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).

Sex

All

Minimum age

16 Years

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)

• DERIVEDMotamedi 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. PMID 37310167
• DERIVEDAppelt 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. PMID 32095545
• DERIVEDvan 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. PMID 32070386
• DERIVEDRombouts 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. PMID 29288190