Evaluating Surrogate Endpoints for Adjuvant Chemotherapy of Bladder Cancer - Expert Commentary
The investigators analyzed individual patient data from 1,075 patients enrolled in 9 randomized controlled trials identified by a systematic review. These trials compared adjuvant cisplatin-based chemotherapy combined with local treatment versus local treatment alone and excluded neoadjuvant chemotherapy. The study measured the patient-level association between DFS/DMFS and OS using Spearman's correlation coefficient (r), and the trial-level association between hazard ratios using R². The strengths of association were qualified as weak if r < 0.7 or R² < 0.50, moderate if 0.7 ≤ r < 0.9 or 0.5 ≤ R² < 0.8, and strong if r > 0.9 or R² > 0.80.
The evaluation of DFS in the intent-to-treat population showed r = 0.89 (95% CI, 0.87−0.90) and R² = 0.69 (95% CI, 0.34−1.00). Corresponding measures for DMFS were r = 0.91 (95% CI, 0.89−0.92) and R² = 0.90 (95% CI, 0.74−1.00). Data were available from 1,082 patients from 9 trials, with 615 DFS events and 553 OS events across the trials. For DMFS analysis, data were available for 884 patients from 6 trials providing separate information on distant recurrence, with 474 DMFS events and 438 death events. Patient-level associations were moderate or strong regardless of lymph node status. At the trial level, DFS displayed a weak association with OS in lymph node-positive patients, but associations were strong for lymph node-negative patients and for DMFS across subgroups.
The study indicates that DFS has strong association with OS at the patient level but only a moderate association at the trial level, with predictions subject to relatively high uncertainty. Subgroup analyses suggest that DFS is a strong surrogate for OS among patients with lymph node-negative disease. For DMFS, strong patient-level and trial-level associations were observed with narrower confidence intervals. The study's limitations include nonconvergence of adjusted models, relatively small sample sizes of some trials, and limited evidence base for DMFS due to fewer trials reporting this outcome. Understanding and extending the performance of these surrogate endpoints to other adjuvant treatments, including immunotherapy.
Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine, New York City, New York
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