Is age just a number? Causal modeling of recurrence risk in rectal cancer

Abstract

Purpose Young-onset rectal cancer (YORC) is increasingly common and often presents with aggressive histological features; however, its effect on recurrence remains uncertain. This study aimed to estimate the causal effect of age at diagnosis on recurrence in patients with rectal cancer using advanced causal inference methods. Methods This multicenter retrospective cohort study was conducted at 2 university hospitals in Thailand. Patients diagnosed with rectal adenocarcinoma between 2013 and 2022 who underwent curative-intent treatment were included. The primary exposure was age at diagnosis, categorized as YORC (<50 years) or late-onset rectal cancer (LORC; ≥50 years). Confounders were prespecified using a directed acyclic graph and addressed using a confounder composite score. Age was also modeled as a continuous variable using natural splines. The primary outcome was cancer recurrence. Results Among 585 patients, 116 (19.8%) had YORC and 469 (80.2%) had LORC. Patients with YORC had fewer comorbidities but more unfavorable histological features than those with LORC. Overall, recurrence occurred in 40.2% of patients and most commonly involved distant metastasis. The estimated average causal effect of age on recurrence was −6.5% (95% confidence interval, −16.6% to 3.5%; P=0.202), indicating that younger age was not associated with an increased risk of recurrence, although a protective effect was not confirmed. Natural spline modeling indicated a nonlinear increase in recurrence hazard with advancing age. Conclusion Younger age at diagnosis was not associated with worse recurrence outcomes despite adverse pathological features, and a potential protective association could not be excluded.