Biology-Guided Adaptive Radiotherapy: From the 6 R’s to Emerging Paradigms

Abstract

Adaptive radiotherapy (ART) has emerged as one of the most significant advances in modern radiation oncology, enabling increasingly precise and individualized treatment through adaptation to patient-specific changes occurring during therapy. While ART encompasses both anatomical and biological adaptation, most clinical implementation and technological development to date have focused on managing geometric variation through advanced imaging, motion management, and online replanning. Biological adaptation, however, remains a largely underexplored frontier with the potential to further personalize radiation delivery according to the evolving characteristics of both tumor and host. In this review, we revisit the classical and emerging 6 R's of radiobiology (repair, redistribution, repopulation, reoxygenation, radiosensitivity, and immune reactivation) as a biological framework for adaptive decision-making during radiotherapy. We summarize advances in molecular, imaging, and liquid-biopsy biomarkers that increasingly permit longitudinal assessment of tumor and host biology, including functional MRI, PET-based hypoxia and proliferation imaging, circulating tumor DNA, radiomics, radiogenomics, and immune profiling. We further examine emerging paradigms of biology-guided adaptation, including response-guided dose escalation and de-escalation, hypoxia-guided dose painting, metabolism-guided adaptation, functional tissue avoidance, adaptive immunologic modulation, and liquid-biopsy-driven treatment personalization. In parallel, we discuss enabling technologies such as PET-guided radiotherapy, MR-guided adaptive platforms, and artificial intelligence. Finally, we highlight key scientific, technical, and workflow challenges, including biomarker validation, quantitative imaging standardization, real-time biological monitoring, and prospective clinical trial development. Collectively, these advances support the evolution of ART from a paradigm centered primarily on geometric adaptation toward a more comprehensive framework that integrates both anatomical and biological information to guide treatment personalization. Biology-guided ART represents an important next step in precision oncology, enabling dynamic adaptation based on the evolving biology of tumors and their microenvironment throughout the course of therapy.