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Name of the study

Neo-adjuvant FOLFOXIRI and chemoradiotherapy for high risk (“ugly”) locally advanced rectal cancer

Researchers and contact information

Project leader
Dr. J.W.A. (Pim) Burger

Coordinating investigators
Drs. D.M.J. (Davy) Creemers
T: +31 (0)40 2396641

Drs. E. (Evi) Banken
T: +31 (0)40 2396641

Summary study

Despite developments in the multidisciplinary treatment of patients with locally advanced rectal cancer (LARC) local and distant recurrence rates remain between 5-10% and 25-40% respectively.
Several studies established tumour characteristics with a particularly bad prognosis; it was demonstrated that the occurrence of mesorectal fascia involvement (MRF+), grade 4 extramural venous invasion (EMVI), tumour deposits (TD) and enlarged lateral lymph nodes (LLN) lead to high local
and distant recurrence rates and decreased survival when compared with LARC without these particularly negative prognostic factors. The addition of induction chemotherapy (ICT) has the ability to induce more local tumour downstaging, possibly leading to resectability of previously unresectable
tumours, more R0 resections and less extensive surgery or even a complete response. ICT may also have the potential to eradicate micrometastases. Since patients with these tumour characteristics have a particularly bad prognosis, both with regard to locoregional and distant failure, a more
intensified neoadjuvant treatment with FOLFOXIRI is anticipated to improve short- and long term

Study design
This is a multicentre, single-arm, open-label, phase II trial in which all included patients will receive induction FOLFOXIRI chemotherapy (ICT) followed by neoadjuvant chemoradiotherapy and surgery.

Primary endpoint
The number of patients with a complete pathological response or sustained clinical complete response (during 1 year) after ICT+CRT.

Secondary endpoint
Clinical response to ICT and ICT+CRT, pathological response, R0 resection rate, local recurrence free survival, distant metastases free survival, progression free survival, disease free survival and overall survival, systemic therapy related toxicity (NCI-CTCAE v5.0 grade ≥3), completion of neoadjuvant treatment, major postoperative complications (Clavien-Dindo grade ≥3, up to 30 days postoperatively), quality of life and costs.

Sample size
After analysing a retrospective series of patients with hr-LARC who received ICT and CRT from our own institution, we expect the pCR/sustained cCR rate to be 20% in our study group. Based on these data and the available literature a 10% pCR would be expected in patients with hr-LARC who received CRT alone. A pCR/sustained cCR rate of 20% (reflecting a 100% increase in pCR/cCR) was predicted for in the study population. With a 5% significance level and a 90% power, a total sample size of 121 patients is required. We expect a low drop-out of 5%, resulting in a total of 128 patients.


mend-it.jpgAll patients start treatment with induction chemotherapy. Patients are referred to the medical oncologists within 2 weeks after inclusion, and induction chemotherapy starts within 4 weeks after inclusion. The treating medical oncologist is responsible for the counselling, administration and followup regarding the neoadjuvant treatment. Induction chemotherapy consists of four two-weekly cycles of FOLFOXIRI. After four cycles of FOLFOXIRI, local- and distant restaging with a pelvic MRI and highdose thoracoabdominal CT-scan (+/- FDG-PET/CT-scan) is performed. If a patient has progressive and unresectable disease or developed distant metastases, the best palliative treatment is offered according to standard of care. If a patient has progressive disease, but surgery is still considered feasible, no further systemic therapy will be administered, and the patient will start with CRT within 3-
6 weeks after the first day of the last administered cycle of chemotherapy. If a patient has stable or responsive disease, induction therapy will be continued with two cycles of FOLFOXIRI. CRT will then start within 3-6 weeks after the first day of the last administered cycle of systemic therapy.

Participating centres

  • Catharina Ziekenhuis Eindhoven
  • Isala
  • Erasmus Medisch Centrum
  • NKI-AvL
  • Elkerliek ziekenhuis
  • St. Anna Ziekenhuis

Planned participating centres

  • Radboud Universitair Medisch Centrum
  • Maastricht Universitair Medisch Centrum
  • Universitair Medisch Centrum Utrecht
  • Amsterdam Universitair Medische Centra
  • Rijnstate
  • Máxima Medisch Centrum
  • St. Jans Gasthuis
  • Maastro