Multicenter Prospective Phase II Trial of Neoadjuvant Dose-Dense Gemcitabine Plus Cisplatin in Patients With Muscle-Invasive Bladder Cancer

Abstract

Purpose Neoadjuvant chemotherapy followed by radical cystectomy (RC) is a standard of care for the management of muscle-invasive bladder cancer (MIBC). Dose-dense cisplatin-based regimens have yielded favorable outcomes compared with standard-dose chemotherapy, yet the optimal neoadjuvant regimen remains undefined. We assessed the efficacy and tolerability of six cycles of neoadjuvant dose-dense gemcitabine and cisplatin (ddGC) in patients with MIBC. Patients and Methods In this prospective, multicenter phase II study, patients received ddGC (gemcitabine 2,500 mg/m on day 1 and cisplatin 35 mg/m on days 1 and 2) every 2 weeks for 6 cycles followed by RC. The primary end point was pathologic downstaging to non-muscle-invasive disease (< pT2N0). Patients who did not undergo RC were deemed nonresponders. Pretreatment tumors underwent next-generation sequencing to identify predictors of chemosensitivity. Results Forty-nine patients were enrolled from three institutions. The primary end point was met, with 57% of 46 evaluable patients downstaged to < pT2N0. Pathologic response correlated with improved recurrence-free survival and overall survival. Nineteen patients (39%) required toxicity-related dose modifications. Sixty-seven percent of patients completed all six planned cycles. No patient failed to undergo RC as a result of chemotherapy-associated toxicities. The most frequent treatment-related toxicity was anemia (12%; grade 3). The presence of a presumed deleterious DNA damage response (DDR) gene alteration was associated with chemosensitivity (positive predictive value for < pT2N0 [89%]). No patient with a deleterious DDR gene alteration has experienced recurrence at a median follow-up of 2 years. Conclusion Six cycles of ddGC is an active, well-tolerated neoadjuvant regimen for the treatment of patients with MIBC. The presence of a putative deleterious DDR gene alteration in pretreatment tumor tissue strongly predicted for chemosensitivity, durable response, and superior long-term survival.

Efficacy of Split Schedule Versus Conventional Schedule Neoadjuvant Cisplatin-Based Chemotherapy for Muscle-Invasive Bladder Cancer

“…Complete pathologic response rates observed with split schedule cisplatin in this study (17.5%) are similar to those in a recent multicenter, prospective trial of dose-dense GC (15%) in which patients received gemcitabine 2,500 mg/m 2 on day 1 and cisplatin 35 mg/m 2 on days 1 and 2 every 2 weeks [7]. However, these response rates should be viewed within the context of historical response rates from transurethral resection alone with immediate cystectomy (15%) [2], ddMVAC using CS cisplatin (26%-43%) [8], and from neoadjuvant immunotherapy (29%-32%) [9,10].…”

Predictive biomarkers for drug response in bladder cancer

“…The overall survival rate after radical cystectomy with NAC in patients with ERCC2 mutations was significantly better than in those without mutations. In the other prospective trial of NAC with dose‐dense gemcitabine plus CDDP in patients with MIBC, ERCC2 missense mutations were also identified most commonly among DDR‐related genes in responders ( n = 4/21), but in none of the non‐responders ( n = 0/11) . Of interest, ERCC2 missense mutations were significantly enriched in primary MIBCs, as well compared with secondary MIBCs, which progress from NMIBCs and are more resistant to NAC than primary MIBCs .…”

“…In the other prospective trial of NAC with dose-dense gemcitabine plus CDDP in patients with MIBC, ERCC2 missense mutations were also identified most commonly among DDR-related genes in responders (n = 4/21), but in none of the non-responders (n = 0/11). 45 Of interest, ERCC2 missense mutations were significantly enriched in primary MIBCs, as well compared with secondary MIBCs, which progress from NMIBCs and are more resistant to NAC than primary MIBCs. 43 Those results corroborated the usefulness of ERCC2 mutations as a biomarker for response to CDDP-based chemotherapy.…”

“…A total of 47 out of 100 patients harbored alterations in the 34 DDR‐related genes, and had improved progression‐free survival (9.3 vs 6.0 months) and overall survival (23.7 vs 13.0 months). The Memorial Sloan Kettering‐Integrated Molecular Profiling of Actionable Cancer Targets was also implemented in the aforementioned multicenter prospective trial of NAC with dose‐dense gemcitabine plus CDDP for MIBC . Deleterious DDR gene alterations were identified in nine patients, eight of which showed the pathological response of <pT2 at cystectomy.…”

“…The Memorial Sloan Kettering-Integrated Molecular Profiling of Actionable Cancer Targets was also implemented in the aforementioned multicenter prospective trial of NAC with dose-dense gemcitabine plus CDDP for MIBC. 45 Deleterious DDR gene alterations were identified in nine patients, eight of which showed the pathological response of <pT2 at cystectomy.…”