Evaluation of 68Ga-Fibroblast Activation Protein Inhibitor vs. 18F-FDG as a Novel Radiotracer for Biologically Guided Radiation Therapy

Abstract

Real-time biology guided radiation therapy (BgRT) uses real-time positron emissions from a PET tracer during treatment to guide targeted radiation to cancerous lesions. Fibroblast activation protein alpha (FAP) is highly expressed on cancer-associated fibroblasts in tumors with low expression in normal tissues. While 18F-FDG-PET requires fasting and has background in the liver and brain, 68-Gallium labeled FAP inhibitor (FAPI) does not require fasting and has less background uptake. The goal of this study was to investigate the utility of FAPI as a potential universal fiducial for BgRT. We hypothesized that 68Ga-FAPI would be a better radiotracer than 18F-FDG, as assessed by the Normalized Minimal kBq/mL and the Normal Target Signal (NTS), two parameters used to gauge the suitability of BgRT. PET-CTs were obtained for 50 patients with pancreatic, liver, lung, head & neck, and cervical cancer using 18F-FDG and 68Ga-FAPI (n = 10 for each). Four DICOM images were obtained per patient (FDG PET + CT, FAPI PET + CT). Radiation oncologists delineated the gross tumor volume (GTV) on PET images. A separate set of auto-contours were generated from the PET using an auto-threshold of 40% maximum SUV for all tumors. A 1 cm expansion was added to the GTV to create a ring around the physician-generated contours and auto-contours. The following parameters were measured: GTV volume, SUV max of GTV, SUV mean of GTV, Normalized Minimal kBq/mL within the GTV, and NTS (= SUV max/Ring SUV mean). Values were compared using paired t-test. For the BgRT product with similar calculations, the required Normalized Minimal kBq/mL is > 5 kBq/mL; the required NTS is > 2.7 for treatment planning and > 2.0 for BgRT delivery. The Normalized Minimal kBq/mL for FAPI was > 5 kBq/mL for all tumors and greater for auto-contoured GTVs compared to physician-contoured GTVs. The mean NTS for the auto-contours for all tumor sites was > 2.0. In addition, there was a statistically significant increase in the NTS for FAPI compared to FDG in pancreatic, liver and head & neck cancers. In pancreatic cancer, there was a statistically significant increase in Normalized Minimal kBq/mL for FAPI compared to FDG (26.0 vs 14.2) (p = 0.01) and the SUVmax of FAPI was almost double that of FDG (15.9 vs 8.2) (p = 0.01). FAPI had no background in the liver, but had high background in the uterus, suggesting it may have a role in liver cancer but not cervical cancer. This is the first study demonstrating the potential superiority of 68Ga-FAPI compared to 18F-FDG as a biologic fiducial for BgRT when treating pancreatic, liver and head & neck cancers, with a similar efficacy for lung cancer. Our results indicate that auto-contoured GTVs generate a higher NTS than physician-contoured GTVs but all are > 2.0. In addition, the Normalized Minimal kBq/mL for auto-contours is > 5 kBq/mL for all tumors. As hypothesized, FAPI-based BgRT is most likely to be successful when treating tumors with significant desmoplastic stroma, such as pancreatic cancer.