Total neoadjuvant therapy (TNT) using 5FU and oxaliplatin followed by higher dose concurrent 5FU in locally advanced high-risk rectal adenocarcinoma including signet ring and mucinous cancers resulting in good complete response rates
Authors: Singh Ashish , John Ajoy Oommen , Bala Divya , Joel Anjana , Georgy Josh Thomas , Chacko Raju Titus , Jesudasan Mark Ranjan , Mittal Rohin , Ram Thomas Samuel , Reddy Jebakarunya Rami , Murthy Arvind , Chandramohan Anuradha , Eapen Anu , Masih Dipti , Ramnath Nithya , Dobrosotskaya Irina , Yadav Bijesh 
Published: January 2023

Abstract
PURPOSE
Preoperative long course chemoradiation (LCCRT) followed by total mesolectal excision (TME) results in excellent local control but distant failure rates remain high. Total neoadjuvant therapy (TNT) with pre-operative delivery of systemic chemotherapy and chemoradiotherapy results in a higher pathological response, improved event free and overall survival and is becoming the new standard of care. We describe our experience with a hybrid TNT consisting of induction chemotherapy followed by chemoradiotherapy using full dose 5FU without oxaliplatin.
METHODS
In this single center study, adults with a LARC were included. Patients were eligible if they were aged 18 years or older, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1, biopsy-proven, newly diagnosed LARC, which was classified as high risk on pelvic MRI (with at least one of the following criteria: clinical tumor [cT] stage cT4a or cT4b, extramural vascular invasion (EMVI), clinical nodal [cN] stage cN2, mesorectal fascia involvement and enlargement/tumor deposits on lateral lymph nodes). The hybrid TNT protocol comprised of six biweekly courses of modified FOLFOX6 (m FOLFOX6) followed by addition of pelvic LCCRT with four concurrent cycles of biweekly 5-FU 2600 mg/m2 + LV 200 mg/m2 without oxaliplatin to complete uninterrupted 20 weeks of full dose 5FU + LV chemotherapy. Pelvic chemoradiotherapy consisted of 28 daily fractions of 2 Gy up to 50.4-54Gy including boost to extra-mesorectal nodes. Surgery was planned 11-13 weeks after completing chemoradiotherapy. Outcomes of interest were pathological complete response (pCR), 2 year disease free survival (DFS) and overall survival (OS).
RESULTS
Between July 2017 to August 2020, 84 adults, predominantly male (65.5%) aged 42.5±13 years with LARC were treated with the TNT protocol. High risk features were T3/T4 in 80 (95.3%), N2 nodes 51(60.7%), signet ring cell histology 22(26.2%), meso-rectal fascia involvement 73(86.9%), EMVI 54 (64.3%) and lateral pelvic nodes 25(29.8%). Eighty- one (96.4%) completed all planned chemotherapy. All but two patients completed the planned RT.
pCR was noted in 27 (32%). Twenty-five (29%) did not undergo surgery- 6(7%) opted for non-operative management (NOM) after complete clinical response (cCR), 5 refused surgery, 13(15.4%) were deemed inoperable due to inadequate tumor regression despite TNT (R0 resection was not feasible) and 2 did not complete treatment. Grade 3 &4 toxicities included neutropenia in 20 (23.8%), diarrhea in 12 (14.2%) and anemia in 9(10.7%) patients. Grade 5 toxicities were seen in one patient who died from neutropenic sepsis, and another who developed a cerebrovascular accident on therapy.
After 24.5 months of median follow-up, 23 (27%) patients recurred, with local recurrence in 5(6%), systemic recurrence in 16 (19%) and both in 2(2.4%). The median disease-free survival (DFS) of the whole cohort was 22.5 months. Those who did not undergo surgery(n=19) despite residual disease (no cCR) had the worst outcomes (mDFS 11.4 months versus 27.7months, p=<0.0001 and mOS 15 months versus 29.2 months p=<0.0001).
CONCLUSION
The hybrid TNT regimen was administered without significant dose delays or interruptions. Toxicity was manageable but with two treatment related deaths. pCR of 32% is comparable to contemporary trials, however the 2-year recurrence rates were not improved. Ability to undergo surgery after TNT predicted for improved DFS and OS.