Combination of Carboplatin, Gemcitabine, and Capecitabine in Patients With Carcinoma of Unknown Primary Site

Carcinoma of unknown primary site (CUP) accounts for approximately 5% of all newly diagnosed malignancies. The overall prognosis for patients with CUP remains poor, with median survival less than one year with modern chemotherapy combinations and virtually no long-term survivors.

It has been recognized that patients with CUP represent a heterogeneous group of tumors. Managing patients with CUP requires a complete medical history, careful consideration of findings on physical exam, targeted radiologic studies and pathologic analysis of biopsy and/or surgical specimens. Within this heterogeneous group there exist at least four subsets of patients with CUP, that based on clinicopathologic features are treated with regimens which have demonstrated efficacy in tumors originating in the most likely primary site of that CUP; squamous carcinoma involving mid or high levels of cervical lymph nodes, women with isolated axillary adenopathy containing adenocarcinoma, women with a predominant presentation of peritoneal carcinomatosis and young men with extragonadal germ cell syndrome.

Unfortunately, a majority of patients with CUP do not fall into any of the above subsets and these represent a therapeutic dilemma, as there is no single regimen to date that has shown significant activity or has resulted in prolonged survival for these patients with particularly poor prognosis. Thus, new therapeutic combinations need to be investigated for treatment of these patients with CUP.

Platinum compounds have been the cornerstone of chemotherapy regimens for a wide variety of solid tumors, including lung, urothelial, head and neck, ovarian and endometrial carcinomas, as well as testicular carcinomas. Cisplatin and its analog carboplatin are currently used in chemotherapy combinations to treat CUP. Carboplatin has fewer non-hematologic side effects compared to cisplatin including less nausea and vomiting, peripheral neuropathy, nephrotoxicity and ototoxicity making it an attractive agent to combine with other drugs.

In recent years, new agents active in solid malignancies have been developed. Gemcitabine is one such agent. It is a deoxycytidine analogue structurally related to cytosine arabinoside. Gemcitabine is activated by deoxycytidine kinase in three steps of phosphorylation into difluorodeoxycytidine triphosphate, which when incorporated into DNA, leads to chain termination. Gemcitabine has been shown to have activity in pancreatic, breast, non-small cell lung carcinomas as well as in carcinomas of unknown primary site. Because of its mild toxicity profile, gemcitabine has been used in combination with other chemotherapy agents. There is evidence of in vitro and in vivo synergy between gemcitabine and the platinum compounds.

Capecitabine is an orally administered fluoropyrimidine that undergoes a three-step conversion into 5-FU, with pharmacokinetics that mimic low dose continuous infusion 5-FU. The oral formulation allows for convenient continuous therapy, avoiding a need for central venous catheters and external infusion pumps.

The final step of conversion of capecitabine into 5-FU is catalyzed by thymidine phosphorylase (TP), an enzyme which has been shown to be over expressed in colorectal tumors. This selective tumor activation has been demonstrated to lead to higher concentrations of 5-FU in tumor cells as compared to normal tissue, suggesting tumor targeting by the oral drug. Capecitabine was initially approved by the FDA for treatment of refractory breast carcinoma and has shown activity in metastatic colorectal carcinoma. Capecitabine is an attractive agent for use in combination chemotherapy due to its non-overlapping toxicity profile with many agents and lack of hematologic toxicity.

Gemcitabine has been combined with 5-FU, and may enhance the activity of 5-FU in vivo. Gemcitabine is an inhibitor of ribonucleotide reductase, an enzyme needed for synthesis of deoxynucleotides, and 5-FU interferes with dTTP synthesis by inhibition of thymidylate synthase (TS). It is plausible that concomitant administration of gemcitabine and capecitabine, may result in increased cytotoxicity by reducing intracellular dTTP thru two different mechanisms, thereby inhibiting DNA replication and repair. Platinum compounds lead to cell death by forming DNA adducts and causing double strand breaks. By inhibiting DNA synthesis and repair, both gemcitabine and 5-FU analogues could potentiate the activity of carboplatin. These interactions may underlie the clinical synergism that has been observed with platinum/5-FU and platinum/gemcitabine combinations.

We propose to combine carboplatin, gemcitabine and capecitabine as a palliative treatment for patients with CUP. Programs evaluating the incorporation of newer chemotherapy agents into combinations are reasonable in an attempt to improve outcome in patients with CUP. In addition to anticipated anti-tumor activity, the proposed combination provides a convenient schedule of brief intravenous treatment, the use of the oral agent capecitabine, and a toxicity profile which is expected to be mild, characteristics which are important in palliative treatment programs.