3011 - Phase II Randomized Study of Short Course Radiotherapy Based Total Neo-Adjuvant Therapy and Brachytherapy Boost with or without Chlorophyllin in Reducing the Incidence of Acute Toxicity in Advanced Re

R. Krishnatry¹, V. Gota², S. Kannan², S. Gudi³, V. Ostwal⁴, A. Ramaswamy⁴, M. Kazi⁵, A. Saklani¹, V. Murthy¹, R. Engineer³, and A. Jain⁵; ¹Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India, ²ACTREC,Tata Memorial Centre,Homi Bhabha National Institute, Navi Mumbai, India, ³Department of Radiation Oncology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India, ⁴Department of Medical Oncology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India, ⁵TATA MEMORIAL CENTRE, MUMBAI, India

Purpose/Objective(s): Total Neoadjuvant treatment (TNT) comprising short-course radiotherapy (SCRT) and neoadjuvant chemotherapy is one of the standard treatment options for locally advanced rectal cancer patients. Adding brachytherapy boost dose, can improve local tumour control and organ preservation rates in select patients. Overall, the increased risk of acute treatment-related toxicity rates with TNT approaches and dose escalation can be a deterrent to compliance, treatment completion and overall outcomes. We aim to evaluate the utility of adding chlorophyllin to SCRT-based TNT interdigitated with brachytherapy in reducing the incidence of >/= grade 2 acute Gastrointestinal (GI)/Genito-urinary (GU)/ haematological toxicity along with improving the rates of complete clinical responses (pathological + clinical). Materials/

Methods: The study is a 2-arm, phase II, prospective, 258andomized, double-blind, placebo-controlled superiority study evaluating the clinical outcome - local tumour response, the feasibility of non-operative management (NOM) with hypofractionated dose-escalated radiotherapy and brachytherapy in TNT setting, and the benefit of Chlorophyllin in reducing toxicity during this treatment approach for select locally advanced rectal cancer patients suitable for wait and watch approach. NOM or standard surgery will be followed based on response to TNT as standard treatment in both arms. After accrual and informed consent of eligible LARC patients, there will be: Arm 1 to receive chlorophyllin, and Arm 2 will receive a matching placebo, blinded centrally for both the investigators and patients. Permuted block 258andomized with a variable block size will be used to 258andomize 76 (38 in each arm), providing 80% power and a two-sided alpha of 10% to test an absolute reduction in >grade 2 GU/GI/Haematological toxicity rates by 30% (from 70% to 40%) with an anticipated dropout of 10%. It will also provide an estimate for NOM and organ preservation success rates. The current sample size is adequate for the estimated overall response rate at two years to be 50% compared to pCR of 28% (est. 95% CI: 24% - 32%) as reported in the RAPIDO study. We will also be estimating organ preservation rates, TME-free survival, Disease-free survival, Distant metastasis-free survival, Loco-regional failure-free survival, and Overall survival, along with toxicities and Quality of Life outcomes as secondary objectives.

Results: The study started accrual on 04^th July 2023 and is currently ongoing.

Conclusion: We anticipate that with improved logistics of SCRT, better compliance to TNT and improved NOM rates with endorectal brachytherapy boost could be achieved with Chylorophyllin by ameliorating acute treatment-related GI/GU /Haematological toxicity rates. Improved NOM rates and lesser toxicity would result in superior QoL and an improved therapeutic ratio and patient satisfaction for these deserving patients.