Chapter 095. Carcinoma of Unknown Primary (Part 6)

Management of Disseminated CUP Patients who present with liver, brain, and adrenal metastatic disease usually have a poor prognosis. Beside primary peritoneal carcinoma, carcinomatosis presenting as CUP in other settings is not uncommon. Gastric, appendicular, colon, pancreas, and cholangiocarcinoma are all possible primaries, and imaging, endoscopy, and pathologic data help in the evaluation. Traditionally, platinum-based combination chemotherapy regimens have been used to treat patients with CUP. In a phase II study by Hainsworth and colleagues, 55 mostly chemotherapy-naive patients were treated with paclitaxel, carboplatin, and oral etoposide every 3 weeks. The overall response rate was 47%, with median overall survival duration...
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Chapter 095. Carcinoma of Unknown Primary (Part 6) Chapter 095. Carcinoma of Unknown Primary (Part 6) Management of Disseminated CUP Patients who present with liver, brain, and adrenal metastatic disease usually have a poor prognosis. Beside primary peritoneal carcinoma, carcinomatosis presenting as CUP in other settings is not uncommon. Gastric, appendicular, colon, pancreas, and cholangiocarcinoma are all possible primaries, and imaging, endoscopy, and pathologic data help in the evaluation. Traditionally, platinum-based combination chemotherapy regimens have been used to treat patients with CUP. In a phase II study by Hainsworth and colleagues, 55 mostly chemotherapy-naive patients were treated with paclitaxel, carboplatin, and oral etoposide every 3 weeks. The overall response rate was 47%, with median overall survival duration of 13.4 months. Briasoulis and colleagues reported similar response rates and survival durations in 77 patients with CUP who had been treated with paclitaxel and carboplatin. In this study, patients with nodal or pleural disease and women with peritoneal carcinomatosis had higher response rates and overall survival durations of 13 and 15 months, respectively. Studies incorporating newer agents, including gemcitabine, irinotecan, and targeted agents, are showing higher response rates. In a phase II randomized trial by Culine and colleagues, 80 patients were randomly assigned to receive gemcitabine with cisplatin or irinotecan with cisplatin; 78 patients were assessible for efficacy and toxicity. Objective responses were observed in 21 patients (55%) in the gemcitabine and cisplatin arm and in 15 patients (38%) in the irinotecan and cisplatin arm. The median survival was 8 months for gemcitabine and cisplatin and 6 months for irinotecan and cisplatin. The role of second-line chemotherapy in CUP is poorly defined. Gemcitabine as a single agent has shown a partial response rate of 8%, and 25% of patients had minor responses or stable disease, with improved symptoms. Combination chemotherapy as a second- and third-line treatment may result in a slightly improved response. Combination targeted therapy is being evaluated. Hainsworth and colleagues studied the combination of bevacizumab and erlotinib in 51 patients; 25% were chemotherapy-naive and had advanced bone or liver metastases, while the rest had been previously treated with 1 or 2 chemotherapy regimens. Responses were noted in 4 patients (8%), and 30 patients (59%) experienced stable disease or a minor response. The median overall survival was 8.9 months, with 42% of patients alive at 1 year. Historically, patients with CUP have been treated with global regimens that work for a variety of primary cancers. With incremental improved responses over the past decade in known cancer types, we anticipate overall better response rates with newer regimens for selected CUP patients. With a more robust immunohistochemical panel (directed approach) and new molecular data, one may be able to create a more tailored algorithm for CUP patients. Summary Patients with CUP should undergo a directed diagnostic search for the primary tumor on the basis of clinical and pathologic data. Subsets of patients have prognostically favorable disease, as defined by clinical or histologic criteria, and may substantially benefit from aggressive treatment and expect prolonged survival. However, for most patients who present with advanced CUP, the prognosis remains poor, with early resistance to available cytotoxic therapy. Research into the metastatic phenotype will help us improve our understanding of CUP tumor biology. Whether the CUP clone is a distinct molecular genotype- phenotype that is different from metastases of known primary tumors remains to be elucidated. The identification of specific CUP-related molecular and biochemical targets may help exploit therapeutic targeted agents for this entity. Further Readings Abbruzzese JL et al: The biology of unknown primary tumors. Semin Oncol 20:238, 1993 [PMID: 8503019] Bugat R et al: Summary of the standards, options and recommendations for the management of patients with carcinoma of unknown primary site. Br J Cancer 89(Suppl 1):S59, 2003 Culine S et al: Cisplatin in combination with either gemcitabine or irinotecan in carcinomas of unknown primary site: Results of a randomized phase II study—trial for the French Study Group on Carcinomas of Unknown Primary (GEFCAPI 01). J Clin Oncol 21:3479, 2003 [PMID: 12972523] Dennis JL, Oien KA: Hunting the primary: novel strategies for defining the origin of tumours. J Pathol 205:236, 2005 [PMID: 15641019] Greco FA, Hainsworth JD: One-hour paclitaxel, carboplatin, and extended- schedule e ...