Gemcitabine/Capecitabine Combination Shows Modest Activity in Patients With Metastatic Renal Cell Carcinoma

LONDON-A combination regimenof gemcitabine (Gemzar) and capecitabine(Xeloda) shows modest activity inpatients with metastatic renal cell carcinomarefractory to immunotherapy. Arecent phase II trial suggests that the combinationis associated with manageabletoxicity, and that it is easily administered.Justin Waters, MD, Royal Marsden Hospital,London, England, reported thesefindings (ASCO abstract 1549)."The response rate is similar to thatproduced by the combination of infused5-FU and gemcitabine, but without theneed for an indwelling intravenous catheter,"Dr. Waters said. "The regimen isreasonably tolerated, the major grade 3/4toxicity being myelosuppression. Howevermild nonhematologic toxicity wascommon and dose reductions and delayswere frequently required."Two-thirds of patients with renal cellcarcinoma develop metastatic disease,with a median survival time from the developmentof metastases of less than 1year. "Standard first-line therapy for metastaticdisease is immunotherapy with interferon-alpha 2a or interleukin-2, producingresponse rates of 10% to 20%," Dr.Waters said."Chemoimmunotherapy with combinationsof fluorouracil (5-FU), interfer-on-alpha 2a (IFN-α) and interleukin-2(IL-2) appears to increase response ratesto between 20% and 39%. Single-agentchemotherapy has generally produced responserates below 10%, and there is currentlyno standard second-line therapyfollowing failure of immunotherapy," headded.Testing CombinationsOne combination that has been testedfollowing immunotherapy failure is gemcitabineplus 5-FU. This combination hasachieved a 17% response in patients withmetastatic renal cell carcinoma. Administrationof this regimen, however, requiresan indwelling IV catheter and ambulatoryinfusion pump.Gemcitabine is a fluorine-substitutedcytarabine analogue with broad experimentalantitumor activity. Phase II trialsof single-agent gemcitabine have producedresponse rates of 6% to 9% inmetastatic renal cell carcinoma. A phaseII trial of the combination of continuousinfusion 5-FU and gemcitabine demonstrateda response rate of 17%.In testing an alternative combination,Dr. Waters considered the potential advantagesof substituting capecitabine for5-FU. "Preclinical models have demonstrateda synergistic activity of gemcitabineand capecitabine in breast and coloncancer cell lines," he said. "In addition, inphase I trials, full single-agent doses ofthe two drugs appear to be tolerated incombination, with myelosuppression andmucositis reported as dose-limiting toxicities,"he said.Substitution Does NotCompromise Activity"Capecitabine has been substituted for5-FU in a chemoimmunotherapy regimenincorporating IFN-α, IL-2, and 13-cis-retinoic acid without compromisingactivity (overall response rate 34%)," Dr.Waters added.Twenty-one patients with metastaticrenal cell carcinoma (median age, 57 years)received gemcitabine 1,200 mg/m² on days1 and 8 plus capecitabine 1,300 mg/m² pobid for 14 days every 3 weeks. The study isdesigned as a single-center, open-label,phase II trial. A two-stage Gehan designwas used with the aim of rejecting a responserate lower than 20%.The primary objective of the studywas to determine the response rate togemcitabine and capecitabine in patientswith metastatic renal cell carcinoma whohave progressed following immunotherapyor are unsuitable for immunotherapy.The secondary objectives were to characterizethe adverse effects of thischemotherapy combination in this patientpopulation, and to determine thetime to disease progression, overall survivalduration, and duration of response.Eligible patients must have: histologicallyconfirmed metastatic renal cell carcinoma;measurable disease outside previouslyirradiated areas; performancestatus 0 to 2; adequate bone marrow, renaland hepatic function; and no priortreatment with gemcitabine, capecitabine,or 5-FU infusion.Responses and ToxicitiesThe overall response rate was 20%.No patients experienced complete response,but four patients (20%) had partialresponses and 10 patients (50%) hadstable disease. Progressive disease occurredin six patients (30%). The medianoverall survival was 12 months, and medianprogression-free survival was 6.7months.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%). Threepatients had thromboembolic events duringtherapy. Dose reductions/delays wererequired in 49 (29%) of cycles."The combination of gemcitabine andcapecitabine proved reasonably well toleratedand demonstrated activity in metastaticrenal cancer," Dr. Waters concluded."Potential future directions mightinclude combination with targeted agents,or further exploration of the concept ofintratumoral chemotherapy activation."