Comparative Evaluation of [68Ga]Ga-Fibroblast Activation Protein Inhibitor vs. [18F]FDG as a Novel Radiotracer for Biology-Guided Image Radiotherapy

<b>Background/Objectives:</b> Biology-guided radiotherapy (BgRT) is a novel technology utilizing PET radiotracer emissions to deliver image-guided adaptive RT. 18F-Fluorodeoxyglucose ([¹⁸F]FDG) is the most common PET radiotracer but has background in the liver and brain because it is taken up by viable tumor cells as well as inflammatory cells. Fibroblast activation protein (FAP) is overexpressed in cancer-associated fibroblasts with minimal expression in normal tissues. FAP inhibitors (FAPIs) bind to FAP, and a FAPI labeled with Gallium-68 (68Ga) is a novel radiotracer with high tumor selectivity. Multiple studies have compared [⁶⁸Ga]Ga-FAPI-04 vs. [¹⁸F]FDG for diagnostic imaging, but [⁶⁸Ga]Ga-FAPI-04 vs. [¹⁸F]FDG have never been compared in terms of their utility for BgRT. <b>Purpose:</b> This study was designed to assess the utility of [⁶⁸Ga]Ga-FAPI-04 vs. [¹⁸F]FDG for BgRT used to treat pancreatic, liver, lung, head and neck, and cervical cancers. Methods: A radiation oncologist specializing in each cancer contoured the gross tumor volume (GTV) on [¹⁸F]FDG PET-CT and [⁶⁸Ga]Ga-FAPI-04 PET-CT images. Auto-contours were generated using an auto-threshold of 40% of the maximum Standardized Uptake Value (SUV). The suitability of [⁶⁸Ga]Ga-FAPI-04 vs. [¹⁸F]FDG for BgRT was evaluated by comparing Normalized Net Activity Concentration (NNA) and Normalized Target Signal (NTS) for each cancer. <b>Results:</b> NNA and NTS for [⁶⁸Ga]Ga-FAPI-04 and [¹⁸F]FDG met the requirements for [¹⁸F]FDG-guided BgRT (NNA > 5.0 kBq/mL, NTS > 2.7) for all disease sites. NNAFAPI was significantly greater than NNAFDG for pancreatic, H&N, and cervical cancer. NTSFAPI was significantly greater than NTSFDG for pancreatic, liver, and lung cancer. <b>Conclusions:</b> [⁶⁸Ga]Ga-FAPI-04 is a novel radiotracer for BgRT and has the greatest potential impact in the treatment of pancreatic cancer.