Neoadjuvant Chemoradiotherapy Versus Total Neoadjuvant Therapy in the Treatment of T3 Rectal Cancer

Patients are eligible to be included in the study only if they meet all of the followingcriteria:

1. Written informed consent must be given according to ICH/GCP and national/localregulations and be obtained prior to any study-related procedures.
2. Histologically or cytologically confirmed surgically resectable adenocarcinoma of therectum.
3. Clinical stage II (T3, N-) \
4. Absence of metastatic disease
5. Eastern Co-operative Oncology Group (ECOG) performance status > 2.
6. Age > to 18.
7. Estimated life expectancy ≥ 12 months.
8. No active infections requiring systemic antibiotic treatment (oral antibiotics areacceptable at the discretion of the treating physician).
9. Measurable disease, as defined by RECIST Version 1.1
10. Adequate haematological, hepatic, and renal function defined as: a. Renal: i. Calculated creatinine clearance (CrCl) > 50ml/min (see Appendix G) b. Liver function tests: i. Total Bilirubin < 1.5 ULN (OR < 3 x ULN (< Grade 2) in the presence of documented Gilbert's syndrome (unconjugated hyperbilirubinemia) or liver metastases at baseline.) ii. ALT and AST < 2.5 x ULN (< 5 x ULN with liver involvement of their cancer) iii. Alkaline Phosphatase < 2.5 x ULN (< 5 x ULN with liver involvement of their cancer) c. Haematology: i. Haemoglobin > 9 g/dL (< Grade 1) ii. Absolute neutrophil count > 1.5 x 109/L iii. Platelet count > 100 x109/L (≤ Grade 1)
11. Normal thyroid function defined as a TSH within normal local institutional range
12. Able to swallow and retain oral medication
13. Women of childbearing potential (WOCBP) and male patients with partners ofchildbearing potential; agree to remain abstinent (refrain from heterosexualintercourse) or use highly effective contraception measures during the treatmentperiod. For women, highly effective contraception should be used, for X months afterlast dose of (INSERT AGENT). For men, highly effective contraception should be used,for X months after (INSERT AGENT). (Highly effective contraception is defined in thestudy as methods that achieve a failure rate of less than 1% per year when usedconsistently and correctly. Such methods include: i. Combined (oestrogen and progestogen containing) hormonal contraception associatedwith inhibition of ovulation (oral, intravaginal, transdermal). ii. Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable and implantable). iii. Intrauterine device (IUD). iv. Intrauterine hormone-releasing system (IUS). v.Bilateral tubal occlusion. vi. Successfully vasectomised partner. vii. Sexualabstinence.)
14. Women of childbearing potential must have pregnancy excluded by urine or serumbeta-HCG testing within 7 days prior to registration.

Exclusion criteria: Patients who meet any of the following criteria at the time of screening will be excludedfrom study registration:

1. Received prior chemotherapy for local or metastatic disease.
2. Locally advanced rectal cancer; >T3, Nodal disease
3. Primary unresectable rectal cancer. A tumour is considered unresectable when invadingadjacent organs and an en bloc resection will not achieve negative margins.
4. Received prior pelvic radiotherapy.
5. Patients unable to undergo MRI.
6. Previous or concurrent active malignancy ≤ 5 years prior to registration with theexception of non-melanotic skin cancer or carcinoma in situ of any type, or othercancers that the treating Investigator does not feel will impact the study objectives.
7. Screening electrocardiogram (ECG) with evidence of:
8. QT prolongation (QTc > 450ms in males and > 470ms in females)
9. Clinically significant cardiac arrhythmias, complete left bundle branch block,high atrioventricular AV block (e.g. bi-vascular block , Mobitz type II and thirddegree AV block
10. Other severe cardiac dysfunction (ECG must be assessed for all patients within 14 days prior to registration).
11. Clinically significant cardiovascular disease including:
12. Cerebrovascular accident within 6 months prior to registration
13. Myocardial infarction within 6 months prior to registration
14. Uncontrolled angina
15. Uncontrolled or poorly controlled arterial hypertension (i.e. BP >150/90mmHgunder treatment with at a maximum three antihypertensive drugs)
16. Clinically significant valvular disease
17. Congestive Heart Failure (NYHA > Class 2 (See Appendix E)
18. Known family history of idiopathic cardiac arrest or sudden death whereby acardiac cause cannot be excluded
19. Known history or family history of Brugada Syndrome.
20. Known pulmonary compromise, as determined by the treating investigator, resulting fromintercurrent pulmonary illness, but not limited to, any pulmonary disorder (e.g.severe asthma, severe chronic obstructive pulmonary disease (COPD), restrictive lungdisease.
21. Creatinine level >1.5x ULN
22. Patients with a history of any arterial thromobotic event within the past 6 months.This includes angina (stable or unstable), MI, TIA or CVA.
23. Patients with a history of venous thrombotic episodes such as DVT, PE occurring morethan 6 months prior to enrolment may be considered for protocol participation,provided they are on stable doses of anticoagulant therapy. Similarly, patients whoare anticoagulated for atrial fibrillation or other conditions may participate,provided they are on stable doses of anticoagulant therapy.
24. Pregnant or nursing women.
25. Concurrent treatment with any other investigational agents within 30 days prior toregistration.
26. Any psychological, physical, familial, sociological or geographical conditionpotentially hampering compliance with the study protocol and follow-up schedule; (those conditions should be discussed with the patient before registration in thetrial).
27. Unable or unwilling to discontinue (and substitute if necessary) use of prohibitedmedications for at least 30 days prior to and for the duration of study treatment (seesection 7.5 for a description of prohibited medications).