Importance of 68Ga-FAPI PET/CT for Detection of Cancer

HomeRadiologyVol. 303, No. 1 PreviousNext Reviews and CommentaryFree AccessEditorialImportance of 68Ga-FAPI PET/CT for Detection of CancerFrancine L. Jacobson , Annick D. Van den AbbeeleFrancine L. Jacobson , Annick D. Van den AbbeeleAuthor AffiliationsFrom the Department of Radiology, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115 (F.L.J., A.D.V.d.A.); and Department of Imaging, Dana-Farber Cancer Institute, Boston, Mass (A.D.V.d.A.).Address correspondence to F.L.J. (e-mail: [email protected]).Francine L. Jacobson Annick D. Van den AbbeelePublished Online:Jan 4 2022https://doi.org/10.1148/radiol.212884MoreSectionsPDF ToolsImage ViewerAdd to favoritesCiteTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinked In See also the article by Wang and Tang et al in this issue.Francine L. Jacobson, MD, MPH, is the medical director for lung cancer screening at Brigham Health, staff radiologist in the Division of Thoracic Imaging at Brigham and Women’s Hospital, and assistant professor of radiology at Harvard Medical School with research interests in radiology perception science and medical image analysis.Download as PowerPointOpen in Image Viewer Annick D. Van den Abbeele, MD, is professor of radiology at Harvard Medical School; Chair Emeritus, Department of Imaging, Founder/Director, Center for Biomedical Imaging in Oncology, Dana-Farber Cancer Institute; Co-Director, Tumor Imaging Metrics Core, Dana-Farber/Harvard Cancer Center; 2021–2022 President of the International Cancer Imaging Society; and co–editor-in-chief of Cancer Imaging. Her research interests focus on translational cancer research testing novel cancer drugs using molecular imaging and therapy, and on tumor metrics.Download as PowerPointOpen in Image Viewer The first indications for Medicare reimbursement for PET examinations in 1998 were the characterization of solitary lung nodules and initial staging of non–small cell lung cancer. Before that time, diagnosis of lung cancer almost always occurred at an advanced stage with poor prognosis, and the incidence and death rates of lung cancer were nearly equal for decades because of late detection. As such, lung cancer became the most frequent cause of cancer death in men and women in the United States, with a 5-year survival rate of only 15% in 1987. Multimodality treatment for lung cancer that began in the 1990s using minimally invasive surgery, chemotherapy, and radiation therapy only slightly increased the 5-year survival rate to 17%–18%.There are some challenges when using PET alone to detect early-stage cancer. Classic late-stage lesions, often described as spiculated masses, show avidity when evaluated with fluorine 18 (18F)–labeled fluorodeoxyglucose (FDG) PET. However, the very metabolically indolent nature of early lung adenocarcinoma, the dominant form of lung cancer in the 21st century, may result in lower 18F-FDG avidity. Also, PET scanners have a lower spatial resolution relative to CT scanners, which may limit the detection of smaller size lung nodules, while high background activity such as physiologic 18F-FDG uptake in the brain limits diagnostic performance for the detection of a metastatic lesion. Nevertheless, combined 18F-FDG PET/CT has a high negative predictive value of 95% in assessing single pulmonary nodules in patients at high risk of lung cancer (1), and smaller size nodules are amenable to detection with lung cancer screening CT.Combined PET/CT scanners provide complementary whole-body anatomic, functional, and molecular scanning in one setting. This complementary scanning improves staging data, including detection of direct extension to pleura and overlying bone as well as distant disease. These findings help decision making and selection of therapy because findings such as extensive lymphadenopathy or distant metastatic disease would make curative surgery futile. However, lung adenocarcinoma is known to metastasize to the brain before the primary lesion reaches the minimum size for reliable detection on 18F-FDG PET/CT scans. Thus, evaluation of brain metastases is better performed with brain MRI given the high physiologic 18F-FDG uptake seen in the normal brain resulting