Time to progression is the main predictor of survival in patients with high-risk nonmuscle invasive bladder cancer: Results from a machine learning-based analysis of a large multi-institutional database

• Published in: Urologic oncology 2024-03, Vol.42 (3), p.69.e17-69.e25
• Main Authors: Porreca, Annamaria, Di Nicola, Marta, Lucarelli, Giuseppe, Dorin, Vartolomei Mihai, Soria, Francesco, Terracciano, Daniela, Mistretta, Francesco Alessandro, Luzzago, Stefano, Buonerba, Carlo, Cantiello, Francesco, Mari, Andrea, Minervini, Andrea, Veccia, Alessandro, Antonelli, Alessandro, Musi, Gennaro, Hurle, Rodolfo, Busetto, Gian Maria, Del Giudice, Francesco, Ferretti, Simone, Perdonà, Sisto, Prete, Paola Del, Porreca, Angelo, Bove, Pierluigi, Crisan, Nicolae, Russo, Giorgio Ivan, Damiano, Rocco, Amparore, Daniele, Porpiglia, Francesco, Autorino, Riccardo, Piccinelli, Mattia, Brescia, Antonio, Tătaru, Sabin Octavian, Crocetto, Felice, Giudice, Arturo Lo, de Cobelli, Ottavio, Schips, Luigi, Ferro, Matteo, Marchioni, Michele
• Format: Article
• Language: English
• Subjects: Adjuvants, Immunologic - therapeutic use; Administration, Intravesical; Bacillus of Calmette-Guerin; BCG Vaccine - therapeutic use; High risk nonmuscle invasive bladder cancer; Humans; Neoplasm Invasiveness; Neoplasm Recurrence, Local; Non-Muscle Invasive Bladder Neoplasms; Overall survival; Progression-free survival; Retrospective Studies; Surrogate endpoint; Treatment Failure; Urinary Bladder Neoplasms - surgery
• ISSN: 1078-1439; 1873-2496
• DOI: 10.1016/j.urolonc.2024.01.001

•Overall survival is the preferred main outcomes in randomized clinical trials design. However, its use is limited in case of rare events.•Time to progression and progression could be used instead of overall survival or as co-primary endpoint. The main advantages are the shorter observation time and the higher event frequency compared to mortality.•Our study showed a statistically significant correlation between progression and mortality in patients affected by high risk nonmuscle invasive bladder cancer, validating the use of this surrogate endpoint. In patients affected by high-risk nonmuscle invasive bladder cancer (HR-NMIBC) progression to muscle invasive status is considered as the main indicator of local treatment failure. We aimed to investigate the effect of progression and time to progression on overall survival (OS) and to investigate their validity as surrogate endpoints. A total of 1,510 patients from 18 different institutions treated for T1 high grade NMIBC, followed by a secondary transurethral resection and BCG intravesical instillation. We relied on random survival forest (RSF) to rank covariates based on OS prediction. Cox's regression models were used to quantify the effect of covariates on mortality. During a median follow-up of 49.0 months, 485 (32.1%) patients progressed to MIBC, while 163 (10.8%) patients died. The median time to progression was 82 (95%CI: 78.0–93.0) months. In RSF time-to-progression and age were the most predictive covariates of OS. The survival tree defined 5 groups of risk. In multivariable Cox's regression models accounting for progression status as time-dependent covariate, shorter time to progression (as continuous covariate) was associated with longer OS (HR: 9.0, 95%CI: 3.0–6.7; P < 0.001). Virtually same results after time to progression stratification (time to progression ≥10.5 months as reference). Time to progression is the main predictor of OS in patients with high risk NMIBC treated with BCG and might be considered a coprimary endpoint. In addition, models including time to progression could be considered for patients’ stratification in clinical practice and at the time of clinical trials design.