Dose-Dense Methotrexate, Vinblastine, Doxorubicin, and Cisplatin or Gemcitabine and Cisplatin as Perioperative Chemotherapy for Patients With Nonmetastatic Muscle-Invasive Bladder Cancer: Results of the GETUG-AFU V05 VESPER Trial

J Clin Oncol. 2022 Jun 20;40(18):2013-2022. doi: 10.1200/JCO.21.02051. Epub 2022 Mar 7.


Purpose: The optimal perioperative chemotherapy regimen for patients with nonmetastatic muscle-invasive bladder cancer is not defined.

Patients and methods: Between February 2013 and March 2018, 500 patients were randomly assigned in 28 French centers and received either six cycles of dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (dd-MVAC) once every 2 weeks or four cycles of gemcitabine and cisplatin (GC) once every 3 weeks before surgery (neoadjuvant group) or after surgery (adjuvant group). We report the primary end point of the GETUG-AFU V05 VESPER trial ( identifier: NCT01812369): progression-free survival (PFS) at 3 years. Secondary end points were time to progression and overall survival.

Results: Four hundred thirty-seven patients (88%) received neoadjuvant chemotherapy; 60% of patients received the planned six cycles in the dd-MVAC arm, 84% received four cycles in the GC arm, and thereafter, 91% and 90% of patients underwent surgery, respectively. Organ-confined response (< ypT3N0) was observed more frequently in the dd-MVAC arm (77% v 63%, P = .001). In the adjuvant group, 40% of patients received six cycles in the dd-MVAC arm, and 81% of patients received four cycles in the GC arm. For all patients in the clinical trial, 3-year PFS was improved in the dd-MVAC arm, but the study did not meet its primary end point (3-year rate: 64% v 56%, hazard ratio [HR] = 0.77 [95% CI, 0.57 to 1.02], P = .066); nevertheless, the dd-MVAC arm was associated with a significantly longer time to progression (3-year rate: 69% v 58%, HR = 0.68 [95% CI, 0.50 to 0.93], P = .014). In the neoadjuvant group, PFS at 3 years was significantly higher in the dd-MVAC arm (66% v 56%, HR = 0.70 [95% CI, 0.51 to 0.96], P = .025).

Conclusion: In the VESPER trial, dd-MVAC improved 3-years PFS over GC. In the neoadjuvant group, a better bladder tumor local control and a significant improvement in 3-year PFS were observed in the dd-MVAC arm.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Carcinoma, Transitional Cell* / drug therapy
  • Cisplatin / adverse effects
  • Deoxycytidine / analogs & derivatives
  • Doxorubicin / adverse effects
  • Gemcitabine
  • Humans
  • Methotrexate / adverse effects
  • Muscles
  • Neoadjuvant Therapy
  • Urinary Bladder Neoplasms* / drug therapy
  • Urinary Bladder Neoplasms* / pathology
  • Urinary Bladder Neoplasms* / surgery
  • Vinblastine / adverse effects


  • Deoxycytidine
  • Vinblastine
  • Doxorubicin
  • Cisplatin
  • Methotrexate
  • Gemcitabine

Associated data