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The types of treatment used for a cancer of unknown primary depend on several factors, including the size and location of the cancer, the results of lab tests, and how likely it is to be a certain type of cancer. Your overall health and ability to tolerate treatment matter also. Of course, if the origin of the cancer can be determined during testing, the cancer would no longer be an unknown primary and would be treated according to where it started.
These cancers usually began somewhere in the mouth, throat, or larynx. They are often treated with surgery and/or radiation therapy.
Surgical treatment removes lymph nodes and other tissue from the neck. This operation is called a neck dissection.
The most common side effects of any neck dissection are numbness of the ear, weakness in raising the arm above the head, and weakness of the lower lip. These side effects are caused by injury during the operation to the nerves that supply these areas. After a selective neck dissection, the weakness of the arm and lower lip usually go away after a few months. But if a nerve is removed as part of surgery, the weakness will be permanent. After any neck dissection, physical therapists can show the patient exercises to improve neck and shoulder movement.
Radiation therapy might be used instead of surgery. One potential advantage is that the area treated would include both the nodes with metastatic cancer and several of the areas of the neck likely to contain a primary tumor.
When large and/or many tumors are present, some patients will be treated with both surgery and radiation therapy. The radiation may be given before or after surgery.
When tumors are very large or present on both sides of the neck, chemotherapy (chemo) and radiation therapy are often used together. A targeted therapy drug may also be used with radiation (instead of chemo).
The outlook for these patients depends on the size, number, and location of the lymph nodes containing metastatic cancer. For more information about the usual treatments for these cancers see Nasal Cavity and Paranasal Sinus Cancers, Oral Cavity and Oropharyngeal Cancer and Laryngeal and Hypopharyngeal Cancer.
Because most cancers that have spread to the axillary nodes (lymph nodes under the arm) in women are breast cancers, the recommended treatment is similar to that for women diagnosed with breast cancer that has spread to these nodes.
Surgery to remove axillary nodes (called an axillary lymph node dissection) is done, and the breast on the same side may be treated with mastectomy (surgery to remove the breast) or radiation therapy.
Depending on the woman’s age and whether the cancer cells contain estrogen and/or progesterone receptors, additional (adjuvant) treatment may include hormonal therapy, chemo, or both. The cancer can also be tested for a protein called HER2. If positive, a drug that targets the HER2 protein may be used. For more information about prognosis and treatment of breast cancer that has spread to the lymph nodes, see Breast Cancer.
Although cancer in axillary lymph nodes in men may represent spread from a breast cancer, spread from a lung cancer is much more likely. An axillary lymph node dissection and/or radiation therapy to the underarm area may be considered in some cases, but many doctors would recommend chemo first and waiting to see how the enlarged lymph nodes respond. The combination of drugs would probably be the same as that given for adenocarcinomas or poorly differentiated carcinomas found in other parts of the body.
It’s important to search carefully for the origin of these cancers, as many of them can be treated effectively if it is found. If the primary tumor can’t be found, surgery is usually the main treatment.
If the cancer appears to be confined to a single lymph node, removing it may be the only treatment. In other cases, more extensive surgery (a lymph node dissection) may be needed. If more than one lymph node is found to contain cancer, radiation therapy and/or chemotherapy may be recommended as well.
Unless tests have found a primary cancer outside the ovaries (in which case the diagnosis of cancer of unknown primary would no longer apply), these cancers are most likely to be spread from either ovarian cancer, fallopian tube cancer, or primary peritoneal carcinoma (PPC). Fallopian tube cancer and PPC are diseases similar to ovarian cancer and they are all treated the same way.
Treatment is typically surgery to remove the uterus, both ovaries, both fallopian tubes, and as much of the cancer as possible. After surgery, 6 to 8 months of chemo may be recommended. For more information, see Ovarian Cancer.
If lab tests of the tumor sample have ruled out lymphoma, the most likely diagnosis (particularly in younger men) is a germ cell tumor. Even cancers in these areas that do not have lab results typical of germ cell tumors often respond to chemotherapy combinations for treating testicular germ cell tumors. More information about the treatment of germ cell tumors can be found in Testicular Cancer and Ovarian Cancer.
