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/m² on day 1 and cisplatin 35 mg/m² 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.

Trial registration: ClinicalTrials.gov NCT01589094.

Fig 1.

(A) Recurrence-free survival (RFS) and (B) overall survival (OS) in 46 patients who were treated with dose-dense gemcitabine and cisplatin. The dashed lines refer to 95% confidence intervals.

Fig 2.

(A) Recurrence-free survival (RFS) and (B) overall survival (OS) stratified by pathologic response (< pT2 v ≥ pT2) for 41 patients who underwent radical cystectomy (RC).

Fig 3.

(A) Onco-print showing the alterations identified in 32 pretreatment transurethral resection specimens from patients who underwent radical cystectomy (RC) –pelvic lymph node dissection after treatment with dose-dense gemcitabine and cisplatin. Samples are organized into responders or nonresponders with mutation burden displayed for each sample. (Top) Alterations within DNA damage response (DDR) genes. (Bottom) Alterations within the top 10 most frequently altered genes within this tumor cohort. (B) Two-year recurrence-free survival (RFS) in patients with or without DDR mutant tumors (DDR mut [mutant] v DDR wt [wild type]). (C) Mutation burden in responders versus nonresponders and in any patient with deleterious DDR gene alterations (Del DDR mut+) compared with those without (Del DDR mut-). Mb, megabase. (*)P < .05.