Total Neoadjuvant Therapy vs Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer: A Phase II Randomized Trial

Total neoadjuvant therapy (TNT) is becoming increasingly popular as a systemic treatment for locally advanced rectal cancer (LARC), serving as an alternative to standard neoadjuvant concurrent chemoradiotherapy (CCRT). This study compared TNT versus neoadjuvant CCRT in cases of LARC. This phase II randomized controlled study included 30 patients with LARC (stages T2N1-2, T3, T4), who were randomized into two groups. The TNT group (n=15) received a long-course CCRTH followed by 2 cycles of consolidation chemotherapy with XELOX before surgery. The CRT group (n=15) received a long course of CCRTH followed by surgery. The cumulative dose of radiation in the current chemoradiation therapy was 50.4 Gy. All patients underwent total mesorectal excision (TME). The primary outcome measures were pathologic complete response (pCR) rate and 3-year event-free survival (EFS). The two groups were compared using Pearson’s Chi-square test, Fisher’s exact test, t-test, or the Mann-Whitney test. Survival analysis was performed using the Kaplan-Meier method, with group comparisons made using the log-rank test. A p-value < 0.05 was considered significant. Five patients in the TNT Group had a pCR compared to none in the CRT group (p=0.042). Moreover, 8 of the remaining 10 patients showed downstaging. In the CRT group, downstaging was observed in 6 patients (40%). Lymph nodes were positive in 3 patients of the TNT group compared to 10 of the CRT group (p=0.010). At 3 years, the overall survival of the TNT group was 86.2% compared to 57% in the CRT group (p=0.034). The event-free survival was 73.3% and 26.7% in the TNT and CRT Groups, respectively (p=0.021). CCRTH toxicity profile was comparable in both groups, mainly in the form of diarrhea, bleeding per rectum, peripheral neuropathy, cystitis, and neutropenia. In patients with LARC, TNT incorporating consolidation chemotherapy after long-course CCRTH before TME is superior to chemoradiation alone. TNT is associated with a higher complete pathological response, reduced local and distant metastases, and enhanced overall and disease-free survival, with a comparable toxicity profile to CRT alone.