Randomized Phase III Trial of Dose-dense Methotrexate, Vinblastine, Doxorubicin, and Cisplatin, or Gemcitabine and Cisplatin as Perioperative Chemotherapy for Patients with Muscle-invasive Bladder Cancer. Analysis of the GETUG/AFU V05 VESPER Trial Secondary Endpoints: Chemotherapy Toxicity and Pathological Responses.

backgroundPerioperative chemotherapy (neoadjuvant or adjuvant) has been developed to increase overall survival for nonmetastatic muscle-invasive bladder cancer (MIBC). Retrospective studies or prospective phase II trials have been reported to use dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (dd-MVAC) or gemcitabine and cisplatin (GC). As dd-MVAC has shown higher response rates in metastatic disease, better efficacy is expected in the perioperative setting.

objectiveWe designed a randomized phase III trial to compare the efficacy of dd-MVAC or GC in MIBC perioperative (neoadjuvant or adjuvant) setting. DESIGN, SETTING AND

participantsA total of 500 patients were randomized from February 2013 to March 2018 in 28 centers and received either six cycles of dd-MVAC every 2 wk or four cycles of GC every 3 wk. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint (progression-free survival at 3 yr) was not reported. We focused on secondary endpoints: chemotherapy toxicity and pathological responses. RESULTS AND LIMITATIONS: In the neoadjuvant group, 218 patients received dd-MVAC and 219 received GC. Of the patients, 60% received six cycles in the dd-MVAC arm and 84% received four cycles in the GC arm; 199 (91%) and 198 (90%) patients underwent surgery, respectively. Complete pathological response (ypT0pN0) was observed in 84 (42%) and 71 (36%) patients, respectively (p=0.2). An organ-confined status (<ypT3pN0) was obtained in 154 (77%) and 124 (63%) patients, respectively (p=0.001). In the adjuvant group, 40% of patients received six cycles in the dd-MVAC arm and 60% received four cycles in the GC arm. Most of Common Terminology Criteria for Adverse Events (CTCAE) grade ≥3 toxicities concerned hematological toxicities, reported for 129 (52%) patients in the dd-MVAC group and 134 (55%) patients in the GC group. Gastrointestinal (GI) grade ≥3 disorders were more frequently observed in the dd-MVAC arm (p=0.003), as well as asthenia of grade ≥3 (p<0.001).

conclusionsThe toxicity of dd-MVAC was manageable with more severe asthenia and GI side effects than that of GC in perioperative chemotherapy. A higher local control rate (complete pathological response, tumor downstaging, or organ confined) was observed in the dd-MVAC arm (p=0.021). However, such data have to be confirmed on progression-free survival, with primary endpoint data expected in mid-2021. PATIENT SUMMARY: The authors have designed a randomized phase III controlled study comparing the efficacy of gemcitabine and cisplatin, and dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (dd-MVAC) in patients for whom chemotherapy has been decided, before or after radical cystectomy. Higher toxicity regarding asthenia and gastrointestinal side effects along with a better bladder control rate were observed in the dd-MVAC arm. However, such data have to be confirmed on progression-free survival, with primary endpoint data expected in mid-2021.