Neoadjuvant Chemoradiotherapy Significantly Improved R0 Resection Rate in Unresectable Locally Advanced Colon Cancer: The Initial Analysis from the Randomized Controlled Phase 3 Trial

Abstract

<h3>Purpose/Objective(s)</h3> Neoadjuvant chemotherapy (NACT) is often used for tumor downstaging in locally advanced colon cancer (LACC) and improves the R0 resection rate. Based on previous findings, we hypothesized that neoadjuvant chemoradiotherapy (NACRT) might bring a higher R0 resection rate and survival benefit to patients with unresectable LACC. Our perspective study aimed at comparing NACRT versus NACT for unresectable LACC to confirm our hypothesis. <h3>Materials/Methods</h3> We performed the world's first randomized controlled phase 3 trial on NACRT for LACC at our institution. Eligible patients had newly diagnosed unresectable LACC. We randomly allocated patients open-label to the NACT group (control group) or the NACRT group (research group). Chemotherapy regimen was XELOX (oxaliplatin 100-130mg/m2, iv drip, d1, every 3 weeks; capecitabine 1,000mg/m2, bid, d1-d14, every 3 weeks). Patients allocated radiotherapy received a daily irradiation schedule (GTV:50Gy/25F/5W, CTV:45Gy/25F/5W). Surgery scheduled 6–8 weeks after radiotherapy and adjuvant chemotherapy were given if patients transformed into resectable LACC. <h3>Results</h3> Between July 2019 and July 2021, 49 patients with unresectable LACC underwent randomization and 45 patients (4 excluded) were analyzed for efficacy finally. There were 23, 6, 8, 7 and 1 patients with primary tumor location at sigmoid colon, descending colon, transverse colon, ascending colon and ileocecus. The median follow-up time was 20.7 months. Allocated groups were balanced, with 25 patients receiving NACRT and 20 patients receiving NACT. Twenty-one (84%) patients in the NACRT group transformed to resectable LACC after planned neoadjuvant treatment and received surgery while there were only 5 (20%) patients in the NACT group. Compared to NACT, the use of NACRT improved the R0 resection rate (80% vs 20%) significantly. The 2-year progression-free survival is 72.2% in the NACRT group and 37.4% in the NACT group (p=0·029). The 2-year overall survival is 95.5% in the NACRT group and 73.1% in the NACT group (p=0·035). No increasing toxicities and postsurgical complications were observed from the NACRT group compared with the NACT group. The trial is terminated since the R0 resection rate and survival between the two groups had shown a significant difference. Also, the patients' MMR/MSI status was not considered at the beginning of the study design. <h3>Conclusion</h3> Based on neoadjuvant chemotherapy, the addition of radiotherapy provided a higher R0 resection rate, longer progression-free survival and even might improve overall survival for patients with unresectable LACC. We concluded that this approach is safe, feasible and might associate with a better survival benefit. We are designing new clinical studies to further demonstrate the value of NACRT in LACC. This trial is registered with ClinicalTrials.gov, number NCT03970694.