Neoadjuvant FOLFOXIRI and Chemoradiotherapy versus Neoadjuvant CAPOX/FOLFOX and Chemoradiotherapy, followed by Surgery or a Watch-and-Wait Approach in High Risk Locally Advanced Rectal Cancer

Prior treatment

• 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
• Any chemotherapy within the past 6 months
• Previous radiotherapy in the pelvic area precluding chemoradiotherapy with a dose of 50 – 50.4 Gy
• 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

Other illness

• Any contraindication for the planned systemic therapy (e.g., severe allergy, pregnancy, kidney dysfunction and thrombocytopenia), as determined by the medical oncologist
• 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

Other

• Homozygous DPD deficiency
• Microsatellite instability (MSI)

• 18 years or older
• WHO performance score 0-1
• Fit for (modified dose) triple chemotherapy (FOLFOXIRI)
• Histopathological confirmed rectal cancer
• Confirmed high-risk locally advanced rectal cancer, at high risk of treatment failure, meeting one of the following imaging-based criteria: cT4b or evident tumour invasion of the MRF, EMVI grade IV, tumour deposits, ≥ 2 enlarged lateral lymph nodes ≥ 7mm
• 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