An indirect assessment of individual-level association between disease-free survival (DFS) and overall survival (OS) for resectable esophageal or gastroesophageal junction cancer (EC/GEJC): A pooled analysis of randomized controlled trials (RCTs) by an illness-death model.

Abstract

369 Background: Validation of intermediate endpoints such as DFS as surrogates for overall survival (OS) in RCTs at individual-level remains as a challenge due to difficulty of collection of individual-level patient data. This study explores the individual-level correlation between DFS and OS indirectly using reconstructed Kaplan-Meier (KM) curves from the RCTs assessing therapies for (neo)adjuvant and perioperative treatment of EC/GEJC. Methods: An illness-death model previously validated in estimating individual-level association between DFS and OS for four correlation meta-analyses, two of which were published by the GASTRIC group, in early and late stage treatment of gastric cancer was employed. Reconstructed DFS and OS data from 25 RCTs published between 1994 - 2020 was pooled separately for each arm and each endpoint. Pooled data was analyzed to estimate the correlation between DFS and OS, as measured by Pearson’s r, Spearman’s rho, and Kendall’s tau. Predictive accuracy of the approach was evaluated by comparing its OS and restricted mean survival time (RMST) predictions to their counterparts obtained from the reported OS data from the RCTs. Sensitivity of correlation measures were assessed with respect to pre-specified variations in pre-recurrence death probability, post-recurrence mortality rate, and choice of the survival model used to extrapolate reported DFS curves from the RCTs. Results: Across all RCTs, the primary cancers covered were EC (n=13), EC/GEJC(n=9), GEJC (n=2) and GEJC/gastric cancer (n=1). According to the histology, 10 RCTs studied only squamous cell carcinoma (SCC) and 9 RCTs studied only adenocarcinoma (AC) of the disease, whereas the remaining 6 RCTs included varying mixtures of SCC and AC patients. The follow-up duration ranged between 27 and 72 months across RCTs. Comparator and intervention arms of the pooled data had 2499 and 2490 patients, respectively. Predicted Pearson’s r, Spearman’s rho, Kendall’s tau were 0.67, 0.79, and 0.70, respectively with negligibly narrow 95% CIs. Across both arms of the pooled data, on average, predicted OS curves laid within the 95% CIs of the pooled OS KM-curves 92% of the time. Average deviation between the RMSTs under the model-predicted OS curves and pooled OS KM curves was 2%. In sensitivity analyses, the ranges for r, r, and t were (0.56-0.88), (0.69-0.89), and (0.61-0.80), respectively. Conclusions: Results indicate moderate-to-strong correlation between DFS and OS in early-stage treatment of EC/GEJC providing supportive evidence for the validation of DFS as a surrogate for OS. Our approach mitigates the lack of patient level data in endpoint correlation assessment but may be prone to changes in the predicted value of pre-recurrence death probability.