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 (<pT2N0) disease. Most patients (54.8%) experienced only grade 1–2 treatment-related toxicities. However, seven patients (23%) had clinically significant vascular events, leading to early closure of the study. Thirty patients (94%) underwent cystectomy. The median time from the start of chemotherapy to cystectomy was 9.3 wk. There was no correlation between molecular subtypes and survival. 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 muscle-invasive bladder cancer (MIBC). This prospective phase 2 study tested a dose-dense schedule of gemcitabine and cisplatin 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.

Adverse Events During Neoadjuvant Chemotherapy for Muscle Invasive Bladder Cancer

“…Correlation between NAC related AEs and dosing are conflicting [11,17]. While Iyer et al found 6 cycles of CG to be safe, Anari et al had to close their study early due to higher than suspected rate of serious vascular events [11,20]. These were both relatively small phase II studies evaluating efficacy and safety.…”

“…In the study by Iyer et al dose adjustment were necessary for 39% of patients and 67% of patients received the chemotherapy as planned [11]. In the study by Anari et al 23% of patients suffered from serious vascular event during NAC, but 94% of the patients were fit for RC showing that even after grade IV complication surgery can be performed in most cases [20]. In Finland, either three or four cycles of CG within three or four week interval is normally given.…”

Predictive biomarkers for drug response in bladder cancer

“…Predictive biomarkers reported so far for CDDP sensitivity in bladder cancer have not been consistent among studies, potentially because of the reliance on small cohorts, retrospective or post-hoc analyses, the difference in chemotherapy regimens, outcome measurements and sequencing techniques, consequently producing conflicting results. 19,46,55 Several prospective clinical trials are underway that will attempt to validate the DDR genes as biomarkers. In addition, the fullyaccrued SWOG S1314 study was a randomized controlled phase II trial assigning patients with MIBC to dose-dense MVAC or gemcitabine plus CDDP in a neoadjuvant setting before cystectomy.…”

Increasing Rates of Perioperative Chemotherapy are Associated With Improved Survival in Men With Urothelial Bladder Cancer With Prostatic Stromal Invasion

“…Taken together, our findings should sensitize the urologic community to the importance of considering and providing CHT in patients with pT4a UCUB, ideally using the most modern criteria that do not rely on a specific chronologic age cutoff and do provide flexibility 23 with respect to other classic exclusion criteria, such as GFR. 24,25 Finally, to the best of our knowledge, our study represents the first report that clearly shows a survival benefit of CHT in men with UCUB with prostatic stromal invasion (pT4a) treated with radical cystectomy in a contemporary population-based cohort.…”