Metastatic Cancer With Unknown Primary Site Treatment & Management

Updated: Apr 04, 2022
  • Author: Winston W Tan, MD, FACP; Chief Editor: Wafik S El-Deiry, MD, PhD  more...
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Medical Care

The treatment of cancer of unknown primary origin continues to evolve. [32, 33] The most common scenario is a patient with progressive, metastatic adenocarcinoma with multiple organ involvement. [34] The treatment of this group of patients remains suboptimal.

Some favorable subsets have been identified that respond well to certain specific treatment strategies. These are discussed below.

See Cancer of Unknown Primary Treatment Protocols for summarized information.

Metastasis to cervical lymph nodes

A histologic diagnosis of metastatic carcinoma in the cervical nodes warrants a careful evaluation of the upper aerodigestive tract, including direct visualization of the hypopharynx, nasopharynx, larynx, and upper esophagus. Histologically, most of these tumors are squamous cell carcinomas, but adenocarcinoma, melanoma, or anaplastic tumors can also be seen in this location. In patients with squamous or undifferentiated carcinoma, tonsillectomy should be considered. [35] Cervical adenopathy can be the primary disease manifestation in 2-5% of patients with primary squamous cell carcinoma of the head and neck region.

In the absence of localization of a primary site, aggressive local therapy is indicated. This may involve any of the following:

  • Radical radiation therapy with curative intent to the neck and possible site of origin
  • Preoperative radiation therapy followed by radical neck dissection
  • Radical neck dissection
  • Radical neck dissection followed by radiation to possible sites of origin

Five-year survival rates as high as 30-50% have been achieved with this approach.

The role of chemotherapy is debated. One randomized study showed an improved response rate and median survival with cisplatin and 5-fluorouracil—based chemotherapy when compared to radiation alone. A single adenocarcinoma-involved lymph node in either the cervical or inguinal areas with no evidence of disease elsewhere may be managed with surgical excision alone and watchful expectation. [36] Radiation therapy to the involved and local fields may be provided as well. Combination therapy may be superior to monotherapy, with 5-year survival rates of 35% reported.

Patients with cervical node metastases from squamous cell carcinoma of unknown primary have an overall survival comparable to that of patients with known primary. In a retrospective study of 89 patients cancer of unknown primary treated with curative intent at a single institution, Mistry et al showed that the overall 5-year and 8-year survival rates were 55% and 51%, respectively. All patients were treated with surgery, and 70 patients received more than 40 Gy postoperative radiotherapy. [37]

Isolated axillary adenopathy in women

Metastatic adenocarcinoma presenting as isolated axillary lymphadenopathy in women is usually a manifestation of an occult breast primary cancer. [8] Mastectomy specimens in this subset of patients have shown a previously undiagnosed breast primary tumor in 40-70% cases. Immunohistochemical stains for estrogen and progesterone receptor should be performed in this setting, as they may aid in diagnosis.

Modified radical mastectomy with axillary node dissection has been advocated. A study with 42 patients, however, showed improved survival with systemic chemotherapy and improved local control with breast and axillary radiation. When these patients are treated with local excision or as having primary breast cancer, 50% of patients achieve 2-10 year survival. Currently, management is based on the guidelines for stage II breast cancer.

Peritoneal carcinomatosis in women

Women with peritoneal carcinomatosis with adenocarcinoma have similarities with patients with ovarian cancer. They often have papillary histology with elevation of CA-125 and a good response to platinum-based chemotherapy, but a primary tumor is not revealed on exploratory laparotomy.

Metastatic melanoma to a single nodal site

Five percent of patients with malignant melanoma may present with nodal metastasis in the absence of a documented primary site. They should be treated with radical lymph node dissection. Survival, surprisingly, is slightly better than that for stage II melanoma in patients with a known primary site.

