Three-year results of the Russian multicenter prospective randomized trial RuCort3

Background. The development of local recurrences and distant metastases make the problem of treating locally advanced rectal cancer one of the main problems in modern oncoproctology. The organ-preserving approach, sphincter-preserving operations, the role of a complete clinical response to therapy and the low compliance of patients with adjuvant treatment remain in the focus of attention of scientists.Aim. Evaluation of the effectiveness of neoadjuvant sequential induction chemotherapy (CT), chemoradiotherapy (CRT), and CapOx consolidating chemotherapy in patients with locally advanced rectal cancer.Methods. From December 2019 to June 2024, an open-label, randomized phase III study enrolled patients with locally advanced rectal cancer from 3 centers. The inclusion criteria for patients in the study were: histologically confirmed adenocarcinoma, lower and middle rectal cancer, magnetic resonance imaging on a Tesla 3 machine CRM+/4N0-2M0, age 18–75 years, ECOG performance status 0–1. Patients were divided into 2 groups: in the study group, treatment began with 2 courses of induction CT according to the CapOx regimen (oxaliplatin 130 mg/m2 on the 1st day of the course intravenously by drip, capecitabine 2000 mg/m2 twice a day at 12-hour intervals for 14 days, 7 days break). Then, a long course of chemoradiotherapy was carried out: 44 Gy to the areas of regional metastasis, 50–54 Gy to the primary tumor against the background of CT with capecitabine 825 mg/m2 2 times a day per os on the days of radiation therapy. One to two weeks after the end of CRT, two more courses of consolidation CT were carried out according to the CapOx scheme. A control examination was performed 10–12 weeks after the end of CRT. In the control group, a prolonged course of CRT was carried out: ROD 2 Gy, SOD 44 Gy to the areas of regional metastasis and SOD 50–54 Gy to the primary tumor against the background of CT with capecitabine 825 mg/m2 2 times a day per os on the days of radiation therapy. The primary endpoint was 3-year disease-free survival, calculated from the start of treatment to the date of progression and/or death from any cause or the date of last follow-up. Situations when a patient did not die and did not have disease progression were considered as censored events. Survival was calculated using the Kaplan–Meier method.Results. 247 patients were included in the study, 178 (72.1 %) underwent a complete course of treatment, 12 (4.9 %) patients are in the process of treatment or waiting for surgery, 25 (10.1 %) patients were excluded from the study for various reasons: organizational problems, refusal of treatment after randomization, detection of a synchronous tumor or metastases before starting treatment. The remaining 32 (12.9 %) patients did not follow the planned treatment protocol due to progression, death or refusal to continue treatment. The prevalence of acute grade III–V toxicities during preoperative treatment was 6.8 % in the CRT + CT group versus 4.7 % in the CRT group. 19 patients with a complete clinical response refused surgical treatment. 6 (5.8 %) patients in the CRT group and 13 (12.1 %) patients from the group in the CRT + CT group (p = 0.05). The disease free median duration of follow-up in group complete clinical response was 1086 days (36.2 months). Sphincter-sparing operations in the CRT + CT group were performed in 54 (65.8 %) patients versus 41 (53.2 %) in the CRT group (p = 0.05). A subgroup analysis of patients with low rectal cancer showed a significant increase in the frequency of sphincter preservation operations in the main group – 23 (46.9 %) versus 16 (31.4 %) in the control group (p = 0.05). On the basis of the Clavien–Dindo classification, the prevalence of surgical complications was similar between the two groups. The total rate of pCR in the CRT + CT group was 41.2 %, which was significantly higher than that in the CRT group (29.8 %). We demonstrated that patients receiving CRT with neoadjuvant CT were well tolerated, with a compliance rate of 71.2 % than those received adjuvant CT (31.2 %, p = 0.05). In particular, 95 % of the patients in the main group underwent 4 planned courses of neoadjuvant CT. 32.5 % of patients in the chemoradiotherapy group did not start adjuvant CT versus 16 % in the study group. The median duration of follow-up was 36 month. Locoregional recurrence was observed in 5 patients: 3 (2.8 %) in the CRT + CT group (1 patient was operated in a non-specialized clinic, after completion of preoperative treatment within the protocol) and 2 (1.9 %) in the CRT group. There was no significant difference in distant metastases: 20 (19.2 %) patients in CRT group and 21 (19.6 %) patients in the study group. There was no significant difference in dieseas-free survival (75 % in the CRT group versus 77 % in the CRT + CT group). Conclusion. Chemoradiotherapy with preoperative CT followed by surgery was efficacious for locally advanced rectal cancer with a significant increase frequency complete clinical response, sphincter-preserving operations, organpreserving treatment including low rectal cancer and rate patient compliance with CT.