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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.

SUBMITTER: Iyer G 

PROVIDER: S-EPMC6049398 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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

Iyer Gopa G   Balar Arjun V AV   Milowsky Matthew I MI   Bochner Bernard H BH   Dalbagni Guido G   Donat S Machele SM   Herr Harry W HW   Huang William C WC   Huang William C WC   Taneja Samir S SS   Woods Michael M   Ostrovnaya Irina I   Al-Ahmadie Hikmat H   Arcila Maria E ME   Riches Jamie C JC   Meier Andreas A   Bourque Caitlin C   Shady Maha M   Won Helen H   Rose Tracy L TL   Kim William Y WY   Kania Brooke E BE   Boyd Mariel E ME   Cipolla Catharine K CK   Regazzi Ashley M AM   Delbeau Daniela D   McCoy Asia S AS   Vargas Hebert Alberto HA   Berger Michael F MF   Solit David B DB   Rosenberg Jonathan E JE   Bajorin Dean F DF  

Journal of clinical oncology : official journal of the American Society of Clinical Oncology 20180509 19


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, mul  ...[more]

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