Adjuvant Chemotherapy for Muscle-invasive Bladder Cancer: A Systematic Review and Meta-analysis of Individual Participant Data from Randomised Controlled Trials

Abstract

Context: Our prior systematic review and meta-analysis of individual participant data (IPD) suggesting a benefit of adjuvant chemotherapy for muscle-invasive bladder cancer was limited by the number and size of included randomised trials. We have updated results to include additional trials, providing the most up-to-date and reliable evidence of the effects of this treatment.

Objective: To investigate the role of adjuvant cisplatin-based chemotherapy in the treatment of muscle-invasive bladder cancer.

Evidence acquisition: Published and unpublished trials were sought via searches of bibliographic databases, trials registers, conference proceedings, and hand searching. Updated IPD were centrally collected, checked, and analysed. Results from individual randomised controlled trials (RCTs) were combined using a two-stage fixed-effect model. Prespecified analyses explored any variation in effect by trial and participant characteristics.

Evidence synthesis: Analyses of ten RCTs (1183 participants) demonstrated a benefit of cisplatin-based adjuvant chemotherapy on overall survival (hazard ratio [HR] = 0.82, 95% confidence interval [CI] = 0.70-0.96, p = 0.02). This represents an absolute improvement in survival of 6% at 5 yr, from 50% to 56%, and a 9% absolute benefit when adjusted for age, sex, pT stage, and pN category (HR = 0.77, 95% CI = 0.65-0.92, p = 0.004). There was no clear evidence that the effect varied by trial or participant characteristics. Adjuvant chemotherapy was also shown to improve recurrence-free survival (HR = 0.71, 95% CI = 0.60-0.83, p < 0.001), locoregional recurrence-free survival (HR = 0.68, 95% CI = 0.55-0.85, p < 0.001), and metastasis-free survival (HR = 0.79, 95% CI = 0.65-0.95, p = 0.01), with absolute benefits of 11%, 11%, and 8%, respectively.

Conclusions: This systematic review and meta-analysis demonstrates that cisplatin-based adjuvant chemotherapy is a valid option for improving outcomes for muscle-invasive bladder cancer.

Patient summary: We looked at the effect of cisplatin-based chemotherapy on outcomes in participants with muscle-invasive bladder cancer. We gathered this information from eligible randomised controlled trials. We demonstrated that cisplatin-based chemotherapy is a valid option for improving outcomes of muscle-invasive bladder cancer.

Keywords: Bladder cancer; Chemotherapy; Individual participant data; Meta-analysis; Systematic review.

Fig. 1

(A) Forest plot and (B) Kaplan-Meier curves (nonstratified) of the effect of adjuvant chemotherapy on overall survival. In figure (A), each trial is represented by a square, the centre of which denotes the hazard ratio for that trial (comparison), with the horizontal lines showing the 95% and 99% confidence intervals (CIs). The size of the square is directly proportional to the amount of information contributed by the trial. The black diamond gives the pooled hazard ratio from the fixed-effect model; the centre of this diamond denotes the hazard ratio and the extremities of the 95% CI. Adj CT = adjuvant chemotherapy; CI = confidence interval; Haz. Ratio = hazard ratio.

Fig. 2

Effect on overall survival adjusted by age, sex, pT stage, and pN status. Adj CT = adjuvant chemotherapy; CI = confidence interval; Haz. Ratio = hazard ratio.

Fig. 3

Interactions between the effect of adjuvant chemotherapy on overall survival and age, pT, and pN. The open circles represent (fixed-effect) meta-analyses of the HRs representing the interactions between the effect of chemotherapy and participant characteristics, with the horizontal line showing the 95% CI. CI = confidence interval; HR = hazard ratio; Haz. Ratio = hazard ratio; Het: Heterogeneity.

Fig. 4

Kaplan-Meier curves (nonstratified) of the effect of adjuvant chemotherapy on (A) recurrence-free survival, (B) local recurrence-free survival, and (C) metastasis-free survival. Adj CT = adjuvant chemotherapy.