Explanatory Role of Conversion Surgery as a Mediator of the Mortality Risk Difference Between Patients With Unresectable Metastatic Colorectal Cancer Treated With First-Line Anti-EGFR Agents Versus Bevacizumab.

ABSTRACT

INTRODUCTION: Bevacizumab and antiepidermal growth factor receptor-blocking (anti-EGFR) agents plus chemotherapy are first-line therapies for metastatic colorectal cancer (mCRC). Conversion surgery may improve outcomes; however, the extent to which it explains the difference in mortality rates among treatments is unclear. Herein, we aimed to assess the effects of conversion surgery on survival outcomes of patients with unresectable mCRC treated with bevacizumab and anti-EGFR agents. MATERIALS AND METHODS: This retrospective cohort study included patients with mCRC treated with bevacizumab and anti-EGFR agents as first-line therapy. We estimated the direct and indirect effects of treatments by comparing the mortality risk associated with targeted therapy type. Hazard ratios (HR) and the corresponding confidence intervals (CI) were estimated. Mediation analysis was used to estimate hazard ratio differences, and the proportion mediated. RESULTS: A total of 5,106 patients were included. The natural indirect effect of conversion surgery reduced mortality risk (HR 0.95; 95% CI, 0.93-0.97), with a mediated proportion of 42% after propensity score adjustment. In subgroup analyses, KRAS wild-type (HR 0.94; 95% CI 0.91-0.97), left tumor sidedness (HR 0.94; 95% CI, 0.91-0.96), and liver resection (HR 0.95; 95% CI, 0.93-0.98) were associated with reduced risks of mortality. The controlled and total direct effects of targeted therapy were associated with reduced mortality risk in the anti-EGFR-treated group compared to those in the bevacizumab-treated group; however, this effect was not statistically significant. CONCLUSION: Conversion surgery may account for the difference in survival outcomes between users of the anti-EGFR agents and bevacizumab.