Bin Cai

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.

Background/Objectives: Patients with early-stage non-small cell lung cancer (NSCLC) or limited lung metastases and compromised lung function, such as those with interstitial lung disease (ILD) or chronic obstructive pulmonary disease (COPD), or other factors rendering them high-risk for surgery or medically inoperable, face increased risks of treatment-related toxicity from stereotactic ablative radiation therapy (SABR). This study evaluated a novel treatment approach to mitigate these risks. Methods: We investigated Personalized Ultra-Fractionated Stereotactic Adaptive Radiotherapy (PULSAR), delivered as pulsed radiation every three weeks, in patients with p = 0.0053), bronchus (p = 0.0003), esophagus (p = 0.0005), spinal cord (p = 0.025), and the lung V20 Gy and V12.5 Gy (p < 0.0001). Treatment-related toxicity included two grade 1–2 adverse events and six grade 3 events consisting of pneumonitis, dyspnea or lung infection, with no grade 4 or 5 events. Median progression-free survival was 21.1 months, with 1-year overall survival of 74% and 1-year local control of 100%. Conclusions: PULSAR shows promise as a feasible treatment option for high-risk patients with NSCLC or lung metastases, demonstrating no grade 5 events and complete tumor control. Additional research is needed to fully evaluate the safety profile of PULSAR in the high-risk subgroups and whether PULSAR’s treatment intervals and adaptive planning advantages lead to improved long-term outcomes compared to conventional, uninterrupted SABR regimens.

Online adaptive radiotherapy (ART) is rapidly transforming clinical radiation oncology by enabling adaptation of treatment plans based on patient-specific anatomical and biological changes. However, most medical physics training programs lack structured education in ART. To address this critical gap, the Medical Physics Adaptive Radiotherapy (MPART) Fellowship was established at our center to train post-residency or practicing physicists in advanced adaptive technologies and workflows. The MPART Fellowship is a two-year program that provides immersive, platform-specific training in CBCT-guided (Varian Ethos), MR-guided (Elekta Unity), and PET-guided (RefleXion X1) radiotherapy. Fellows undergo modular clinical rotations, hands-on training, and dedicated research projects. The curriculum incorporates competencies in imaging, contouring, online planning, quality assurance, and team-based decision-making. Evaluation is based on the Accreditation Council for Graduate Medical Education competency domains and includes milestone tracking, mentor reviews, and structured presentations. The fellowship attracted applicants from both domestic and international institutions, reflecting strong demand for formal ART training. Out of 22 applications, two fellows have been successfully recruited into the program since 2024. Fellows actively participate in all phases of adaptive workflows and are expected to function at near-attending levels by the second year of their training. Each fellow also leads at least one translational or operational research project aimed at improving ART delivery. Fellows contribute to clinical coverage and lead developmental projects, resulting in presentations and publications at the national and international levels. The MPART Fellowship addresses a vital educational need by equipping medical physicists with the advanced competencies necessary for implementing and leading ART. This program offers a replicable framework for other institutions seeking to advance precision radiation therapy through structured post-residency training in adaptive radiotherapy. As this fellowship program is still in its early phase of establishment, the primary goal of this paper is to introduce the structure, framework, and implementation model of the program. Comprehensive outcome analyses—such as quantitative assessments, fellow feedback, and longitudinal competency evaluations—will be incorporated in future work as additional cohorts complete training.

Purpose: To develop a workflow for systemically reviewing the doses received by organs at risk (OARs) in a BgRT treatment session, as a means of monitoring delivery constancy and possibly identifying changes of clinical concern in the patient. Methods: We implemented a workflow consisting of a qualitative review of the reconstructed delivered-dose information provided by the RefleXion system, followed by its quantitative evaluation using in-house software. For the latter we developed a framework for calculating custom OAR dose–volume metrics from the delivered-dose distribution and graphing them. We retrospectively applied our workflow to three select BgRT patient cases to appraise its clinical utility. Results: Our workflow efficiently incorporates existing RefleXion TPS features and in-house software into a process for thoroughly evaluating doses to OARs after BgRT delivery. The spreadsheet we created for graphing the trends of normalized OAR dose–volume metrics readily shows if OAR doses have significantly changed or tolerance limits have been violated, thereby potentially revealing if changes of concern occurred in the targeted region. Our workflow also yields a cumulative delivered-dose record at the end of treatment. Conclusions: We established a post-BgRT dose evaluation workflow which supplements the information provided by RefleXion with calculation and graphing of custom OAR dose–volume metrics. This workflow is now routinely used in our clinic following all BgRT treatments. Future improvements could include increased automation, updating the dose calculation to reflect changes in patient anatomy, incorporation of PET metrics, and consideration of target dose data.

