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| ID | Type | Description | Link |
|---|---|---|---|
| 2016-000862-49 | EudraCT Number |
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Bowel cancer is the second most common tumour with 41 000 new cases diagnosed annually in the UK, 447 000 across Europe and 1.36 million worldwide; of which one third are located in the rectum. 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 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.
STAR-TREC is a rolling phase II/III study. Phase II aimed to assess the feasibility of a large, multi-centre randomised trial comparing radical surgery versus two contrasting organ saving treatments followed by selective transanal microsurgery. Phase III will evaluate two contrasting organ preservation strategies in terms of organ preservation rates, toxicity (clinician and patient-reported) and Health-Related Quality of Life (HRQoL).
The Phase II component of STAR-TREC (now completed) was a randomised, three arm (1:1:1) study using the following arms:
Standard TME surgery (control)
Organ saving treatments using:
Long course concurrent chemoradiation:
Short course radiotherapy:
The phase III component of STAR_TREC is now open and has a partially randomised patient preference design where patients choose between organ saving treatment or standard surgery.
Those who prefer organ preservation will undergo randomisation 1:1 between:
Those who prefer standard surgery or have no preference, will undergo standard TME surgery without neoadjuvant radiotherapy treatment.
For organ-preserving strategies in phase II and III, clinical response to radiotherapy determines the next treatment step. Radiotherapy response is evaluated using clinical exam, endoscopy and MRI. The first assessment at 11-13 weeks (from radiotherapy start) using composite clinical, endoscopic and MRI based assessment 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 at 16-20 weeks determines if the STAR-TREC criteria for complete response (CR) are met. Patients who achieve CR may progress directly to active surveillance. Those who do not fulfil the criteria for CR will progress to excision biopsy with transanal endoscopic microsurgery (TEM).
The phase II component of the study aimed to evaluate the feasibility of accelerating patient recruitment from 2 per month, as attained in the previous TREC study, to 6 per month internationally over a two-year period.
The STAR-TREC phase III study will evaluate whether a CRT or SCRT organ preservation strategy leads to higher organ preservation rates and should become first line treatment for early rectal cancer.
This objective can be divided into two main questions:
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Standard TME surgery | Active Comparator | Radical total mesorectal excision |
|
| Long course concurrent chemoradiation | Experimental | 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. |
|
| Short course radiotherapy | Experimental | A dose of 25Gy, applied, to the primary tumour and surrounding mesorectum in 5 fractions of 5 Gy, 5 days a week. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Standard TME surgery | Procedure | Total mesorectal excision |
| |
| Measure | Description | Time Frame |
|---|---|---|
| Phase II (Feasibility study) Primary Outcome: Recruitment Rate | Measured at 12 and 24 months. Target recruitment rates are ≥4 and ≥6 patients randomised per month at 12 and 24 months respectively for total accrual of 120 international cases. Each individual country will attempt to exceed the minimum recruitment required to sustain phase III (UK 75, the Netherlands 75, Denmark 30). If recruitment is on target in year two then consideration will be given to an early application for transition to phase III with a funding application and a formal protocol amendment. | 24 Months |
| Phase III Primary Outcome: Organ Preservation | The primary endpoint of the STAR-TREC phase III study is the proportion of patients with successful organ preservation at 30 months from the start day of (chemo)radiotherapy treatment. This endpoint will be assessed for patients who prefer organ preservation and is defined as an in-situ rectum (includes patients subject to transanal local resection), no defunctioning stoma and an absence of active loco-regional cancer failure. The expected incidence of this outcome is approximately 60%. | 30 Months from start day of (chemo)radiotherapy treatment. |
| Measure | Description | Time Frame |
|---|---|---|
| Phase II (Feasibility study): Core Endpoint - Funding | Incidence of procurement of funding by one STAR-TREC international partner | 12 Months |
| Phase II (Feasibility study): Core Endpoint - International Recruitment |
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Inclusion Criteria:
Biopsy proven adenocarcinoma of the rectum
MRI-defined ≤T3b (with ≤5mm of mesorectal invasion) rectal tumour or endorectal ultrasound-defined ≤uT3b rectal cancer (optional: in centres where high quality endorectal ultrasound (ERUS) is available or patient unable to tolerate MRI)
MDT determines that all of the following treatment options are reasonable and feasible:
--TME surgery, (b) CRT (c) SCRT d) TEM.
