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