What is the treatment approach for carcinoma of unknown primary (CUP) origin with metastasis?

From the Guidelines

Treatment of metastatic carcinoma of unknown primary (CUP) should prioritize a multidisciplinary approach focusing on symptom management and targeted therapy based on the cancer's characteristics, with a platinum-based combination chemotherapy regimen such as carboplatin/paclitaxel or cisplatin/gemcitabine recommended as first-line treatment for most patients 1.

Key Considerations

• Initial management includes comprehensive diagnostic workup with immunohistochemistry, molecular profiling, and genomic testing to identify potential therapeutic targets.
• Targeted therapies may be appropriate for specific subtypes, such as HER2-positive cases benefiting from trastuzumab, or EGFR mutations responding to tyrosine kinase inhibitors like erlotinib.
• Immunotherapy with checkpoint inhibitors (pembrolizumab or nivolumab) should be considered for tumors with high microsatellite instability or PD-L1 expression.

Supportive Care

• Pain management, nutritional support, and treatment of specific complications like hypercalcemia or bone metastases (often with bisphosphonates) are essential components of care.
• Prognosis remains guarded for most CUP patients, with median survival typically ranging from 6-12 months, though outcomes are improving with advances in molecular diagnostics and targeted therapies 1.

Subtype-Specific Treatment

• Poorly differentiated neuroendocrine carcinomas of an unknown primary may benefit from platinum + etoposide combination chemotherapy.
• Well-differentiated neuroendocrine tumors of unknown primary may be treated with somatostatin analogues, streptozocin+5-FU, sunitinib, or everolimus.
• Peritoneal adenocarcinomatosis of a serous papillary histological type in females may be managed with optimal surgical debulking followed by platinum–taxane-based chemotherapy 1.

From the Research

Diagnosis and Treatment of Metastatic Carcinoma without a Primary Source

• Metastatic carcinoma without a primary source, also known as cancer of unknown primary (CUP) origin, refers to patients who present with histologically confirmed metastatic cancer in whom a detailed medical history, complete physical examination, and diagnostic tests fail to identify the primary site 2.
• The standard diagnostic procedure for CUP includes histopathologic review of biopsy specimens with the use of immunohistochemistry, chest radiography, computed tomography of the abdomen and pelvis, and in certain cases mammography 2.
• The prognosis for most patients with unknown primary tumors is poor, with survival often less than 6 months from diagnosis, but approximately 40% of patients can be categorized within subsets for which specific treatment has been defined 2.

Clinical Features and Treatment Approaches

• CUPs are characterized by a set of distinct features comprising early metastatic dissemination in an atypical pattern, an aggressive clinical course, poor response to empiric chemotherapy, and consequently, a short life expectancy 3.
• Two opposing strategies to change the dismal prognosis for the better are pursued: the traditional tissue-gnostic approach and the tissue-agnostic strategy targeting actionable genomic alterations 3.
• Precision medicine approaches have already transformed the treatment for many known tumor types, but an unmet need remains for well-designed clinical trials to scrutinize its potential role in CUP beyond anecdotal case reports 3.

Diagnostic Approach using Immunohistochemistry

• Immunohistochemistry is a reliable, inexpensive, and widely available resource for pathologists in approaching CUP lesions 4.
• New markers continue to emerge, which, in combination with other historically useful antibodies, allow rapid and accurate identification of primary site in an increasing number of cases 4.
• The use of lineage-restricted transcription factors, including CDX2, NKX3-1, PAX8, SATB2, TTF-1, and SF1, can aid in the diagnosis of CUP using immunohistochemistry 4.

Mechanisms of Cancer Metastasis

• Metastatic cancer is almost always terminal, and more than 90% of cancer deaths result from metastatic disease 5.
• Combating cancer metastasis and post-therapeutic recurrence successfully requires understanding each step of metastatic progression, including the etiology and mechanism of cancer progression from primary tumor growth to the formation of new tumors in other parts of the body 5.