Eastern Cooperative Oncology Group (ECOG) performance status 0-1
For patients choosing organ preservation only:
If female and of childbearing potential, must:
If non-sterilised male male with a partner of childbearing potential, must:
Agree to use adequate, medically approved, contraceptive precautions from trial entry until 6 months after the end of study treatment
Patient able and willing to provide written informed consent for the study
Exclusion Criteria:
Concomitant or previous malignancies within 3 years prior to trial entry, except those that in the opinion of the MDT are unlikely to relapse within 3 years or lead to death within 5 years
Unequivocal evidence of metastatic disease (includes resectable metastases)
-- Patients with equivocal radiological lesions (e.g. retroperitoneal, liver, lung) that are not classified as M1 are eligible if agreed by MDT
MRI node positive (≥N1, defined by protocol guidelines)
-- Patients with equivocal radiological findings that are either classified as NX or N0 are eligible
MRI extramural vascular invasion (mriEMVI) positive (defined by protocol guidelines)
MRI defined mucinous tumour
Mesorectal fascia threatened (≤1 mm on MRI or ERUS)
Maximum tumour diameter > 40mm (either measured from everted edges on sagittal MRI or on ERUS)
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 or arrhythmia within 6 months prior to trial entry)
Known complete dihydropyrimidine dehydrogenase (DPYD) deficiency
Known Gilbert's disease (hyperbilirubinaemia)
Taking coumarin-derivative anticoagulants (e.g. warfarin) that cannot be discontinued at least 7 days prior to starting treatment or substituted by low molecular weight heparin
Taking phenytoin or sorivudine or its chemically related anologues, such as brivudine, within 4 weeks of trial entry (see Section 8.3.5 for further details)
Taking metronidazole at study entry
Pregnant or lactating women
History of severe and unexpected reactions to fluoropyrimidine therapy
Age <16 years (UK), <18 years (other countries)
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| Name | Affiliation | Role |
|---|---|---|
| Simon Bach, MD | University Hospitals Birmingham | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University Hospital UZ Leuven | Leuven | Belgium | ||||
| Odense University Hospital |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 37310167 | Derived | Motamedi MAK, Mak NT, Brown CJ, Raval MJ, Karimuddin AA, Giustini D, Phang PT. Local versus radical surgery for early rectal cancer with or without neoadjuvant or adjuvant therapy. Cochrane Database Syst Rev. 2023 Jun 13;6(6):CD002198. doi: 10.1002/14651858.CD002198.pub3. | |
| 32095545 | Derived | Appelt AL, Kerkhof EM, Nyvang L, Harderwijk EC, Abbott NL, Teo M, Peters FP, Kronborg CJS, Spindler KG, Sebag-Montefiore D, Marijnen CAM; STAR-TREC collaborative group. Robust dose planning objectives for mesorectal radiotherapy of early stage rectal cancer - A multicentre dose planning study. Tech Innov Patient Support Radiat Oncol. 2019 Oct 15;11:14-21. doi: 10.1016/j.tipsro.2019.09.001. eCollection 2019 Sep. |
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| Long course concurrent chemoradiation with capecitabine and radiotherapy |
| Drug |
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. |
|
|
| Short course radiotherapy | Radiation | A dose of 25Gy, applied, to the primary tumour and surrounding mesorectum in 5 fractions of 5 Gy, 5 days a week. |
|
Incidence of opening of STAR-TREC by one international partner
| 12 Months |
| Phase II (Feasibility study): Core Endpoint - Efficacy | Efficacy of organ preserving treatment arm on completion of phase II study: Is the organ saving rate more than 50% of patients with early stage rectal cancer at 12 months (following randomisation) achieved in the experimental arms? [Name of Measurement: Rate of organ saving >50% at 12 months; Unit of Measurement: no record of radical surgery at 12 months] | 12 Months |
| Phase II: Safety- Accuracy of MRI in predicting STAR-TREC eligibility | MRI - Accuracy of MRI in predicting STAR-TREC eligibility (We will report the accuracy of MRI based patient selection according to each national standard, compared to the reference standard of post-operative histological staging. STAR-TREC will help develop international consensus in MRI reporting of mesorectal lymph node involvement by rectal cancer) | 24 Months |
| Phase II: Safety - 30 day Mortality | - Mortality | 30 days |
