ESTRO 2025 - Abstract Book

S50

Invited Speaker

ESTRO 2025

4728

Speaker Abstracts Limitations of RCTs in radiation oncology Sarah R Brown Leeds CRUK Clinical Trials Unit, University of Leeds, Leeds, United Kingdom

Abstract: Randomised controlled trials (RCTs) are widely recognised as the mainstay of evidence-based medicine [i] , including in radiation oncology [ii] . As with all designs, RCTs come with limitations, and a large proportion of trials are designed without randomisation. In a cross-sectional analysis of oncology trials registered between 2007 and 2017, 65.9% of radiotherapy trials identified were non-randomised, with the majority of trials included being phase 0-2 (81.1%) [iii] . More recently, evaluating randomisation by phase, 1902/2815 (67.6%) phase II radiotherapy oncology trials registered on clinicaltrials.gov from January 2015 to March 2025 were non-randomised. At phase III, however, 674/707 (95.3%) trials had a randomised design, highlighting their mainstay in the practice-changing setting. The limitations of RCTs were highlighted in a 2022 panel discussion on the pros and cons of RCTs vs. observational studies [iv] . Translation of methodological innovations into practice was recognised as a limitation in moving forward with planning and conducting high-quality non-randomised trials. In selecting the most appropriate methodology for designing a clinical trial in radiation oncology, understanding the limitations of the methodology is critical. Obvious limitations to RCTs are size and cost. Increasing the number of patients required in a trial due to randomisation necessarily increases trial duration and therefore cost. Assessing feasibility of randomisation in a specific population is critical. With the increase in risk-stratified approaches to treatment, the size of patient populations under evaluation becomes smaller, a challenge also for rarer disease areas. Whilst single arm trials offer an obvious alternative to reduce sample size, there are inherent limitations to this approach too [v] . Radiotherapy clinical trials are also typically associated with long follow-up times, to determine long-term toxicity and survival outcomes. Within the context of an RCT this results in costly ongoing follow-up and reporting, which may alternatively be determined through routine data collection. The generalisability of RCTs can also be questioned [vi] . RCTs designed to elicit the true efficacy of an intervention typically incorporate strict eligibility criteria, meaning generalisability of such trials to real-world populations can be limited. This is also the case where patients with strong preferences for one intervention over another accept or decline randomisation. Understanding the limitations of RCTs in this context is critical to determining what supporting evidence, or alternative design approaches, may be required to ensure generalisability. Specific to radiotherapy, with rapidly developing radiotherapy delivery techniques changes in treatment delivery can often hinder the development and delivery of radiotherapy clinical trials, where common control arms may be difficult to specify in a national or international clinical trial protocol. Rapidly emerging, potentially low-level, evidence can often lead to a lack of equipoise clinically, and with incremental adjustments to radiotherapy delivery, mission creep can limit the ability to feasibly undertake an RCT. This array of complexity and limitation to RCTs, some of which are not unique to radiotherapy, requires us to look methodologically at alternative options to generate a reliable evidence basis to bring treatment advances to patients. Within this presentation we will explore some of these opportunities, including single arm trials and trials designed to incorporate external controls as an alternative to concurrently randomised controls. References [i] Sibbald B, Roland M. Understanding controlled trials: Why are randomised controlled trials important? BMJ 1998; 316 :201 doi:10.1136/bmj.316.7126.201 [ii] Verkooijen HM, Kerkmeijer LGW, Fuller CD, Huddart R, Faivre-Finn C, Verheij M, Mook S, Sahgal A, Hall E, Schultz C. R-IDEAL: A Framework for Systematic Clinical Evaluation of Technical Innovations in Radiation Oncology. Front Oncol. 2017 Apr 3;7:59. doi: 10.3389/fonc.2017.00059. PMID: 28421162; PMCID: PMC5378068. [iii] Liu X, Zhang Y, Tang L, et al. Characteristics of Radiotherapy Trials Compared With Other Oncological Clinical Trials in the Past 10 Years. JAMA Oncol. 2018;4(8):1073–1079. doi:10.1001/jamaoncol.2018.0887