Triplet vs doublet induction therapy with chemoradiotherapy for high-risk locally advanced rectal cancer, followed by surgery or watch-and-wait

Is this trial a fit for you?

A plain-English reading of the study's rules. Only the study team can confirm whether you qualify.

What this trial studies

Patients with high-risk locally advanced rectal cancer are assigned to receive either FOLFOXIRI or CAPOX/FOLFOX induction chemotherapy, followed by chemoradiotherapy and then either surgery or a watch-and-wait approach. The study aims to determine if the triplet regimen yields higher complete response rates, improved quality of life, and better oncologic outcomes despite higher toxicity. The design reflects total neoadjuvant therapy principles and may influence future practice in selecting induction regimens. Outcomes include pathological complete response, survival metrics, and toxicity profiles. The trial is phase 3 and compares two induction strategies prior to definitive local treatment.

Why it matters

Who can join: the full rules

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).

Where it's running

• Rijnstate
  Arnhem, Gelderland, Netherlands Recruiting
• Maastricht UMC+
  Maastricht, Limburg, Netherlands Recruiting
• Jeroen Bosch ziekenhuis
  's-Hertogenbosch, North Brabant, Netherlands Recruiting
• Catharina Hospital Eindhoven
  Eindhoven, North Brabant, Netherlands Recruiting
• Amsterdam UMC
  Amsterdam, North Holland, Netherlands Recruiting
• Deventer Ziekenhuis
  Deventer, Overijssel, Netherlands Recruiting

Study contacts

• Principal investigator: Jacobus WA Burger, Prof. dr. — Catharina Ziekenhuis Eindhoven
• Study coordinator: Maaike M Borg, Drs.
• Email: mend-it@catharinaziekenhuis.nl
• Phone: +31 40 239 6641

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How to take part

1. Review the eligibility criteria above with your treating physician.
2. Check the official listing on ClinicalTrials.gov for the latest contact details and recruitment status.
3. Contact the study coordinator or principal investigator to ask for pre-screening. Pre-screening is free and never obligates you to enroll.