| Phase II: Safety - 6 month Mortality | - Mortality | 6 Months |
| Phase II: Safety - Surgical Morbidity | - Surgical morbidity | 36 Months |
| Phase II: Safety - Tumour Recurrence/ Regrowth within Bowel Wall | - Rate of tumour recurrence or regrowth within the bowel wall (experimental arm) | 36 Months |
| Phase II: Safety - Tumour Recurrence within Mesorectum | - Rate of tumour recurrence within the mesorectum (experimental arm) | 36 Months |
| Phase II: Safety - Distant Metastasis | - Rate of distant metastases | 36 Months |
| Phase II: Safety - Pelvic Failure | - Pelvic failure rate: expressed as a sum of the following (i) unresectable pelvic tumour, (ii) cases requiring beyond TME surgery or (iii) tumour recurrence or regrowth ≤1mm from the circumferential surgical margin after TME surgery. | 36 Months |
| Phase II: Safety - Bowel | Bowel dysfunction measured by EORTC QLQ CR29 [The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) ColoRectal cancer (CR) with 29 items] & C30 [The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) Core with 30 items], LARS score [The Low Anterior Resection Syndrome score], and ICIQ-MLUTS/ICIQ-FLUTS [International Consultation on Incontinence Questionnaire Male/Female Lower Urinary Tract Symptoms Module]. Multiple measurements and scores will be aggregated to arrive at one reported value. Scores at different time points after randomisation will be compared to baseline scores. | 36 Months |
| Phase II: Safety - Bladder | Bladder dysfunction measured by EORTC QLQ CR29 [The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) ColoRectal cancer (CR) with 29 items] & C30 [The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) Core with 30 items], LARS score [The Low Anterior Resection Syndrome score], and ICIQ-MLUTS/ICIQ-FLUTS [International Consultation on Incontinence Questionnaire Male/Female Lower Urinary Tract Symptoms Module]. Multiple measurements and scores will be aggregated to arrive at one reported value. Scores at different time points after randomisation will be compared to baseline scores. | 36 Months |
| Phase II: Safety - Sexual dysfunction | Sexual dysfunction measured by EORTC QLQ CR29 [The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) ColoRectal cancer (CR) with 29 items] & C30 [The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) Core with 30 items], LARS score [The Low Anterior Resection Syndrome score], and ICIQ-MLUTS/ICIQ-FLUTS [International Consultation on Incontinence Questionnaire Male/Female Lower Urinary Tract Symptoms Module]. Multiple measurements and scores will be aggregated to arrive at one reported value. Scores at different time points after randomisation will be compared to baseline scores. | 36 Months |
| Phase II: Efficacy - Stoma | Additional outcome measures pertinent to the phase III study examining the efficacy of organ saving versus standard surgery will also be collected: - Proportion of patients with/ without a stoma at 30 days and one year | 24 Months |
| Phase II: Efficacy - Tumour Down-staging | - Histopathological assessment of tumour down-staging following radiotherapy according to depth of tumour invasion and the incidence of other high-risk features in comparison to non-irradiated (control) group | 4.5 Months |
| Phase II: Efficacy - Active Monitoring | - Proportion of patients identified by clinical and MRI assessment as suitable for active monitoring | 4.5 Months |
| Phase II: Efficacy - Conversion Rate | - Conversion rates from organ saving to radical surgery | 36 Months |
| Phase II: Efficacy - Disease Survival | - Disease free survival | 36 Months |
| Phase II: Efficacy - Health-related Quality of Life score | Quality of life measured by EORTC QLQ CR29 [The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) ColoRectal cancer (CR) with 29 items] & C30 [The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) Core with 30 items], LARS score [The Low Anterior Resection Syndrome score], and ICIQ-MLUTS/ICIQ-FLUTS [International Consultation on Incontinence Questionnaire Male/Female Lower Urinary Tract Symptoms Module]. Multiple measurements and scores will be aggregated to arrive at one reported value. Scores at different time points after randomisation will be compared to baseline scores. | 3 months |
