Long-term recurrence patterns in rectal cancer after neoadjuvant therapy: 25-years of real-world data

The management of locally advanced rectal cancer has significantly evolved over the past 25-years, most recently with the adoption of total neoadjuvant therapy (TNT). Nevertheless, optimal treatment selection for individual patients remains challenging. This study evaluated recurrence patterns in rectal cancer to improve risk stratification and guide neoadjuvant treatment decisions in the TNT era.

We conducted a prospective cohort study including 850 rectal cancer patients treated with neoadjuvant radio- and chemotherapy over a 25-year period.

After a median follow-up of 12 years, 5-year overall survival (OS) and disease-free survival (DFS) were 86.8 % and 75.5 %. Recurrence occurred in 167 patients (19.6 %), including 31 (3.6 %) with locoregional recurrence (LRR), 158 (18.6 %) with distant metastases (DM) and 22 (2.6 %) with both. Five-year recurrence-free survival (RFS), DM-free survival (DMFS) and LRR-free survival (LRFS) were 76.9 %, 77.8 % and 85.3 %. Mesorectal fascia involvement (p = 0.006) and extra-mural vascular invasion (p = 0.028) were associated with recurrence on univariable analysis, although their impact diminished after adjusting for neoadjuvant treatment. Independent predictors of DM were lymphovascular invasion (p < 0.001), perineural invasion (p = 0.004), positive circumferential resection margin (p = 0.046) and higher lymph node ratio (LN-ratio) (p < 0.001). Tumor diameter (p = 0.025) and LN-ratio (p = 0.047) independently predicted LRR. Early recurrence was associated with worse OS, although post-recurrence survival did not differ significantly.

Histopathological features and tumor response to neoadjuvant therapy are strong predictors of recurrence risk in rectal cancer. Identifying reliable baseline biomarkers of treatment response is essential to refine patient risk stratification and personalize neoadjuvant treatment strategies in the TNT era.