Inclusion Criteria

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:

- T3b T3c or T3d, N0-N2

- OR presence of macroscopic extramural venous invasion (V2 disease)

- AND T3 tumour must be >2mm 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 ≥8.0 g/dL

- 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 >1+ 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 70 years

- Willing and able to give informed consent, comply with treatment and follow up
schedule

Exclusion

- Primary tumour or lymph node on MRI extending <1mm from, or breaching the
circumferential resection margin

- 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