The aim of this clinical trial is to compare triplet induction therapy (FOLFOXIRI) with doublet induction therapy (CAPOX/FOLFOX), followed by chemoradiotherapy and either surgery or a watch-and-wait approach, in patients with high-risk locally advanced rectal cancer. The primary questions it seeks to address are whether triplet induction therapy results in higher complete response rates, improved quality of life, and better long-term oncological outcomes compared to doublet induction therapy, despite the anticipated increased risk of toxicity.

Rationale Total neoadjuvant therapy (TNT) with induction chemotherapy (ICT) is currently considered a standard of care option for locally advanced rectal cancer (LARC) in the Dutch national guideline, primarily due to improved tumour response and a reduced risk of distant metastases (1, 2). However, the supporting evidence remains inconsistent regarding its impact on long-term oncological outcomes. While several studies using doublet-based TNT have reported higher pathological complete response rates (pCR) compared to neoadjuvant chemoradiotherapy, few have convincingly demonstrated a survival benefit (2-6). In contrast, the PRODIGE-23 trial demonstrated a survival benefit for patients treated with TNT, yet this benefit was achieved with use of a triplet chemotherapy regimen (mFOLFIRINOX) (1). In the Netherlands, triplet chemotherapy is widely used in the palliative setting. It has been shown to be more effective than doublet chemotherapy, although it is associated with increased toxicity (7-9). Although triplet chemotherapy has not yet been routinely adopted in the TNT setting, its use as part of TNT for patients with high-risk LARC has increased rapidly in recent years, despite the lack of definitive evidence supporting its superior efficacy in these patients. Patients with high-risk tumour characteristics, such as mesorectal fascia (MRF) invasion, grade IV extramural venous invasion (EMVI), tumour deposits (TD), or extensive lateral lymph node metastases (LLN), represent a subgroup with a particularly poor prognosis (10-12), referred to as high-risk LARC. It has been hypothesized that triplet-based TNT could further improve complete response rates compared with doublet-based TNT, and that patients with high-risk tumour characteristics may derive greater benefit from intensified treatment with triplet chemotherapy. Higher complete response rates may translate into improved oncological outcomes and enable organ preservation. However, whether the increased toxicity of triplet chemotherapy is justified by greater efficacy compared with doublet chemotherapy remains the key question of this trial. The primary aim of this study is to investigate whether triplet-based TNT (FOLFOXIRI) provides superior complete response rates compared with doublet-based TNT (CAPOX/FOLFOX) in patients with high-risk LARC.

Objective The objective of this study is to evaluate the effect of neoadjuvant triplet chemotherapy (FOLFOXIRI), chemoradiotherapy, and surgery or a W&W approach (arm A) compared with neoadjuvant doublet chemotherapy (CAPOX/FOLFOX), chemoradiotherapy, and surgery or a W&W approach (arm B) on complete response rates and oncological outcomes in patients with high-risk LARC.

Main trial endpoints The primary endpoint of this study is pCR or sustained clinical complete response (cCR) rate (defined as cCR 1 year after the last day of chemoradiotherapy).

Secondary trial endpoints Secondary endpoints of this study are regrowth rate, local recurrence rate, distant metastases rate, 3- and 5-years regrowth free survival (RFS), 3- and 5-years local recurrence free survival (LRFS), 3- and 5-years distant metastases free survival (DMFS), 3- and 5-years disease free survival (DFS), 3- and 5-years overall survival (OS), successful organ preservation at 2 years, radiological response after ICT, radiological response after chemoradiotherapy, toxicity of ICT, toxicity of chemoradiotherapy, dose reductions during ICT, dose reductions during chemoradiotherapy, completion rate of ICT, completion rate of chemoradiotherapy, the number of patients undergoing surgery, surgical characteristics, pathological response, post-operative morbidity, quality of life, work-productivity, and cost-effectiveness and -utility.

Trial design This is a national, multicentre, open-label, randomised controlled phase III trial. Patients will be randomised to receive FOLFOXIRI followed by chemoradiotherapy (arm A) or CAPOX/FOLFOX followed by chemoradiotherapy as neoadjuvant treatment (arm B). The neoadjuvant treatment will be followed by surgery or a W&W approach.

Patients who meet the inclusion criteria but are not willing to participate in the randomised study, will be treated in accordance with the treating hospital's standard of care. If this corresponds to chemoradiotherapy, patients are asked to participate in the observational cohort (registration arm).

Trial population Patient with non-metastasised, LARC with the presence of at least one high-risk tumour characteristic: MRF invasion, EMVI grade IV, TD, bilateral or extensive enlarged LLN. Patients are required to have a WHO performance status of 0-1 and no contra-indications for the planned neoadjuvant treatment.