If a carcinoma is in the mediastinum in an older patient it may be treated as a non-small cell lung cancer.
Once a cancer of unknown primary (CUP) has been diagnosed as a melanoma, it’s no longer a true CUP. This situation is mentioned, nonetheless, because some tests to identify melanomas may take several days. Until they are complete, these patients are considered to have CUP.
The recommended initial treatment of melanoma of unknown primary with only lymph node spread is surgery to remove the lymph nodes in the affected area. If spread to other nodes becomes apparent at a later time and all of the cancer can be removed, these nodes are also removed. For more information see Melanoma Skin Cancer.
This group represents the majority of people with CUP. Usually the cancer is in the bones, lung, or liver. Once lab testing of the biopsy specimen has excluded cancers of the breast, prostate, thyroid, and lymphoma (all of which often respond well to specific treatments), many of the remaining patients are treated with chemo to try to shrink the tumor and reduce symptoms.
Most doctors use a standard chemotherapy regimen. It’s important to stop chemo if it’s not working to relieve symptoms or shrink the cancer, as the side effects of these drugs can be severe and impair quality of life.
Sometimes chemo can be quite helpful. About 15% of patients treated with aggressive chemo will have a complete response (with no visible cancer left after treatment), and in some of these the cancer stays away for years.
Patients in poor health who would not be able to tolerate the side effects of aggressive chemo are sometimes treated with lower doses or with drugs that cause fewer side effects. But the benefit of this approach is not clearly proven. Another option is to focus on relieving symptoms as they occur. Many patients with cancer spread to bones benefit from treatment with bisphosphonates (discussed in Other Drugs for a Cancer of Unknown Primary). These drugs can help strengthen bones weakened by cancer, preventing fractures (breaks), and reducing pain.
Some poorly differentiated small cell cancers of unknown origin can shrink dramatically when chemo combinations originally developed to treat small cell lung cancer are used. The benefit usually lasts for several months, but these cancers almost always return.
Some neuroendocrine cancers may respond to treatment with octreotide (Sandostatin) or lanreotide (Somatuline). These drugs may be able to slow or stop growth for some time. The tumors most likely to respond are the ones able to be seen on somatostatin receptor scintigraphy (imaging). Some other drugs known as targeted therapy that are helpful in treating pancreatic neuroendocrine cancers may be used as well. More information can be found in Chemotherapy for Pancreatic Cancer.
More information about treatments for cancers that have spread can be found in Advanced Cancer.
The American Cancer Society medical and editorial content team
Our team is made up of doctors and oncology certified nurses with deep knowledge of cancer care as well as journalists, editors, and translators with extensive experience in medical writing.
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National Cancer Institute. Physician Data Query (PDQ). Cancer of Unknown Primary Treatment. 07/25/2015. Accessed at: https://www.cancer.gov/types/unknown-primary/hp/unknown-primary-treatment-pdq on February 9, 2018.
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Occult Primary. v.1.2018. Accessed at https://www.nccn.org/professionals/physician_gls/pdf/occult.pdf on February 9, 2018.
Tomuleasa C, Zaharie F, Muresan MS, Pop L, Fekete Z, Dima D, Frinc I, Trifa A, Berce C, Jurj A, Berindan-Neagoe I, Zdrenghea M. How to diagnose and treat a cancer of unknown primary site. J Gastrointestin Liver Dis. 2017 Mar;26(1):69-79. doi: 10.15403/jgld.2014.1121.261.haz.
Varadhachary GR, Lenzi R, Raber MN, Abbruzzese JL. Carcinoma of Unknown Primary In: Neiderhuber JE, Armitage JO, Doroshow JH, Kastan MB, Tepper JE, eds. Abeloff’s Clinical Oncology. 5th ed. Philadelphia, PA. Elsevier: 2014:1792-1803.
Last Revised: March 9, 2018
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