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

Study Overview
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Brief Summary
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The gold standard treatment for locally advanced, non-metastatic rectal cancer includes neoadjuvant chemoradiotherapy (NACRT), total mesorectal excision (TME) and adjuvant chemotherapy (AC). The primary goal of treatment is to achieve local disease control, reduce tumour volume and minimise the risk of distant metastases. While this multimodal treatment approach has offered improvements in local control and sphincter preservation, it has had little effect on distant recurrence and overall survival. We aim to compare NACRT and TME using the following endpoints: Primary -->To compare the effects neoadjuvant chemoradiotherapy versus total neoadjuvant therapy (TNT) for T3 rectal cancer on overall survival. Secondary --> To compare the effects neoadjuvant chemoradiotherapy (NARCT) and total neoadjuvant therapy (TNT) for cT3 rectal cancer on clinical outcomes: Clinical complete response (cCR) Pathological complete response (pCR) Disease-free survival (DFS) Organ preservation Overall morbidity / mortality Treatment-related morbidity / mortality Peri-operative outcomes

Official Title
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A Phase III, Multi-institutional Randomised Trial Comparing Neoadjuvant Chemoradiotherapy (NARCT) and Total Neoadjuvant Therapy (TNT) in Patients With T3 (a/b/c) Rectal Cancer

Conditions
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Rectal Cancer

Intervention / Treatment
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* Drug: Neoadjuvant Chemoradiotherapy
* Drug: Total Neoadjuvant Therapy


