{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T12:17:32Z","timestamp":1784204252705,"version":"3.55.0"},"reference-count":31,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2025,11,13]],"date-time":"2025-11-13T00:00:00Z","timestamp":1762992000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"RefleXion grant to City of Hope"},{"name":"NIH\/NCI","award":["R00CA256526"],"award-info":[{"award-number":["R00CA256526"]}]},{"DOI":"10.13039\/100000043","name":"AACR","doi-asserted-by":"crossref","award":["Award 23-40-21-MCGE"],"award-info":[{"award-number":["Award 23-40-21-MCGE"]}],"id":[{"id":"10.13039\/100000043","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background\/Objectives: 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. Purpose: 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. Results: NNA and NTS for [68Ga]Ga-FAPI-04 and [18F]FDG met the requirements for [18F]FDG-guided BgRT (NNA &gt; 5.0 kBq\/mL, NTS &gt; 2.7) for all disease sites. NNAFAPI was significantly greater than NNAFDG for pancreatic, H&amp;N, and cervical cancer. NTSFAPI was significantly greater than NTSFDG for pancreatic, liver, and lung cancer. Conclusions: [68Ga]Ga-FAPI-04 is a novel radiotracer for BgRT and has the greatest potential impact in the treatment of pancreatic cancer.<\/jats:p>","DOI":"10.3390\/cancers17223648","type":"journal-article","created":{"date-parts":[[2025,11,13]],"date-time":"2025-11-13T12:57:13Z","timestamp":1763038633000},"page":"3648","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Comparative Evaluation of [68Ga]Ga-Fibroblast Activation Protein Inhibitor vs. [18F]FDG as a Novel Radiotracer for Biology-Guided Image Radiotherapy"],"prefix":"10.3390","volume":"17","author":[{"given":"Lin","family":"Qiu","sequence":"first","affiliation":[{"name":"Department of Nuclear Medicine, Affiliated Hospital of Southwest Medical University and Institute of Nuclear Medicine, Southwest Medical University, Luzhou 646000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4088-7649","authenticated-orcid":false,"given":"Yue","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine, Affiliated Hospital of Southwest Medical University and Institute of Nuclear Medicine, Southwest Medical University, Luzhou 646000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trevor","family":"Ketcherside","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, City of Hope National Medical Center, Duarte, CA 91010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8189-0601","authenticated-orcid":false,"given":"Zhixing","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, City of Hope National Medical Center, Duarte, CA 91010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3897-3011","authenticated-orcid":false,"given":"Todd","family":"DeWees","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, City of Hope National Medical Center, Duarte, CA 91010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1020-0845","authenticated-orcid":false,"given":"Terence M.","family":"Williams","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, City of Hope National Medical Center, Duarte, CA 91010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arya","family":"Amini","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, City of Hope National Medical Center, Duarte, CA 91010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sagus","family":"Sampath","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, City of Hope National Medical Center, Duarte, CA 91010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott","family":"Glaser","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, City of Hope National Medical Center, Duarte, CA 91010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Jen","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, City of Hope National Medical Center, Duarte, CA 91010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4465-5813","authenticated-orcid":false,"given":"Liu","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine, Affiliated Hospital of Southwest Medical University and Institute of Nuclear Medicine, Southwest Medical University, Luzhou 646000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7556-2927","authenticated-orcid":false,"given":"David","family":"Leung","sequence":"additional","affiliation":[{"name":"RefleXion Medical, Inc., Hayward, CA 94545, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"An","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, City of Hope National Medical Center, Duarte, CA 91010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather M.","family":"McGee","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, City of Hope National Medical Center, Duarte, CA 91010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,13]]},"reference":[{"key":"ref_1","first-page":"106","article-title":"The technical design and concept of a PET\/CT linac for biology-guided radiotherapy","volume":"29","author":"Oderinde","year":"2021","journal-title":"Clin. Transl. Radiat. Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"20200873","DOI":"10.1259\/bjr.20200873","article-title":"Biology-guided radiotherapy: Redefining the role of radiotherapy in metastatic cancer","volume":"94","author":"Shirvani","year":"2021","journal-title":"Br. J. Radiol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Lancia, A., Ingrosso, G., Detti, B., Festa, E., Bonzano, E., Linguanti, F., Camilli, F., Bertini, N., La Mattina, S., and Orsatti, C. (2024). Biology-guided radiotherapy in metastatic prostate cancer: Time to push the envelope?. Front. Oncol., 14.","DOI":"10.3389\/fonc.2024.1455428"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1016\/j.soc.2023.02.006","article-title":"Biology-Guided Radiation Therapy: An Evolving Treatment Paradigm","volume":"32","author":"Ladbury","year":"2023","journal-title":"Surg. Oncol. Clin. N. Am."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Cuaron, J., Dunphy, M., and Rimner, A. (2012). Role of FDG-PET scans in staging, response assessment, and follow-up care for non-small cell lung cancer. Front. Oncol., 2.","DOI":"10.3389\/fonc.2012.00208"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Dendl, K., Koerber, S.A., Kratochwil, C., Cardinale, J., Finck, R., Dabir, M., Novruzov, E., Watabe, T., Kramer, V., and Choyke, P.L. (2021). FAP and FAPI-PET\/CT in Malignant and Non-Malignant Diseases: A Perfect Symbiosis?. Cancers, 13.","DOI":"10.3390\/cancers13194946"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"81","DOI":"10.2967\/jnumed.120.258467","article-title":"68Ga-DOTA-FAPI-04 PET\/MR in the Evaluation of Gastric Carcinomas: Comparison with 18F-FDG PET\/CT","volume":"63","author":"Qin","year":"2022","journal-title":"J. Nucl. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1186\/s40001-023-00997-9","article-title":"[68Ga]Ga-FAPI-04 PET MRI\/CT in the evaluation of gastric carcinomas compared with [18F]-FDG PET MRI\/CT: A meta-analysis","volume":"28","author":"Wang","year":"2023","journal-title":"Eur. J. Med. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1406","DOI":"10.21037\/jtd-23-238","article-title":"Integrating single-cell and bulk RNA sequencing to develop a cancer-associated fibroblast-related signature for immune infiltration prediction and prognosis in lung adenocarcinoma","volume":"15","author":"Huang","year":"2023","journal-title":"J. Thorac. Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"801","DOI":"10.2967\/jnumed.119.227967","article-title":"(68)Ga-FAPI PET\/CT: Tracer Uptake in 28 Different Kinds of Cancer","volume":"60","author":"Kratochwil","year":"2019","journal-title":"J. Nucl. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"4089","DOI":"10.1007\/s00259-021-05378-0","article-title":"(68)Ga-FAPI-PET\/CT in patients with various gynecological malignancies","volume":"48","author":"Dendl","year":"2021","journal-title":"Eur. J. Nucl. Med. Mol. Imaging"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1097\/RLU.0000000000004438","article-title":"Comparison of the Detection Performance Between FAP and FDG PET\/CT in Various Cancers: A Systemic Review and Meta-analysis","volume":"48","author":"Chang","year":"2023","journal-title":"Clin. Nucl. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"4377","DOI":"10.1007\/s00259-021-05307-1","article-title":"Head-to-head intra-individual comparison of biodistribution and tumor uptake of (68)Ga-FAPI and (18)F-FDG PET\/CT in cancer patients","volume":"48","author":"Giesel","year":"2021","journal-title":"Eur. J. Nucl. Med. Mol. Imaging"},{"key":"ref_14","unstructured":"Surucu, M., Vitzthum, L., Chang, D.T., Gensheimer, M., Kovalchuk, N., Han, B., lagaru, A., Silva, A.J.D., Narayanan, M., and Aksoy, D. (2023, January 23\u201327). Evaluation of Measured PET Activity Metrics from the First-in-Human Biology-Guided Radiotherapy Clinical Trial. Proceedings of the AAPM 65th Annual Meeting & Exhibition: AAPM, Houston, TX, USA."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"7","DOI":"10.4103\/ijnm.IJNM_134_20","article-title":"Optimal Standardized Uptake Value Threshold for Auto contouring of Gross Tumor Volume using Positron Emission Tomography\/Computed Tomography in Patients with Operable Nonsmall-Cell Lung Cancer: Comparison with Pathological Tumor Size","volume":"36","author":"Tibdewal","year":"2021","journal-title":"Indian J. Nucl. Med."},{"key":"ref_16","first-page":"1808","article-title":"18F-FDG PET definition of gross tumor volume for radiotherapy of non-small cell lung cancer: Is a single standardized uptake value threshold approach appropriate?","volume":"47","author":"Biehl","year":"2006","journal-title":"J. Nucl. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"711","DOI":"10.2967\/jnumed.122.264689","article-title":"Fibroblast-Activation Protein PET and Histopathology in a Single-Center Database of 324 Patients and 21 Tumor Entities","volume":"64","author":"Hirmas","year":"2023","journal-title":"J. Nucl. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"15330338251365334","DOI":"10.1177\/15330338251365334","article-title":"Expanding SCINTIX Biology-Guided Radiotherapy Beyond Lung and Bone: A Planning Feasibility and Dosimetric Study on the RefleXion X1 System","volume":"24","author":"Zhang","year":"2025","journal-title":"Technol. Cancer Res. Treat."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Cai, B., Banks, T.I., Shen, C., Prasad, R., Bal, G., Lin, M.H., Godley, A., Pompos, A., Garant, A., and Westover, K. (2025). Strategies for Offline Adaptive Biology-Guided Radiotherapy (BgRT) on a PET-Linac Platform. Cancers, 17.","DOI":"10.3390\/cancers17152470"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"4389","DOI":"10.1002\/mp.17114","article-title":"Commissioning of a novel PET-Linac for biology-guided radiotherapy (BgRT)","volume":"51","author":"Surucu","year":"2024","journal-title":"Med. Phys."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Wang, Q., Zhao, Y., Wang, F., and Tan, G. (2023). Clustering and machine learning-based integration identify cancer associated fibroblasts genes\u2019 signature in head and neck squamous cell carcinoma. Front. Genet., 14.","DOI":"10.3389\/fgene.2023.1111816"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Sunami, Y., Boker, V., and Kleeff, J. (2021). Targeting and Reprograming Cancer-Associated Fibroblasts and the Tumor Microenvironment in Pancreatic Cancer. Cancers, 13.","DOI":"10.3390\/cancers13040697"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1717","DOI":"10.1002\/hep.31792","article-title":"Cancer-Associated Fibroblast-Mediated Cellular Crosstalk Supports Hepatocellular Carcinoma Progression","volume":"73","author":"Song","year":"2021","journal-title":"Hepatology"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1097\/RLU.0000000000004505","article-title":"First Clinical Experience With [68Ga]Ga-FAPI-46-PET\/CT Versus [18F]F-FDG PET\/CT for Nodal Staging in Cervical Cancer","volume":"48","author":"Wegen","year":"2023","journal-title":"Clin. Nucl. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"20220463","DOI":"10.1259\/bjr.20220463","article-title":"Non-oncologic incidental uptake on FAPI PET\/CT imaging","volume":"96","author":"Hotta","year":"2023","journal-title":"Br. J. Radiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1186\/s12943-023-01744-8","article-title":"Extracellular matrix remodeling in tumor progression and immune escape: From mechanisms to treatments","volume":"22","author":"Yuan","year":"2023","journal-title":"Mol. Cancer"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1171","DOI":"10.2967\/jnumed.119.236786","article-title":"Radiation Dosimetry and Biodistribution of (68)Ga-FAPI-46 PET Imaging in Cancer Patients","volume":"61","author":"Meyer","year":"2020","journal-title":"J. Nucl. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.2967\/jnumed.121.262426","article-title":"Correlation of (68)Ga-FAPi-46 PET Biodistribution with FAP Expression by Immunohistochemistry in Patients with Solid Cancers: Interim Analysis of a Prospective Translational Exploratory Study","volume":"63","author":"Mona","year":"2022","journal-title":"J. Nucl. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"6935","DOI":"10.7150\/thno.103399","article-title":"(68)Ga-FAPI-46 PET\/CT in the evaluation of gliomas: Comparison with (18)F-FDG PET\/CT and contrast-enhanced MRI","volume":"14","author":"Ruan","year":"2024","journal-title":"Theranostics"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"201","DOI":"10.2967\/jnumed.120.245084","article-title":"FAPI-74 PET\/CT Using Either (18)F-AlF or Cold-Kit (68)Ga Labeling: Biodistribution, Radiation Dosimetry, and Tumor Delineation in Lung Cancer Patients","volume":"62","author":"Giesel","year":"2021","journal-title":"J. Nucl. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1225","DOI":"10.2967\/jnumed.123.265486","article-title":"Initial Evaluation of [(18)F]FAPI-74 PET for Various Histopathologically Confirmed Cancers and Benign Lesions","volume":"64","author":"Watabe","year":"2023","journal-title":"J. Nucl. Med."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/17\/22\/3648\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,15]],"date-time":"2025-11-15T05:31:51Z","timestamp":1763184711000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/17\/22\/3648"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,13]]},"references-count":31,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2025,11]]}},"alternative-id":["cancers17223648"],"URL":"https:\/\/doi.org\/10.3390\/cancers17223648","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,13]]}}}