Gemcitabine, Cisplatin, and Sunitinib for Metastatic Urothelial Carcinoma and as Preoperative Therapy for Muscle-Invasive Bladder Cancer

Parallel trials in advanced disease and neoadjuvant settings are attractive for accelerating drug development in bladder cancer. However, the combination of gemcitabine and cisplatin plus sunitinib was poorly tolerated in both settings, which highlighted the difficulties in combining targeted therapies with cytotoxic agents. Background: Data support chemotherapy combined with antiangiogenic therapy in metastatic urothelial cancer (mUC) and muscle-invasive bladder cancer (MIBC). We investigated the efficacy and safety of gemcitabine, cisplatin, and sunitinib (GCS) in mUC and MIBC in parallel phase II trials. Patients and Methods: Trial 1 enrolled 36 patients with mUC who were chemotherapy naive; trial 2 enrolled 9 patients with MIBC. The primary endpoints for trials 1 and 2 were response rate and pathologic complete response, respectively. GCS was given as first-line treatment for patients with mUC and as neoadjuvant therapy for patients with MIBC. The Simon minimax 2-stage design was used for an objective response rate in trial 1 and for the pathologic complete response rate in trial 2. Results: The initial trial 1 GCS dose was gemcitabine 1000 mg/m(2) intravenously, days 1 and 8; cisplatin 70 mg/m2 intravenously, day 1; and sunitinib 37.5 mg orally daily, days 1 to 14 of a 21-day cycle. These doses proved intolerable. The doses of gemcitabine and cisplatin were subsequently reduced to 800 and 60 mg/m2, respectively, without an improvement in drug delivery, and the trial was closed. This lower-dose regimen was applied in trial 2, which was stopped early due to excess toxicity. Grade 3 to 4 hematologic toxicities occurred in 70% (23/33) of patients in trial 1 and 22% (2/9) of patients in trial 2. In trial 1, the response rate was 49% (95% CI, 31%-67%); in trial 2, the pathologic complete response was 22% (2/9). Due to early closure secondary to toxicity, the sample sizes of both trials were small. Conclusions: Delivery of GCS was hampered by excessive toxicity in both advanced and neoadjuvant settings. (C) 2013 Elsevier Inc. All rights reserved.