doctor about clinical trials regarding side effects. In addition, there are ongoing studies about ways to prevent cancer.

Patients decide to participate in clinical trials for many reasons. For some patients, a clinical trial is the best treatment option available. Because standard treatments are not perfect, patients are often willing to face the added uncertainty of a clinical trial in the hope of a better result. Other patients volunteer for clinical trials because they know that these studies are the only way to make progress in treating cancer. Even if they do not benefit directly from the clinical trial, their participation may benefit future patients with cancer.

Sometimes people have concerns that, by participating in a clinical trial, they may receive no treatment by being given a placebo or a “sugar pill.” The use of placebos in cancer clinical trials is rare. When a placebo is used in a study, it is done with the full knowledge of the participants. Find out more about placebos in cancer clinical trials.

To join a clinical trial, patients must participate in a process known as informed consent. During informed consent, the doctor should list all of the patient’s options so that the person understands how the new treatment differs from the standard treatment. The doctor must also list all of the risks of the new treatment, which may or may not be different from the risks of standard treatment. Finally, the doctor must explain what will be required of each patient in order to participate in the clinical trial, including the number of doctor visits, tests, and the schedule of treatment.

For specific topics being studied for CUP, learn more in the Latest Research section.

Patients who participate in a clinical trial may stop participating at any time for any personal or medical reason. This may include that the new treatment is not working or there are serious side effects. Clinical trials are also closely monitored by experts who watch for any problems with each study. It is important that patients participating in a clinical trial talk with their doctor and researchers about who will be providing their treatment and care during the clinical trial, after the clinical trial ends, and/or if the patient chooses to leave the clinical trial before it ends.

Cancer.Net offers a lot of information about cancer clinical trials in other areas of the website, including a complete section on clinical trials and places to search for clinical trials for a specific type of cancer.

The next section helps explain the areas of research going on today about this type of cancer. Use the menu on the side of your screen to select Latest Research, or you can select another section, to continue reading this guide.

Unknown Primary - Latest Research

This section has been reviewed and approved by the Cancer.Net Editorial Board, 03/2014

ON THIS PAGE: You will read about the scientific research being done now to learn more about this type of cancer and how to treat it. To see other pages, use the menu on the side of your screen.

Doctors are working to learn more about 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 diagnostic and treatment options best 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, some of the genes expressed by healthy lung cells are different from those expressed by healthy colon cells.  When cancers develop in these organs, they usually have the same organ-specific pattern of gene expression. It is now possible to analyze a tumor sample from a biopsy to find the genes being expressed, which usually predicts the place where the cancer began.

As mentioned in the Treatment Options section, site-specific treatment based on molecular tumor profiling prediction is replacing empiric chemotherapy as the standard treatment for patients with CUP who do not fit into any of the specific subgroups described. Ongoing clinical trials are further examining the outcome of assay-directed treatment in order to better define its role in treating CUP.

Targeted therapy. As outlined in the Treatment Options section, targeted therapy is directed at specific molecular abnormalities within the cancer cell or the surrounding tissue environment that contributes to cancer growth and spread. These abnormalities include gene mutations in the cancer and abnormal activity of various signaling proteins within the cancer cell. Learn more about targeted treatments.

Several targeted therapies are approved by the FDA for specific cancers, either used alone or with chemotherapy. However, no targeted therapies are currently approved to treat CUP, and the targeted agents approved for other cancers have not been tested in CUP. Since CUP actually covers many tumor types, such as tumors that begin in the lung, breast, colon, etc., it is likely that some patients would benefit from the targeted therapies already proven to treat specific tumor types. For example, therapies targeting HER2, which is a molecular abnormality found in about one-fifth of breast cancers, have dramatically improved treatment results for these patients. Could a patient with CUP who is predicted to have breast cancer according to molecular profiling have an abnormality in HER2? If so, would treatment with a therapy targeting HER2 benefit this patient? The answer to both questions is likely to be “yes,” but no clinical trials have addressed this issue for HER2 or any other molecular abnormality. Current and future clinical trials will address these important questions.

New types of treatment. Patients with CUP that no longer responds to standard treatment may want to consider clinical trials that test new types of treatment, called phase I clinical trials. The goals of these studies are to find the side effects and best doses for these new drugs, as well as to learn if they are effective against cancer.

Supportive care. Clinical trials are underway to find better ways of reducing symptoms and side effects of current cancer treatments in order to improve patients’ comfort and quality of life.

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

The next section addresses how to cope with the symptoms of the disease or the side effects of its treatment. Use the menu on the side of your screen to select Coping with Side Effects, or you can select another section, to continue reading this guide.

Unknown Primary - Coping with Side Effects

This section has been reviewed and approved by the Cancer.Net Editorial Board, 03/2014

ON THIS PAGE: You will find out more about steps to take to help cope with physical, social, and emotional side effects. This page includes several links outside of this guide to other sections of this website. To see other pages, use the menu on the side of your screen.

Fear of treatment side effects is common after a diagnosis of cancer, but it may help to know that preventing and controlling side effects is a major focus of your health care team. This is called palliative or supportive care, and it is an important part of every patient’s overall treatment plan.

