Induction Chemotherapy for Locally Recurrent Rectal Cancer

Study Overview
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Brief Summary
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This is a multicentre, open-label, parallel arms, phase IIII study that randomises patients with locally recurrent rectal cancer in a 1:1 ratio to receive either induction chemotherapy followed by neoadjuvant chemoradiotherapy and surgery (experimental arm) or neoadjuvant chemoradiotherapy and surgery alone (control arm)

Official Title
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Multicentre, Open-label, Randomised, Controlled, Parallel Arms Clinical Trial of Induction Chemotherapy Followed by Chemoradiotherapy Versus Chemoradiotherapy Alone as Neoadjuvant Treatment for Locally Recurrent Rectal Cancer - PelvEx II

Conditions
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Recurrent Rectal Cancer

Intervention / Treatment
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* Drug: Combination drug
* Radiation: Chemoradiotherapy
* Procedure: Surgery locally recurrent rectal cancer


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 years or older Confirmed locally recurrent rectal cancer after total or partial mesorectal resection for rectal or distal sigmoidal cancer either by histopathology ór clinically proven (evidence on imaging in combination with clinical findings, with consensus in MDT) Resectable disease determined by magnetic resonance imaging (MRI) or deemed resectable after neoadjuvant treatment with chemoradiotherapy. WHO performance score 0-1 Written informed consent Exclusion Criteria: Radiological evidence of metastatic disease (e.g. liver, lung) at time of randomisation or in the six months prior to randomisation. Known homozygous DPD deficiency Any chemotherapy in the past 6 months. Any contraindication for the planned chemotherapy, as determined by the medical oncologist. Radiotherapy in the past 6 months for primary rectal cancer. Any contraindication for the planned chemoradiotherapy, as determined by the medical oncologist and/or radiation oncologist. Any contraindication for surgery, as determined by the surgeon and/or anaesthesiologist. Concurrent malignancies that interfere with the planned study treatment or the prognosis of resected LRRC.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Induction chemotherapy + chemoradiotherapy + surgery<br>Induction chemotherapy followed by neoadjuvant chemoradiotherapy and surgery | Drug: Combination drug<br>* Induction chemotherapy consists of either three three-weekly cycles of CAPOX (oxaliplatin 130 mg/m2 BSA IV + capecitabine 1000 mg/m2 BSA, orally, twice daily) or four two-weekly cycles of FOLFOX (85 mg/m2 BSA of oxaliplatin IV + 400 mg/m2 BSA of leucovorin IV + 400 mg/m2 BSA of bolus 5-fluorouracil IV followed by 2400 mg/m2 BSA of continuous 5-fluorouracil IV). It is left to the discretion of the treating medical oncologist which of the two will be administered. In case of (previous) unacceptable toxicity (physician's discretion) to oxaliplatin, FOLFIRI may be prescribed. FOLFIRI (180 mg/m2 BSA of irinotecan IV + 400 mg/m2 BSA of leucovorin IV + 400 mg/m2 BSA of bolus 5-fluorouracil IV followed by 2400 mg/m2 BSA of continuous 5-fluorouracil IV) consists of four two-weekly cycles. If a patient has stable or responsive disease, induction chemotherapy will be continued with either one three-weekly cycle of CAPOX or two two-weekly cycles of FOLFOX/FOLFIRI.<br>* Other names: FOLFIRI;Radiation: Chemoradiotherapy<br>* Concomitant chemotherapy agent: capecitabine Radiotherapy dose: full course radiotherapy consists of 25x2.0 or 28x1.8 Gy. In case of previous radiotherapy, the radiotherapy dose will consist of 15x2.0 Gy.<br>Procedure: Surgery locally recurrent rectal cancer<br>* Type of surgery depends on the location of the recurrence and involvement of adjacent structures and is left to the discretion of the operating surgeon. Intraoperative radiotherapy is optional.<br>|
| Active Comparator: Neoadjuvant chemotherapy + surgery<br>Neoadjuvant chemoradiotherapy followed by surgery | Radiation: Chemoradiotherapy<br>* Concomitant chemotherapy agent: capecitabine Radiotherapy dose: full course radiotherapy consists of 25x2.0 or 28x1.8 Gy. In case of previous radiotherapy, the radiotherapy dose will consist of 15x2.0 Gy.<br>Procedure: Surgery locally recurrent rectal cancer<br>* Type of surgery depends on the location of the recurrence and involvement of adjacent structures and is left to the discretion of the operating surgeon. Intraoperative radiotherapy is optional.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients with a clear resection margin | A resection margin is considered clear (R0), if there are no tumour cells in any of the resection surfaces as determined by microscopy (resection margin > 0mm) | Scored within 1 one month of surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Local recurrence free survival |  | Assessed up to 5 years | 
| Progression free survival |  | Assessed up to 5 years | 
| Metastasis free survival |  | Assessed up to 5 years | 
| Disease free survival |  | Assessed up to 5 years | 
| Overall survival |  | Assessed up to 5 years | 
| Pathologic response | Scored according to Mandard | Scored within 1 month of surgery | 
| Toxicity induction chemotherapy | Adverse events grade 3 or higher according to the NCI-CTCAE v5.0 | Scored until one month after the last administration of the chemotherapy | 
| Compliance induction chemotherapy |  | Scored within 1 month after start chemoradiotherapy | 
| Toxicity chemoradiotherapy | Adverse events grade 3 or higher according to the NCI-CTCAE v5.0 | Scored until 3 months after the last administration of the radiotherapy | 
| Compliance chemoradiotherapy |  | Evaluation at time of surgery | 
| Number of patients undergoing surgery |  | Surgery is scheduled 10-14 weeks after finishing chemoradiotherapy | 
| Surgical characteristics | including data on intra-operative radiotherapy | Evaluation directly postoperative | 
| Major surgical morbidity | Clavien-Dindo grade 3 or higher | 30 and 90-days postoperative | 
| Radiological response | mrTRG | Restaging is performed after 3 cycles of CAPOX (1 cycle is 3 weeks) or 4 cycles of CAPOX/FOLFOX (1 cycle is 2 weeks). Second restaging is performed 4-6 weeks after finishing chemoradiotherapy | 
| Cancer specific quality of life | QLQ-C30 | at baseline, 3 months and 12 months postoperative | 
| Cost-effectiveness | EQ-5D-5L | at baseline, 3 months and 12 months postoperative | 
| Colorectal cancer specific quality of life | QLQ-CR29 | at baseline, 3 months and 12 months postoperative | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Locally recurrent rectal cancer, Neoadjuvant therapy, Induction chemotherapy, Resection margin