Total neoadjuvant therapy in high risk locally advanced rectal cancer: A multicentric observational study in the Indian population (TIDE-R study).

Locally advanced rectal cancer (LARC) with high-risk features, such as cT4 tumors, N2 lymph node involvement, mesorectal fascia involvement (MRF), and extramural vascular invasion (EMVI), presents significant treatment challenges. Preoperative long course chemo-radiation therapy (LCCRT) or short-course radiation therapy (SCCRT), which had been established as the standard of care, resulted in better local control. However, risk of loco regional failure (LRF) and distant metastases remained a concern. Consequently, postoperative chemotherapy was included in the treatment sequence, but patient adherence to this approach was  poor, and it did not lead to an improvement in over all survival (OS).

Recently, total neoadjuvant therapy(TNT),combining neoadjuvant chemotherapy(NACT) with either SCCRT or LCCRT, has been suggested as a strategy to enhance adherence, reduce distant metastases, and potentially improve OS.

RAPIDO trial, first among the TNT trials, compared SCRT followed by two-drug NACT followed by total mesorectal excision to preoperative LCCRT and showed an improvement in disease-related treatment failure at 3 years 4. PRODIGE-23 trial used a three-drug intensive NACT followed by chemo radiation and total mesorectal excision followed by adjuvant chemotherapy and demonstrated improvement in disease free survival (DFS) at 3years. OPRA trial compared two-drug induction chemotherapy followed by LCCRT to LCCRT followed by two-drug consolidation chemotherapy, with patients either undergoing selective watchful waiting or TME as the next step and established a similar DFS in both the groups.

While critically analysing the above TNT trials, RAPIDO which used a short course RT had shown to have a numerically more LRF, PRODIGE which used a three-drug intensive NACT resulted in a slightly higher serious adverse event. And OPRA trial proved that a two- drug regimen as induction or consolidation in TNT can bring similar DFS. This highlights the need for a TNT protocol tailored to the Indian population, one that is well-tolerated and can be implemented in clinics without concerns and integrates the best aspects of existing TNT protocols. Interestingly most of the studies have left the option of adjuvant chemotherapy, it needs to be seen if patients can tolerate all the chemotherapy and concurrent chemo- radiation upfront and whether that would lead to improved outcomes with manageable toxicity profiles. This study aims to evaluate the efficacy and tolerability of a CTNT protocol, involving eight cycles of two-drug induction chemotherapy followed by LCCRT and surgery, with regard to pathological complete response (pCR) rates, grade 3-4 toxicities, LRF, DFS , and OS particularly for Indian population.