Objective: To describe the risk of multiple recurrences in intermediate-risk non-muscle invasive bladder cancer (IR-NMIBC) and their impact on progression. Prognostic studies of IR-NMIBC have focused on initial recurrences, yet little is known about subsequent recurrences and their impact on progression. Materials and Methods: IR-NMIBC patients from the Be-Well Study, a prospective cohort study of NMIBC patients diagnosed from 2015 to 2019 at Kaiser Permanente Northern California, were identified. The frequency of first, second, and third intravesical recurrences of urothelial carcinoma were characterized using conditional Kaplan-Meier analyses and random-effects shared-frailty models. The association of multiple recurrences with progression was examined. Results: In 291 patients with IR-NMIBC (median follow-up 38 months), the 5-year risk of initial recurrence was 54.4%. After initial recurrence (n = 137), 60.1% of patients had a second recurrence by 2 years. After second recurrence (n = 70), 51.5% of patients had a third recurrence by 3 years. In multivariable analysis, female sex (Hazard Ratio 1.51, P< .01), increasing tumor size (HR 1.14, P< .01) and number of prior recurrences (HR 1.24, P< .01) were associated with multiple recurrences; whereas maintenance BCG (HR 0.66, P = .03) was associated with reduced recurrences. The 5-year risk of progression varied significantly (P< .01) by number of recurrences: 9.5%, 21.9%, and 37.9% for patients with 1, 2, and 3+ recurrences, respectively. Conclusions: Multiple recurrences are common in IR-NMIBC and are associated with progression. Female sex, larger tumors, number of prior recurrences, and lack of maintenance BCG were associated with multiple recurrences. Multiple recurrences may prove useful as a clinical trial endpoint for IR-NMIBC.
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