Resource-Sparing Curative Treatment for Rectal Cancer

Study Overview
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Brief Summary
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This is a prospective, multicentre, randomized clinical trial comparing two different neo-adjuvant radiation-based strategies prior to intended surgery for locally advanced adenocarcinoma of the rectum. This trial may establish the investigational therapy to be superior to, or at least not inferior to conventional treatment.

Detailed Description
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This phase III randomised clinical trial compares the outcome of two different neo-adjuvant radiation based treatments for locally advanced rectal carcinoma. This encompasses patients at risk for a positive circumfrential resection margin (CRM+) on baseline assessment imaging and pateints identified as being with a T-descriptor T4 at baseline assessment. The arms compared are as follows: The investigational arm: short chemo-radiation course(25Gy in 5 daily fractions over 1 week) +/- surgery. The conventional arm: protracted chemo-radiation course (50Gy in 25 daily fractions over 5 weeks combined with chemotherapy)+/- surgery. The outcomes include four domains: overall survival, biological effect, quality of life and health-related economics.

Official Title
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Resource-Sparing Curative Treatment for Rectal Cancer

Conditions
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Rectal Carcinoma

Intervention / Treatment
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* Radiation: Radiotherapy
* Radiation: Radiotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 years of age or older Clinical (i.e. surgical determination) and/or diagnostic image findings consistent with c/uT4 or CRM+ (note that CRM+ must be established by MRI), primary rectal Adenocarcinoma (i.e. histology consistent with origin from rectal mucosa); these constitute LARC for the purpose of this protocol Treatment will be directed at the primary cancer, being clinically appropriate and given with an initial intent to cure the patient (this includes accepting up front that radiation and surgery are feasible; for surgery, this means that the patient has been determined fit for major surgery by an anaesthesiologist prior to the request for randomization) Performance status is sufficient to undertake the treatment in either arm (KPS>50%) Patient is accessible for required follow-up and data collection Radiation oncologist expects survival to exceed 6 months from date of diagnosis Patient provides informed consent Exclusion Criteria: Recurrent rectal cancer Primary wholly in the sigmoid colon Considered to be arising in the anal canal Metastatic disease beyond the pelvis (by clinical assessment and/or diagnostic imaging) Contraindications to protocol RT or to protocol chemotherapy, such as one or more of the following: any prior RT to the pelvis; a solitary pelvic kidney within the intended radiation volume consideration by the most responsible radiation oncologist that the treatment volume is too large, or the amount of small bowel or other critical organs within the treatment volume is too much for safe treatment significantly abnormal laboratory tests such as impaired renal/liver function a haemoglobin that is < 8.0 (or 80, SI) and the patient is not transfused to exceed 8.0 (or 80, SI) on-going medications that are not compatible with protocol neo-adjuvant chemotherapy as described in this protocol Significant development issues (such as with age < 18 yr) Co-morbidity Psychiatric diagnosis Physical impairment Pregnancy or continuing breast-feeding, that precludes administration of protocol treatments, or that precludes data collection (such as likely to preclude follow-up visits or completing questionnaires)

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: Arm A: Conventional Long Course Chemo-Radiation<br>Conventional long course chemo-radiation | Radiation: Radiotherapy<br>* Conventional long course chemo-radiation: Radiation 50Gy in 25 daily fractions over 5 weeks Bolus 5 Fluorouracil 350mg/m2/d for 5 days Injected Leucovorin 20mg in both the first and last (5th) week of radiation Oral Capecitabine (CAPE) 825mg/m2 b.i.d. during the entire radiotherapy course over 5 weeks.<br>|
| Experimental: Arm B: Short Course Radiation Followed by Chemotherapy<br>Experimental short course radiation followed by chemotherapy. | Radiation: Radiotherapy<br>* Short course radiotherapy: 25Gy in 5 daily fractions over 1 week Chemotherapy: - Bolus 5 Fluorouracil 450 mg/m2/day Injected Leucovorin 20 mg/m2/day for 5 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival |  | From commencement of radiation (day 1) to death or last follow-up up to 5 years. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Biological Effect and Tumour Biology | Maximum size of the tumor based on imaging and/or up to 3D measures reported by radiologists, comparing baseline and pre-surgical decision inverstigations If definitive surgery is conducted: Proportion obtaining R0 Proportion undergoing TME Status of the neurovascular and neural invasion(s) Nodal ratio Tumor sizes CEA results | Prior to surgical decision in weeks 13-15 and 4 weeks after surgery | 
| Quality of Life |  | From date of randomization till the end of follow-up (5 years) | 
| Health-related Economics | Number of days in hospital Number of surgical procedures Number of days with stomas Protocol required therapies, as actually administered Adverse events that have significant cost implications (i.e. cost-drivers) | From date of randomization till the end of follow-up (5 years) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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rectal carcinoma, long course chemo-radiation, short course chemo-rdiation, Locally Advanced Rectal Carcinoma