Rectal Cancer And Pre-operative Induction Therapy Followed by Dedicated Operation. The RAPIDO Trial

Study Overview
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Brief Summary
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Currently the 3-year disease free survival of patients with locally advanced rectal cancer is about 50%. Current standard treatment for patients at high risk of failing locally and/or systemically includes pre-operative long course radiotherapy (5 weeks) in combination with chemotherapy (so called neoadjuvant chemoradiotherapy). The neoadjuvant chemoradiotherapy has been demonstrated to improve local control, but had no effect on the overall survival. Different studies in patients with rectal cancer studying the effect of adjuvant post operative chemotherapy did not result in an improved survival. This may be due the fact that rectal cancer surgery (TME) is associated with a high complication rate so substantial proportion of patients cannot receive chemotherapy postoperatively. An alternative approach is to administer the systemic therapy preoperative. To guarantee control of the rectum tumor short-course radiotherapy (5 days) is given, as different studies showed local control of the tumor for a long time. During this waiting period the patient is in a good condition to receive an optimal dose of chemotherapy. The investigators hypothesize that with this proposed protocol both the local tumour and possible micrometastases are effectively treated and that this will result in an increased survival. The investigators will compare this with the standard treatment of neoadjuvant chemoradiation followed by TME surgery and optional adjuvant chemotherapy.

Detailed Description
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Patients will be randomized between an experimental group (arm B) in which short course 5 x 5 Gy radiation scheme is followed by six cycles of combination chemotherapy (capecitabine/5FU and oxaliplatin) and surgery and a control group (arm A) with long course chemoradiotherapy followed by surgery. In arm A adjuvant chemotherapy is allowed according to the local protocol of the institution. In both groups the rectal tumour will be removed by TME surgery or more extensive surgery if required because of tumour extent.

Official Title
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Randomized Multicentre Phase III Study of Short Course Radiation Therapy Followed by Prolonged Pre-operative Chemotherapy and Surgery in Primary High Risk Rectal Cancer Compared to Standard Chemoradiotherapy and Surgery and Optional Adjuvant Chemotherapy.

Conditions
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Rectal Cancer

Intervention / Treatment
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* Other: M1 scheme
* Other: standard long course chemoradiotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Primary tumour characteristics: Histological proof of newly diagnosed primary adenocarcinoma of the rectum Locally advanced tumour fulfilling at least one of the following criteria on pelvic MRI indicating high risk of failing locally and/or systemically (T4a, i.e. overgrowth to an adjacent organ or structure like the prostate, urinary bladder, uterus, sacrum, pelvic floor or side wall (according to TNM version 5), cT4b, i.e. peritoneal involvement, extramural vascular invasion (EMVI+). N2, i.e. four or more lymph nodes in the mesorectum showing morphological signs on MRI indicating metastatic disease. Positive MRF, i.e. tumor or lymph node < 1 mm from the mesorectal fascia. Enlarged lateral nodes, > 1 cm (lat LN+) Exclusion Criteria: Extensive growth into cranial part of the sacrum (above S3) or the lumbosacral nerve roots indicating that surgery will never be possible even if substantial tumour down-sizing is seen Presence of metastatic disease or recurrent rectal tumour Familial Adenomatosis Polyposis coli (FAP), Hereditary Non-Polyposis Colorectal Cancer (HNPCC), active Crohn¡¦s disease or active ulcerative Colitis Concomitant malignancies, except for adequately treated basocellular carcinoma of the skin or in situ carcinoma of the cervix uteri. Subjects with prior malignancies must be disease-free for at least 5 years Known DPD deficiency Any contraindications to MRI (e.g. patients with pacemakers) Medical or psychiatric conditions that compromise the patient's ability to give informed consent Concurrent uncontrolled medical conditions Any investigational treatment for rectal cancer within the past month Pregnancy or breast feeding Patients with known malabsorption syndromes or a lack of physical integrity of the upper gastrointestinal tract Clinically significant (i.e. active) cardiac disease (e.g. congestive heart failure, symptomatic coronary artery disease and cardiac dysrhythmia, e.g. atrial fibrillation, even if controlled with medication) or myocardial infarction within the past 12 months Patients with symptoms or history of peripheral neuropathy

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
Interventional Model Description: standard arm: 5.5 weeks chemoradiation -> surgery -> optional chemotherapy experimental arm: 5x5Gy -> 12 wks chemotherapy -> surgery
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: B: 5x5Gy -> CAPOX -> surgery<br>experimental group (arm B) M1 scheme | Other: M1 scheme<br>* short course 5 x 5 Gy radiation scheme is followed by six cycles of combination chemotherapy (capecitabine and oxaliplatin (CAPOX)) and surgery. FOLFOX4 may be given as alternative for CAPOX<br>|
| Active Comparator: A: 5 weeks chemoradiation -> surgery<br>control group (arm A) standard long course chemoradiotherapy | Other: standard long course chemoradiotherapy<br>* long course chemoradiotherapy followed by surgery. Optional adjuvant chemotherapy (CAPOX or FOLFOX) is allowed in the control group.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease related Treatment Failure (DrTF) | DrTF = Either local or distant relapse or death caused by the rectal carcinoma whichever comes first. In case of nonrectal cancer related death patients will be censored at date of death. In case of a second primary tumour patients will be censored at the date of diagnosis of the second primary tumour. In case of local regrowth after wait & watch strategy, followed by no resection or R2 resection, diagnosis local regrowth is taken. Patients lost to follow-up will be censored the last date of patient visit. Survival curves for Disease related Treatment Failure after 3 years of follow-up will be constructed using the method of Kaplan and Meier. | 3 year follow-up after surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | Overall survival will be computed as the time between randomization and colorectal cancer or treatment related death. Patients lost to follow-up will be censored the last date of patient visit. In case of a second primary tumour patients will be censored at the date of diagnosis of the second primary tumour. | 10 year | 
| CRM negative rate | Circumferential resection margin > 1 mm | within 30 days | 
| pCR rate | Pathological complete response after neo-adjuvant treatment | within 30 days | 
| Short and long-term toxicity | Treatment associated toxicity | 3 year follow-up | 
| Surgical complications | Wound rupture, bleeding, infection, rectal anastomotic leak | 3 year follow-up | 
| Quality of life QLQ-C30 | Quality of life QLQ-C30 | 3 year after surgery | 
| Quality of life QLQ-CR-29+ | Quality of life QLQ-CR-29+ | 3 year after surgery | 
| Quality of life QLQ-CIPN20 | Quality of life QLQ-CIPN20 | 3 year after surgery | 
| Quality of life LARS | LARS | 3 year after surgery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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rectal cancer, radiotherapy, chemotherapy, 5x5, capecitbine, oxaliplatin, CAPOX, FOLFOX, folinic acid, fluorouracil