Abstract
Newer technical improvements in radiation oncology have been rapidly implemented in recent decades, allowing an improved therapeutic ratio. The development of strategies using local and systemic treatments concurrently, mainly targeted therapies, has however plateaued. Targeted molecular compounds and immunotherapy are increasingly being incorporated as the new standard of care for a wide array of cancers. A better understanding of possible prior methodology issues is therefore required and should be integrated into upcoming early clinical trials including individualized radiotherapy-drug combinations. The outcome of clinical trials is influenced by the validity of the preclinical proofs of concept, the impact on normal tissue, the robustness of biomarkers and the quality of the delivery of radiation. Herein, key methodological aspects are discussed with the aim of optimizing the design and implementation of future precision drug-radiotherapy trials.