Towards Response ADAptive Radiotherapy for organ preservation for intermediate-risk rectal cancer (preRADAR): protocol of a phase I dose-escalation trial

Maaike E Verweij; Max D Tanaka; Chavelli M Kensen; Uulke A van der Heide; Corrie A M Marijnen; Tomas Janssen; Tineke Vijlbrief; Wilhelmina M U van Grevenstein; Leon M G Moons; Miriam Koopman; Miangela M Lacle; Manon N G J A Braat; Myriam Chalabi; Monique Maas; Inge L Huibregtse; Petur Snaebjornsson; Brechtje A Grotenhuis; Remond Fijneman; Esther Consten; Apollo Pronk; Anke B Smits; Joost T Heikens; Hidde Eijkelenkamp; Sjoerd G Elias; Helena M Verkooijen; Maartje M C Schoenmakers; Gert J Meijer; Martijn Intven; Femke P Peters

doi:10.1136/bmjopen-2022-065010

Towards Response ADAptive Radiotherapy for organ preservation for intermediate-risk rectal cancer (preRADAR): protocol of a phase I dose-escalation trial

BMJ Open. 2023 Jun 15;13(6):e065010. doi: 10.1136/bmjopen-2022-065010.

Authors

Maaike E Verweij^{1

2}, Max D Tanaka³, Chavelli M Kensen³, Uulke A van der Heide³, Corrie A M Marijnen³, Tomas Janssen³, Tineke Vijlbrief³, Wilhelmina M U van Grevenstein², Leon M G Moons⁴, Miriam Koopman⁵, Miangela M Lacle⁶, Manon N G J A Braat⁷, Myriam Chalabi⁸, Monique Maas⁹, Inge L Huibregtse¹⁰, Petur Snaebjornsson¹¹, Brechtje A Grotenhuis¹², Remond Fijneman¹¹, Esther Consten^{13

14}, Apollo Pronk¹⁵, Anke B Smits¹⁶, Joost T Heikens¹⁷, Hidde Eijkelenkamp¹⁸, Sjoerd G Elias¹⁹, Helena M Verkooijen¹⁸, Maartje M C Schoenmakers¹⁸, Gert J Meijer¹⁸, Martijn Intven¹⁸, Femke P Peters³

Affiliations

¹ Department of Radiation-Oncology, University Medical Centre Utrecht, Utrecht, The Netherlands m.e.verweij-5@umcutrecht.nl.
² Department of Surgery, University Medical Centre Utrecht, Utrecht, The Netherlands.
³ Department of Radiation-Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
⁴ Department of Gastroenterology, University Medical Centre Utrecht, Utrecht, The Netherlands.
⁵ Department of Medical Oncology, University Medical Centre Utrecht, Utrecht, The Netherlands.
⁶ Department of Pathology, University Medical Centre Utrecht, Utrecht, The Netherlands.
⁷ Department of Radiology, University Medical Centre Utrecht, Utrecht, The Netherlands.
⁸ Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
⁹ Department of Radiology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
¹⁰ Department of Gastroenterology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
¹¹ Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
¹² Department of Surgery, Netherlands Cancer Institute, Amsterdam, The Netherlands.
¹³ Department of Surgery, Meander Medical Centre, Amersfoort, The Netherlands.
¹⁴ Department of Surgery, University Medical Centre Groningen, Groningen, The Netherlands.
¹⁵ Department of Surgery, Diakonessenhuis Utrecht Zeist Doorn, Utrecht, The Netherlands.
¹⁶ Department of Surgery, Sint Antonius Hospital, Nieuwegein, The Netherlands.
¹⁷ Department of Surgery, Hospital Rivierenland, Tiel, The Netherlands.
¹⁸ Department of Radiation-Oncology, University Medical Centre Utrecht, Utrecht, The Netherlands.
¹⁹ Department of Epidemiology, Julius Center for Health Sciences and Primary Care, Utrecht, The Netherlands.

Abstract

Introduction: Organ preservation is associated with superior functional outcome and quality of life (QoL) compared with total mesorectal excision (TME) for rectal cancer. Only 10% of patients are eligible for organ preservation following short-course radiotherapy (SCRT, 25 Gy in five fractions) and a prolonged interval (4-8 weeks) to response evaluation. The organ preservation rate could potentially be increased by dose-escalated radiotherapy. Online adaptive magnetic resonance-guided radiotherapy (MRgRT) is anticipated to reduce radiation-induced toxicity and enable radiotherapy dose escalation. This trial aims to establish the maximum tolerated dose (MTD) of dose-escalated SCRT using online adaptive MRgRT.

Methods and analysis: The preRADAR is a multicentre phase I trial with a 6+3 dose-escalation design. Patients with intermediate-risk rectal cancer (cT3c-d(MRF-)N1M0 or cT1-3(MRF-)N1M0) interested in organ preservation are eligible. Patients are treated with a radiotherapy boost of 2×5 Gy (level 0), 3×5 Gy (level 1), 4×5 Gy (level 2) or 5×5 Gy (level 3) on the gross tumour volume in the week following standard SCRT using online adaptive MRgRT. The trial starts on dose level 1. The primary endpoint is the MTD based on the incidence of dose-limiting toxicity (DLT) per dose level. DLT is a composite of maximum one in nine severe radiation-induced toxicities and maximum one in three severe postoperative complications, in patients treated with TME or local excision within 26 weeks following start of treatment. Secondary endpoints include the organ preservation rate, non-DLT, oncological outcomes, patient-reported QoL and functional outcomes up to 2 years following start of treatment. Imaging and laboratory biomarkers are explored for early response prediction.

Ethics and dissemination: The trial protocol has been approved by the Medical Ethics Committee of the University Medical Centre Utrecht. The primary and secondary trial results will be published in international peer-reviewed journals.

Trial registration number: WHO International Clinical Trials Registry (NL8997; https://trialsearch.who.int).

Keywords: clinical trials; colorectal surgery; gastrointestinal tumours; magnetic resonance imaging; radiotherapy.

Publication types

Clinical Trial Protocol

MeSH terms

Clinical Trials, Phase I as Topic
Humans
Organ Preservation
Quality of Life
Radiation Injuries* / etiology
Radiation Injuries* / prevention & control
Rectal Neoplasms* / pathology
Rectal Neoplasms* / radiotherapy
Rectal Neoplasms* / surgery