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 (ClinicalTrials.gov 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.
By Dr. Francesco Del Giudice
A high level of evidence from randomized trials and meta-analyses demonstrates an absolute overall survival (OS) benefit of 5-8% for cisplatin-based neoadjuvant chemotherapy (NAC) in patients with MIBC, before radical cystectomy (RC) and pelvic lymph node dissection (PLND) [1-2].
Two regimens of cisplatin-based chemotherapy, i.e., dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (dd-MVAC) or Gemcitabine and Cisplatin (GEM-CIS) are equally supported by current guidelines, although no pair-wise comparison has been explored among the regimens, in a dedicated clinical trial.
In the present article, Pfister and colleagues [4] report on the primary endpoint from the GETUG-AFU V05 VESPER Trial; a randomized phase III-controlled study comparing the efficacy of dd-MVAC vs GEM-CIS in patients with non-metastatic MIBC for whom perioperative chemotherapy was indicated. This study is the result of a multidisciplinary effort from the French Genito-urinary Tumor Group and the Cancerology Committee of the French Association of Urology, and combines a multicentric experience among 28 French institutions, between 2013 and 2018.
Patients with cT2–T4aN0M0 urothelial carcinoma of the bladder receiving NAC as well as patients with pT3-pT4, pN1 of any pT and M0 receiving AC were included and further assessed for the primary endpoint of 3-year progression free-survival (PFS). As perioperative chemotherapy regimens, the experimental arm was 6-cycles of dd-MVAC vs. the standard of 4-cycles of GEM-CIS.
Secondary outcomes include toxicity (according to NCI Common Terminology Criteria for Adverse Events v4.0) and response rate (RR) according to RECIST 1.1 criteria in the NAC setting with pathologic responses previously reported [5].
The study did not meet the primary end point of PFS (3-year rate: 64% v 56%, HR=5 0.77 [95% CI, 0.57 to 1.02], P= 0.066); Nevertheless, given the existence of significant interaction between treatment arm and mode of administration of chemotherapy (i.e., NAC vs AC), the individual HR were separately reported. Therefore, Cox proportional hazard regression for 3-year PFS in the NAC sub-group (n=437) demonstrated longer PFS in the dd-MVAC arm (HR=0.70 [95% CI, 0.51 to 0.96], P=0.025) while there was no significant difference for the sub-group receiving AC (HR= 1.90 [0.86 to 4.19]).
Additionally, the dd-MVAC arm was associated with a significantly longer time to progression (TTP) (3-year rate: 69% vs 58%, HR= 0.68 [95% CI, 0.50 to 0.93], P=0.014). This was particularly true in the only NAC group (3-year rate: 71% vs 59%, HR=0.62 [95% CI, 0.44 to 0.85], P=0.005). The 3-years OS resulted in favor of dd-MVAC (HR= 0.74 [ 95% CI, 0.47 to 0.92]).
Finally, higher local control rate (pCR, tumour downstaging or organ-confined) was observed in the dd-MVAC arm (P=0.021) while no difference in complete pathologic response (pCR; ypT0pN0) was noted among the two arm regimens.
As per safety associated with the specific chemotherapy regimen, most of the grade ≥ 3 toxicities were hematologic, reported for 129 patients (52%) in the dd-MVAC arm and 134 (55%) patients in the GC arm, but severe anemia was most frequently observed in the dd-MVAC arm (P=0.001). Additionally, asthenia was reported for 14% of patients in the dd-MVAC arm and only 4.1% of patients in the GC arm (P=0.001), whereas GI grade ≥ 3 disorders with nausea/vomiting were observed in the dd-MVAC arm (P=0.003). Furthermore, no specific nor clinically relevant differences were detected in the short and long-term complications following RC according to both of the arm regimens.
One of the key points from the VESPER trial is the adoption of the 6-cycles dd-MVAC rather than the 4-cycles previously proposed with an acceptable safety profile. This aspect is meant to deliver an overall higher dose of cisplatin (420 mg vs 280 mg) which ultimately may be considered as the rationale for the survival benefit in perioperative chemotherapy for MIBC. Moreover, these data are particularly consistent with a NAC preference testifying for a paradigmatic shift over NAC adoption in Europe (i.e., France) and on the other hand confirm lack of adequate evidence to corroborate the efficacy profile for AC. It’s worth to underline the important effort of delivering NAC in this cohort with a 88% rate of NAC.
In conclusion, the VESPER trial did not meet its primary endpoint of identifying PFS benefit among dd-MVAC and GEM-CIS regimens in the setting of perioperative chemotherapy for MIBC undergoing RC. Nevertheless, separating the NAC from the AC population, dd-MVAC demonstrated its superiority on GEM-CIS for the PFS and TTP endpoints at 3 years in the sole NAC setting. International guidelines may be modified once the follow-up will be longer regarding the OS.
References