Current clinical guidelines, including those of the European Association of Urology (EAU), consider a prior NMIBC tumor as a marker for increased risk of future recurrence and progression to muscle-invasive disease (MIBC) and metastatic disease (mBC).2 Consequently, they recommend intensifying treatment and surveillance after a first recurrence. However, the evidence supporting these recommendations is limited. A more nuanced understanding of the NMIBC disease course after the first recurrence is therefore essential to ensure appropriate follow-up and treatment strategies.
In our study, we described patterns and characteristics of subsequent recurrences in a contemporary, population-based cohort of 1,915 patients with NMIBC. Main findings include robust risk estimates of subsequent recurrences, a high correlation between tumor characteristics (including stage, grade, and location) of subsequent recurrences, and distinct recurrence patterns preceding progression to MIBC/mBC.
The findings of our study suggest that the prognostic impact of a recurrence is not “one-dimensional”. Regarding recurrence, we find that on a population-level, subsequent recurrences tend to develop earlier than first recurrences, which aligns with current guidelines assumptions. However, when we examined individual patients who experienced at least two recurrences, we found no difference between the time to first recurrence and time to second recurrence,5 (Supplemental Figure 8). This challenges the belief that the timing of recurrences accelerates over time.6 Instead, we think that the observation of increased recurrence risk for subsequent recurrences on a population level may be caused by limited follow-up time: only frailer individuals that develop “fast” recurrences have been recorded for subsequent recurrences within follow-up time, creating spuriously high recurrence rates for later recurrences.
Regarding progression, our results showed that a substantial part of the primary high-risk tumors directly progress to MIBC/mBC, without any NMIBC recurrence. Our results also confirmed that individuals who develop high-risk recurrence(s) face an increased risk of subsequent progression to MIBC/mBC. In contrast, individuals with low-risk recurrence(s) (e.g., stage Ta low-grade) tend to develop subsequent recurrences of similar low-risk characteristics. Notably, in our cohort, not a single primary low-risk patient progressed after experiencing Ta-low grade recurrence(s). Current risk scoring models up-classify such patients to intermediate-risk with related intensification of treatment and follow-up.2,7 In our observational study, it was not possible to discern if and to what extent the lack of stage and grade progression for primary low-risk patients was a result of this intensification. However, the data do substantiate the opportunities and need for further research into de-escalation approaches for this group of patients (see e.g. 8).
Taken together, these findings suggest that tumor status (primary or recurrent) alone is an imprecise predictor of future outcomes in NMIBC, and that the tumor characteristics of the recurrence hold meaningful prognostic information. Our results also underscore the importance of viewing NMIBC as a multiple recurrent disease, as this perspective reveals patterns that are not apparent when focusing on the first recurrence only. To advance clinical understanding and improve patient management, data on subsequent recurrences should be routinely collected and analyzed.
Written by: Jasper Hof,1 and Sita Vermeulen2
- Center for Quantitative Genetics and Genomics, Aarhus University, Aarhus, Denmark
- IQ Health Science Department, Radboud University Medical Center, Nijmegen, The Netherlands
- Ślusarczyk A, Zapała P, Zapała Ł, Borkowski T, Radziszewski P. Cancer-specific survival of patients with non-muscle-invasive bladder cancer: a population-based analysis. Annals of Surgical Oncology. 2023;30(12):7892–902.
- Sylvester RJ, Rodríguez O, Hernández V, Turturica D, Bauerová L, Bruins HM, et al. European Association of Urology (EAU) prognostic factor risk groups for non–muscle-invasive bladder cancer (NMIBC) incorporating the WHO 2004/2016 and WHO 1973 classification systems for grade: an update from the EAU NMIBC Guidelines Panel. European urology. 2021;79(4):480–8.
- Smedinga H, Steyerberg EW, Beukers W, van Klaveren D, Zwarthoff EC, Vergouwe Y. Prediction of multiple recurrent events: a comparison of extended Cox models in bladder cancer. American journal of epidemiology. 2017;186(5):612–23.
- Sharma V, Chamie K, Schoenberg M, Lee VS, Fero K, Lec P, et al. Natural history of multiple recurrences in intermediate-risk non-muscle invasive bladder cancer: lessons from a prospective cohort. Urology. 2023;173:134–41.
- Hof JP, Kiemeney LALM, Aben KKH, van der Heijden AG, Vrieling A, Vermeulen SH. Recurrence Patterns in a Large Contemporary Cohort of Patients With Non-Muscle Invasive Bladder Cancer. Clinical Genitourinary Cancer. 2026;24(1).
- Sankin A, Dave P, Cherrill L-R, Boucher RH, Zeegers MP, Cheng K, et al. Low-grade Urothelial Carcinoma Recurs at a Tempo that Naturally Accelerates Over Time. Urology. 2024;193:166–72.
- Fernandez-Gomez J, Madero R, Solsona E, Unda M, Martinez-Piñeiro L, Gonzalez M, et al. Predicting nonmuscle invasive bladder cancer recurrence and progression in patients treated with bacillus Calmette-Guerin: the CUETO scoring model. The Journal of urology. 2009;182(5):2195–203.
- Contieri R, Soloway MS, Gontero P, Herr H, Kassouf W, Mertens LS, et al. Deintensification of Treatment for Low-grade Bladder Tumors: A Collaborative Review by the International Bladder Cancer Group (IBCG). Eur Urol Oncol. 2025;8(1):179-189.