A Prospective Trial of Non-Operative Radiation Management of Adenocarcinoma of the Lower Rectum (NORMAL-R): Interim Analysis

Purpose/Objective(s): Recent data show promising results of short course radiation therapy followed by chemotherapy as total neoadjuvant therapy for rectal cancer (SC-TNT). The use of SC-TNT for organ preservation is unknown. We hypothesized that SC-TNT would result in a complete clinical response (cCR) rate of at least 20%. Materials/Methods: NORMAL-R is a phase I, prospective trial of SC-TNT for stage I-IIIB (cT1-3, N0-2, M0) lower rectal adenocarcinoma. All patients were candidates for TME. After closure of the OPERA study, the protocol was modified from stage I only to include stages II-III, and increased from 6 to 8 cycles of FOLFOX (or 5 cycles of CAPOX). Patients received 25 Gy / 5 fxs to the pelvis with a simultaneous integrated boost to 35 Gy for extra-mesorectal pelvic lymph nodes. FOLFOX or CAPOX was initiated 2-4 weeks after RT completion. Patients with cCR by MRI, endoscopy and digital rectal examination were followed with non-operative management with the latter assessments every 3 months. Patient reported symptoms were assessed by baseline, post-treatment and 1-year Functional Assessment of Cancer Therapy-Colorectal (FACT-C) assessments. An interim analysis after 10 patients was planned to ensure a cCR of at least 20%. Baseline and post-treatment FACT-C values were compared with Wilcoxon signed-rank test. The primary endpoint of the study is 1-year cCR. Results: Between June 2016 and January 2019, 19 patients were treated on trial, with 17 patients accrued in the last 14 months after protocol amendment (11/2017). At the planned interim analysis of 10 patients, 9 patients were evaluable (one patient had an allergic reaction to chemotherapy and was excluded). Eight of nine (89%) evaluable patients had a cCR after SC-TNT. Of the patients included in the interim analysis, 4 patients received 8 cycles, and 6 patients received 6 or less cycles of FOLFOX. At a median follow-up 10.9 months, 88% have a persistent cCR. FACT-C for social/family, emotional, and functional wellbeing were not different post-treatment. As expected, FACT-C values for colorectal cancer subscale [24.5 (2.2) vs 19.5 (4.9), p=.019] and physical wellbeing [26.8 (1.5) vs 22.5 (3.2), p=.016] were decreased immediately post-treatment. Conclusion: Our preliminary data show that SC-TNT results in a high cCR and is well tolerated. Further follow-up is required to evaluate durability of response and toxicity. A phase II study is indicated to validate the clinical efficacy of SC-TNT. [Figure presented