| Phase II: Efficacy - Health-related Quality of Life score | Quality of life measured by EORTC QLQ CR29 [The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) ColoRectal cancer (CR) with 29 items] & C30 [The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) Core with 30 items], LARS score [The Low Anterior Resection Syndrome score], and ICIQ-MLUTS/ICIQ-FLUTS [International Consultation on Incontinence Questionnaire Male/Female Lower Urinary Tract Symptoms Module]. Multiple measurements and scores will be aggregated to arrive at one reported value. Scores at different time points after randomisation will be compared to baseline scores. | 12 Months |
| Phase II: Efficacy - Health-related Quality of Life score | Quality of life measured by EORTC QLQ CR29 [The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) ColoRectal cancer (CR) with 29 items] & C30 [The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) Core with 30 items], LARS score [The Low Anterior Resection Syndrome score], and ICIQ-MLUTS/ICIQ-FLUTS [International Consultation on Incontinence Questionnaire Male/Female Lower Urinary Tract Symptoms Module]. Multiple measurements and scores will be aggregated to arrive at one reported value. Scores at different time points after randomisation will be compared to baseline scores. | 24 Months |
| Phase II: Efficacy - Health-related Quality of Life score | Quality of life measured by EORTC QLQ CR29 [The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) ColoRectal cancer (CR) with 29 items] & C30 [The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) Core with 30 items], LARS score [The Low Anterior Resection Syndrome score], and ICIQ-MLUTS/ICIQ-FLUTS [International Consultation on Incontinence Questionnaire Male/Female Lower Urinary Tract Symptoms Module]. Multiple measurements and scores will be aggregated to arrive at one reported value. Scores at different time points after randomisation will be compared to baseline scores. | 36 Months |
| Phase II: Efficacy - Overall Survival | - Overall survival | 36 Months |
| Phase III: For the randomised comparison between organ-preserving strategies | Clinician-reported acute treatment related toxicity up to 30 days following completion of (chemo)radiotherapy | 30 days from start day of (chemo)radiotherapy treatment. |
| Phase III: Complete Response *For the randomised comparison between organ-preserving strategies | Proportion of patients with Complete Response to (chemo)radiation therapy | 30 months |
| Phase III: For the randomised comparison between organ-preserving strategies - Local Excision | Proportion of patients undergoing transanal local excision | 20 weeks |
| Phase III: For the randomised comparison between organ-preserving strategies - Organ Loss | Time to event of organ loss assessed for patients who prefer organ preservation | Defined as the length of time from the start date of trial treatment until TME surgery |
| Phase III: For the randomised comparison between organ-preserving strategies - Non-Regrowth | Non-regrowth pelvic tumour control to 36 months; defined as the length of time from the start date of trial treatment until death (any cause) or development of unequivocal pelvic recurrence but not including patients who developed local regrowth which was resected with clear margins using standard TME surgery | 36 months |
| Phase III: For the randomised comparison between organ-preserving strategies - Metastasis Free Survival | Metastasis free survival to 36 months; defined as the length of time from the start date of trial treatment until death (any cause) or detection of distant metastasis | 36 months |
| Phase III: For the randomised comparison between organ-preserving strategies - Non-regrowth Disease Free Survival | Non-regrowth -disease free survival to 36 months; defined as the length of time from the start of trial treatment until death (any cause), detection of local pelvic recurrence or distant metastasis but not including patients who developed local regrowth which was resected with clear margins using standard TME surgery | 36 months |
| Phase III: For the randomised comparison between organ-preserving strategies - Overall Survival | Overall survival to 60 months defined as the length of time from the start date of trial treatment until death (any cause) | 60 months |
| Phase III: For analyses incorporating the non-randomised standard surgery comparator - Toxicity | Clinician-reported acute treatment related toxicity up to 30 days following completion of (chemo)radiotherapy or date of initial surgery | 30 days |
