LONDON-A combination regimen of gemcitabine(Drug information on gemcitabine) (Gemzar) and capecitabine(Drug information on capecitabine) (Xeloda) shows modest activity in patients with metastatic renal cell carcinoma refractory to immunotherapy. A recent phase II trial suggests that the combination is associated with manageable toxicity, and that it is easily administered. Justin Waters, MD, Royal Marsden Hospital, London, England, reported these findings (ASCO abstract 1549). "The response rate is similar to that produced by the combination of infused 5-FU and gemcitabine, but without the need for an indwelling intravenous catheter," Dr. Waters said. "The regimen is reasonably tolerated, the major grade 3/4 toxicity being myelosuppression. However mild nonhematologic toxicity was common and dose reductions and delays were frequently required." Two-thirds of patients with renal cell carcinoma develop metastatic disease, with a median survival time from the development of metastases of less than 1 year. "Standard first-line therapy for metastatic disease is immunotherapy with interferon- alpha 2a or interleukin-2, producing response rates of 10% to 20%," Dr. Waters said. "Chemoimmunotherapy with combinations of fluorouracil(Drug information on fluorouracil) (5-FU), interfer- on-alpha 2a (IFN-α) and interleukin-2 (IL-2) appears to increase response rates to between 20% and 39%. Single-agent chemotherapy has generally produced response rates below 10%, and there is currently no standard second-line therapy following failure of immunotherapy," he added. Testing Combinations One combination that has been tested following immunotherapy failure is gemcitabine plus 5-FU. This combination has achieved a 17% response in patients with metastatic renal cell carcinoma. Administration of this regimen, however, requires an indwelling IV catheter and ambulatory infusion pump. Gemcitabine is a fluorine-substituted cytarabine(Drug information on cytarabine) analogue with broad experimental antitumor activity. Phase II trials of single-agent gemcitabine have produced response rates of 6% to 9% in metastatic renal cell carcinoma. A phase II trial of the combination of continuous infusion 5-FU and gemcitabine demonstrated a response rate of 17%. In testing an alternative combination, Dr. Waters considered the potential advantages of substituting capecitabine for 5-FU. "Preclinical models have demonstrated a synergistic activity of gemcitabine and capecitabine in breast and colon cancer cell lines," he said. "In addition, in phase I trials, full single-agent doses of the two drugs appear to be tolerated in combination, with myelosuppression and mucositis reported as dose-limiting toxicities," he said. Substitution Does Not Compromise Activity "Capecitabine has been substituted for 5-FU in a chemoimmunotherapy regimen incorporating IFN-α, IL-2, and 13- cis-retinoic acid without compromising activity (overall response rate 34%)," Dr. Waters added. Twenty-one patients with metastatic renal cell carcinoma (median age, 57 years) received gemcitabine 1,200 mg/m2 on days 1 and 8 plus capecitabine 1,300 mg/m2 po bid for 14 days every 3 weeks. The study is designed as a single-center, open-label, phase II trial. A two-stage Gehan design was used with the aim of rejecting a response rate lower than 20%. The primary objective of the study was to determine the response rate to gemcitabine and capecitabine in patients with metastatic renal cell carcinoma who have progressed following immunotherapy or are unsuitable for immunotherapy. The secondary objectives were to characterize the adverse effects of this chemotherapy combination in this patient population, and to determine the time to disease progression, overall survival duration, and duration of response. Eligible patients must have: histologically confirmed metastatic renal cell carcinoma; measurable disease outside previously irradiated areas; performance status 0 to 2; adequate bone marrow, renal and hepatic function; and no prior treatment with gemcitabine, capecitabine, or 5-FU infusion. Responses and Toxicities The overall response rate was 20%. No patients experienced complete response, but four patients (20%) had partial responses and 10 patients (50%) had stable disease. Progressive disease occurred in six patients (30%). The median overall survival was 12 months, and median progression-free survival was 6.7 months. Grade 3/4 toxicity included lethargy (9.5% patients), vomiting (4.8%), diarrhea (14.3%), hand-foot syndrome (19.0%), rash (9.5%), anemia (9.5%), neutropenia (52.4%), thrombocytopenia (23.8%), and infection (33.3%). Three patients had thromboembolic events during therapy. Dose reductions/delays were required in 49 (29%) of cycles. "The combination of gemcitabine and capecitabine proved reasonably well tolerated and demonstrated activity in metastatic renal cancer," Dr. Waters concluded. "Potential future directions might include combination with targeted agents, or further exploration of the concept of intratumoral chemotherapy activation."