Short Course Radiation Therapy Followed by Pre-operative Chemotherapy and Surgery in High-risk Rectal Cancer

Study Overview
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Brief Summary
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Patients with a primary rectal cancer without detectable distant metastasis who after locoregional therapy only, meaning preoperative radio(chemo)therapy plus surgery have at least a 40% risk of not having a CRM negative resection or a recurrence, local or distant, within three years will be treated with the short course 5 x 5 Gy radiation scheme followed by four cycles of combination chemotherapy (capecitabine and oxaliplatin) and TME surgery

Detailed Description
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The multicentre, multinational RAPIDO (Rectal cancer And Pre-operative Induction therapy followed by Dedicated Operation, EudraCT number 2010-023957-12) closed patient entry in June 2016 after having randomised the planned number of 920 patients. In the study, patients were randomised to conventional chemoradiotherapy (CRT) to 50 Gy with capecitabine followed by surgery or to short-course radiotherapy (scRT, 5 x 5 Gy), 6 cycles of oxaliplatin-capecitabine (CAPOX) followed by surgery. In the CRT arm, adjuvant chemotherapy with 8 cycles of CAPOX was optional. At the time of closure of the RAPIDO study, it was discussed in Uppsala whether CRT should be the reference treatment for these high-risk rectal cancers, the experimental treatment or an alternative. Influenced by a Polish study reported by Bujko et al in 2016 with a similar design comparing CRT with scRT followed by 3 cycles of FOLFOX), it was decided that the reference treatment for patient with primary rectal cancer at high risk of failing either locally or systemically should be scRT followed by 4 cycles of CAPOX and surgery. This regimen, identical to the experimental arm in a Chinese trial (Stellar trial (ClinicalTrials.gov NCT02533271), preliminarily revealing promising pCR rates has since then been the reference treatment for patients having the same inclusion criteria as in the RAPIDO trial. Other centres in Sweden have also decided to use this regimen as reference treatment. A formal protocol is written and approved.

Official Title
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Phase II of Short Course Radiation Therapy Followed by Pre-operative Chemotherapy and Surgery in Primary High-risk Rectal Cancer

Conditions
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Rectal Cancer

Intervention / Treatment
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* Combination Product: radiotherapy, capecitabine, oxaliplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: • 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 (T4b, 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 7), cT4a, 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. Four or more nodes, whether enlarged or not, with a rounded, homogeneous appearance is thus not sufficient. Positive MRF, i.e. tumour 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 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
Intervention Model: Single Group Assignment
Interventional Model Description: Treatment with short-course radiotherapy (scRT) followed by 4 cycles of CAPOX chemotherapy and surgery in locally advanced rectal cancer while waiting for the results of the randomized phase III RAPIDO trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LARCT-US<br>Short Course Radiation Therapy (5 x 5 Gy in 1 week, scRT) followed by 4 cycles of Pre-operative Chemotherapy using capecitabine and oxaliplatin (CAPOX) and Surgery in High-risk Rectal Cancer | Combination Product: radiotherapy, capecitabine, oxaliplatin<br>* 5x5 Gy radiotherapy in 1 week, 4 cycles of CAPOX (capecitabine 1000 mg/m2 x2 d 1-14, oxaliplatin 130 mg/m2 d 1 every third week), surgery<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathological complete response (pCR) rate and clinical complete response (cCR) rate | pCR assessed at pathological examination of the surgical specimen, cCR at clinical and radiological (MRI) examination | pCR assessed directly after surgery and cCR 12 months after end of treatment if no surgery is performed (cCR)] | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease-free survival | non-radical surgery, recurrence or death within 3 years | 3 years | 
| Neoadjuvant rectal score (NAR score) | Score from 0 - 100, where 0 is best | After surgery when the patological examination of the surgical specimen is completed | 
| Incidence of Treatment-Emergent Adverse Events | CTCAE v 4.0 | within 60 days after end of treatment | 
| Long-term Adverse Events | CTCAE v 4.0 | 4 years after end of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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rectal cancer, high risk, total neoadjuvant treatment