Toxicity and Treatment Completion of Neoadjuvant FOLFOXIRI and Chemoradiotherapy in Patients With High-Risk Locally Advanced Rectal Cancer: A Secondary Outcome Analysis of the MEND-IT Trial

Purpose: Total neoadjuvant therapy (TNT) is a promising strategy to improve tumor response and oncological outcomes in patients with locally advanced rectal cancer (LARC), particularly in those with high-risk tumor characteristics. Although triplet chemotherapy (ie, FOLFOXIRI) is currently used exclusively for metastatic disease, it may offer benefits in the curative treatment of high-risk LARC by enhancing tumor response and reducing the risk of distant metastases. However, its broader use is limited by concerns regarding toxicity. The MEND-IT trial evaluated an intensified TNT regimen in high-risk LARC. Methods and Materials: This was a national, multicenter, phase 2 trial to evaluate neoadjuvant FOLFOXIRI followed by chemoradiotherapy in patients with high-risk LARC, enrolled between November 2021 until October 2024. The primary outcome was complete response rate. This manuscript focuses on secondary outcomes, including treatment completion rate, dose reductions, and short-term toxicity (= grade 3 serious adverse events [SAEs] and adverse events). Associations with toxicity were analyzed using binary logistic regression. Results: Of 128 enrolled patients, 124 were eligible for evaluation and monitored until 3 months after completion of TNT. Dose reductions were required in 67 patients (54%), most often for oxaliplatin (n = 59; 47.6%). A total of 116 patients (93.5%) completed at least 4 cycles of FOLFOXIRI and chemoradiotherapy, and 102 patients (82.3%) completed all 6 cycles and chemoradiotherapy. No patients were unable to start with chemoradiotherapy due to chemotherapy-related toxicity. SAEs and adverse events (= grade 3/hematologic = grade 4) occurred in 46 patients (37.1%), of whom 31 (25.0%) had SAEs. Diarrhea and nausea were reported most frequently, representing 26.9% (n = 18) and 17.9% (n = 12) of all reported events, respectively. Conclusions: Patients treated with neoadjuvant FOLFOXIRI and chemoradiotherapy had manageable toxicity levels and high treatment completion rates, supporting its feasibility in well-selected patients with high-risk LARC. Randomized trials are warranted to compare efficacy and toxicity of triplet versus other TNT regimens.