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Publications

Journal Article Multicenter Study Randomized Controlled Trial Clinical Trial, Phase II Clinical Trial, Phase III Comparative Study Ppublish

PubMed: 42633754 DOI: 10.1016/S1470-2045(26)00228-7

Chemoradiotherapy versus short-course radiotherapy for response-adapted organ preservation in early-stage and intermediate-stage rectal cancer (STAR-TREC): 12-month results of an international, multicentre, open-label, parallel-group, randomised, phase 2/3 trial.

Lancet Oncol 27(9):1120-1132

Authors: Simon P Bach, David Sebag-Montefiore, Victoria Homer, Alexandra Gilbert, Ane Appelt, Ian Geh, Geerard L Beets, Jacobus Burger, Eva Angenete, Gunnar Baatrup, Karen-Lise Garm Spindler, Karin Haustermans, Fabian Holman, Ellen M Kerkhof, Emily Lam, Stephan Korsgen, Anna Martling, Albert Wolthuis, Issam Al-Najami, Pehr Lind, Femke P Peters, Mark Teo, Nicholas P West, Simon Gates, Corrie A M Marijnen, Johannes H W de Wilt

Affiliations

  • Division of Surgery and Interventional Science, University College London, London, UK; Cancer and Genomic Sciences, College of Medicine and Health, University of Birmingham, Birmingham, UK.
  • Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK; St James's University Hospital, Leeds Teaching Hospitals NHS Trust, Leeds, UK.
  • Cancer Research UK Clinical Trials Unit, University of Birmingham, Birmingham, UK; NIHR Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.
  • Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.
  • Department of Surgery, Maastricht University Medical Centre, Maastricht, Netherlands; Department of Surgery, The Netherlands Cancer Institute, Amsterdam, Netherlands.
  • Department of Surgery, Catharina Hospital, Eindhoven, Netherlands.
  • Department of Surgery, Scandinavian Surgical Outcomes Research Group (SSORG), Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Department of Surgery, Region Västra Götaland, Sahlgrenska Östra Sjukhuset-Sahlgrenska University Hospital, Gothenburg, Sweden.
  • Department of Surgery, Odense University Hospital, Svendborg, Denmark; Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
  • Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
  • Department of Radiation Oncology, Universitair Ziekenhuis Leuven, Leuven, Belgium.
  • Department of Surgery, Leiden University Medical Center, Leiden, Netherlands.
  • Department of Radiation Oncology, Leiden University Medical Center, Leiden, Netherlands.
  • Patient advocate.
  • Good Hope Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.
  • Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Tema Cancer, Karolinska University Hospital, Stockholm, Sweden.
  • Department of Oncology, KU Leuven, Louvain, Belgium; Department of Abdominal Surgery, University Hospitals Leuven, Louvain, Belgium.
  • Surgical Research Unit, Odense University Hospital, Odense, Denmark; Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
  • Department of Clinical Science and Education, Karolinska Institutet, Södersjukhuset, Stockholm, Sweden.
  • Department of Radiation Oncology, Netherlands Cancer Institute, Amsterdam, Netherlands.
  • Radiotherapy Research Group, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK.
  • Cancer Research UK Clinical Trials Unit, University of Birmingham, Birmingham, UK.
  • Department of Radiation Oncology, Leiden University Medical Center, Leiden, Netherlands; Department of Radiation Oncology, Netherlands Cancer Institute, Amsterdam, Netherlands.
  • Radboud University Medical Center, Nijmegen, Netherlands.

Abstract

BACKGROUND

Total mesorectal excision (TME) is the standard treatment for most early-stage and intermediate-stage rectal cancer but can cause substantial perioperative morbidity, functional impairment, and reduced quality of life. We assessed whether long-course chemoradiotherapy (LCCRT) or short-course radiotherapy (SCRT) could increase organ preservation and reduce surgery, toxicity, and quality-of-life harms without compromising oncological outcomes.

