Induction Chemotherapy for Locally Advanced Rectal Cancer

NCT ID: NCT04838496

Last Updated: 2021-04-09

Basic Information

• Recruitment Status: NOT_YET_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 128 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-06-01
• Study Completion Date: 2026-06-01

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.

Conditions

Rectal Cancer

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Single-arm study

All patients will receive induction chemotherapy consisting of 4-6 cycles of FOLFOXIRI. Restaging will be performed after 4 cycles with a pelvic MRI and a thoraco-abdominal CT-scan. In case of stable or responsive disease, the remaining 2 cycles of FOLFOXIRI will be provided. In case of progressive, but still resectable disease, chemoradiation will be provided immediately, without the remaining 2 cycles of FOLFOXIRI. Restaging will be performed after chemoradiation. In case of resectable disease, surgery is performed.

Group Type: EXPERIMENTAL

FOLFOXIRI Protocol

Intervention Type: DRUG

FOLFOXIRI consists of oxaliplatin, irinotecan, leucovorin and 5-fluorouracil and is administered every 2 weeks:

Dosing:

• Day 1: irinotecan 165 mg/m2 body-surface area (BSA) intravenously (IV), followed by oxaliplatin 85mg/m2 BSA IV in combination with leucovorin 400mg/m2 BSA, followed by:
• Day 1-2: 3200 mg/m2 BSA of continuous 5-fluorouracil IV
• Day 3-14: rest days.

Both regimen are initially administered for four cycles. In case of responsive or stable disease, a 5th and 6th cycle of FOLFOXIRI will be administered.

In case of unacceptable toxicity, the aforementioned dosages can be reduced or one or more chemotherapeutical agents can be omitted at discretion of the medical oncologist and will be noted in the patient's medical file. At discretion of the medical oncologist, a start dosage of 75% of the advised dosage could be considered in patients above 70 years of age.

Interventions

FOLFOXIRI Protocol

FOLFOXIRI consists of oxaliplatin, irinotecan, leucovorin and 5-fluorouracil and is administered every 2 weeks:

Dosing:

• Day 1: irinotecan 165 mg/m2 body-surface area (BSA) intravenously (IV), followed by oxaliplatin 85mg/m2 BSA IV in combination with leucovorin 400mg/m2 BSA, followed by:
• Day 1-2: 3200 mg/m2 BSA of continuous 5-fluorouracil IV
• Day 3-14: rest days.

Both regimen are initially administered for four cycles. In case of responsive or stable disease, a 5th and 6th cycle of FOLFOXIRI will be administered.

In case of unacceptable toxicity, the aforementioned dosages can be reduced or one or more chemotherapeutical agents can be omitted at discretion of the medical oncologist and will be noted in the patient's medical file. At discretion of the medical oncologist, a start dosage of 75% of the advised dosage could be considered in patients above 70 years of age.

Intervention Type: DRUG

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Catharina Ziekenhuis Eindhoven

OTHER

Sponsor Role: lead

Responsible Party

J. W. A. Burger

Principal investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Pim J.W.A. Burger, MD. PhD.

Role: PRINCIPAL_INVESTIGATOR

Catharina Ziekenhuis Eindhoven

Locations

Catharina Hospital Eindhoven

Eindhoven, North Brabant, Netherlands

Netherlands Cancer Institute

Amsterdam, North Holland, Netherlands

Maastricht University Medical Centre

Maastricht, , Netherlands

Radboud University Medical Centre

Nijmegen, , Netherlands

Erasmus MC Cancer institute

Rotterdam, , Netherlands

University Medical Centre

Utrecht, , Netherlands

Isala hospital

Zwolle, , Netherlands

Countries

Netherlands

Central Contacts

Kim van den Berg, MD

Role: CONTACT

kim.vd.berg@catharinaziekenhuis.nl

040-2396641

Facility Contacts

Pim Burger, MD/PhD

Role: primary

pim.burger@catharinaziekenhuis.nl

References

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.

Reference Type: DERIVED

PMID: 36068495 (View on PubMed)

Other Identifiers

NL74465.100.20

Identifier Type: -

Identifier Source: org_study_id