Reply to Qiao et al.

We extend our gratitude to Qiao et al. [1] for their insightful comments on our article [2], and we are more than pleased to provide further clarification. We appreciate Qiao et al. for the potential type I error they mentioned in multiple comparisons. We conducted these comparisons to demonstrate the heterogeneity of clinical features between early-onset and late-onset patients, while the noninferiority findings of treatment outcome were based on the survival analyses of age-onset subgroups, which would be less susceptible to the multiple comparisons of clinical features. Therefore, we concluded that neoadjuvant chemotherapy is non-inferior to chemoradiotherapy for both early-onset and late-onset patients. We acknowledge that a type II error might occur when the age-onset subgroups with limited sample sizes were compared in the survival analyses, which might impair the statistical power.

The other limitation derived from the post-hoc analyses, as we stated in the article and Qiao et al’s comment, is the imbalance between intervention and age-onset groups in baseline features, although no significant difference was found in most clinicopathological features. In addition, the rectal tumours had a closer distance from their distal margin to the anal verge in the FOWARC trial, and more patients with cT4 disease were enrolled in the chemoradiotherapy group [3]. Therefore, the findings of this study need to be validated in the broader population of patients with early-onset colorectal cancer patients.