Participation Criteria
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Eligibility Criteria
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Patients are eligible to be included in the study only if they meet all of the following criteria: Written informed consent must be given according to ICH/GCP and national/local regulations and be obtained prior to any study-related procedures. Histologically or cytologically confirmed surgically resectable adenocarcinoma of the rectum. Clinical stage II (T3, N-) \ Absence of metastatic disease Eastern Co-operative Oncology Group (ECOG) performance status > 2. Age > to 18. Estimated life expectancy ≥ 12 months. No active infections requiring systemic antibiotic treatment (oral antibiotics are acceptable at the discretion of the treating physician). Measurable disease, as defined by RECIST Version 1.1 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) Normal thyroid function defined as a TSH within normal local institutional range Able to swallow and retain oral medication Women of childbearing potential (WOCBP) and male patients with partners of childbearing potential; agree to remain abstinent (refrain from heterosexual intercourse) or use highly effective contraception measures during the treatment period. For women, highly effective contraception should be used, for X months after last dose of (INSERT AGENT). For men, highly effective contraception should be used, for X months after (INSERT AGENT). (Highly effective contraception is defined in the study as methods that achieve a failure rate of less than 1% per year when used consistently and correctly. Such methods include: i. Combined (oestrogen and progestogen containing) hormonal contraception associated with 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. Sexual abstinence.) Women of childbearing potential must have pregnancy excluded by urine or serum beta-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 excluded from study registration: Received prior chemotherapy for local or metastatic disease. Locally advanced rectal cancer; >T3, Nodal disease Primary unresectable rectal cancer. A tumour is considered unresectable when invading adjacent organs and an en bloc resection will not achieve negative margins. Received prior pelvic radiotherapy. Patients unable to undergo MRI. Previous or concurrent active malignancy ≤ 5 years prior to registration with the exception of non-melanotic skin cancer or carcinoma in situ of any type, or other cancers that the treating Investigator does not feel will impact the study objectives. Screening electrocardiogram (ECG) with evidence of: QT prolongation (QTc > 450ms in males and > 470ms in females) Clinically significant cardiac arrhythmias, complete left bundle branch block, high atrioventricular AV block (e.g. bi-vascular block , Mobitz type II and third degree AV block Other severe cardiac dysfunction (ECG must be assessed for all patients within 14 days prior to registration). Clinically significant cardiovascular disease including: Cerebrovascular accident within 6 months prior to registration Myocardial infarction within 6 months prior to registration Uncontrolled angina Uncontrolled or poorly controlled arterial hypertension (i.e. BP >150/90mmHg under treatment with at a maximum three antihypertensive drugs) Clinically significant valvular disease Congestive Heart Failure (NYHA > Class 2 (See Appendix E) Known family history of idiopathic cardiac arrest or sudden death whereby a cardiac cause cannot be excluded Known history or family history of Brugada Syndrome. Known pulmonary compromise, as determined by the treating investigator, resulting from intercurrent pulmonary illness, but not limited to, any pulmonary disorder (e.g. severe asthma, severe chronic obstructive pulmonary disease (COPD), restrictive lung disease. Creatinine level >1.5x ULN Patients with a history of any arterial thromobotic event within the past 6 months. This includes angina (stable or unstable), MI, TIA or CVA. Patients with a history of venous thrombotic episodes such as DVT, PE occurring more than 6 months prior to enrolment may be considered for protocol participation, provided they are on stable doses of anticoagulant therapy. Similarly, patients who are anticoagulated for atrial fibrillation or other conditions may participate, provided they are on stable doses of anticoagulant therapy. Pregnant or nursing women. Concurrent treatment with any other investigational agents within 30 days prior to registration. Any psychological, physical, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; (those conditions should be discussed with the patient before registration in the trial). Unable or unwilling to discontinue (and substitute if necessary) use of prohibited medications for at least 30 days prior to and for the duration of study treatment (see section 7.5 for a description of prohibited medications).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Neoadjuvant chemoradiotherapy<br>The NARCT regimen is prescribed specifically as standard 5-FU over several weeks. The CRT regimen consists of the standard algorithms: a total of 5400-5600 cGy of radiation (4500 cGy to the pelvis, with an integrated boost to the primary tumour and involved nodes of 500 cGy followed by an option boost to the primary tumour and involved nodes) delivered in 27-28 fractions, respectively, of 180-200 cGy each over a 5-6 week period. | Drug: Neoadjuvant Chemoradiotherapy<br>* 5-FU is a fluoropyrimidine antimetabolite considered to act primarily as an inhibitor of thymidylate synthase. 5-FU is supplied as a colourless-to-faint yellow solution in 10-mL single use vials. Each 10 mL of solution contains 500 mg 5-FU, with pH adjusted to approximately 9.2 with sodium hydroxide. The CRT regimen consists of the standard algorithms: a total of 5400-5600 cGy of radiation (4500 cGy to the pelvis, with an integrated boost to the primary tumour and involved nodes of 500 cGy followed by an option boost to the primary tumour and involved nodes) delivered in 27-28 fractions, respectively, of 180-200 cGy each over a 5-6 week period.<br>* Other names: NACRT;|
| Active Comparator: Total Neoadjuvant Therapy<br>Sequence of TNT regimen can be classified as induction (chemotherapy first) or consolidation (radiation first) treatment. All patients received the same chemotherapy (FOLFOX) and long-course chemoradiotherapy (50.4 Gy in 28 fractions) before surgery. However timing of TNT can differ depending on concerns of local and distal failure. | Drug: Total Neoadjuvant Therapy<br>* 5-FU is a fluoropyrimidine antimetabolite considered to act primarily as an inhibitor of thymidylate synthase. 5-FU is supplied as a colourless-to-faint yellow solution in 10-mL single use vials. Each 10 mL of solution contains 500 mg 5-FU, with pH adjusted to approximately 9.2 with sodium hydroxide. Oxaliplatin is an organoplatinum complex in which the platinum atom is complexed with 1,2- diaminocyclohexane with an oxalate ligand as a leaving group. Platinum content is 48.1% to 50.1%. All patients received the same chemotherapy (FOLFOX) and long-course chemoradiotherapy (50.4 Gy in 28 fractions) before surgery.<br>* Other names: TNT;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | Alive | Five years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical complete response | No residual tumour visible on imaging | 6 months | 
| Pathological complete response | Absence of residual invasive or in situ tumour on biopsy / resected specimen. | 6 months | 
| Disease-free survival | Measure of time after treatment where no evidence of disease is found. | 5 years | 
| Progression-free survival | Time from randomisation to occurrence of disease progression or death | 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neoadjuvant chemoradiotherapy, Total neoadjuvant therapy, Survival, Rectal cancer