Background: Traditional randomised controlled trials (RCTs) are foundational to clinical research, yet in radiation oncology, their limitations are increasingly evident. Rapid technological innovation, complex treatment protocols, and diverse patient populations challenge the feasibility, generalisability, and timeliness of RCTs. This has prompted exploration of alternative methodologies that better align with real-world practice and patient-centred care.
Methods: This narrative review was developed following a joint ESTRO-EORTC session at the May 2025 ESTRO meeting. It synthesises expert perspectives and recent literature to examine the limitations of RCTs and the potential of alternative designs, including real-world evidence (RWE), pragmatic trials, and Trials within Cohorts (TwiCs).
Findings: RCTs in radiation oncology face challenges including high cost, recruitment barriers, limited external validity, and ethical constraints. RWE, derived from registries and electronic health records, is increasingly used for regulatory decisions and post-market surveillance, though concerns about data quality and bias remain. Pragmatic trials offer inclusive, flexible designs that reflect routine care, but require robust infrastructure and statistical methods. TwiCs embed randomisation within observational cohorts, improving recruitment and reducing burden, yet raise ethical and methodological concerns. Examples such as OligoCARE, RAPID-RT and SPRINT illustrate how these designs can support scalable, patient-centred research.
Conclusion: To advance societal sustainability and equity in radiation oncology, methodological pluralism is essential. RWE, pragmatic trials, and TwiCs offer promising alternatives to traditional RCTs, enabling more responsive and inclusive research. Their success depends on investment in infrastructure, training, and ethical frameworks that support transparency and trust.

