Approach

A primary goal of the diagnostic workup is to identify subgroups of patients who can receive site-specific treatment tailored to the presumed primary site: namely, those with a more favorable prognosis. Unfortunately, the majority of patients remain unclassified after thorough workup, and thus have unfavorable risk subtype.[2]

Chemotherapy: general considerations

Historically, chemotherapy has been the cornerstone of treatment of adenocarcinoma of unknown primary site (AUP), and has been used with palliative intent in unfavorable risk subtypes.​[2][15]​​

Many chemotherapeutic regimens have been assessed, but systematic reviews and meta-analyses have failed to demonstrate superiority of one regimen over another.[43][44][45]​​​ One meta-analysis reported a tendency toward improved survival with regimens containing platinum agents or taxanes.[45]

Performance status

The performance status of the patient is a critical determinant of treatment recommendations. The Eastern Cooperative Oncology Group (ECOG) scale, ranging from 0 to 5, is commonly used to assess performance.

Eastern Cooperative Oncology Group: ECOG performance status scale Opens in new window​​

  • 0: Fully active, able to carry on all predisease performance without restriction.

  • 1: Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature (e.g., light housework, office work).

  • 2: Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours.

  • 3: Capable of only limited self-care, confined to bed or chair more than 50% of waking hours.

  • 4: Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair.

  • 5: Dead.

The majority of patients with AUP are older adults, with some functional impairment related to the advanced disease. US guidelines recommend that systemic therapy for patients with disseminated disease should be reserved for the following patients:[15]​​

  • Symptomatic with performance status of 1-2, or

  • Asymptomatic with aggressive cancer and performance status 0.

Supportive care should be initiated, ideally under the guidance of a palliative care physician or team.

Supportive care

Initial treatment strategies are aimed at controlling symptoms attributable to the underlying process, such as pain or local obstruction, and the focus should be on palliation of symptoms. Specific treatment will depend upon the site involved. Expedited diagnostic workup allows initiation of appropriate chemotherapy in a timely fashion.[30]

Typical symptoms requiring attention include fatigue, depression, nausea, and delirium. Pain control strategies can differ based upon the site and character of pain.

  • Bone pain: typically requires treatment with a nonsteroidal anti-inflammatory drug (NSAID), an opioid analgesic, or a corticosteroid, or a suitable combination of these agents. Zoledronic acid (a bisphosphonate) or denosumab can be given for pain due to bone metastases, and to decrease risk of skeletal-related events such as fractures. Palliative radiation therapy can also be considered.

  • Neuropathic pain: may respond to anticonvulsant therapy (e.g., gabapentin) or antidepressant therapy (e.g., duloxetine).

  • Local pain: can be treated with regional nerve blocks or radiation therapy.

  • Obstructive symptoms: are related to tumor mass or localized inflammation, and are common (e.g., bowel, biliary, and bronchial obstruction). Obstructive symptoms should be aggressively managed, using a multidisciplinary approach, with interventional radiology, endoscopic or surgical intervention, radiation therapy, and medications, as appropriate.

Frequent reassessment typically includes a repeat history and physical exam to assess performance status and tolerance of therapy, with basic laboratory data to assess organ function. If there is a deterioration in performance status, or if tolerance of therapy is poor (either by patient report or significant laboratory derangement: neutropenia, thrombocytopenia, renal, or liver dysfunction), then chemotherapy should be reevaluated and/or discontinued. Symptom management should continue as required.

Patients with multiple metastases: unfavorable subtypes

For the majority of patients in whom a favorable clinicopathologic subtype is not identified, the recommended initial chemotherapeutic regimen is a combination of agents, either platinum-based (cisplatin or carboplatin) or taxane/platinum-containing (docetaxel or paclitaxel with cisplatin or carboplatin).[3]​ European guidelines suggest platinum-based doublets combined with either a taxane or gemcitabine as standard of care.[2]​ Responses are not durable (median survival approximately 12 months among patients with good performance status).[46][47]​​​

There is no agreement on appropriate second-line therapy for patients previously treated with platinum-containing regimens; no single agent or combination has proven beneficial (response rate or median survival). Decisions about second-line therapy are based on oncologist preference, or on other patient characteristics that may prevent the use of certain cytotoxic drug classes.

Patients with multiple metastases: favorable subtypes

Patients with a favorable clinicopathologic subtype are offered more specific treatment according to the likely primary site.

Women with isolated axillary lymphadenopathy

Female patients presenting with isolated axillary lymphadenopathy and documented adenocarcinoma should undergo mammography and breast magnetic resonance imaging (MRI). Retrospective studies indicate that breast MRI can help to identify the primary cancer in approximately two-thirds of patients with negative clinical exam and negative mammography.[48]​ Immunohistochemical markers for estrogen receptor (ER) and progesterone receptor (PR) should be performed in all women with adenocarcinoma, especially in those with isolated axillary lymphadenopathy. Tumors exhibiting these receptors are sensitive to hormonal therapy. Patients with likely breast primary should be managed according to primary breast cancer protocols.​[2][15]​​​​ See Primary invasive breast cancer.