Background: The RefleXion X1 is a novel PET/CT‐guided ring gantry linac that introduces unique geometry and workflow compared to conventional systems. Existing QA guidelines (AAPM TG‐142, 148, 306) cover standard linacs and tomotherapy but do not address this platform's needs. Therefore, an automated daily QA solution is required to ensure accurate output, imaging guidance, and couch positioning, which motivated the development and evaluation of the workflow presented in this study. Purpose: To develop and evaluate an automated, efficient, and comprehensive daily quality assurance (QA) workflow for a novel PET/CT‐guided ring gantry linear accelerator (RefleXion X1), incorporating tests for dosimetry, imaging guidance, and couch positioning accuracy. Methods: An IMRT QA plan was designed following the CT scan of the TomoDose 2D diode detector array (Sun Nuclear, Melbourne, FL) within the RefleXion treatment planning system (TPS). Several spherical targets of varying sizes were contoured to conform the dose distribution to these targets and evaluate beam output, laser localization, profile constancy, and CT‐MV isocenter coincidence. Linear models correlating spatial location of dose peak with intentional shifts in different directions were developed and integrated into an in‐house analysis software, iQA, written in C#. The software was validated for robustness and successfully implemented in clinical practice. Results: Validation with 42 intentional shifts showed submillimeter accuracy, with mean deviations of 0.2 mm (X), 0.1 mm (Y), and 0.79 mm (Z), and R ² values ≥ 0.98. Over 1 year, daily QA data showed stable output constancy (1.006 ± 0.016), left/right target dose constancy (1.007 ± 0.005 and 0.996 ± 0.004), and consistent CT‐MV isocenter offsets (–0.335 ± 0.23 mm in X, 0.19 ± 0.19 mm in Y, and –0.544 ± 0.36 mm in Z). The software also detected a gradual output drift in between, prompting a timely linac adjustment. Conclusion: This fully automated, single‐delivery QA workflow enables efficient and robust evaluation of multiple IGRT performance parameters. It improves standardization, reduces human error, and reliably monitors long‐term machine stability. The tools and methodology may be adopted by other clinics seeking a practical and automated daily QA solution. Future developments will focus on incorporating PET QA and rotational couch validations to further enhance the system's comprehensiveness and adaptability.

Background/Objectives: The aim of this study was to establish the relationship between target size and the required diagnostic PET maximum standard uptake value (SUVmax) thresholds needed for successful Biology-guided Radiotherapy (BgRT) delivery on RefleXion X1 PET-linac. The current clinical eligibility recommendation is an SUVmax ≥ 6 at simulation, but the RefleXion system subsequently evaluates Activity Concentration (AC), which must exceed 5 kBq/mL for successful BgRT planning. Methods: A custom 3D-printed phantom containing six spherical targets (8 to 20 mm diameter) was used with varying target-to-background ratios (5:1 to 20:1) of 18F-FDG to systematically achieve a range of SUVmax values for each target size. Images were acquired on Siemens Biograph mCT for SUVmax quantification and RefleXion X1 for AC measurements. Twenty-four BgRT plans were evaluated, and delivery accuracy was validated using ArcCHECK. Additionally, retrospective data from 18 patients across four institutions were analyzed to validate the phantom-derived findings. Results: The PET-linac successfully planned treatments for 13/24 experiments, all achieving an AC > 5 kBq/mL. SUVmax requirements varied by target size: 16–20 mm targets required an SUVmax > 6, consistent with current recommendations, while smaller targets required higher thresholds (e.g., 13 mm: SUVmax > 10, and 11 mm: SUVmax > 15). 8 and 9 mm targets failed to meet AC requirements even at SUVmax 14. Successful deliveries maintained acceptable accuracy, with gamma passing rates of 92.4% ± 5.0% (3%/2 mm) and 97.6% ± 1.9% (3%/3 mm). Analysis revealed that Volume (cc) × SUVmax > 11 consistently predicted successful BgRT planning across all target sizes. This threshold was validated using multi-institutional PET-CT patient data (mean: 11.36, 95% CI: 9.1–12.9), correctly predicting treatment eligibility in 15 of 18 cases. Conclusions: Target size significantly influences BgRT eligibility. We derived a new criterion, Volume(cc) × SUVmax > 11 (95% CI: 9.1–12).

Background/Objectives: 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. Methods: 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. Results: 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. Conclusions: 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.

Introduction: SCINTIX ^® therapy, a form of biology-guided radiotherapy using real-time positron emission tomography (PET) imaging on the RefleXion ^® X1 platform, recently received FDA clearance for FDG-guided treatment of lung and bone tumors. This study evaluates the feasibility and dosimetric quality of Biology-Guided Radiotherapy (BgRT) plans for FDG-avid lesions in anatomical sites beyond current indications using processed diagnostic PET (dPET) images. Methods: Eleven previously treated FDG-avid lesions in ten patients (sites: liver, head and neck, pancreas, kidney, pelvic/abdominal nodes) were retrospectively analyzed. dPET images were processed to emulate RefleXion X1 PET characteristics. BgRT plans were generated using a non-clinical version of the RefleXion treatment planning system, delivering stereotactic body radiation therapy-level doses (48Gy/3fx for liver, 40Gy/5fx for other sites). Plan deliverability was evaluated based on normalized target signal (NTS >2.7) and activity concentration (AC > 5 kBq/ml). Plans were categorized based on the presence of dose-limiting organs at risk (OAR) constraints. Dosimetric parameters were assessed according to institutional standards. Statistical analyses examined relationships between dPET standardized uptake value (SUV), PET-derived parameters, planning target volume (PTV) characteristics, and plan complexity. Results: BgRT plans were successfully generated for all lesions. All met the NTS threshold (mean = 9.3); 72.7% met the AC goal (mean = 12.1 kBq/ml). Among cases with dPET SUV > 6, 87.5% met AC criterion, supporting this threshold as a reasonable selection criterion. Plans without dose-limiting OARs (n = 6) achieved higher PTV coverage (V100%=94.4%, conformity index (CI) = 1.08) compared to plans with OAR constraints (n = 5, V100%=78.0%, CI = 1.4). All plans were deemed clinically acceptable despite observed heterogeneity within target regions. MLC modulation intensity correlated strongly with target volume (r = 0.907) and superior-inferior extent (r = 0.896) rather than OAR proximity. Conclusion: BgRT planning using processed dPET is feasible for non-lung/bone FDG-avid lesions. SUV > 6 may serve as a reasonable threshold, though feasibility is affected by tumor location, FDG background, and nearby critical structures. Findings support clinical potential of SCINTIX expansion into new anatomical sites.

Treatment planning in the field of radiation therapy has evolved from three-dimensional (3D) planning to inverse planning and, most recently, to personalized adaptive radiotherapy (ART)