in lower tumor-to-background ratios.Begun in 2002, the National Lung Cancer Screening Trial continues to increase radiologists’ understanding of the CT appearance of early lung cancer. CT scanners with slip-ring technology were introduced in the late 1980s, and trials of low-dose CT for lung cancer detection occurred in the 1990s. Size-detection limitations of PET scanners and the indolent metabolic nature of early lung adenocarcinoma regarding glucose metabolism have limited the value of 18F-FDG PET/CT for screening evaluation and incidentally identified early lung cancer. Uncontrolled diabetes may also lead to nondiagnostic 18F-FDG PET scans because of altered 18F-FDG biodistribution. Therefore, PET/CT molecular imaging performed with gallium 68 (68Ga)–labeled fibroblast-activation protein inhibitor (FAPI), known as 68Ga-FAPI, is worth exploring. The tracer 68Ga-FAPI is a quinoline-based novel tracer targeting cancer-associated fibroblasts in the tumor microenvironment. 68Ga-FAPI has low uptake in normal tissue and high expression across a wide range of cancers, including cancers that show low 18F-FDG avidity. This tracer may, therefore, offer a more suitable approach to the early diagnosis of lung cancer as well as other common cancers. But one must take into account that this tracer will also bind to benign processes characterized by fibrosis that may be present in the lungs, such as pulmonary fibrosis, asbestosis, radiation pneumonitis, and other inflammatory conditions.In this issue of Radiology, Wang and colleagues (2) performed a single-center prospective study assessing PET/CT detection of lung cancer with 18F-FDG compared with 68Ga-FAPI in 34 patients with metastatic lung cancer. Direct comparison of lesions on both 18F-FDG and 68Ga-FAPI scans showed that the stromal-targeting agent 68Ga-FAPI appeared to be more sensitive and more specific than the metabolic tracer 18F-FDG. 68Ga-FAPI also helped provide relevant clinical information regarding the extent of tumor burden in a patient with uncontrolled diabetes who had a nondiagnostic 18F-FDG PET scan because of altered 18F-FDG biodistribution. Furthermore, given the lack of physiologic uptake of 68Ga-FAPI in normal brain tissue, increased visualization of brain metastases was observed on 68Ga-FAPI PET/CT images (23 suspected metastases vs 10 identified on 18F-FDG PET/CT images). Of note, both PET/CT techniques still depicted fewer brain lesions than brain MRI. This may be related to limitations in tumor size and/or biologic activity in tumor cells and tumor-associated fibroblasts within the tumor microenvironment. 68Ga-FAPI PET/CT outperformed 18F-FDG PET/CT for the detection of pleural disease, while similar results were seen for both agents in the detection of adrenal and liver metastases. The authors concluded that 68Ga-FAPI PET/CT may outperform conventional 18F-FDG PET/CT in the detection of metastases to the brain, lymph nodes, bone, and pleura.To date, at least 28 different cancers have demonstrated 68Ga-FAPI avidity (3), requiring further studies and experience. If this new tracer is validated, however, having a molecular imaging tracer that targets the tumor microenvironment may add enormous value to the characterization of cancer and complementary information to other molecular imaging tracers currently used in the clinic, including 18F-FDG. It may also open the door to novel diagnostic and therapeutic approaches in lung cancer and many other cancers (4–8).There are two key limitations of the study. First, clinical care for patients such as those in this study with advanced-stage cancers has limited pathologic correlation for metastases that are generally not biopsied or resected in the setting of known metastatic lung cancer. Although multifocal lung adenocarcinoma is relatively common, including in patients who also have advanced disease with distant metastases, the current study has limited direct applicability to the detection of lung cancer metastases at the time of initial lung cancer diagnosis, particularly in the setting of early lung cancer diagnosed with lung cancer screening CT. This weakness should not be judged harshly, as 68Ga-FAPI as an imaging agent has the potential to improve image-based lung cancer staging. Second, additional studies will be required to reduce and potentially eliminate the need for separate brain MRI in the initial staging of lung cancer and finally allow molecular imaging to replace surgical staging of mediastinal lymph nodes. However, the study by Wang et al has promising results that point toward more streamlined care for patients with cancer. This streamlined care would allow more rapid initiation of individualized treatments, thereby also supporting improvement in cancer outcomes with higher patient satisfaction and reduced cost to the health care system.68Ga-FAPI PET/CT scanning marks an important paradigm shift to more specific identification and characterization of a variety of cancers, including their tumor microenvironment, and might not only be suitable for use before initial definitive diagnosis but also give the ability to make early informed clinical decisions. Additional radiotracers along this line will likely follow and support the need for better biologic cancer characterization and balance differentiation between tumors. The approach used by Wu et al provides an efficient model for comparing the clinical utility of novel tracers that can be applied to other cancers besides lung cancer. It would not be unprecedented for very specific anatomic patterns to become less specific through our learning as we include molecular imaging using tracers specific to oncologic biologic processes, which provides more details and more clinically relevant information than previously seen and increases our knowledge of cancer biology in living patients. More sensitive and specific molecular imaging tracers may fulfill and complement the promises of 18F-FDG PET, CT, and MRI in the diagnosis and staging of lung cancer while sparing patients invasive procedures for pathologic examination of tumor tissue.This may also mark the arrival of a new era in nuclear medicine where molecular imaging helps visualize and characterize the entire tumor burden in one setting. Other potential advantages of molecular imaging include providing noninvasive in vivo phenotypic information, adding specificity to various biologic oncologic mechanisms in the cancer cell and its tumor microenvironment, providing critical prognostic and predictive information, and guiding therapeutic decisions. These advantages would indeed give new meaning to radiology and cancer imaging as an all-inclusive specialty that embraces anatomic, functional, and molecular imaging for the benefit of patients with cancer and other diseases.Disclosures of conflicts of interest: F.L.J. No relevant relationships. A.D.V.d.A. Dana-Farber/Harvard Cancer Center grant 2 P30 CA006516-52 from NCI National Comprehensive Cancer Center; Co-PI, Tumor Imaging Metrics Core; research funding support to the Dana-Farber/Harvard Cancer Center from Novartis, Pfizer, Bayer, GSK, BMS, AAA, Endocyte, Ipsen, ImaginAb, Immunomic Therapeutics, and Astellas Pharma US; site Principal Investigator on a phase II trial and Imaging Scientific Advisory Board (iSAB) member, ImaginAb; royalties from Thieme Publishers as textbook co-editor of Case-Based Nuclear Medicine, 2nd edition; small stipend for editorial services from Biomed Central for the ICIS Cancer Imaging journal as co–Editor-in-Chief; travel expenses to attend investigators’ or board meetings from Ipsen, ImaginAb, and Centre for Probe Development and Commercialization; Imaging Scientific Advisory board (iSAB) member, ImaginAb; unpaid 2021–2022 President of the International Cancer Imaging Society (ICIS); unpaid board member for the Centre for Probe Development and Commercialization.References1. Kagna O, Solomonov A, Keidar Z, et al. The value of FDG-PET/CT in assessing single pulmonary nodules in patients at high risk of lung cancer. Eur J Nucl Med Mol Imaging 2009;36(6):997–1004. Crossref, Medline, Google Scholar2. Wang L, Tang G, Hu K, et al. Comparison of 68Ga-FAPI and 18F-FDG PET/CT in the Evaluation of Advanced Lung Cancer. Radiology 2022;303(1):191–199. Link, Google Scholar3. Kratochwil C, Flechsig P, Lindner T, et al. 68Ga-FAPI PET/CT: tracer uptake in 28 different kinds of cancer. J Nucl Med 2019;60(6):801–805. Crossref, Medline, Google Scholar4. Hicks RJ, