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Capecitabine

Antimetabolites

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.

A dose of 25Gy, applied, to the primary tumour and surrounding mesorectum in 5 fractions of 5 Gy, 5 days a week.

Standard TME surgery

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.

Long course concurrent chemoradiation with capecitabine and radiotherapy

Short course radiotherapy

Leila Freidoony, PhD

Bishnupriya Bhattacharya, PhD

Albert Wolthuis, Prof Dr

Gunnar Baatrup, Prof

Hans de Wilt, Prof

Pehr Lind, Assoc Prof

Simon Bach, MD

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:

1. Standard TME surgery (control)
2. Organ saving treatments using:

   1. Long course concurrent chemoradiation:

      * Capecitabine: 825 mg/m² orally, b.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.
   2. Short course radiotherapy:

      * A dose of 25 Gy applied to the primary tumour and surrounding mesorectum in 5 fractions of 5 Gy, 5 days a week.

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:

1. Long course concurrent chemoradiation (as described above)
2. Short course radiotherapy (as described above)

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:

1. Determine the optimal radiation schedule to achieve the highest rate of organ preservation
2. Determine the optimal radiation schedule to achieve the best quality of life after organ preservation

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

STAR-TREC: Can we Save the Rectum by Watchful Waiting or TransAnal Surgery Following (Chemo)Radiotherapy Versus Total Mesorectal Excision for Early REctal Cancer?

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.

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%.

Incidence of procurement of funding by one STAR-TREC international partner

Incidence of opening of STAR-TREC by one international partner

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? \[Name of Measurement: Rate of organ saving \>50% at 12 months; Unit of Measurement: no record of radical surgery at 12 months\]

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)

- Rate of tumour recurrence or regrowth within the bowel wall (experimental arm)

- Rate of tumour recurrence within the mesorectum (experimental arm)

- 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.

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.

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.

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.

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

- 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

- Proportion of patients identified by clinical and MRI assessment as suitable for active monitoring

- Conversion rates from organ saving to radical surgery

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.

Clinician-reported acute treatment related toxicity up to 30 days following completion of (chemo)radiotherapy

Proportion of patients with Complete Response to (chemo)radiation therapy

Proportion of patients undergoing transanal local excision

Time to event of organ loss assessed for patients who prefer organ preservation

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

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

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

Overall survival to 60 months defined as the length of time from the start date of trial treatment until death (any cause)

Clinician-reported acute treatment related toxicity up to 30 days following completion of (chemo)radiotherapy or date of initial surgery

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

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

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

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))

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).

University of Birmingham

Pathologically confirmed stage II/III rectal adenocarcinoma patients who received neoadjuvant chemoradiotherapy followed by a clinical complete response, and refused surgery but went on with the watch and wait approach.

Pathologically confirmed stage II/III rectal adenocarcinoma patients who received neoadjuvant chemoradiotherapy followed by a clinical complete response, and received radical resection.

standard TME surgery

Yuan-hong Gao, MD

This was a propensity-score matched observational analysis, comparing the oncological outcome of surgical resection vs watch and wait apporach for rectal cancer patients with a cCR.

Pathologically confirmed stage II/III rectal adenocarcinoma patients who received neoadjuvant chemoradiotherapy followed by a clinical complete response from the year 2010 to 2018 were included. Sequential subjects were identified from a prospective maintained database in the Sun Yat-sen University Cancer Center. Clinical experts on rectal cancer from other 5 regional medical centers in China were also invited to participate, and provided data of cCR patients. Standardized forms for data collection were sanded to researchers in each center. Patients received radical resection will constituted our surgery group. Those refused surgery constituted the observation group who went on with the watch and wait approach. A propensity-score matched observational analysis will be used to compare the oncological outcome of these two groups.

Treatment Strategy for Rectal Cancer Patients With Complete Clinical Response

Watch-and-wait Approach Versus Surgical Resection for Rectal Cancer Patients With Complete Clinical Response After Chemoradiotherapy: a Multi-center Cohort Study

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Can we Save the Rectum by Watchful Waiting or TransAnal Surgery Following (Chemo)Radiotherapy Versus Total Mesorectal Excision for Early REctal Cancer?	NCT02945566	Adenocarcinoma ...	Standard TME su... Long course con... Short course ra...	16 Years -	University of Birmingham
Treatment Strategy for Rectal Cancer Patients With Complete Clinical Response	NCT03846726	Rectal Cancer Organ Preservat...	standard TME su...	16 Years - 90 Years	Sun Yat-sen University

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