| Phase III: For analyses incorporating the non-randomised standard surgery comparator - Non-regrowth Pelvic Tumour Control | Non-regrowth pelvic tumour control to 36 months; defined as the length of time from the start date of (chemo)radiotherapy or date of initial surgery until death (any cause) or development of unequivocal pelvic recurrence but not including patients who preferred organ preservation and developed local regrowth which was resected with clear margins using standard TME surgery | 36 months |
| Phase III: For analyses incorporating the non-randomised standard surgery comparator - Metastasis Free Survival | Metastasis-free survival to 36 months; defined as the length of time from the start date of trial treatment or date of initial surgery until death (any cause) or detection of distant metastasis | 36 months |
| Phase III: For analyses incorporating the non-randomised standard surgery comparator - Disease-free Survival | Disease-free survival to 36 months; defined as the length of time from the start date of trial treatment or date of initial surgery until death (any cause), detection of local pelvic recurrence or distant metastasis but not including patients who developed local regrowth which was resected with clear margins using standard TME surgery | 36 months |
| Phase III: For analyses incorporating the non-randomised standard surgery comparator - Overall Survival | Overall survival to 60 months defined as the length of time from the start date of trial treatment or date of initial surgery until death (any cause)) | 60 months |
| Phase III: For analyses incorporating the non-randomised standard surgery comparator - Decision Regret | Decision regret at 24 months measured using the validated Decision regret scale questionnaire. The Decision Regret Scale is a 5-item Likert-type measure written to assess regret or remorse following a medical decision that takes less than 5 minutes to complete. High scores suggest high regret over a health care decision. Scores may be transformed to a scale of 0 (no regret) to 100 (high regret). | 24 months |
| Odense |
| Denmark |
| Radboud University medical center | Nijmegen | Netherlands |
| Region Stockholm, Onkologkliniken Södersjukhuset AB | Stockholm | Sweden |
| University of Birmingham | Birmingham | B15 2TT | United Kingdom |
| 32070386 | Derived | van den Ende RPJ, Peters FP, Harderwijk E, Rutten H, Bouwmans L, Berbee M, Canters RAM, Stoian G, Compagner K, Rozema T, de Smet M, Intven MPW, Tijssen RHN, Theuws J, van Haaren P, van Triest B, Eekhout D, Marijnen CAM, van der Heide UA, Kerkhof EM. Radiotherapy quality assurance for mesorectum treatment planning within the multi-center phase II STAR-TReC trial: Dutch results. Radiat Oncol. 2020 Feb 18;15(1):41. doi: 10.1186/s13014-020-01487-6. |
| 29288190 | Derived | Rombouts AJM, Al-Najami I, Abbott NL, Appelt A, Baatrup G, Bach S, Bhangu A, Garm Spindler KL, Gray R, Handley K, Kaur M, Kerkhof E, Kronborg CJ, Magill L, Marijnen CAM, Nagtegaal ID, Nyvang L, Peters FP, Pfeiffer P, Punt C, Quirke P, Sebag-Montefiore D, Teo M, West N, de Wilt JHW; for STAR-TREC Collaborative Group. Can we Save the rectum by watchful waiting or TransAnal microsurgery following (chemo) Radiotherapy versus Total mesorectal excision for early REctal Cancer (STAR-TREC study)?: protocol for a multicentre, randomised feasibility study. BMJ Open. 2017 Dec 28;7(12):e019474. doi: 10.1136/bmjopen-2017-019474. |
| ID | Term |
|---|---|
| D012004 | Rectal Neoplasms |
| ID | Term |
|---|---|
| D015179 | Colorectal Neoplasms |
| D007414 | Intestinal Neoplasms |
| D005770 | Gastrointestinal Neoplasms |
| D004067 | Digestive System Neoplasms |
| D009371 | Neoplasms by Site |
| D009369 | Neoplasms |
| D004066 | Digestive System Diseases |
| D005767 | Gastrointestinal Diseases |
| D007410 | Intestinal Diseases |
| D012002 | Rectal Diseases |
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| ID | Term |
|---|---|
| D000069287 | Capecitabine |
| D011878 | Radiotherapy |
| ID | Term |
|---|---|
| D003841 | Deoxycytidine |
| D003562 | Cytidine |
| D011741 | Pyrimidine Nucleosides |
| D011743 | Pyrimidines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D005472 | Fluorouracil |
| D014498 | Uracil |
| D011744 | Pyrimidinones |
| D003853 | Deoxyribonucleosides |
| D009705 | Nucleosides |
| D009706 | Nucleic Acids, Nucleotides, and Nucleosides |
| D013812 | Therapeutics |
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