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

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/ 5-fluorouracil 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.

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 (clinical T4a, i.e. overgrowth to an adjacent organ or structure like the prostate, urinary bladder, uterus, sacrum, pelvic floor or side wall (according to tumor node metastasis (TNM-Classification version 5)), clinical T4b, 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 Mesorectal Fascia (MRF+), i.e. tumor or lymph node < 1 mm from the mesorectal fascia. Enlarged lateral nodes (LN), > 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 Dihydro-Pyrimidine Dehydrogenase (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