Common side effects from each treatment option for CUP are described within the Treatment Options section. Learn more about the most common side effects of cancer and different treatments, along with ways to prevent or control them. Side effects depend on a variety of factors, including the length and dosage of each treatment and your overall health.

Before treatment begins, talk with your doctor about possible side effects of each type of treatment you will be receiving. Ask which side effects are most likely to happen, when they are likely to occur, and what can be done to prevent or relieve them. And, ask about the level of caregiving you may need during treatment and recovery, as family members and friends often play an important role in the care of a person with CUP. Learn more about caregiving.

In addition to physical side effects, there may be emotional and social effects as well. Patients and their families are encouraged to share their feelings with a member of their health care team who can help with coping strategies, including concerns about managing the cost of your cancer care

During and after treatment, be sure to tell the health care team about the side effects you experience, even if you feel they are not serious. Sometimes, side effects can last beyond the treatment period, called a long-term side effect. A side effect that occurs months or years after treatment is called a late effect. Treatment of both types of effects is an important part of survivorship care. Learn more by reading the After Treatment section or talking with your doctor.

The next section helps explain medical tests and check-ups needed after finishing cancer treatment. Use the menu on the side of your screen to select After Treatment, or you can select another section, to continue reading this guide.

Unknown Primary - After Treatment

This section has been reviewed and approved by the Cancer.Net Editorial Board, 03/2014

ON THIS PAGE: You will read about your medical care after cancer treatment is finished and why this follow-up care is important. To see other pages, use the menu on the side of your screen.

After treatment for CUP ends, talk with your doctor about developing a follow-up care plan. This plan may include regular physical examinations and/or medical tests to monitor your recovery for the coming months and years. ASCO offers cancer treatment summary forms to help keep track of the cancer treatment you received and develop a survivorship care plan once treatment is completed.

Since patients with CUP are a diverse group of people and recommended treatments vary, 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. Recommendations in this section are directed primarily to patients who are in remission after successful treatment.

For patients in specific, treatable subgroups (see the Treatment Options section) who receive treatment following guidelines for various cancers of a known primary site, the side effects and post-treatment recommendations are similar to that specific cancer. Please refer to the specific cancer type section for more information.

For patients who receive chemotherapy and experience remission, treatment is usually stopped after four to six months. Most of the treatment-related side effects, such as low blood counts, fatigue, weakness, and joint aches, go away within four to six weeks after treatment. However, other possible side effects like peripheral neuropathy, which is numbness or discomfort in the hands and feet, improve slowly and may take six to 12 months to go away.

Close follow-up care is recommended during the first year after treatment ends, with physical examinations and routine laboratory tests every two months and appropriate x-rays/scans every three to four months. 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.

People recovering from CUP are encouraged to follow established guidelines for good health, such as maintaining a healthy weight, not smoking, limiting alcohol, eating a balanced diet, and having recommended cancer screening tests. Talk with your doctor to develop a plan that is best for your needs. Moderate physical activity can help you rebuild your strength and energy level. Your doctor can help you create an appropriate exercise plan based upon your needs, physical abilities, and fitness level. Learn more about the next steps to take in survivorship, including making positive lifestyle changes.

The next section offers a list of questions you may want to ask. Use the menu on the side of your screen to select Questions to Ask the Doctor, or you can select another section, to continue reading this guide.

Unknown Primary - Questions to Ask the Doctor

This section has been reviewed and approved by the Cancer.Net Editorial Board, 03/2014

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

Talking often with the doctor 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 an e-list and other interactive tools to manage your care.

During the initial evaluation

  • Where exactly 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 profiling assay of my biopsy specimen be helpful in predicting a primary site?
  • Is another biopsy necessary to provide the pathologist with an optimal specimen to examine?
  • What tests or scans are available to help identify a primary site?
  • Should I get a second opinion?

Before receiving treatment

  • Does my cancer fit into any of the subgroups of CUP that require specific treatment?
  • Have specialized pathologic studies of my tumor biopsy resulted in a prediction of where my cancer started. If so, will my treatment follow the guidelines for the predicted cancer type?
  • What are my treatment options?
  • Are there clinical trials that are available to 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 coordinating my overall treatment and follow-up care?
  • 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 related to my cancer care, who can help me with these concerns?
  • What follow-up tests will I need, and how often will I need them?
  • What support services are available to me? To my family?
  • Whom should I call for questions or problems?

The next section offers some more resources that may be helpful to you. Use the menu on the side of your screen to select Additional Resources, or you can select another section, to continue reading this guide.

Unknown Primary - Additional Resources

This section has been reviewed and approved by the Cancer.Net Editorial Board, 03/2014

ON THIS PAGE: You will find some helpful links to other areas of Cancer.Net that provide information about cancer care and treatment. This is the final page of Cancer.Net’s Guide to Cancer of Unknown Primary. To go back and review other pages, use the menu on the side of your screen.

Cancer.Net includes many other sections about the medical and emotional aspects of cancer, both for the person diagnosed and their family members and friends. This website is meant to be a resource for you and your loved ones from the time of diagnosis, through treatment, and beyond. Here are a few sections that may get you started in exploring the rest of Cancer.Net:

This is the end of Cancer.Net’s Guide to Cancer of Unknown Primary. Use the menu on the side of your screen to select another section to continue reading this guide.