Brazil-TNT: A Randomized Phase 2 Trial of Neoadjuvant Chemoradiation Followed by FOLFIRINOX Versus Chemoradiation for Stage II/III Rectal Cancer

Background Neoadjuvant radiation and oxaliplatin-based systemic therapy (Total Neoadjuvant Therapy – TNT) has been shown to increase response and organ-preservation rates in localized rectal cancer. However, trials have been heterogeneous regarding treatment protocols and few have used a watch-and-wait (WW) approach for complete responders. This trial evaluates if conventional long-term chemoradiation followed by consolidation FOLFIRINOX increases complete response rates and number of patients managed by WW. Methods This was a pragmatic randomized phase II trial conducted in 2 Cancer Centers in Brazil that included patients with T3+ or N+ rectal adenocarcinoma. After completing long-course 54Gy chemoradiation with capecitabine patients were randomized 1:1 to 4 cycles of mFOLFIRINOX (Oxaliplatin 85, irinotecan 150, 5-FU 2400) - TNT- arm – or to the control arm, that did not include further neo-adjuvant treatment. All patients were re-staged with dedicated pelvic MRI and sigmoidoscopy 12 weeks after the end of radiation. Patients with a clinical complete response were followed using a WW protocol. Primary endpoint was complete response: complete clinical response (cCR) or pathological response(pCR). Results Between Apr 2021 and Jun 2023, 55 patients were randomized to TNT and 53 to standard of care. Tumors were 74% stage 3, median distance from anal verge was 6cm, 63% had at-risk circumferential margin and 33% involved sphincter. The rates of cCR+pCR were (31%) for TNT vs (17%) for controls (OR 2.19, CI95% 0.8-6.22 p=0.091) and rates of WW were 16%% and 9% (p=ns). Median follow-up has been 8.1 months and recurrence rates were 16% vs 21% for TNT and controls (p=ns). Conclusions TNT with consolidation FOLFIRINOX is feasible and has high response rates, consistent with the current literature for TNT. This trial was supported by a grant from the Brazilian Government (PROADI-SUS)