Multicenter prospective phase ii trial of neoadjuvant dose-dense gemcitabine plus cisplatin in patients with muscle-invasive bladder cancer

Gopa Iyer, Arjun V. Balar, Matthew I. Milowsky, Bernard H. Bochner, Guido Dalbagni, S. Machele Donat, Harry W. Herr, William C. Huang, Samir S. Taneja, Michael Woods, Irina Ostrovnaya, Hikmat Al-Ahmadie, Maria E. Arcila, Jamie C. Riches, Andreas Meier, Caitlin Bourque, Maha Shady, Helen Won, Tracy L. Rose, William Y. KimBrooke E. Kania, Mariel E. Boyd, Catharine K. Cipolla, Ashley M. Regazzi, Daniela Delbeau, Asia S. McCoy, Hebert Alberto Vargas, Michael F. Berger, David B. Solit, Jonathan E. Rosenberg, Dean F. Bajorin

Research output: Contribution to journalArticlepeer-review


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 2 on day 1 and cisplatin 35 mg/m 2 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.

Original languageEnglish (US)
Pages (from-to)1949-1956
Number of pages8
JournalJournal of Clinical Oncology
Issue number19
StatePublished - Jul 1 2018


  • Adult
  • Aged
  • Antineoplastic Combined Chemotherapy Protocols/adverse effects
  • Chemotherapy, Adjuvant
  • Cisplatin/administration & dosage
  • Cystectomy
  • Deoxycytidine/administration & dosage
  • Disease-Free Survival
  • Female
  • Filgrastim/administration & dosage
  • Humans
  • Male
  • Middle Aged
  • Neoadjuvant Therapy
  • Neoplasm Invasiveness
  • Neoplasm Recurrence, Local/diagnostic imaging
  • Neoplasm Staging
  • Polyethylene Glycols/administration & dosage
  • Prospective Studies
  • Urinary Bladder Neoplasms/diagnostic imaging

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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