Real‐World Outcomes of Total Neoadjuvant Therapy Versus Standard Neoadjuvant Chemoradiotherapy in Stage II–III Locally Advanced Rectal Cancer: A Comparative Cohort Study

AIM: Total neoadjuvant therapy has been adopted to improve systemic disease control in locally advanced rectal cancer, yet long-term real-world outcomes, particularly in non-Western populations, remain incompletely defined. We compared total neoadjuvant therapy with neoadjuvant chemoradiotherapy and assessed the prognostic impact of posttreatment lymphovascular and perineural invasion. METHODS: We retrospectively analyzed 171 patients with Stage II-III locally advanced rectal cancer treated between 2016 and 2023 with total neoadjuvant therapy (n = 76) or neoadjuvant chemoradiotherapy (n = 95) followed by total mesorectal excision. Overall survival was the primary endpoint; secondary endpoints included disease-free survival, local recurrence-free survival, distant metastasis-free survival, and treatment response. RESULTS: At a median follow-up of 45 months, total neoadjuvant therapy was associated with numerically higher 5-year overall survival than neoadjuvant chemoradiotherapy (74.3% vs 60.0%; hazard ratio 0.58, 95% confidence interval 0.32-1.06; log rank p = 0.048). Disease-free survival, local recurrence-free survival, and distant metastasis-free survival numerically favored total neoadjuvant therapy but did not reach statistical significance. Pathologic complete response occurred in 39.5% versus 30.5% with total neoadjuvant therapy and neoadjuvant chemoradiotherapy, respectively (p = 0.221), and was associated with improved local recurrence-free survival and distant metastasis-free survival. The absence of lymphovascular and perineural invasion predicted favorable outcomes. Adjuvant chemotherapy was more frequently administered after neoadjuvant chemoradiotherapy. CONCLUSION: In this real-world cohort, total neoadjuvant therapy was associated with numerically higher overall survival than neoadjuvant chemoradiotherapy, whereas recurrence-based endpoints were comparable. Posttreatment lymphovascular invasion and perineural invasion provided clinically informative prognostic stratification beyond response assessment and may help inform postoperative risk assessment in the TNT era.