Association of BCG Vaccine Treatment With Death and Dementia in Patients With Non-Muscle-Invasive Bladder Cancer

Abstract

Importance: The BCG vaccine-used worldwide to prevent tuberculosis-confers multiple nonspecific beneficial effects, and intravesical BCG vaccine is currently the recommended treatment for non-muscle-invasive bladder cancer (NMIBC). Moreover, BCG vaccine has been hypothesized to reduce the risk of Alzheimer disease and related dementias (ADRD), but previous studies have been limited by sample size, study design, or analyses.

Objective: To evaluate whether intravesical BCG vaccine exposure is associated with a decreased incidence of ADRD in a cohort of patients with NMIBC while accounting for death as a competing event.

Design, setting, and participants: This cohort study was performed in patients aged 50 years or older initially diagnosed with NMIBC between May 28, 1987, and May 6, 2021, treated within the Mass General Brigham health care system. The study included a 15-year follow-up of individuals (BCG vaccine treated or controls) whose condition did not clinically progress to muscle-invasive cancer within 8 weeks and did not have an ADRD diagnosis within the first year after the NMIBC diagnosis. Data analysis was conducted from April 18, 2021, to March 28, 2023.

Main outcomes and measures: The main outcome was time to ADRD onset identified using diagnosis codes and medications. Cause-specific hazard ratios (HRs) were estimated using Cox proportional hazards regression after adjusting for confounders (age, sex, and Charlson Comorbidity Index) using inverse probability scores weighting.

Results: In this cohort study including 6467 individuals initially diagnosed with NMIBC between 1987 and 2021, 3388 patients underwent BCG vaccine treatment (mean [SD] age, 69.89 [9.28] years; 2605 [76.9%] men) and 3079 served as controls (mean [SD] age, 70.73 [10.00] years; 2176 [70.7%] men). Treatment with BCG vaccine was associated with a lower rate of ADRD (HR, 0.80; 95% CI, 0.69-0.99), with an even lower rate of ADRD in patients aged 70 years or older at the time of BCG vaccine treatment (HR, 0.74; 95% CI, 0.60-0.91). In competing risks analysis, BCG vaccine was associated with a lower risk of ADRD (5-year risk difference, -0.011; 95% CI, -0.019 to -0.003) and a decreased risk of death in patients without an earlier diagnosis of ADRD (5-year risk difference, -0.056; 95% CI, -0.075 to -0.037).

Conclusions and relevance: In this study, BCG vaccine was associated with a significantly lower rate and risk of ADRD in a cohort of patients with bladder cancer when accounting for death as a competing event. However, the risk differences varied with time.

Figure 1.. Patient Flowchart

TURBT indicates transurethral resection of bladder tumor.

Figure 2.. Overall and Stratified Alzheimer Disease and Related Dementia–Free Survival

Survival, balanced for sex, age, and Charlson Comorbidity Index score. A, Overall cohort. B, Patients younger than 70 years. C, Patients aged 70 years or older.

Figure 3.. Competing Risks Analyses of Alzheimer Disease and Related Dementias (ADRD) and Death

A, The time-invariant Cox proportional hazards regression ratios for ADRD (hazard ratio, 0.80; 95% CI, 0.69-0.99) and death (hazard ratio, 0.75; 95% CI, 0.69-0.82) and nonparametric (time-varying) cumulative hazard ratios based on weighted Aalen-Johansen estimators for ADRD and death; shaded areas of corresponding colors indicate 95% CIs. B, Overall risk difference for ADRD and death before ADRD; shaded areas of corresponding colors indicate 95% CIs. C, Stratified analyses of patients younger than 70 years; shaded areas of corresponding colors indicate 95% CIs. D, Stratified analyses of patients aged 70 years or older; shaded areas of corresponding colors indicate 95% CIs.