Our study aimed to determine whether delays between NAT completion and RC (the NAT-to-RC interval) influence overall survival (OS), particularly in patients receiving modern immunotherapy-based regimens. Using a single-institution cohort of 717 consecutive MIBC patients treated between 2015 and 2024, we identified 246 individuals who received NAT—either neoadjuvant chemotherapy (NAC), immunotherapy (NAI), or chemoimmunotherapy (NACI)—followed by RC with bilateral pelvic lymph-node dissection.
Median NAT-to-RC interval was 46 days (IQR 28–71). Over a median follow-up of 40 months, 43 patients (17%) died from any cause. In multivariable Cox models adjusting for pathological stage and comorbidities, every two-week increase in the NAT-to-RC interval was associated with a 6% increase in the risk of death (HR 1.06, p = 0.004). The first statistically significant cut-off emerged at 11 weeks, beyond which three-year OS dropped from 86% to 75% (adjusted HR 1.88, p = 0.048).
In the subgroup treated with NAI/NACI, the detrimental effect of delay was confirmed: a 14-week threshold was associated with more than a fourfold higher mortality risk (HR 4.27, p = 0.043), nevertheless, the number of events in this group was limited, and probably the week cut-off is very similar to the full cohort group. Taken together, these findings indicate that prolonged intervals after neoadjuvant therapy, irrespective of the regimen, are independently linked to worse survival.
Why does time matter? Several mechanisms may explain this effect. Post-treatment tumor repopulation and clonal selection of resistant subclones can occur during surgical delays, potentially increasing the risk of micrometastatic spread. In addition, treatment-related toxicity—whether chemotherapy- or immune-related—often leads to postponed surgery, which itself may identify frailer patients with poorer tolerance and outcomes. Although our analysis cannot fully disentangle these factors, the consistent association across therapeutic modalities highlights the clinical importance of performing a timely cystectomy.
The message is straightforward but highly relevant to daily practice: once neoadjuvant therapy is complete, radical cystectomy should not be delayed. In addition, we confirmed that, compared to previous data, this time-sensitive window appears to extend to modern immunotherapy combinations as well. With increasing adoption of perioperative immunotherapy trials such as the NIAGARA, understanding and adhering to optimal surgical timing will be essential to maximize benefit from systemic therapy and avoid jeopardizing long-term survival.
Future research should focus on identifying modifiable causes of delay, optimizing perioperative management after immune-related adverse events, and validating these thresholds in larger, multi-institutional cohorts. Integrating precise scheduling metrics into ongoing clinical trials could help define standardized benchmarks for “timely cystectomy” in the era of combined systemic-surgical management of MIBC.
Written by: Pietro Scilipoti,1,2 Paolo Zaurito,1,2 Mattia Longoni,1,2 Mario de Angelis,1,2 Alessandro Viti,1,2 Alfonso Santangelo,1,2 Angelo Occhi,1,2 Leonardo Quarta,1,2 Giuseppe Basile,1,2 Giovanni Tremolada,1,2 Alessandro Reale,2 Giusy Burgio,1 Giuseppe Rosiello,1 Chiara Mercinelli,1 Antonio Cigliola,1 Brigida Maiorano,1 Valentina Tateo,1 Francesco Montorsi,1,2 Andrea Salonia,1,2 Andrea Necchi,1,2 Alberto Briganti,1,2 Marco Moschini,1
- Division of Experimental Oncology/Unit of Urology, Urological Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy.
- Vita-Salute San Raffaele University, Milan, Italy.