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

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

Eligibility Criteria:
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:

    * Have a negative pregnancy test within 7 days prior to study entry
    * Agree to use adequate, medically approved, contraceptive precautions from trial entry until 6 months after the end of study treatment
  * 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)