A national, multicentre, randomised, controlled, parallel-arms, phase III clinical trial of neoadjuvant FOLFOXIRI and chemoradiotherapy versus neoadjuvant CAPOX/FOLFOX and chemoradiotherapy in patients with high-risk locally advanced rectal cancer: study protocol of the MEND-IT II trial.

BACKGROUND: Total neoadjuvant therapy (TNT) has emerged as a promising treatment strategy for locally advanced rectal cancer (LARC), demonstrating higher pathological complete response (pCR) rates and enhanced disease-free survival. However, evidence specifically addressing high-risk LARC and the potential for organ-preserving approaches remains limited. The potential benefit of TNT may be further optimised when administered to patients with specific high-risk characteristics, associated with poor prognosis. The optimal TNT regimen for achieving favourable organ preservation and survival outcomes has not yet been established, as no studies have directly compared triplet-based induction chemotherapy with doublet-based TNT strategies. Consequently, there is considerable heterogeneity in the administration of chemotherapy within TNT regimens in clinical practice. METHODS: This multicentre, parallel-arms, open-label, randomised, controlled, phase III trial will include 394 patients with non-metastasised, high-risk LARC, with WHO-performance status 0-1 and fit for FOLFOXIRI. High-risk LARC is defined as the presence of at least one of the following tumour characteristics: invasion of the mesorectal fascia (MRF) (i.e. T4b or evident invasion), extramural venous invasion (EMVI) grade IV, tumour deposits (TD), ≥ 2 enlarged lateral lymph nodes (LLN) (≥ 7 mm). Patients are informed about TNT versus chemoradiotherapy. Patients who will undergo TNT will be randomised 1:1 between 6 cycles of FOLFOXIRI, followed by chemoradiotherapy (25 × 2 or 28 × 1.8 Gy) or 4 cycles CAPOX/6 cycles FOLFOX, followed by chemoradiotherapy. Patients either undergo surgery or enter a watch-and-wait approach after neoadjuvant treatment. A watch-and-wait approach is considered in case of a clinical complete response (cCR), determined maximal 26 weeks after start of treatment. The primary outcome is complete response rate (i.e. pCR or sustained cCR at 1 year). The main secondary outcomes are disease-free survival, overall survival, regrowth rate, radicality, toxicity and completion rate of neoadjuvant treatment, treatment related toxicity, quality of life, and post-operative morbidity. Patients who are eligible and undergo neoadjuvant chemoradiotherapy, will be asked to participate in the observational cohort. DISCUSSION: This protocol describes the MEND-IT II study, which compares complete response rates (pCR and cCR) between FOLFOXIRI-based and CAPOX/FOLFOX-based TNT in a homogeneous high-risk LARC population. The results of this study may contribute to optimise neoadjuvant treatment strategies and tailored treatment. TRIAL REGISTRATION: Overview of Medical-Scientific Research in the Netherlands (OMON): NL-011486. CLINICALTRIALS: gov: NCT07472868.