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

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2026年5月18日

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E. Banken,
M. Borg,
I. E. G. van Hellemond,
S. G. van Ravensteijn,
H. M. U. Peulen,
A. E. Verrijssen,
J. Nederend,
A. W. Daniels-Gooszen,
T. R. van Oudheusden,
G. van Lijnschoten,
J. G. Bloemen,
H. J. T. Rutten,
H. L. van Westreenen,
J. W. B. de Groot,
C. Verhoef,
P. J. Tanis,
B. A. Grotenhuis,
A. G. J. Aalbers,
I. M. Werter,
M. D. den Hartogh,
J. A. J. Douma,
T. G. A. Calon,
L. B. J. Valkenburg-van Iersel,
G. L. Beets,
J. B. Tuynman,
M. P. W. Intven,
S. M. J. van Kuijk,
M. Berbée,
T. E. Buffart,
J. M. L. Roodhart,
J. W. A. Burger

摘要

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.