Comparison of Two Intensified Regimens in Advanced Urothelial Cancer: A Prospective, Randomized, Phase 3 Study

CHICAGO—Dose dense (DD) gemcitabine/cisplatin (GC) therapy was not superior to DD methotrexate/vinblastine/doxorubicin HCl/cisplatin (MVAC) in patients with inoperable or recurrent urothelial cancer; however, DD GC was better tolerated, results of a Phase 3 randomized trial presented at the American Society of Clinical Oncology's 2011 Annual Meeting have found.

Aristotelis Bamias, MD, of Hellenic Cooperative Oncology Group, Athens, Greece, and colleagues also reported that with the DD GC regimen, the dose intensity of gemcitabine can most likely be increased. The multicenter trial randomized 175 patients with advanced transitional cell urothelial carcinoma, performance status (PS) <2 and CrCl >50 to receive either DD MVAC (M: 30mg/m2, V: 3mg/m2, A: 30mg/m2, C: 70mg/m2 every 2 weeks) or DD GC (G: 2,500mg/m2, C: 70mg/m2 every 2 weeks), both  G-CSF.

The primary objective was overall survival and the secondary objectives were progression-free survival, toxicity, and response rate. A total of 124 patients received DD MVAC and 63 received DD GC. The initial hypothesis, based on a 1:1 randomization, was amended to a 2:1 randomization and included a single-arm, nonrandomized phase in which an additional 60 patients—including those with an ECOG PS=2—received only DD MVAC.

Groups were well balanced for baseline characteristics; however, 21.7% of patients in the DD MVAC nonrandomized group vs. 6.3% in the DD GC arm had ≥3 metastatic sites.. Median follow-up was 39 months.

The median OS for the DD MVAC group was 18.4 months [12.7–24.1] and 18.0 months [9.7–26.3] for the DD GC group (HR [95% CI]), P=0.90. The median PFS for the DD MVAC group was 8.5 [7.2–9.3] months and was 7.8 [6.4–9.2] months for the DD GC group (HR [95% CI]), P =0.48.  There was a significant interaction between PS and treatment for OS that remained significant in a multivariate analysis (wald P=0.029). This interaction was not significant for PFS.

Adverse events include the following Grade 3/4 toxicities for DD MVAC compared to DD GC, respectively: neutropenia (20% vs. 15%), anemia (12% vs. 11%), and fatigue (11% vs. 6%). There were three toxic deaths, from sepsis, in the DD MVAC arm.

Dr. Bamias and colleagues concluded that although DD GC was not superior to DD MVAC, DD GC is better tolerated. The subgroup analysis suggesting a significant interaction between PS and treatment for OS needs confirmation. DD GC is more convenient than the conventional weekly GC and could be an alternative to the existing standards for advanced urothelial cancer.