Intraoperative Electron Radiotherapy in Rectal Cancer - A Feasibility Trial

Study Overview
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Brief Summary
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Single centre double-blinded three-arm randomised controlled trial of extended margin surgery + IOERT at standard dose (10 Gy) versus extended margin surgery + IOERT at higher dose (15 Gy) versus extended margin surgery alone in a 1:1:1 ratio in patients with Locally Advanced Rectal Cancer (LARC) or Locally Recurrent Rectal Cancer (LRRC).

Detailed Description
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Rectal cancer is a cancer that occurs in the pelvis from the rectum. Locally advanced rectal cancer outgrows the rectum and attaches to other body parts in the pelvis and locally recurrent rectal cancer is a rectal cancer that comes back after surgery, and usually attaches to many different pelvic structures. They are both difficult to manage. The standard of care treatment involves chemotherapy and radiotherapy, followed by what is known as an extended margin operation to remove all cancer affected organs and not leave any cancer cells behind. If cancer cells reach the edge of the removed tissue, there is a high chance of leaving cancer cells behind. This is a key predictor of negative outcome in patients. Intraoperative electron beam radiotherapy (IOERT) was developed to help improve patient outcomes. Once the cancer has been removed, the surgeon and a cancer radiotherapy specialist examine the patient's scans, the cancer specimen and the area the cancer was in, and if there is concern about small numbers of cancer cells being left behind they treat the area with radiotherapy to destroy these cells. Patients that are due to receive treatment for these subsets of rectal cancer will be approached to take part. If eligible on the day of surgery the patient will be randomised to one of three arms: Arm A - standard of care (No IOERT), Arm B - extended margin surgery plus IOERT (10 Gy), or Arm C - extended margin surgery plus higher dose IOERT (15 Gy). The surgeon, cancer specialist team and patient will be blinded to study treatment. Patients will be followed up at 30 days, 3 months and for a minimum of 12 months post surgery as part of the trial and they will be followed up for 5 years as part of standard care.

Official Title
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Intraoperative Electron Radiotherapy in Rectal Cancer - A Feasibility Trial

Conditions
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Locally Advanced Rectal Cancer, Locally Recurrent Rectal Cancer

Intervention / Treatment
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* Radiation: Intraoperative Electron Radiotherapy (IOERT)
* Procedure: Extended Margin Surgery


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 16 Non-metastatic/oligo-metastatic (up to 3 lesions from 2 sites predicted to be radically treatable) - locally advanced or locally recurrent disease involving the posterior or lateral components of the pelvis and predicted to be resectable but with close margins from imaging as determined by a specialist MDT (sMDT) Colorectal sMDT review with experience in pelvic exenteration, which has proposed IntrOperative Electron Radiotherapy (IOERT) as an option for treatment Patient suitable for IOERT as component of treatment in the view of the responsible Clinical Oncologist Performance status ≤1 as defined by the Eastern Cooperative Oncology Group (ECOG) Deemed medically fit for surgery Written informed consent Exclusion Criteria: Unresectable disease/likelihood of R2 resection sMDT determined excess prior radiotherapy within IOERT target zone Women who are pregnant or breastfeeding Participation within an interventional clinical trial within 3 months of the point of registration within ELECTRA

Ages Eligible for Study
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Minimum Age: 16 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
Interventional Model Description: A single centre double-blinded three-arm randomised controlled trial of extended margin surgery + IOERT at standard dose (10 Gy) versus extended margin surgery + IOERT at higher dose (15 Gy) versus extended margin surgery alone (no IOERT) in a 1:1:1 ratio in patients with LARC or LRRC.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: No IOERT<br>Extended margin surgery | Procedure: Extended Margin Surgery<br>* Surgery intended to remove both a tumour and any metastases<br>|
| Experimental: Low Dose IOERT<br>Extended margin surgery and IOERT at standard dose (10 Gy) | Radiation: Intraoperative Electron Radiotherapy (IOERT)<br>* IOERT can be defined as the direct application of high-energy electron beam irradiation to a tumour bed during an operative procedure. This approach permits precise delivery of a single large fraction of radiation directly and specifically to high recurrence risk anatomical target areas, which the treating clinicians (surgeon and attending clinical oncologist) predict will be a close or involved margin, while simultaneously displacing and shielding dose-limiting radiosensitive structures such as the small bowel or ureter or any anastomoses, if not involved by tumour.<br>Procedure: Extended Margin Surgery<br>* Surgery intended to remove both a tumour and any metastases<br>|
| Experimental: High Dose IOERT<br>Extended margin surgery and IOERT at higher dose (15 Gy) | Radiation: Intraoperative Electron Radiotherapy (IOERT)<br>* IOERT can be defined as the direct application of high-energy electron beam irradiation to a tumour bed during an operative procedure. This approach permits precise delivery of a single large fraction of radiation directly and specifically to high recurrence risk anatomical target areas, which the treating clinicians (surgeon and attending clinical oncologist) predict will be a close or involved margin, while simultaneously displacing and shielding dose-limiting radiosensitive structures such as the small bowel or ureter or any anastomoses, if not involved by tumour.<br>Procedure: Extended Margin Surgery<br>* Surgery intended to remove both a tumour and any metastases<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patients meeting eligibility criteria | Number and percentage of patients meeting eligibility criteria and number of patients referred to a sMDT over the trial period | 2 years | 
| Patients accepting randomisation | Number and percentage of patients accepting randomisation | 2 years | 
| Successful delivery of IOERT | Number and percentage of patients for which IOERT was successfully delivered as planned as part of the trial | 2 years | 
| Blind maintained for patients and clinicians | Number and percentage of patients and clinicians for which blinding was maintained for IOERT delivery | 2 years | 
| Questionnaire analysis | Percentage of patients whose questionnaires can be analysed | 2 years | 
| Availability of potential primary outcome data | Percentage of patients for whom we can collect information on potential primary outcomes | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Morbidity | Clavien Dindo classification | Up to 30 days post randomisation | 
| Mortality | Mortality | 30 days post randomisation | 
| IOERT Field Recurrence | IOERT Field Recurrence is defined as the area directly within the IOERT field as marked by ligaclips or identified by the surgical oncologist for future radiological surveillance. | 12 months post randomisation | 
| Overall local recurrence | Overall local recurrence (OLR) is defined as including both IOERT-field and non-IOERT field loco-regional recurrences. | 12 months post randomisation | 
| Overall survival | Overall survival | 12 months post randomisation | 
| Treatment related toxicity | Treatment related toxicity graded by CTCAE v5 | 12 months post randomisation | 
| Time to local or systemic recurrence | Time to local or systemic recurrence | Time from randomisation to local or systemic recurrence or 3 years post the start of recruitment, whichever comes first | 
| R1 Rate | R1 Rate | At randomisation | 
| EQ-5D-5L | Quality of life scored from EQ-5D-5L | At 3 and 12 months post randomisation | 
| LRRC QoL | Quality of life scored from LRRC QoL | At 3 and 12 months post randomisation | 
| QLQ-C30 | Quality of life scored from QLQ-C30 | At 3 and 12 months post randomisation | 
| SF-36 | Quality of life scored from SF-36 | At 3 and 12 months post randomisation | 
| Resource use and cost | Cost will be estimated for the NHS. An NHS and social care perspective will be used, including intervention costs, outpatient visits and investigations, A&E attendances, hospital admissions, number and dose of each radiotherapy treatment. Itemised resource usage date will be priced using appropriate national sources: Personal Social Services Research Unit (PSSRU), NHS Reference costs and BNF (British National Formulary) for the UK. | At 3 and 12 months post randomisation |