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Background: Pre-operative chemoradiation for rectal cancer is often associated with severe gastrointestinal (GI) toxicity which can interrupt, delay, and/or lead to termination of treatment. In this study, we evaluated whether the addition of YIV-906, a novel herbal medicine proven to reduce GI toxicity associated with chemotherapy could also reduce GI side effects during standard pre-operative capecitabine and pelvic radiation therapy (RT) in the neoadjuvant setting for the treatment of locally advanced rectal cancer., Methods: This single arm clinical study enrolled 24 patients between Dec 23, 2014-Sep 17, 2018 at Smilow Cancer Hospital, a comprehensive cancer center at Yale New Haven Hospital. All patients were age ≥18 years, Eastern Cooperative Oncology Group 0-1 and with histologically confirmed T3-T4 and N0-N2, M0 adenocarcinoma of the rectum. Median follow-up was 61.9 months. All patients received concurrent pelvic external beam RT (50.4 Gy in 28 fractions), YIV-906 (taken orally 800 mg twice daily on days 1-4 of RT each week), and oral capecitabine delivered in a neo-adjuvant fashion, followed by definitive surgery. Toxicity was assessed weekly during radiation and until acute symptoms resolved and then at 28 days, 4 months, 7 months and 10 months. Toxicities were graded in accordance with Common Terminology Criteria for Adverse Events (CTCAE) version 4.0., Results: At the time of surgery, 4 patients (16.7%) had a complete or near-complete response. At a median follow-up of 61.9 months, the mean overall survival (OS) of our patient cohort was 74.9 months [95% confidence interval (CI): 67.3-82.5]. The estimated 5-year OS was 82.0%. We observed 0% acute grade 4 toxicities, and only two cases of acute grade 3 diarrhea (8.3%)., Conclusions: The addition of YIV-906 to capecitabine based chemoradiation for locally advanced rectal cancer led to reduced rates of GI toxicity compared to historical controls, in particular grade 3 or greater diarrhea. These findings suggest YIV-906 should be evaluated in a randomized clinical trial to further assess potential reductions in the toxicity profile of chemoradiation for GI cancers., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-23/coif). K.L.J. is a member of the National Comprehensive Cancer Network (NCCN) colorectal cancer guidelines panel and NCCN provides reimbursement to travel to meetings at their headquarters to review the guidelines. J.L. has served on the advisory board for Ipsen, Genentech and Bristol Myers Squibb. J.L. has served on leadership for ASCO and editor for SEP. J.L. has consulted for First World, Techspert, Guidepoint, Ipsen, Bristol Myers Squibb, MarketPlus, Equinox, KeyUwest, FirstWord Group, Genentech, AptitudeHealth, Novartis and Deciphera. M.C. is supported by a NCI Mentored Clinical Scientist Research Career Development Award (1K08CA255465-01A1) and has consulted for Daiichi Sankyo, Seattle Genetics, Taiho, Regeneron, Agenus, Elevate Oncology, Loxo@Lilly, I-MAB, Bayer, Macrogenics and Incendia Therapeutics. Y.C.C. is the inventor of YIV-906 (aka PHY906/KD018) for its usage for its usage in cancer treatment. Yale holds the patent. It is licensed to Yiviva which is cofounded with Yale. He did receive funding from the National Foundation of Cancer Research (NFCR) and nominal amount from Yiviva. He received no funding from NIH. Y.C.C. has new drug discovery patent being considered with Yale owning the patent. Y.C.C. serves on the Scientific Advisory Board for Yiviva and serves as a Chair of Consortium for the Globalization of Chinese Medicine. Y.C.C. holds stock or stock options as Cofounder of Yiviva options. W.L. received payments from Yiviva, Inc. as a consultant. S.H.L. is the co-inventor of YIV-906 and is included in the patent that Yale University holds; and is the co-founder and employee of Yiviva Inc. who has licensed the YIV-906 world-wide right from Yale University. The other authors have no conflicts of interest to declare., (2024 Journal of Gastrointestinal Oncology. All rights reserved.)