The VESPER phase III trial answers some key questions regarding the optimal management of muscle-invasive bladder cancer. The study found that the neoadjuvant regimen of dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (dd-MVAC) was superior to standard gemcitabine/cisplatin in extending progression-free survival and time to disease progression, with a strong suggestion that there will be an overall survival benefit for this regimen as well. Furthermore, six cycles of dd-MVAC appears to be the optimal neoadjuvant regimen. The data were presented during the European Society for Medical Oncology (ESMO) Congress 2021.¹

“The VESPER trial is a milestone in the history of chemotherapy for muscle-invasive bladder cancer. The dd-MVAC regimen should now become the gold standard for neoadjuvant chemotherapy because of higher local control and significant improvement in 3-year progression-free survival,” said lead author Christian Pfister, MD, of Charles Nicolle–Rouen University Hospital, France. “Final data on overall survival are expected to confirm these results and will affect the design of future trials with optimal chemotherapy and immunotherapy.”

The standard of care for muscle-invasive bladder cancer remains radical cystectomy and perioperative chemotherapy. Level 1 evidence supports neoadjuvant therapy over adjuvant therapy. Cisplatin-based chemotherapy is the only regimen to show an improvement in overall survival at present.

In clinical practice, dd-MVAC and gemcitabine/cisplatin are used, but this is based on retrospective or phase II trials. No randomized trial has compared these regimens until VESPER, and the optimal regimen remains to be defined. “The challenge has been to find less toxic chemotherapy for neoadjuvant treatment,” Dr. Pfister explained.

Study Details

VESPER was a randomized phase III study enrolling patients who require chemotherapy before or after surgery for muscle-invasive bladder cancer. The study was conducted at 28 centers in France. Patients with stage T2 nonmetastatic muscle-invasive bladder cancer were assigned to neoadjuvant therapy (n = 437, 88%). Those with stage T2 and a positive lymph node received adjuvant therapy (n = 56, 12%). The experimental arm received six cycles of dd-MVAC given every 2 weeks. The control arm received a standard six cycles of gemcitabine/cisplatin every 3 weeks.

The intention-to-treat arm consisted of 493 patients (who received perioperative therapy). The primary endpoint was progression-free survival at 3 years. In the neoadjuvant group, 60% received the planned six cycles of dd-MVAC, and 84% received four cycles of gemcitabine/cisplatin. The dd-MVAC regimen was given as methotrexate at 30 mg/m² on day 1, vinblastine at 3 mg/m² on day 2, doxorubicin at 30 mg/m² on day 2, and cisplatin at 70 mg/m² on day 2 plus granulocyte colony-stimulating factor support. Gemcitabine/cisplatin was given as gemcitabine at 1,250 mg/m² on days 1 and 8 and cisplatin at 70 mg/m² on day 1. About 90% of patients underwent radical cystectomy.

“Organ-confined response was observed more frequently in the dd-MVAC arm,” Dr. Pfister reported—77% vs 66%, respectively.

For the primary endpoint in the perioperative analysis, 3-year progression-free survival was improved by 34% in the dd-MVAC arm: 64% vs 56% (P = .077).Focusing on the neoadjuvant group, 3-year progression-free survival was improved by 30% in the dd-MVAC arm: 66% vs 56%, respectively (P = .025).

In the perioperative analysis, time to disease progression was significantly improved by 32% with dd-MVAC (P = .014). In the neoadjuvant analysis, a 35% improvement in the time to disease progression was found for dd-MVAC compared with gemcitabine/cisplatin (P = .005).

At 40-month follow-up, survival remained immature but was numerically in favor of dd-MVAC over gemcitabine/cisplatin in both the perioperative analysis and the neoadjuvant group. A final survival analysis will be performed at 5 years of follow-up. 

DISCLOSURE: Dr. Pfister reported no conflicts of interest.

REFERENCE

1. Pfister C, Gravis G, Flechon A, et al: Dose-dense methotrexate, vinblastine, doxorubicin and cisplatin (dd-MVAC) or gemcitabine and cisplatin (GC) as perioperative chemotherapy for patients with muscle-invasive bladder cancer. ESMO Congress 2021. Abstract 652O. Presented September 17, 2021.