Chemotherapy for Muscle-invasive Bladder Cancer: Impact of Cisplatin Delivery on Renal Function and Local Control Rate in the Randomized Phase III VESPER (GETUG-AFU V05) Trial.

Cisplatin-based combination chemotherapy before surgery is the standard of care for muscle-invasive bladder cancer. However, the optimal chemotherapy modalities have not been precisely defined to date. In the VESPER trial, patients received after randomization either gemcitabine and cisplatin (GC, 4 cycles) or methotrexate, vinblastine, doxorubicin and cisplatin (dose dense [dd]-MVAC, 6 cycles). Creatinine clearance (CrCl) was calculated before each cycle according to the Cockroft and Gault formula. Definition criteria for local control after neoadjuvant chemotherapy included pathological complete response (ypT0N0), pathological downstaging (<ypT2N0) and organ-confined disease (<ypT3N0) at cystectomy. Baseline and treatment characteristics were studied in multivariate logistic models to determine their potential role for each type of pathological responses. A total of 2128 cycles of chemotherapy were delivered, including 2120 (99.6%) with cisplatin. Full doses of cisplatin were given in 1866 (88%) cycles. Twenty-three (4.7%) patients had to stop chemotherapy (12 GC, 11 dd-MVAC) because of renal failure. No difference in CrCl median values was observed between the 2 regimens during the first 4 cycles. A mild decrease occurred thereafter in patients treated with 2 additional cycles of dd-MVAC. A minimum total dose of 270 mg/m2 for cisplatin was mandatory to optimize pathological complete responses. At least 4 cycles of cisplatin-based chemotherapy should be delivered before cystectomy. Increasing the number of cycles beyond 4 cycles does not lead to a clinically significant deterioration in renal function but without obvious gain on local control.

Culine S ，Harter V ，Gravis G ，Fléchon A ，Chevreau C ，Mahammedi H ，Laguerre B ，Guillot A ，Joly F ，Abadie-Lacourtoisie S ，Geoffrois L ，Fiore FD ，Roubaud G ，Barthélémy P ，Voog E ，Emambux S ，Serrate C ，Saldana C ，Nguyen-Tan-Hon T ，Loriot Y ，Eymard JC ，Huillard O ，Rolland F ，Houédé N ，Spano JP ，Demery ME ，Vieillot S ，L'Haridon T ，Hilgers W ，Allory Y ，Pfister C ，VESPER Trial Investigators ... -  《-》

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 Seconda

Perioperative 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. We designed a randomized phase III trial to compare the efficacy of dd-MVAC or GC in MIBC perioperative (neoadjuvant or adjuvant) setting. A 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. The primary endpoint (progression-free survival at 3 yr) was not reported. We focused on secondary endpoints: chemotherapy toxicity and pathological responses. 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). The 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. 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.

Pfister C ，Gravis G ，Fléchon A ，Soulié M ，Guy L ，Laguerre B ，Mottet N ，Joly F ，Allory Y ，Harter V ，Culine S ，VESPER Trial Investigators ... -  《-》

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.

Pfister C ，Gravis G ，Fléchon A ，Chevreau C ，Mahammedi H ，Laguerre B ，Guillot A ，Joly F ，Soulié M ，Allory Y ，Harter V ，Culine S ，VESPER Trial Investigators ... -  《-》

Perioperative dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin in muscle-invasive bladder cancer (VESPER): survival endpoints at 5 years in an open-label, randomised, phase 3 study.

Pfister C ，Gravis G ，Flechon A ，Chevreau C ，Mahammedi H ，Laguerre B ，Guillot A ，Joly F ，Soulie M ，Allory Y ，Harter V ，Culine S ，VESPER Trial Investigators ... -  《-》

Downstaging of Muscle-Invasive Bladder Cancer Using Neoadjuvant Gemcitabine and Cisplatin or Dose-Dense Methotrexate, Vinblastine, Doxorubicin, and Cisplatin as Single Regimens or as Switch Therapy Modalities.

Consensus guidelines recommend gemcitabine and cisplatin (GC) or dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) as equally preferable neoadjuvant chemotherapy before cystectomy for muscle-invasive bladder cancer. This study sought to compare the ability of GC and ddMVAC to achieve pathologic response; and to evaluate the benefit of switching regimens after 1 or 2 cycles of the other. Patients aged ≥ 18 with muscle-invasive bladder cancer (≥ cT2) and who had received either GC or ddMVAC as neoadjuvant chemotherapy followed by cystectomy were retrospectively evaluated using the electronic medical record. Patients who received 1 or 2 cycles of one regimen followed by several cycles of the other regimen before cystectomy were classified as switch therapy patients. This study assessed the rates of pathologic complete response (pCR) and any degree of downstaging. Among 109 patients who received GC or ddMVAC, 7 (21%) of 33 ddMVAC patients demonstrated pCR, and 19 (25%) of 76 GC patients demonstrated pCR (odds ratio, 1.24; 95% confidence interval, 0.46-3.31; P = .67). Downstaging rates were 39% for ddMVAC and 50% for GC (P = .31). Thirty-three of 36 patients aged ≥ 70 years received GC (P < .001). Four of 7 patients treated with switch therapy showed downstaging, and 2 of 7 experienced pCR. There was no difference in pCR rates between GC and ddMVAC, and patients were most often able to receive 3 or 4 cycles of treatment. Switch therapy may be of benefit in patients whose disease has a poor initial response.

Ruplin AT ，Spengler AMZ ，Montgomery RB ，Wright JL ... -  《-》