Poorly differentiated and undifferentiated carcinoma

One third of patients with cancer of unknown primary origin have poorly or undifferentiated carcinoma. A subpopulation of these can be potentially curable. This subgroup includes patients with lymphomas, germ cell tumors, or neuroendocrine tumors. The features that point toward a treatment-responsive tumor include the following:

  • Patient younger than 50 years
  • Midline distribution, with elevated levels of beta-HCG or AFP
  • Beta-HCG/AFP positive on immunohistochemistry
  • Neuroendocrine granules

  • Rapid tumor growth

  • Iso-chromosome 12p in midline tumors

Platinum-based combination chemotherapy regimens specific for germ cell tumors have been employed in these patients with a response rate of 63%, a complete response rate of 26%, and a 10-year survival rates of 16%.

Poorly differentiated neuroendocrine carcinomas

These tumors are characterized by positive histochemical stains for chromogranin or neuron-specific enolase. These patients often present with extensive liver or bone metastases. In a series of 29 patients, 19 were treated with intensive cisplatin-based chemotherapy, and 6 others received doxorubicin-based combinations. Complete responses were achieved in 6 patients, and 4 of these patients were alive 19-100 months after diagnosis. [29]

Inguinal node metastasis

Metastatic carcinoma in inguinal nodes from an unknown site can be found in 1-3.5% of patients. Squamous cell histology in this area is usually metastatic from the genital/anorectal area. The anorectal area should be carefully inspected in both sexes. Vulvar, vaginal, and cervical examination in women and penile examination in men is warranted. Treatment can involve groin dissection alone or with radiation and chemotherapy. In some patients, local excision with or without radiation may be adequate. [38]

Cancer of unknown primary origin in unselected patients

The results from the favorable patient subsets do not apply to most of the patients with cancer of unknown primary origin (CUP). The most effective chemotherapy regimens for this group of patients involve combination therapy with a platinum compound (cisplatin or carboplatin) and a taxane (preferably paclitaxel). This combination gives a response rate of about 12-26% and a median survival of 5-7 months. Triple drug therapy does not appear to offer any additional benefit.

Docetaxel and carboplatin chemotherapy was found to be convenient, safe and effective outpatient palliative treatment for CUP. In a phase II cycle, Pentheroudakis et al treated 47 patients with CUP with sequential 30-minute infusions of docetaxel 75 mg/m2 and carboplatin area under the concentration time-curve (AUC) of 5 (30 min each) every 3 weeks.  A median of six cycles were given, response rate was 32% (46% for favorable risk, 17% for unfavorable risk), and granulocyte colony stimulating factor support was used in a third of the patients. Toxicity was mild including grade 3-4 neutropenia (26%), febrile neutropenia (7%), and severe nonhematologic side effects in fewer than 8% of patients. Median time to progression and overall survival were 5.5 and 16.2 months, respectively. (Survival in the favorable risk was 22.6 months; visceral metastases had poor median survival 5.3 months.) [39]

Patients in whom combination therapy fails may benefit from single-agent treatment with gemcitabine with median time to progression of 5 months. A phase II clinical trial with bevacizumab and erlotinib reported a median survival of 7-8 months with 33% of patients alive at 1 year. [40]

A subsequent trial found that empiric treatment with paclitaxel, carboplatin, bevacizumab, and erlotinib is effective and well tolerated as first-line treatment for patients with CUP. Major responses to treatment occurred in 32 of 60 patients (53%), and an additional 18 patients had stable disease. The median progression-free survival time was 8 months, with 38% of patients progression free at 1 year; the 2-year overall survival rate was 27%. [41]

Future directions

Newer agents, such as sorafenib, bevacizumab, antineoplaston, CS-1008 (humanized anti-CD-5 antibody), BMS-690514, and ZD1839, are currently being tested in various clinical trials. Also, combinations of older drugs such as capecitabine, carboplatin with weekly paclitaxel, and oxaliplatin with capecitabine are being evaluated in this group of patients.

Insights into the molecular biology of CUP are needed for the development of targeted therapeutic approaches to the treatment of these patients.