NEO: Neoadjuvant Chemotherapy, Excision and Observation for Early Rectal Cancer

Inclusion Criteria:

• Histologically confirmed invasive well-moderately differentiated rectaladenocarcinoma diagnosed within 90 days prior to enrollment.

• Tumour stage cT1-T3abN0 based on pelvic MRI

• cT1N0- tumour invasion into submucosa, no radiographic evidence of mesorectalnodal metastasis, tumour deposits or vascular invasion.

• cT2N0 - tumour invasion into muscularis propria, no radiographic evidence ofmesorectal nodal metastasis, tumour deposits or vascular invasion.

• cT3a,bN0- tumour invasion through the muscularis propria no more than 5 mm intothe subserosa/perirectal tissue and clear of the circumferential radial margin (CRM). Absence of radiographic evidence of mesorectal nodal metastasis, tumourdeposits or lymphovascular invasion.

Note: If the tumour is not visualized in the MRI but there is histological confirmation of rectal adenocarcinoma the patient is eligible.

• cN0 stage based on pelvic MRI. Any nodes ≥ 10 mm in longest dimension are consideredmalignant, regardless of nodal morphology. For pelvic nodes < 10 mm in longestdimension, if nodes are seen and are deemed to be morphologically benign in theopinion of the radiologist and surgeon, the patient is eligible. Patients withvisible pelvic sidewall nodes are excluded

• M0 stage based on no evidence of metastatic disease by CT imaging.

• Mid to low-lying tumour eligible for local tumour excision in the opinion of thetreating surgeon.

• Age of at least 18 years.

• Medically fit to undergo radical surgery as per treating surgeon's discretion

• No contraindications to protocol chemotherapy.

• Adequate normal organ and marrow function as defined below (must be done within 30days prior to enrolment):

• ANC ≥ 1.5 x 109/L

• platelet count ≥100 x 109/L

• bilirubin < 1.5 ULN, excluding Gilbert's syndrome

• Calculated creatinine clearance of ≥ 50 ml/min.

• Clearance to be calculated using Cockcroft formula: Males: 1.23 x (140 - age) xweight (kg) - serum creatinine (μmol/l) ; Females: 1.05 x (140 - age) x weight (kg) - serum creatinine (μmol/l)

• The patient must have an ECOG performance status of 0, 1.

• Patient is able (i.e. sufficiently fluent) and willing to complete the quality oflife and health utility questionnaires.

• Patient consent must be appropriately obtained in accordance with applicable localand regulatory requirements. Each patient must sign a consent form prior toenrollment in the trial to document their willingness to participate.

• Must be accessible for treatment and follow up. Patients registered on this trialmust be treated with chemotherapy and followed at the enrolling centre.

• Protocol treatment is to begin within 5 working days of patient enrollment.

• Women/men of childbearing potential must have agreed to use a highly effectivecontraceptive method during and for 6 months after completion of chemotherapy.

Exclusion Criteria:

• Patient has pathologic high risk factors on either the initial biopsy specimenreport or follow-up biopsy (if done): high histologic grade, mucinous histology,lymphatic or vascular invasion.

• History of other malignancies, except: adequately treated non-melanoma skin cancer,curatively treated in-situ cancer of the cervix, or other solid tumours curativelytreated with no evidence of disease for ≥ 5 years.

• Synchronous cancer.

• Prior treatment for rectal cancer.

• Previous pelvic radiation for any reason.

• Patients with known dihydropyrimidine dehydrogenase deficiency

• Treatment with other investigational drugs or anti-cancer therapy within 28 daysprior to enrolment.

• Clinically significant (i.e. active) cardiovascular disease for example cerebrovascular accidents (< 6 months prior to enrolment), myocardial infarction (< 6months prior to enrolment), unstable angina, New York Heart Association (NYHA) gradeII or higher, congestive heart failure, serious cardiac arrhythmia requiringmedication.

• Any contra-indications to undergo MRI imaging.