Impact of timing between neoadjuvant therapy and radical cystectomy on survival in muscle-invasive bladder cancer

Abstract

Introduction: Previous studies investigated the impact of timing between neoadjuvant therapy (NAT) and radical cystectomy (RC) (NAT-to-RC interval) on overall survival (OS). However, these studies primarily focused on neoadjuvant chemotherapy (NAC), leaving the effects of neoadjuvant immunotherapy (NAI) and chemoimmunotherapy (NACI) unexplored.

Methods: We retrospectively reviewed 717 treated with RC between 2015 and 2024 at a tertiary referral center. For the purpose of the study, patients receiving either NAC, NAI, or NACI were included. Multivariable Cox regression analysis (MCR) was used to assess the association between the NAT-to-RC interval and any cause of death. MCRs models together with the Harrell's C-index, were used to test progressively increasing weekly NAT-to-RC interval cut-offs. Kaplan-Meier analysis was used to estimate OS based on the first interval threshold significantly associated with survival outcomes.

Results: Among 246 eligible patients, 110 (45%) received NAC, 101 (41%) NAI, and 35 (14%) NACI. The NAT-to-RC interval was 46 days (IQR: 28-71 days). Over a median follow-up of 40 months, 43 patients (17%) died from any cause. In MCR, longer NAT-to-RC intervals were significantly associated with reduced OS (per 2-week increase: Hazard ratio [HR] 1.06, p = 0.004). The first statistically significant cut-off was at 11 weeks (adjusted HR: 1.88, p = 0.048, C-index: 74%). Patients with an interval of 11 weeks or more (n = 53, 22%) had significantly lower 3-year OS than those with shorter intervals (86% vs. 75%, adjusted HR: 1.88, p = 0.048). Similar results were observed in the NAI/NACI subgroup with a 14-week cut-off (unadjusted HR: 4.27, p = 0.043, C-index: 59%).

Conclusion: A prolonged NAT-to-RC interval is independently associated with poorer OS, even in patients receiving NAI or NACI. An interval of 11 weeks is associated with a decline in OS, suggesting a potential time-sensitive impact of delayed RC. These findings underscore the importance of timely RC following NAT, particularly as the use of NAT strategies continues to expand.

Keywords: Bladder cancer; Immunotherapy; Muscle invasive bladder cancer; Neoadjuvant therapy; Oncological outcomes; Radical cystectomy; Timing to surgery.