Folfoxiri Plus Bevacizumab Followed by Chemoradiotherapy Plus Bevacizumab in Patients With Resectable Rectal Cancer

Inclusion Criteria:

• Histologically proven diagnosis of rectal adenocarcinoma. Diagnosis obtained by abiopsy technique which leaves the major portion of the tumor intact.

• Locally advanced, resectable disease defined by the presence of at least one of thefollowing features: tumour extending to within 1 mm of or beyond the mesorectal fascia (ie, circumferential radial margin threatened or involved); lower third (≤ 6 cm fromthe anal verge) cT3 tumours; tumour extending 5 mm or more into perirectal fat; T4tumour (ie, invading surrounding structures or peritoneum); clinical stage III disease (T1-4, N1-2), with the definition of a clinically positive lymph node being any node ≥ 1.0 cm;

• Distal border of the tumor must be located < 12 cm from the anal verge.

• No evidence of metastatic disease by CT scan of the chest and abdomen and total bodyPET-CT scan.

• Tumor must be amenable to curative resection (curative resection can include pelvicexenteration).

• No history of invasive rectal malignancy, regardless of disease-free interval.

• No other rectal cancers (i.e., sarcoma, lymphoma, carcinoid, squamous cell carcinoma,or cloacogenic carcinoma) or synchronous colon cancer.

• No clear indication of involvement of the pelvic side walls by imaging.

• Age between 18 and 75 years.

• ECOG Performance status < 2 if age < 70 years and = 0 if age 71-75 years.

• Life expectancy of at least 5 years (excluding diagnosis of cancer).

• Hematopoietic: absolute neutrophil count ≥ 1,000/mm3; platelet count ≥ 100,000/mm3;haemoglobin level ≥ 10 g/dL.

• Hepatic: total bilirubin ≤ 1.5 times upper limit of normal (ULN); alkaline phosphatase ≤ 2 times ULN; AST ≤ 2 times ULN. [Note: *If AST>ULN, serologic testing for HepatitisB and C must be negative].

• Renal: creatinine clearance > 50 mL/min; no renal disease that would preclude studytreatment or follow-up.

• Written informed consent to experimental treatment and pharmacogenomic analyses.

Exclusion Criteria:

• Previous treatment with oxaliplatin, irinotecan or bevacizumab. Previous 5-fluorouracil or capecitabine treatment is allowed.

• Previous pelvic radiation therapy.

• Hepatic disease that would preclude study treatment or follow-up; uncontrolledcoagulopathy; history of viral hepatitis or other chronic liver disease.

• Cardiovascular disease that would preclude study treatment or follow-up; New YorkHeart Association class III or IV heart disease; active ischemic heart disease;myocardial infarction within the past 6 months; symptomatic arrhythmia; uncontrolledhypertension.

• Lack of upper gastrointestinal tract integrity or malabsorption syndrome; activeinflammatory bowel disease (i.e., patients requiring current medical interventions orwho are symptomatic).

• Pregnant or lactating women. Fertile patients must use effective contraception (i.edouble-barrier contraceptive measures, oral contraception or avoidance of intercourseduring the study and for 30 days after surgery).

• Patients with prior malignancies (with the exception of rectal cancer), includinginvasive colon cancer, are eligible provided they have been disease-free for ≥ 5 yearsand are deemed by their physician to be at low risk for recurrence.

• Other malignancy within the past 5 years with the exception of effectively treatedsquamous cell or basal cell skin cancer, melanoma in situ, carcinoma in situ of thecervix, or carcinoma in situ of the colon or rectum.

• Known hypersensitivity to fluorouracil, oxaliplatin or irinotecan or to Chinesehamster ovary cell proteins.

• Clinically significant peripheral neuropathy (i.e., neurosensory or neuromotortoxicity ≥ grade 2).

• Psychiatric or addictive disorders, or other conditions that, in the opinion of theinvestigator, would preclude study participation