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

Study Overview
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Brief Summary
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The purpose of this study is to find out the effects of chemotherapy followed by less invasive surgery on patients and their early rectal cancer. The approach of this trial will be considered a success if at least 65% of participants are able to keep the rectum.

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

Conditions
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Rectal Cancer

Intervention / Treatment
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* Drug: Folfox Protocol
* Drug: Capox


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed invasive well-moderately differentiated rectal adenocarcinoma diagnosed within 90 days prior to enrollment. Tumour stage cT1-T3abN0 based on pelvic MRI cT1N0- tumour invasion into submucosa, no radiographic evidence of mesorectal nodal metastasis, tumour deposits or vascular invasion. cT2N0 - tumour invasion into muscularis propria, no radiographic evidence of mesorectal nodal metastasis, tumour deposits or vascular invasion. cT3a,bN0- tumour invasion through the muscularis propria no more than 5 mm into the subserosa/perirectal tissue and clear of the circumferential radial margin (CRM). Absence of radiographic evidence of mesorectal nodal metastasis, tumour deposits 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 considered malignant, regardless of nodal morphology. For pelvic nodes < 10 mm in longest dimension, if nodes are seen and are deemed to be morphologically benign in the opinion of the radiologist and surgeon, the patient is eligible. Patients with visible 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 the treating 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 30 days 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) x weight (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 of life and health utility questionnaires. Patient consent must be appropriately obtained in accordance with applicable local and regulatory requirements. Each patient must sign a consent form prior to enrollment in the trial to document their willingness to participate. Must be accessible for treatment and follow up. Patients registered on this trial must 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 effective contraceptive method during and for 6 months after completion of chemotherapy. Exclusion Criteria: Patient has pathologic high risk factors on either the initial biopsy specimen report 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 curatively treated 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 days prior to enrolment. Clinically significant (i.e. active) cardiovascular disease for example cerebro vascular accidents (< 6 months prior to enrolment), myocardial infarction (< 6 months prior to enrolment), unstable angina, New York Heart Association (NYHA) grade II or higher, congestive heart failure, serious cardiac arrhythmia requiring medication. Any contra-indications to undergo MRI imaging.

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
Intervention Model: Single Group Assignment
Interventional Model Description: This is a two staged, single arm phase II trial of chemotherapy (FOLFOX or CAPOX) followed by tumour excision in patients with early stage rectal cancer
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: chemotherapy (FOLFOX or CAPOX) followed by tumour excision<br> | Drug: Folfox Protocol<br>* 6 cycles of q2weekly FOLFOX, or<br>Drug: Capox<br>* 4 cycles of q3weekly CAPOX<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measurement of organ preservation rate | The primary endpoint of this study is the protocol specified organ preservation rate, defined as the proportion of patients with tumour downstaging to ypT0/T1good N0 and who avoid radical surgery. The 95% confidence interval for the organ preservation rate will be calculated | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Locoregional Relapse Rate (LRR) |  | 3 years | 
| Distant Relapse Rate (DRR) estimated based on Kaplan-Meier method |  | 3 years | 
| Disease Free Survival (DFS) estimated based on Kaplan-Meier method |  | 3 years | 
| Rate of post-operative complications |  | 3 years | 
| Number and severity of adverse events using CTCAE V5 |  | 3 years | 
| Quality of Life using QLQ-C30 |  | 3 years | 
| Cost effectiveness using the EQ-5D-5L questionnaire |  | 3 years |