Total neoadjuvant treatment with long-course radiotherapy versus concurrent chemoradiotherapy in local advanced rectal cancer with high risk factors (TNTCRT): A multicenter, randomized, open-label, phase 3 trial.

Background: Distant metastases remain a common problem in locally advanced rectal cancer (LARC) patients who received neoadjuvant chemoradiotherapy (NCRT) and surgery. Previous researchers have demonstrated the survival benefits of total neoadjuvant treatment (TNT) using short-course radiotherapy with CAPOX and long-course radiotherapy (LCRT) with mFOLFIRINOX. This study aimed to explore the efficacy of TNT using long-course radiotherapy (LCRT) combined with CAPOX. Methods: In this phase 3, open-label, multicenter, randomized trial, eligible pts were diagnosed as stage II/III and had at least one high risk factor: cT4a-b (resectable), cT3c-d with extramural venous invasion, cN2; involved mesorectal fascia, or enlarged lateral lymph nodes. Pts were randomly assigned to either Arm A to receive TNT (LCRT with six cycles of neoadjuvant CAPOX (one cycle of induction CAPOX, two cycles of concurrent CAPOX, and three cycles of consolidation CAPOX) followed by total mesorectal excision (TME)) or Arm B to receive NCRT (LCRT with concomitant capecitabine, followed by TME and adjuvant CAPOX). Radiotherapy in both groups was administered at 50-50.4 Gy in 25-28 fractions. The primary endpoint was disease free survival (DFS). The secondary endpoints were pathological response complete (pCR) rate, overall survival (OS), metastasis-free survival (MFS) and postoperative 30-day morbidity. Results: (ITT) Between June 6, 2017, and Mar 5, 2024, 458 pts were randomly assigned to two Arms (232 in Arm A, and 226 in Arm B). At a median follow-up of 44 months (IQR, 24-57.25), the 3-yr DFS was significantly increased in Arm A (77.0% vs 67.9% in Arm A/B respectively, HR 0.623, 95% CI 0.435-0.892, p = 0.009). 3-yr MFS was also significantly higher in arm A: 83.0% vs 74.2% in arm B (HR 0.595, 95% CI 0.392-0.903, p= 0.013). A total of 56 OS events was reported, and the 3-yr OS was 90.3% vs 87.9% (HR 0.747, 95% CI 0.441-1.266, p = 0.276) in arm A/B, respectively. TNT and NCRT in both arms were well tolerated. Thrombocytopenia was the most frequent grade 3-4 hematological adverse event in Arm A, occurring in 24 (10.3%) of 232 pts. Until now, 27.5% of pts achieved pCR in Arm A, compared to only 9.9% in Arm B. (OR 3.436, [1.1.941-6.084], p= 0.0001). In Arm A and B, 13 and 2 pts achieved clinical complete response (cCR) and received watch-and-wait strategy, respectively. No significant difference in severe morbidity within 30 days post-operation were found between the two arms. Conclusions: TNT with LCRT combined with CAPOX significantly improve DFS, MFS and pCR compared to standard concurrent neoadjuvant chemoradiotherapy in LARC patients with high risk factors, with acceptable toxicities. Clinical trial information: NCT03177382.