Originally published as JCO Early Release 10.1200/JCO.2008.21.4924 on September 28 2009

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Randomized Phase II/III Trial Assessing Gemcitabine/ Carboplatin and Methotrexate/Carboplatin/Vinblastine in Patients With Advanced Urothelial Cancer "Unfit" for Cisplatin-Based Chemotherapy: Phase II—Results of EORTC Study 30986

From the Kaiser Franz Josef Hospital and Applied Cancer Research–Institution for Translational Research; Central European Anticancer Drug Development Platform; Ludwig Boltzmann-Institute for Applied Cancer Research, Vienna, Austria; Hospital Vall d'Hebrón, Barcelona, Spain; Southampton General Hospital, Southampton; St. James's University Hospital, Leeds, United Kingdom; Netherlands Cancer Institute, Amsterdam; Erasmus University Medical Center, Rotterdam, the Netherlands; University Hospital of San Pablo, Barcelona, Spain; Maria Sklodowska-Curie Memorial Cancer Centre, Warsaw, Poland; and European Organisation for Research and Treatment of Cancer Headquarters, Brussels, Belgium.

Corresponding author: Maria De Santis, MD, Kaiser Franz Josef Hospital and ACR-ITR Vienna/CEADDP and LBI-ACR Vienna-CTO, Kundratstraße 3, 1100 Vienna, Austria; e-mail: maria.desantis{at}wienkav.at.

Purpose There is no standard treatment for patients with advanced urothelial cancer who are ineligible ("unfit") for cisplatin-based chemotherapy (CHT). To compare the activity and safety of two CHT combinations in this patient group, a randomized phase II/III trial was conducted by the EORTC (European Organisation for Research and Treatment of Cancer). We report here the phase II results of the study.

Patients and Methods CHT-naïve patients with measurable disease and impaired renal function (30 mL/min < glomerular filtration rate [GFR] < 60 mL/min) and/or performance status (PS) 2 were randomly assigned to receive either GC (gemcitabine 1,000 mg/m² on days 1 and 8 and carboplatin area under the serum concentration-time curve [AUC] 4.5) for 21 days or M-CAVI (methotrexate 30 mg/m² on days 1, 15, and 22; carboplatin AUC 4.5 on day 1; and vinblastine 3 mg/m² on days 1, 15, and 22) for 28 days. End points of response and severe acute toxicity (SAT) were evaluated with respect to treatment group, renal function, PS, and Bajorin risk groups.

Results Three of 178 patients who were ineligible or did not start treatment were excluded. SAT was reported in 13.6% of patients on GC and in 23% on M-CAVI. Overall response rates were 42% (37 of 88) for GC and 30% (26 of 87) for M-CAVI. Patients with PS 2 and GFR less than 60 mL/min and patients in Bajorin risk group 2 showed a response rate of only 26% and 20% and an SAT rate of 26% and 25%, respectively.

Conclusion Both combinations are active in this group of unfit patients. However, patients with PS 2 and GFR less than 60 mL/min do not benefit from combination CHT. Alternative treatment modalities should be sought in this subgroup of poor-risk patients.

Supported by Grants No. 2U10 CA11488-28 through 5U10 CA011488-38 from the National Cancer Institute, Bethesda, MD, and by Eli Lilly Study Code B9E-MC-S018.

Presented in part at the Genitourinary Cancers Symposium of the American Society of Clinical Oncology, February 14-16, 2008, San Francisco, CA, and at the 44th Annual Meeting of the American Society of Clinical Oncology, May 30-June 3, 2008, Chicago, IL.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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