Clinical trial NCT04838496: Induction Chemotherapy for Locally Advanced Rectal Cancer
Official title: Neo-adjuvant FOLFOXIRI and Chemoradiotherapy for High Risk ("Ugly") Locally Advanced Rectal Cancer
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE2
Conditions: Rectal Cancer
Keywords: Locally advanced rectal cancer
Induction chemotherapy
Neoadjuvant chemotherapy
Chemoradiotherapy
Lead sponsor: Catharina Ziekenhuis Eindhoven
Sponsor class: OTHER
First posted: 2021-04-09
Enrollment: 128
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: This is a multicentre, single-arm, prospective phase 2 study.
Primary purpose: TREATMENT

Brief summary: Despite developments in the multidisciplinary treatment of patients with locally advanced rectal cancer (LARC), such as the introduction of total mesorectal excision (TME) by Heald et al. and the shift from adjuvant to neoadjuvant (chemo)radiotherapy ((C)RT), local and distant recurrence rates remain between 5-10% and 25-40% respectively. Several studies established tumour characteristics with 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. This type of LARC is described as high risk LARC (hr-LARC). Achieving a resection with clear resection margins (R0) is an important prognostic factor for local (LR) and distant recurrence (DM) as well as survival. With the aim to further reduce the risk of recurrent rectal cancer, to diminish distant metastasis and to improve overall survival for patients with LARC, induction chemotherapy (ICT) became a growing area of research. The addition of 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. In the case of a complete clinical response, surgery may even be omitted. ICT may also have the potential to eradicate micrometastases. Hence, increased local downstaging and reducing distant metastatic spread may reduce LR and DM rates and improve survival and quality of life. In recent years, the use of ICT was investigated and showed promising results, but little is known about the addition of ICT in patients with high risk LARC. Since these patients 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 results.


Eligibility criteria: Inclusion Criteria:

* 18 years or older
* WHO performance score 0-1.
* Histopathologically confirmed rectal cancer.
* Lower border of the tumour located below the sigmoidal take-off as established on MRI of the pelvis.
* Confirmed high-risk locally advanced rectal cancer, meeting one of the following imaging based criteria:

  * Tumour invasion of mesorectal fascia (MRF+)
  * The presence of grade 4 extramural venous invasion (mrEMVI)
  * The presence of tumour deposits (TD)
  * The presence of Extramesorectal lymph nodes with a short-axis size \> 7mm (LNN)
* 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 ischiadic nerve and invasion of the cortex from S3 and upwards are considered not resectable • Written informed consent.

Exclusion Criteria:

* Evidence of metastatic disease at the moment of inclusion or within six months prior to inclusion except for patients with enlarged iliac or inguinal lymph nodes and aspecific lung noduli.
* Homozygous DPD (Dihydropyrimidine dehydrogenase) deficiency.
* Any chemotherapy within the past 6 months.

  o Any contraindication for the planned systemic therapy (e.g. severe allergy, pregnancy, kidney dysfunction and thrombocytopenia), as determined by the medical oncologist.
* Radiotherapy in the pelvic area within the past 6 months.
* 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.

Primary outcomes:
measure: The main study parameter is the proportion of patients with a pathological complete response (pCR) and those patients who started a wait and see strategy and have sustained clinical complete response (cCR) at 1 year.
timeFrame: pCR is determined after surgery directly. There is a cCR in case of a sustained clinical response until at least one year after chemoradiotherapy
Secondary outcomes:
measure: 3-year and 5-year local recurrence free survival.
timeFrame: 3 and 5 year
measure: 3-year and 5-year distant metastasis free survival.
timeFrame: 3 and 5 year
measure: 3-year and 5-year progression free survival.
timeFrame: 3 and 5 year
measure: 3-year and 5-year disease free survival.
timeFrame: 3 and 5 year
measure: 3-year and 5-year overall survival.
timeFrame: 3 and 5 year
measure: Radiological response after induction therapy.
timeFrame: Directly after induction chemotherapy
measure: Radiological response after chemoradiotherapy.
timeFrame: 6-8 weeks after chemoradiotherapy
measure: Pathologic response
timeFrame: Directly after surgery
measure: Toxicity related to induction therapy.
timeFrame: During induction chemotherapy
measure: The induction therapy compliance rate.
timeFrame: During induction chemotherapy
measure: Toxicity of chemoradiotherapy.
timeFrame: During chemoradiotherapy
measure: The compliance rate related to chemoradiotherapy.
timeFrame: During chemoradiotherapy
measure: Number of patients undergoing surgery.
timeFrame: immediately after surgery
measure: Type of surgery, including the use of intra-operative radiotherapy.
timeFrame: During the surgical procedure
measure: Major surgical morbidity rate
timeFrame: During admission for surgery.
measure: Generic and cancer-specific Quality of life (QoL) assessments during treatment using Quality of life Questionnaires (QLQ)
timeFrame: At the moment of inclusion, after 3 months and after 12 months.
measure: Generic and cancer-specific Quality of life (QoL) assessments during treatment
timeFrame: At the moment of inclusion, after 3 months and after 12 months.
measure: Generic and cancer-specific Quality of life (QoL) assessments during treatment
timeFrame: At the moment of inclusion, after 3 months and after 12 months.
measure: Costs
timeFrame: At the moment of inclusion, after 3 months and after 12 months.
Other outcomes:
Locations:
city: Eindhoven
country: Netherlands
facility: Catharina Hospital Eindhoven
state: Noord-Brabant
city: Amsterdam
country: Netherlands
facility: Netherlands Cancer Institute
state: Noord-Holland
city: Maastricht
country: Netherlands
facility: Maastricht University Medical Centre
city: Nijmegen
country: Netherlands
facility: Radboud University Medical Centre
city: Rotterdam
country: Netherlands
facility: Erasmus MC Cancer institute
city: Utrecht
country: Netherlands
facility: University Medical Centre
city: Zwolle
country: Netherlands
facility: Isala hospital
Study officials:
affiliation: Catharina Ziekenhuis Eindhoven
name: Pim J.W.A. Burger, MD. PhD.
role: PRINCIPAL_INVESTIGATOR
References:
citation: van den Berg K, Schaap DP, Voogt ELK, Buffart TE, Verheul HMW, de Groot JWB, Verhoef C, Melenhorst J, Roodhart JML, de Wilt JHW, van Westreenen HL, Aalbers AGJ, van 't Veer M, Marijnen CAM, Vincent J, Simkens LHJ, Peters NAJB, Berbee M, Werter IM, Snaebjornsson P, Peulen HMU, van Lijnschoten IG, Roef MJ, Nieuwenhuijzen GAP, Bloemen JG, Willems JMWE, Creemers GJM, Nederend J, Rutten HJT, Burger JWA. Neoadjuvant FOLFOXIRI prior to chemoradiotherapy for high-risk ("ugly") locally advanced rectal cancer: study protocol of a single-arm, multicentre, open-label, phase II trial (MEND-IT). BMC Cancer. 2022 Sep 6;22(1):957. doi: 10.1186/s12885-022-09947-w.