Gemcitabine chemotherapy for the treatment of metastatic bladder carcinoma

What’s known on the subject? and What does the study add? Metastatic bladder cancer is a devastating disease that often proves fatal. Systemic chemotherapy with MVAC (methotrexate, vinblastine, adriamycin, cisplatin) has been the first choice of treatment for many years but toxicity can be severe and overall survival poor. The search for more effective drug combinations continues. Clinical data indicate that gemcitabine has activity in this disease in terms of tumour response and overall survival. This systematic review comprehensively presents the available clinical evidence on gemcitabine chemotherapy for the management of metastatic bladder cancer. Limited data from randomized trials suggest that cisplatin plus gemcitabine may be considered a viable first-line option for this disease and that the less toxic combination of gemcitabine plus carboplatin may be suitable for patients with poor renal function or low performance status. Data from observational studies highlight the wide variation in drug combinations and schedules used and the need for a systematic approach to clinical research with gemcitabine. OBJECTIVE • To systematically review the literature on gemcitabine chemotherapy for advanced or metastatic bladder cancer. MATERIALS AND METHODS • The Medical Literature Analysis and Retrieval System Onlinedatabase (MEDLINE), the Excerpta Medicadatabase (EMBASE), the Cumulative Index to Nursing and Allied Health Literature database(CIHNAL), the Cochrane database of randomized trials, the Literatura Latino-Americana e do Caribe emCiências da Saúdedatabase (LILACS), and Web of Science were searched to identify trials of gemcitabine for metastatic bladder cancer. Also searched were international guidelines on metastatic prostate cancer, trial registries, and recent systematic reviews. Data on trial design, survival, tumour response and toxicity outcomes were extracted from relevant studies. RESULTS • This review identified six randomized trials of combined chemotherapy with gemcitabine for the management of unresectable, locally advanced or metastatic bladder cancer. • One trial compared gemcitabine plus cisplatin (GCis) with methotrexate/vinblastine/doxorubicin/cisplatin(MVAC) and found no difference in overall survival (OS; hazard ratio 1.09) but a better safety profile with GCis, which was suggested as the treatment of choice. • A second trial evaluated GCis against gemcitabine plus carboplatin (GCarbo) and reported similar median OS (12.8 vs 9.8 months), disease progression (8.3 vs 7.3 months) and tumour response rates (66% vs 56%) for the two patient groups. • A third trial compared GCis with GCis plus paclitaxel (GCisPac) and showed no significant difference in median OS (12.3 vs 15.3 months) and response rates (44% vs 43%) but greater toxicity with GCisPac. • A fourth trial assessed GCarbo against methotrexate plus carboplatin plus vinblastine in patients unfit for cisplatin-based chemotherapy and found similar tumour response rates for each regime (38% vs 20%) but the triplet regime was more toxic. • Two other randomized studies compared a 2-weekly maintenance regime of gemcitabine plus paclitaxel with a 3-weelky regime given for a maximum of six cycles and found that the maintenance schedule did not confer any additional survival benefit. • In all, 53observational studies of gemcitabine chemotherapy were identified that varied considerably in the drug combinations used and schedules. Overall response rates (17–78%) and median OS (6.4–24.0 months) were variable with no combination being clearly superior. CONCLUSIONS • Gemcitabine combined chemotherapy is active in the management of metastatic bladder cancer. • GCis may be considered an alternative regime to MVAC. • GCarbo should be considered for patients unfit for cisplatin-based therapy