Prospective, randomized phase III study comparing two intensified regimens (methotrexate/vinblastine/doxorubicin hydrochloride/cisplatin [MVAC] versus gemcitabine/cisplatin) in patients with inoperable or recurrent urothelial cancer.

Abstract

4510 Background: The combinations of methotrexate, vinblastine, doxorubicin hydrochloride (Adriamycin), cisplatin (MVAC) and gemcitabine, cisplatin (GC) are standard regimens for advanced urothelial cancer. Dose-dense (DD) MVAC prolonged progression-free survival (PFS) compared to classic MVAC (Sternberg 2001). Recent data also suggested a benefit by increased gemcitabine dose density (Sternberg 2001). Methods: We initiated a phase III, randomized study of DD MVAC (M 30mg/m2, V 3mg/m2, A 30mg/m2, C 70mg/m2 q 2 wks) vs. DD GC (G 2500mg/m2, C 70mg/m2 q 2 wks) (with G-CSF). Patients with advanced transitional cell urothelial carcinoma, PS < 2 and CrCl > 50 were eligible. Accrual closed at 130 patients. This analysis also includes 61 patients who subsequently received DD MVAC, in order to increase the statistical power. Selection criteria, doses and follow-up were identical to that of the randomized study. Results: 174 eligible patients were analysed: DD MVAC (n=118) and DD GC (n=57). Groups were well balanced for baseline characteristics, although a non-significant higher frequency of PS 0 (64% vs. 46%, p=0.064) was noted in the MVAC arm. Median fup was 39 months. Efficacy results were similar (Table). Nevertheless, subgroup analysis suggested a superiority of DD GC among patients with PS 1 (Table). This interaction was significant (p=0.018 for OS and 0.083 for PFS). Grade 3/4 toxicities included myelosuppression (48% vs. 42%), neutropenic infections (12% vs. 8%), GI (15% vs. 6%), and constitutional symptoms (14% vs. 6%). Conclusions: DD GC was not superior to DD MVAC but a benefit in symptomatic patients by DD GC was suggested. DD GC is more convenient than the conventional weekly GC and could be an alternative to the existing standards for advanced urothelial cancer. Efficacy results per treatment arm overall and according to PS. DD MVAC DD GC P value Responses 47.4% 47.4% 0.9 OS (months) Median (95% CI) 18.4 (12.2-24.6) 20.7 (12.9-28.5) 0.7 HR (95% CI) PS 0 1 1.22 (0.68-2.18) 0.5 PS 1 1 0.47 (0.28-0.89) 0.018 PFS (months) Median (95% CI) 8.5 (6.6-10.4) 7.8 (6.1-9.5) 0.6 HR (95% CI) PS 0 1 1.11 (0.64-1.92) 0.7 PS 1 1 0.60 (0.35-1.03) 0.066