Can the Rectum be Saved by Watchful Waiting or TransAnal Surgery Following (Chemo)Radiotherapy Versus Total Mesorectal Excision for Early REctal Cancer?

Study Overview
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Brief Summary
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Colorectal cancer is the third most common tumour in the UK, Netherlands and Denmark with 41000, 14000 and 4000 new cases per year respectively. Standard primary radical Total Mesorectal Excision (TME) surgery is an oncologically effective treatment for early stage rectal cancer. However, resection of a low rectal tumour requires a permanent stoma in approximately 5-10% of cases while many more patients have a temporary stoma, some of which are not reversed. Radical surgery, which evolved to treat locally advanced, symptomatic tumours, may not be the optimal method of treatment for early screen-detected tumours and an organ preserving strategy may generate significantly less morbidity without substantially compromising oncological outcomes. TREC was a randomised phase II trial to test the feasibility of randomisation between TME and an organ preserving policy of short course pre-operative radiotherapy (SCPRT) delay followed by transanal endoscopic microsurgery (TEM). STAR-TREC is a phase II feasibility study that will evaluate whether it is possible to accelerate the patient recruitment attained in the TREC study, to 4 per month in the first year of recruitment and 6 per month in the second. This would demonstrate deliverability of a phase III study.

Detailed Description
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STAR-TREC is a randomised, three arm (1:1:1) study using the following arms: Standard TME surgery (control) Organ saving using: long course concurrent chemoradiation short course radiotherapy For organ-preserving strategies clinical response to radiotherapy determines the next treatment step. Radiotherapy response is evaluated using endoscopy and the tumour regression grade, as assessed by MRI. The first assessment at 11-13 weeks (from radiotherapy start) using MRI and endoscopy will identify a minority of non-responders who should convert to TME surgery. Patients demonstrating a satisfactory radiotherapy response at 11-13 weeks will be reassessed by endoscopy at 16-20 weeks. Re-evaluation determines if the STAR-TREC criteria for complete clinical response (cCR) are met. Patients who achieve cCR may progress directly to active surveillance. Those who do not fulfil the criteria for cCR will progress to excision biopsy with transanal endoscopic microsurgery (TEM). Patients in the organ saving arm will be assigned to either; A. Long course concurrent chemoradiation: Capecitabine: 825 mg/m² orally, b.i.d., on radiotherapy days Radiotherapy: A dose of 50 Gy, applied to the primary tumour and surrounding mesorectum, in 25 fractions of 2 Gy, 5 days a week. or B. Short course preoperative radiotherapy A dose of 25Gy, applied, to the primary tumour and surrounding mesorectum in 5 fractions of 5 Gy, 5 days a week. As a feasibility study, this trial will have recruitment rate as it's primary outcome.

Official Title
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STAR-TREC:Can the Rectum be Saved by Watchful Waiting or TransAnal Surgery Following (Chemo)Radiotherapy Versus Total Mesorectal Excision for Early REctal Cancer

Conditions
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Adenocarcinoma of the Rectum

Intervention / Treatment
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* Procedure: Standard TME surgery
* Drug: Long course concurrent chemoradiation
* Radiation: Short course radiotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Biopsy proven adenocarcinoma of the rectum mriT1-3bN0 (with ≤5mm of mesorectal invasion) rectal tumour or endorectal ultrasound defined rectal cancer uT1-uT3b (optional: in centres where high quality ERUS is available and patient unable to tolerate MRI) MDT determines that all of the following treatment options are feasible: TME surgery CRT SCPRT TEM Patients with equivocal radiological lesions e.g. mesorectal, retroperitoneal, liver, lung are eligible if agreed by MDT Aged 16 or over in UK (18 or over in the Netherlands and Denmark). Pre-(chemo)radiotherapy treatment, the following criteria must be met : Estimated creatinine clearance >50 mls/min -Absolute neutrophil count >1.5x109/l; platelets >100 x 109/L- Serum transaminase <3 x Upper Limit Normal/l (ULN) Bilirubin <1.5 x ULN ECOG performance status 0-1 If female and of childbearing potential, must: Have a negative pregnancy test ≤72hours prior to initiating study treatment Agree to avoid pregnancy during and for 6 months after study treatment If male with a partner of childbearing potential, must: Agree to use adequate, medically approved, contraceptive precautions during and for 90 days after the last dose of study treatment Patient able and willing to provide written informed consent for the study Exclusion Criteria: Unequivocal evidence of metastatic disease (includes resectable metastases) as determined by MRI showing: node positive extramural vascular invasion (mriEMVI) positive defined mucinous tumour Maximum tumour diameter > 40mm as measured from everted edges (sagittal) Mesorectal fascia threatened (< 1 mm on MRI) Tumour position anterior, above the peritoneal reflection on MRI or EUS No residual luminal tumour following endoscopic resection Contraindications to radiotherapy including previous pelvic radiotherapy Uncontrolled cardiorespiratory comorbidity (includes patients with inadequately controlled angina or myocardial infarction within 6 months prior to randomisation) Known dihydropyrimidine dehydrogenase (DPYD) deficiency Known Gilberts disease (hyperbilirubinaemia) Taking warfarin that cannot be discontinued at least 7 days prior to starting treatment or substituted by low molecular weight heparin

