Introduction:

Historically, prognostic studies of intermediate-risk non-muscle invasive bladder cancer (NMIBC) have focused on the risk of initial recurrence, yet little is known about subsequent recurrences and their impact on progression. In a prospective cohort study, we describe the full spectrum of multiple recurrences and their impact on progression for intermediate-risk NMIBC.

Methods:

Intermediate-risk patients from the Be-Well Study, a prospective cohort study of NMIBC patients diagnosed from 2015-2019 at Kaiser Permanente Northern California, were identified using the AUA NMIBC risk criteria: recurrence within 1 year among initial low grade Ta disease, over 3cm / multifocal low grade Ta at diagnosis, high grade Ta 3cm or less at diagnosis, or low grade T1 at diagnosis. The primary objective was to characterize the frequency of first, second, and third intravesical recurrences of urothelial carcinoma using conditional Kaplan-Meier analyses censored at death, disenrollment, or end of study (2020 July 7). Then, the association of multiple recurrences with progression (any grade or stage) was examined.

Results:

Out of 808 eligible patients, 291 patients with intermediate-risk NMIBC were identified (median follow-up 38 months). Patients had a 54.4% 5-year risk of recurrence. 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. These risks did not vary significantly by initial tumor grade(Figure 1). The majority of second and third recurrences occurred within 2 years of the prior recurrence. Females were more likely than males to have 2 or more recurrences(39.7% vs 19.7%, p<0.001). Neither receipt of Mitomycin C (N=125, 43%) or BCG (N=127, 44%) was associated with 2 or more recurrences (p=0.09 and p=0.87, respectively). The 5-year risk of progression was 9.4%, and this varied significantly (p<0.001) by number of recurrences: 9.5%, 21.9%, 37.9% for patients with 1, 2, and 3 or more recurrences, respectively(Figure 2).

Conclusion:

Patients with intermediate-risk NMIBC frequently have multiple recurrences, and female patients are more likely to have multiple recurrences. In turn, patients with multiple recurrences are more likely to experience grade or stage progression. Delineating the burden of multiple recurrences provides a more comprehensive understanding of the natural history of intermediate-risk NMIBC and can prove useful as a clinical trial endpoint for this understudied subgroup of bladder cancer patients.

Funding: Vidit Sharma was supported by the VA Health Services Research and Development Fellowship