Evaluating surrogates for overall survival in the adjuvant treatment of bladder cancer with chemotherapy.

INTRODUCTION

Surrogates for overall survival (OS) can expedite the development of adjuvant treatments for bladder cancer. We evaluated whether disease-free survival (DFS) or distant metastasis-free survival (DMFS) are valid surrogates for OS in patients with muscle-invasive disease treated with cisplatin-based chemotherapy after radical cystectomy.

METHODS

We analyzed individual patient data from 1075 patients enrolled in 9 randomized controlled trials (RCTs) identified by systematic review. These RCTs compared adjuvant cisplatin-based chemotherapy combined with local treatment versus local treatment alone and excluded neoadjuvant chemotherapy. We measured the patient-level association between DFS/DMFS and OS using Spearman's correlation coefficient (ρ), and the trial-level association between hazard ratios (HRs) using R2. For both measures, values close to 1.00 are required for surrogate validation. We assessed the intent-to-treat (ITT) populations and subgroups defined by lymph node status.

RESULTS

The evaluation of DFS in the ITT population showed ρ = 0.89 (95% confidence interval [CI] 0.87-0.90) and R2 = 0.69 (95% CI, 0.34-1.00). Corresponding measures for DMFS were ρ = 0.91 (95% CI, 0.89-0.92) and R2 = 0.90 (95% CI, 0.74-1.00). Patient-level associations were moderate or strong regardless of the lymph node status. At the trial level, DFS displayed weak association with OS in lymph node-positive patients, but associations were strong for lymph node-negative patients and for DMFS.

CONCLUSION

In the adjuvant treatment of bladder cancer with cisplatin-based chemotherapy, DFS is a moderate to strong surrogate for OS, while DMFS is a strong surrogate for OS.