medwireNews: Neoadjuvant use of dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (dd-MVAC) is associated with a reduced mortality risk versus gemcitabine plus cisplatin in people with nonmetastatic muscle-invasive bladder cancer (MIBC), suggest phase 3 data.
At the 5-year mark, both overall survival (OS) and time to death due to bladder cancer were significantly improved in the subgroup of patients who received neoadjuvant dd-MVAC compared with those given gemcitabine plus cisplatin, report Christian Pfister (Charles Nicolle University Hospital, Rouen, France) and colleagues.
However, there was no significant improvement in OS with dd-MVAC in the intention-to-treat (ITT) population that included all patients treated in the perioperative setting, they add in The Lancet Oncology.
These results are in accordance with the primary endpoint analysis conducted at 3 years, which showed a significant improvement in progression-free survival in the neoadjuvant subgroup, but not the overall population, notes the team.
In the phase 3 study, 493 patients with nonmetastatic MIBC (ITT population) who were scheduled to receive perioperative chemotherapy were randomly assigned to receive either six cycles of dd-MVAC every 2 weeks or four cycles of gemcitabine plus cisplatin every 3 weeks in the neoadjuvant (n=437) or adjuvant (n=56) setting.
The current analysis was done at a median follow-up of 5.3 years and showed no significant difference between the dd-MVAC and control groups with respect to the 5-year OS rates in the ITT population, at 64% and 56%, respectively, and a nonsignificant hazard ratio (HR) of 0.79.
But the between-group difference was significant in the neoadjuvant subgroup, at rates of 66% versus 57%, and an HR for death of 0.71 in favor of the dd-MVAC regimen.
For the endpoint of time to death due to bladder cancer, the cumulative incidence of bladder cancer-related deaths at 5 years was significantly lower with dd-MVAC than gemcitabine–cisplatin in the ITT population and the neoadjuvant subgroup, at 27% versus 40%, and 24% versus 38%, respectively, with corresponding HRs of 0.61 and 0.55.
Pfister et al say that although the results for both outcomes “were not conclusive” in the adjuvant subgroup “due to the small sample size,” they “did not support the usefulness of the dd-MVAC protocol for these patients.”
The team believes that “[t]he results of VESPER have the potential to be practice-changing and should influence future trials of immunotherapy in bladder cancer.”
Writing in an accompanying commentary, Laura Mertens and Michiel van der Heijden – both from the Netherlands Cancer Institute in Amsterdam – congratulate the study authors on this study, saying it “offers unique, high-quality data, providing a head-to-head comparison between two commonly used regimens in clinical practice, which have previously lacked randomised trial evidence.”
But they highlight two “notable” shortcomings, the first one being that “combining neoadjuvant and adjuvant populations in the analyses complicates the results,” and the second that the use of six cycles of dd-MVAC versus four cycles of gemcitabine–cisplatin puts dd-MVAC at an advantage.
“Although the authors argue that this decision ensured an equivalent length of neoadjuvant therapy, the study design provided favourable odds for dd-MVAC, ultimately rendering it insufficient to provide indisputable evidence for either regimen (dd-MVAC vs [gemcitabine–cisplatin]) or number of cycles (six vs four),” the commentators explain.
Nevertheless, they conclude that “[g]iven the common use and the absence of other evidence for these regimens in the neoadjuvant setting, we feel the data support dd-MVAC as the preferred regimen.”
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