Approach

Treatment for adenocarcinoma of unknown primary site (ACUP) is guided by the patient’s performance status (i.e., fitness) and symptoms, and whether or not they have a favorable clinicopathologic subtype (e.g., a likely primary site; single metastatic lesion; oligometastatic disease) that allows for tailored treatment with site-specific therapy.[3] Approximately 20% of patients with cancer of unknown primary (CUP) have a favorable subtype.[2][3] See Etiology (Classification) for details on favorable subtypes.

Most patients with ACUP have multiple metastases and/or no obvious likely primary site (i.e., unfavorable subtype).

Chemotherapy: general considerations

Chemotherapy has been the cornerstone of treatment of ACUP and is used empirically with palliative intent in patients with an unfavorable subtype.[2][3]​​​​

Many chemotherapeutic regimens have been assessed, but systematic reviews and meta-analyses have failed to demonstrate superiority of one regimen over another.[35][36][37]​​​ One meta-analysis reported a tendency toward improved survival with regimens containing platinum agents or taxanes.[37]

Performance status

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

The majority of patients with ACUP are older adults, with some functional impairment related to the advanced disease.

National Comprehensive Cancer Network (NCCN) guidelines recommend consideration of systemic therapy for patients who are:[2]​​

  • Symptomatic with performance status of 1-2, or

  • Asymptomatic with aggressive cancer and performance status 0.

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. Supportive care should continue as required.

Supportive care

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

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.

  • 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 pharmacotherapy, as appropriate.

Other symptoms requiring attention include fatigue, depression, nausea, and delirium.

Patients with multiple metastases and/or without a likely primary site (unfavorable subtype)

For patients with ACUP in whom a favorable clinicopathologic subtype is not identified, the recommended initial treatment is empiric chemotherapy.[2][3]

Standard empiric chemotherapy for patients with ACUP is a doublet regimen comprising a platinum agent combined with either a taxane (paclitaxel or docetaxel) or gemcitabine.[2][3] Responses are not durable (median survival approximately 12 months among patients with good performance status).[38][39]​​​​

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 a likely primary site (favorable subtype)

Patients with clinicopathologic features analogous to a known primary cancer may be treated with site-specific therapy tailored to this site.

Women with isolated axillary lymphadenopathy

Female patients presenting with isolated axillary lymphadenopathy and documented adenocarcinoma should undergo mammography for suspected breast cancer.[2] Contrast-enhanced breast MRI and/or breast ultrasound is indicated if mammography is not diagnostic but there is histopathologic evidence for breast cancer.[2] 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.[40]

Evaluation of immunohistochemical markers of breast cancer (e.g., GATA3; estrogen receptor/progesterone receptor [ER/PR]) is recommended in women with isolated axillary lymphadenopathy.[2] Tumors that are ER-/PR-positive may be treated with hormonal therapy. Patients with likely breast primary should be managed according to primary breast cancer protocols.[2][3]​​​​​​ See Primary invasive breast cancer.

Women with peritoneal carcinomatosis of a serous papillary adenocarcinoma

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 is similar to that for advanced-stage ovarian cancer, which includes optimal surgical debulking and adjuvant platinum-based chemotherapy, generally a taxane/platinum doublet.[3]​ 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.[41][42][43]​​​​​​​​ Patients with ovarian-like cancer of unknown primary are treated per ovarian cancer guidelines.​​[2]​​​[3] 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.[3]

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.[44]​ In a subsequent phase 2 study, irinotecan and cisplatin was not inferior to etoposide and cisplatin in patients with poorly differentiated gastroenteropancreatic neuroendocrine carcinoma.[45]​ Enrollment to the study was terminated early (n=66 patients) because initial analyses reported similar response rates.[45] Poorly differentiated neuroendocrine tumors are treated per small cell lung cancer guidelines.[2][46]​​​ 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.[3]

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.[4]​ Well-differentiated neuroendocrine tumors should be treated as carcinoid tumors.[2] 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., capecitabine plus oxaliplatin [CapeOX]; fluorouracil/leucovorin plus oxaliplatin [FOLFOX or FLOX] or irinotecan [FOLFIRI], with or without bevacizumab).​​[2][3]​​​​​[47]​ See Colorectal cancer.

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

These patients should be assessed for testicular germ cell tumors (using alpha-fetoprotein [AFP] and beta-human chorionic gonadotropin [hCG] serum tumor markers).[2][4]​​​​ 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]).[2] 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.[3]

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 most likely indicate a prostate primary. Treatment with androgen deprivation therapy (with or without radiation therapy), or other treatments appropriate for newly diagnosed prostate cancer, should be administered.[4] See Prostate cancer.

Patients with a single metastatic lesion or oligometastatic disease (favorable subtype)

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][3]​​​ Adjuvant chemotherapy may be considered to control metastatic foci that are not yet evident.[4]

Common sites of solitary lesions include the liver, adrenal gland, brain, and bone. Treatment varies depending on suspected primary. IHC testing can help to determine a likely primary site and guide treatment. A chemotherapy 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.[3][48]​​​ Candidate patients should satisfy the following criteria:[3]

  • 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 and 52.5 months, respectively, has been reported following local ablative treatment of single-site and oligometastatic carcinoma of unknown primary.[48]

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