METHODS

STAR-TREC is an international, multicentre, open-label, parallel-group, randomised, phase 2/3 trial in five European countries. Eligible patients were aged 16 years or older in the UK or aged 18 years or older elsewhere, had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and rectal adenocarcinoma (≤40 mm staged as mrT1-T3bN0). In phase 2, participants were randomly assigned (1:1:1) to LCCRT-based organ preservation (LCCRT-OP; 50 Gy in 25 fractions plus oral capecitabine 825 mg/m 2 twice daily), SCRT-based organ preservation (SCRT-OP; 25 Gy in five fractions), or primary TME. Phase 2 assessed feasibility, with recruitment at months 12 and 24 as the primary endpoint and feasibility thresholds of four or more and six or more randomisations per month, respectively. Phase 3 adopted a partially randomised patient-preference design, allowing participants to choose either organ preservation or TME. Participants that chose organ preservation were randomly assigned (1:1) to receive LCCRT-OP or SCRT-OP using centralised, computer-generated assignment, with stratification by country and MRI T category (≤T3a vs T3b) using minimisation. The phase 3 primary endpoint was organ-preservation 30 months after treatment initiation, defined as absence of TME, stoma, or local recurrence, which was assessed in the modified intention-to-treat population, which included participants in phase 2 and phase 3. After a planned interim analysis of unmasked phase 2 data, the trial steering committee and independent data monitoring committee recommended reporting a 12-month, modified intention-to-treat analysis of implementation outcomes for participants recruited before Aug 8, 2023. This study is registered with ISRCTN (14240288) and is closed.

FINDINGS

Between June 14, 2017, and April 8, 2024, 503 participants were enrolled at 37 sites. Phase 2 enrolled 120 participants, with recruitment rates of three and six participants per month at months 12 and 24, respectively. Overall, 12-month TME-free survival was 60% (47 of 78 participants). After phase 3 recruitment ended, interim analysis of unmasked phase 2 data showed an early TME-free survival benefit with LCCRT versus SCRT (12-month median TME-free survival not reached [95% CI not reached-not reached] vs 7·6 months [95% CI 6·4-not reached]; hazard ratio [HR] 3·7 [95% CI 1·7-8·0]; posterior probability of superiority >99·5%). The trial steering committee and independent data monitoring committee therefore recommended expanded analysis of 426 participants recruited before Aug 8, 2023: 120 from phase 2 and 306 from phase 3. 17 participants withdrew before treatment, leaving 409 in the modified intention-to-treat population: 163 allocated to LCCRT, 168 to SCRT, and 78 to primary TME. 116 (28%) participants were female and 293 (72%) were male. Among participants who opted for organ preservation, 12-month TME-free survival was 78·5% (95% CI 72·4-85·1) with LCCRT and 60·6% (53·6-68·4) with SCRT (HR 1·90 [95% CI 1·29-2·81]). The most common grade 3-4 serious adverse events were gastrointestinal disorders (four [2%] with LCCRT vs six [4%] with SCRT vs six [8%] with TME) and procedural complications (three [2%] with LCCRT vs five [3%] with SCRT vs five [6%] with TME). One participant allocated to primary TME died after an anastomotic leak.

INTERPRETATION

These early results support a response-adapted organ-preservation approach, with LCCRT appearing more effective than SCRT at 12 months. Organ-preservation might also reduce treatment-related toxicity compared with primary TME. Longer follow-up is needed for the prespecified 30-month endpoint and definitive functional and oncological outcomes.

FUNDING

Cancer Research UK, Stand Up to Cancer, Dutch Cancer Society, Danish Cancer Society, Kom Op Tegen Kanker, Cancerfonden, ALF Region Stockholm, RCC Region Stockholm.

MeSH

Radiotherapy, Organ Preservation, Neoplasms, Aged, Chemoradiotherapy, Rectal Neoplasms, Therapeutics