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.

person Xin Wang Division of Abdominal Tumor Multimodality Treatment, Department of Radiation Oncology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China info_outline Xin Wang, Ping Liu, Yi Xiao, Wenjian Meng, Yuanling Tang, Jitao Zhou, Pei-Rong Ding, Ke-Feng Ding, Biao Wang, Qing Guo, Hao Sun, Jian Qiu, Yongyang Yu, Bing Wu, Hanjiang Zeng, Xiang-bing Deng, Dan Jiang, Ya-li Shen, Zongguang Zhou, Ziqiang Wang

Authors person Xin Wang Division of Abdominal Tumor Multimodality Treatment, Department of Radiation Oncology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China info_outline Xin Wang, Ping Liu, Yi Xiao, Wenjian Meng, Yuanling Tang, Jitao Zhou, Pei-Rong Ding, Ke-Feng Ding, Biao Wang, Qing Guo, Hao Sun, Jian Qiu, Yongyang Yu, Bing Wu, Hanjiang Zeng, Xiang-bing Deng, Dan Jiang, Ya-li Shen, Zongguang Zhou, Ziqiang Wang Organizations Division of Abdominal Tumor Multimodality Treatment, Department of Radiation Oncology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China, Third Affiliated Hospital of Kunming Medical University, Kunming, China, Division of Colorectal Surgery, Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China, Colorectal Cancer Center, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China, Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China, Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China, Department of General Surgery, Dazhou Central Hospital, Dazhou, China, Department of Gastrointestinal Surgery, The Affiliated Nanchong Central Hospital of North Sichuan Medical College, Nanchong, China, Gastrointestinal Cancer Center, Chongqing University Cancer Hospital, Chongqing, China, The First Department of General Surgery, Shaanxi Provincial People's Hospital, Xian, China, Colorectal Cancer Center, Department of General Surgery, West China Hospital, Sichuan University; Department of General Surgery Depart.2 (Colorectal Gastrointestinal Surgery), West China Tianfu Hospital, Sichuan University, Chengdu, China, Department of Radiology, West China Hospital, Sichuan University, Chengdu, China, Department of Pathology, West China Hospital, Sichuan University, Chengdu, China, West China Hospital, Sichuan University, Chengdu, China Abstract Disclosures Research Funding No funding sources reported 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.

Clinical