Women with papillary adenocarcinoma of the peritoneal cavity

Histologically analogous to stage III ovarian cancer. BRCA1/2 germline mutations may be present and CA 125 is typically elevated, consistent with an ovarian cancer profile. First-line therapy includes optimal surgical debulking and systemic chemotherapy, generally a taxane/platinum doublet.[2]​ There is some evidence, although not consistent, to support the use of intraperitoneal chemotherapy for advanced-stage ovarian cancer; its potential role in the management of papillary adenocarcinoma of the peritoneal cavity has not yet been evaluated.[49][50][51]​​​​​​​ Patients with ovarian-like cancer of unknown primary site are treated per ovarian cancer guidelines.​[2][15]​​ See Ovarian cancer.

Poorly differentiated carcinoma with neuroendocrine features

A significant minority of poorly differentiated or undifferentiated carcinomas have neuroendocrine features identified by histologic assessment. Favorable neuroendocrine carcinoma subtypes are not considered in European guidelines because an elusive primary cancer is a common finding.[2]

Combination chemotherapy with paclitaxel, carboplatin, and etoposide was associated with a major response rate of 53% (median survival 14.5 months; 2- and 3-year survival rates of 33% and 24%, respectively) in one phase 2 clinical trial of treatment-naive patients with metastatic poorly differentiated neuroendocrine carcinoma.[52]​ In a subsequent phase 2 study, irinotecan and cisplatin was not inferior to etoposide and cisplatin in patients with poorly differentiated gastroenteropancreatic neuroendocrine carcinoma.[53]​ Enrollment to the study was terminated early (n=66 patients) because initial analyses reported similar response rates.[53] Poorly differentiated neuroendocrine tumors are treated per small cell lung cancer guidelines.[15][54]​​​ See Small cell lung cancer.

Well-differentiated neuroendocrine tumors

Neuroendocrine tumors include islet cell tumors, carcinoid tumors, and gastrinomas, among others. Favorable neuroendocrine carcinoma subtypes are not considered in European guidelines because an elusive primary cancer is a common finding.[2]

If feasible, surgical debulking or chemoembolization is preferred as an initial therapy, as control of tumor bulk appears to delay progression of systemic disease. Chemotherapy is variably effective, depending on the underlying tumor type, with pancreatic neuroendocrine tumors exhibiting much better response rates than carcinoid tumors derived from other primary sites. Treatments appropriate for well-differentiated metastatic neuroendocrine tumors should be considered, including somatostatin analogs (e.g., octreotide, lanreotide), everolimus, sunitinib, or peptide receptor radiation therapy.[3]​ Well-differentiated neuroendocrine tumors should be treated as carcinoid tumors.[15] See VIPoma.

Adenocarcinoma with colorectal immunohistochemistry (IHC)

Patients with IHC suggestive of colorectal primary site (CDX2-positive, CK20-positive, CK7-negative) may benefit from chemotherapy regimens used for treatment of metastatic colorectal cancer (e.g., fluorouracil/leucovorin with oxaliplatin [FOLFOX or FLOX] or irinotecan [FOLFIRI], with or without bevacizumab).​[2][15]​​​​[55]​ See Colorectal cancer.

Poorly differentiated carcinoma of the mediastinum or retroperitoneum in males <40 years

These patients should be assessed for germ cell tumors (using alpha-fetoprotein [AFP] and beta-human chorionic gonadotropin [hCG] serum tumor markers).​[3][15]​​ Male patients should be considered for testicular ultrasound, particularly if tumor markers are elevated, and primarily treated with curative intent with a cisplatin-based regimen (e.g., bleomycin, etoposide, cisplatin [BEP]).[15] See Testicular cancer.

Historically, many patients with poorly differentiated carcinoma with midline distribution actually had extragonadal germ cell tumors. European guidelines, therefore, suggest that the poorly differentiated carcinoma with midline distribution subtype should no longer be used.[2]

Men with blastic bone metastases with IHC/serum prostate-specific antigen (PSA) expression

Blastic bone metastases in older men (ages ≥40 years) with elevated PSA are most likely to be prostate carcinoma. Treatment with androgen deprivation therapy (with or without radiation therapy), or other treatments appropriate for newly diagnosed prostate cancer, should be administered.[3] See Prostate cancer.

Patients with a single metastatic lesion

Patients presenting with a single metastatic lesion of unknown primary site are rare, and treatment should be individualized. However, the general consensus is to consider definitive local therapy, usually surgical; definitive radiation therapy may be appropriate depending on anatomic location.​[2][15]​ Adjuvant chemotherapy may be considered to control metastatic foci that are not yet evident.[3]

Common sites of solitary lesions include the liver, adrenal gland, brain, and bone. Treatment varies depending on suspected primary. Cytokeratin staining and other IHC markers assist in determining the likely primary site of the tumor and thus the best treatment option. A chemotherapeutic regimen with broad activity across tumor types (encompassing most likely sites of disease, such as occult lung carcinoma, or gastrointestinal tumors) is often preferred.

Oligometastatic disease

European guidelines suggest that selected patients with oligometastatic disease may be managed using local ablative surgery and/or radiation therapy.[2][56]​​​ Candidate patients should satisfy the following criteria:[2]

  • Local ablative treatment of all lesions by surgery and/or radiation therapy is deemed feasible

  • Oligometastatic state has been confirmed by imaging including positron emission tomography/computed tomography (PET/CT) and brain MRI

  • Number of metastases does not exceed five

  • No involvement of a diffuse organ, such as malignant pleural, peritoneal, or leptomeningeal carcinomatosis.

Median event-free and overall survival of 15.6 months and 52.5 months, respectively, has been reported following local ablative treatment of single-site and oligometastatic carcinoma of unknown primary.[56]

Use of this content is subject to our disclaimer