Strategies for Offline Adaptive Biology-Guided Radiotherapy (BgRT) on a PET-Linac Platform.

: This study aims to present a structured clinical workflow for offline adaptive Biology-guided Radiotherapy (BgRT) using the RefleXion X1 PET-linac system, addressing challenges introduced by inter-treatment anatomical and biological changes. : We propose a decision tree offline adaptation framework based on real-time assessments of Activity Concentration (AC), Normalized Target Signal (NTS), and bounded dose-volume histogram (bDVH%) metrics. Three offline strategies were developed: (1) preemptive adaptation for minor changes, (2) partial re-simulation for moderate changes, and (3) full re-simulation for major anatomical or metabolic alterations. Two clinical cases demonstrating strategies 1 and 2 are presented. : The preemptive adaptation strategy was applied in a case with early tumor shrinkage, maintaining delivery parameters within acceptable limits while updating contours and dose distribution. In the partial re-Simulation case, significant changes in PET signal necessitated a same-day PET functional modeling session and plan re-optimization, effectively restoring safe deliverability. Both cases showed reduced target volumes and improved OAR sparing without additional patient visits or tracer injections. : Offline adaptive workflows for BgRT provide practical solutions to address inter-fractional changes in tumor structure and function. These strategies can help maintain the safety and accuracy of BgRT delivery and support clinical adoption of PET-guided radiotherapy, paving the way for future online adaptive capabilities.