Neoadjuvant Dose-dense Gemcitabine and Cisplatin in Muscle-Invasive Bladder Cancer: Results of a Phase 2 Trial

Abstract Background Accelerated (also termed dose-dense, DD) chemotherapy regimens such as accelerated methotrexate, vinblastine, doxorubicin, and cisplatin have shown better efficacy and tolerability in the metastatic setting, and shortened the time to surgery in the neoadjuvant setting compared to standard-schedule regimens. We hypothesized that a DD schedule of gemcitabine and cisplatin (GC) would shorten the time to surgery and yield similar pathologic complete response rates (pT0) in patients with muscle-invasive bladder cancer (MIBC) compared with historical controls with standard GC. Objective To determine the safety and efficacy of neoadjuvant DDGC in MIBC. Design, setting, and participants Patients with cT2–4a, N0–1, M0 MIBC were eligible and received three 14-d cycles of DDGC with pegfilgrastim support followed by radical cystectomy with lymph node dissection. The primary end point was the pT0 rate. Molecular subtypes were assigned and correlated with survival. Results and limitations Thirty-one patients were evaluable for toxicity and response, of whom 58% had baseline clinical stage >T2N0M0; the median age was 69 yr. Ten patients (32%, 95% confidence interval [CI] 16–49%) achieved ypT0N0 status at cystectomy. Another four patients (13%, 95% CI 1–25%) were downstaged to non–muscle-invasive ( Conclusions DDGC yielded a similar pT0 rate to that noted retrospectively with standard GC. Vascular events precluded, delayed, or increased the risk of surgery for 23% of patients, resulting in early closure of the study. Additional prospective studies with embedded biomarker correlatives of GC in the neoadjuvant setting are critical to accurately define both the activity and toxicity of this combination in MIBC. Patient summary Neoadjuvant chemotherapy before cystectomy is the standard of care for MIBC. This prospective phase 2 study tested a DD schedule of GC in MIBC. The study was closed early because of a higher than expected rate of vascular events. These data suggest that caution is required in using this regimen, particularly when there is better prospective evidence for the safety and efficacy of alternative regimens such as dose-dense or accelerated methotrexate, vinblastine, doxorubicin, and cisplatin. This clinical trial is registered at ClinicalTrials.gov as NCT01611662.