Interventions In arm A, patients receive neoadjuvant FOLFOXIRI and chemoradiotherapy as neoadjuvant treatment, followed by surgery or a W&W approach. In arm B, patients receive neoadjuvant CAPOX/FOLFOX and chemoradiotherapy as neoadjuvant treatment, followed by surgery or a W&W approach. Restaging with a pelvic MRI and CT-scan will be performed after 3 or 4 cycles of ICT. Patients with stable or responsive disease receive additional 1 or 2 cycles ICT and continue with neoadjuvant chemoradiotherapy, followed by surgery or a W&W approach. In the observational cohort, patients receive chemoradiotherapy as neoadjuvant treatment, followed by surgery or a W&W approach. First restaging with a pelvic MRI and CT-scan will be performed 6-8 weeks after the last day of chemoradiotherapy. In case of a good or complete response, an endoscopy is performed ≤ 2 weeks and second restaging is planned 14-16 weeks after the last day of chemoradiotherapy. Patients with an incomplete response and resectable disease at first restaging will undergo surgery 10-14 weeks after the last day of chemoradiotherapy. Patients with a good or (near) complete response at second restaging (14-16 weeks) will undergo a third restaging at 26 weeks after the last day of chemoradiotherapy. If a cCR is achieved at that time, patients continue follow-up in a watch-and-wait approach (W&W). Patients with no further improvement in response (sustained incomplete response) will proceed to TME-surgery. In highly selected patients with an ongoing good, but not complete response, a TAMIS can be considered if technically feasible as alternative for TME-surgery.

Ethical considerations relating to the clinical trial including the expected benefit to the individual subject or group of patients represented by the trial subjects as well as the nature and extent of burden and risks The potential benefits of participation in this trial include a higher likelihood of achieving a complete tumour response, which may allow for organ-preserving treatment strategies and thereby improve quality of life. Enhanced tumour regression could also translate into better long-term oncological outcomes, such as improved disease-free and OS. However, these potential benefits must be weighed against the increased toxicity associated with triplet chemotherapy.

Trial-specific risk is limited. The investigational medicinal product has a well-documented and established safety profile and, is in broad use in the palliative setting, proved safe in the phase II MEND-IT trial and is increasingly being used in the neoadjuvant setting. It will be used in the authorised form for its authorised indication. The primary risk associated with participating in the trial is increased toxicity related to the use of ICT, compared to chemoradiotherapy alone. To mitigate this risk, only patients who are deemed fit to receive FOLFOXIRI, with a WHO performance status of 0-1, are eligible for inclusion. The national multidisciplinary writing committee and the Dutch Colorectal Cancer Group anticipate that the potential benefits of the trial outweigh the associated risks. Trial-specific burden is minimal, as it is limited to completing quality of life questionnaires. Participation in these questionnaires is optional, as they pertain to secondary outcome measures.

Inclusion Criteria:

• 18 years or older

• WHO performance score 0-1.

• Fit for (modified dose) triple chemotherapy (FOLFOXIRI)

• Histopathological confirmed rectal cancer. (Lower border of the tumour located on or below the sigmoidal take-off as established on MRI of the pelvis.)

• Confirmed high-risk locally advanced rectal cancer, at high risk of treatment failure, meeting one of the following imaging-based criteria:

  • cT4b-tumour or evident tumour invasion of the MRF: distance to MRF 0 mm AND thickening of the MRF over a length of approximately 5 mm (MRF ≤ 1 mm is not considered sufficient).
  • The presence of grade 4 extramural venous invasion (mrEMVI)
  • The presence of tumour deposits (TD)
  • The presence of bilateral extramesorectal lymph nodes with a short-axis size ≥ 7mm (LLN) or extensive LLN involving pelvic side wall structures, at high risk of an incomplete resection.

• Resectable disease as determined on magnetic resonance imaging (MRI) or deemed resectable disease after neoadjuvant treatment. (Expected gross incomplete resection with overt tumour remaining in the patient after resection, tumour invasion in the neuroforamina, encasement of the ischiatic nerve and invasion of the cortex from S2 and upwards are considered not resectable.)

• Written informed consent.

Exclusion Criteria:

• Evidence of metastatic disease at time of inclusion or within six months prior to inclusion except for patients with enlarged iliac or inguinal lymph nodes and non-specific lung noduli.
• Homozygous DPD deficiency.
• Any chemotherapy within the past 6 months.
• Any contraindication for the planned systemic therapy (e.g., severe allergy, pregnancy, kidney dysfunction and thrombocytopenia), as determined by the medical oncologist.
• Previous radiotherapy in the pelvic area precluding chemoradiotherapy with a dose of 50 - 50.4 Gy.
• Any contraindication for the planned chemoradiotherapy (e.g., severe allergy to the chemotherapy agent or no possibility to receive radiotherapy), as determined by the medical oncologist and/or radiation oncologist.
• Any contraindication to undergo surgery, as determined by the surgeon and/or anaesthesiologist.
• Concurrent malignancies that interfere with the planned study treatment or the prognosis of the resected tumour.
• Microsatellite instability (MSI).