PET-guided therapy: synergies, strategies, and future directions in external beam radiation therapy and radiopharmaceutical therapy

Positron Emission Tomography (PET) has evolved from a purely diagnostic modality into a cornerstone of precision radiation oncology. PET now informs patient selection, target delineation, treatment personalization, and post-therapy evaluation across External Beam Radiation Therapy (EBRT) and Radiopharmaceutical Therapy (RPT). Radiotracers provide quantitative data on tumor biology, heterogeneity, receptor expression, and therapeutic response, enabling a shift from morphology-based to biology-driven oncology. PET-guided therapy is increasingly used to select patients for molecular radiotherapy, guide EBRT boost volumes, monitor receptor occupancy, and personalize activity prescription. Combined modality approaches-such as EBRT plus PSMA-RLT in prostate cancer or EBRT plus SSTR-RLT in neuroendocrine tumors-are supported by biological rationales involving synergy between external and internal radiation sources. Adaptive strategies based on mid-treatment PET show promise in improving local control while minimizing toxicity. This review summarizes the current landscape and emerging applications of PET-guided therapy, highlighting methodological synergies between EBRT and RPT, strategies for treatment sequencing, biological dose painting, and adaptive therapy. It provides practical recommendations for implementing PET-guided workflows and discusses advances in radiobiology-informed dosimetry, whole-body PET technologies, and novel imaging biomarkers, including fibroblast activation protein inhibitors (FAPI), as key drivers of innovation. As PET technology evolves toward ultra-low-dose, ultra-fast total-body systems, the role of molecular imaging in therapeutic decision-making is expected to expand, ushering in a new era of biologically guided radiation oncology.