Towards Response ADAptive Radiotherapy for organ preservation for intermediate-risk rectal cancer (preRADAR): protocol of a phase I dose-escalation trial
Verweij, Maaike E; Tanaka, Max D; Kensen, Chavelli M; van der Heide, Uulke A; Marijnen, Corrie A M; Janssen, Tomas; Vijlbrief, Tineke; van Grevenstein, Wilhelmina M U; Moons, Leon M G; Koopman, Miriam; Lacle, Miangela M; Braat, Manon N G J A; Chalabi, Myriam; Maas, Monique; Huibregtse, Inge L; Snaebjornsson, Petur; Grotenhuis, Brechtje A; Fijneman, Remond; Consten, Esther; Pronk, Apollo; Smits, Anke B; Heikens, Joost T; Eijkelenkamp, Hidde; Elias, Sjoerd G; Verkooijen, Helena M; Schoenmakers, Maartje M C; Meijer, Gert J; Intven, Martijn; Peters, Femke P
(2023) BMJ Open, volume 13, issue 6, pp. 1 - 10
(Article)
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
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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).
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Keywords: Clinical Trials, Phase I as Topic, Humans, Organ Preservation, Quality of Life, Radiation Injuries/etiology, Rectal Neoplasms/radiotherapy, magnetic resonance imaging, gastrointestinal tumours, radiotherapy, colorectal surgery, clinical trials, General Medicine, Journal Article
ISSN: 2044-6055
Publisher: BMJ Publishing Group
Note: Funding Information: The departments of radiotherapy of both the UMC Utrecht and the Netherlands Cancer Institute have received funding from Elekta, Sweden and Philips Healthcare. PS reports consulting fees from MSD and Bayer and fees for MEDtalks educational presentations. RF reports grants from Personal Genome Diagnostics, Delfi Diagnostics, Cergentis and Merck. HMV is a member of the European Commission and the Netherlands Organization of Health Research and Development and reports grants from the Dutch Cancer Foundation. MI has received personal fees from Elekta, Sweden. Publisher Copyright: © Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
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