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: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard TME surgery<br>Radical total mesorectal excision | Procedure: Standard TME surgery<br>* Total mesorectal excision<br>|
| Experimental: Long course concurrent chemoradiation<br>Capecitabine: 825 mg/m² orally, b.i.d., on radiotherapy days Radiotherapy: A dose of 50 Gy, applied to the primary tumour and surrounding mesorectum, in 25 fractions of 2 Gy, 5 days a week. | Drug: Long course concurrent chemoradiation<br>* Capecitabine 825 mg/m² orally, b.i.d., on radiotherapy days. Radiotherapy: A dose of 50 Gy, applied to the primary tumour and surrounding mesorectum, in 25 fractions of 2 Gy, 5 days a week.<br>|
| Experimental: Short course radiotherapy<br>A dose of 25Gy, applied, to the primary tumour and surrounding mesorectum in 5 fractions of 5 Gy, 5 days a week. | Radiation: Short course radiotherapy<br>* A dose of 25Gy, applied, to the primary tumour and surrounding mesorectum in 5 fractions of 5 Gy, 5 days a week.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Year 1: randomise at least 4 cases per month internationally | randomise at least 4 cases per month internationally (n=48) | 1 years | 
| Year 2: randomise at least 6 cases per month internationally | randomise at least 6 cases per month internationally (n=72) | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Achieve funding from international partners | assessed through seeing whether the study being carried out internationally | 1 year | 
| Achieve recruitment from international partners | assessed through seeing whether the study being carried out internationally | 1 year | 
| Organ saving rate in the experimental arms at 12 months (from randomisation) | Percent of relevant organs saved during 12 months | 1 year | 
| Number of eligible patients undergoing accurately staged TME surgery | Proportion of eligible patients undergoing accurately staged TME surgery | 2 years | 
| Number of patients identified by MRI suitable for active monitoring based on mrTRG assessment | Proportion of patients identified by MRI suitable for active monitoring based on mrTRG assessment | 2 years | 
| 3 year pelvic failure rate | defined as the proportion of patients in each arm with: unresectable pelvic tumor pelvic tumour requiring beyond TME surgery ≤1mm circumferential resection margin after TME surgery | 3 years | 
| Overall survival | Absence of death | 3 years | 
| Stoma free survival | Time for randomisation without the need for a stoma | 1 year | 
| Health related quality of life by EORTC CR29 | Assessed by EORTC CR29 score | 2 years | 
| Health related quality of life by EORTC CR30 | Assessed by EORTC CR30 score | 2 years | 
| Health related quality of life by EQ-5D score | Assessed by EQ-5D | 2 years | 
| Sexual dysfunction | Measured by LARS | 2 years | 
| Bowel function | Measured by LARS | 2 years | 
| Bladder function | Measured by LARS | 2 years | 
| Sexual dysfunction in male patients | Measured by ICICQ-MLUTS | 2 years | 
| Bowel function in male patients | Measured by ICICQ-MLUTS | 2 years | 
| Bladder function in male patients | Measured by ICICQ-MLUTS | 2 years | 
| Sexual dysfunction in female patients | Measured by ICICQ-FLUTS | 2 years | 
| Bowel function in female patients | Measured by ICICQ-FLUTS | 2 years | 
| Bladder function in female patients | Measured by ICICQ-FLUTS | 2 years |