Bevacizumab And Combination Chemotherapy in Rectal Cancer Until Surgery

Inclusion * Histologically confirmed diagnosis of adenocarcinoma of the rectum * Distal part of the tumour within 4-12 cm of the anal verge * No unequivocal evidence of established metastatic disease (on chest/abdominal/pelvis CT).Patients with equivocal lesions (as determined at MDT) are eligible * MRI-evaluated locally advanced tumour with the following: * T3 tumours extending (≥ 4 mm), beyond the muscularis propria N0-N2 * Or tumours (involving or threatening the peritoneal surface) * OR presence of macroscopic extramural venous invasion (V2 disease) * AND for tumours below the peritoneal reflection, the primary tumour or involved lymph node (on MRI) must be \>1 mm from the mesorectal fascia * Measurable disease (using RECIST criteria v1.1) * WHO performance status 0 - 1 * In the opinion of the investigator: * General condition considered suitable for radical pelvic surgery * Candidate for systemic therapy with FOLFOX/FOLFOXIRI plus bevacizumab * Adequate bone marrow, hepatic and renal function: * Haemoglobin ≥80 g/L * ANC ≥2 x 109/L * Platelet count ≥100 x 109/L * ALT or AST ≤1.5 x ULN (upper limit of normal) * ALP ≤1.5 x ULN * Total bilirubin ≤1.5 x ULN * Serum creatinine ≤1.5 x ULN * Creatinine clearance ≥50 mL/min using the Cockcroft-Gault formula * INR ≤ 1.1 * Urine protein ≤1+ with dipstick or urine analysis \- For proteinuria ≥2+ or urine protein/creatinine ratio ≥ 1.0, 24-h urine protein should be obtained and the level must be ≤2 g for eligibility * No evidence of established or acute ischaemic heart disease on ECG and normal clinical cardiovascular assessment * No known significant impairment of intestinal absorption * At least 18 years of age, but not more than 75 years * Willing and able to give informed consent, comply with treatment and follow up schedule Exclusion * Disease outside of the mesorectal envelope (internal iliac/lateral pelvic lymph node) * Clinically significant cardiovascular or coronary disease \<2 years before randomisation * History of interstitial lung disease e.g. pneumonitis or pulmonary fibrosis or evidence of interstitial lung disease on baseline chest CT scan * History of an arterial thromboembolic event during the previous 2 years * Evidence of bleeding problems or coagulopathy * Significant and continuing rectal bleeding leading to a haemoglobin \<8 g/dL * Patients receiving warfarin/coumarin derived anticoagulants at full therapeutic doses are excluded, but prophylactic doses of 1mg to prevent Hickman line clotting are eligible * Chronic use of aspirin (\>325 mg/day) or clopidogrel (\>75 mg/day) within 10 days of first planned study treatment * Require regular use of anti-diarrhoeal (e.g. daily use of loperamide) * Serious uncontrolled intercurrent illness including poorly controlled diabetes mellitus * Known hypersensitivity to any of the study drugs * Serious wound, ulcer or bone fracture * Current or impending rectal obstruction * Metallic colonic or rectal stent in situ * Previous pelvic radiotherapy * Previous intolerance to fluoropyrimidine chemotherapy * Previous treatment with bisphosphonates * Infectious illness requiring antibiotics within 1 week of randomisation * Previous treatment with another investigational agent within 30 days prior to randomisation * Patients with a history of previous malignancy in the past 5 years, excepting basocellular or squamous cell skin cancer, or properly treated cervicouterine cancer in situ * Known HIV, HBV or HCV infection * Current smoker, or clinically relevant history of drug or alcohol abuse * Pregnant or lactating women or pre menopausal women not using adequate contraception. Men and women of child-bearing potential must use adequate contraception * Patients with any other condition or concurrent medical or psychiatric disease who, in the opinion of the investigator, is not eligible to enter the study * Inability or unwillingness to comply with the protocol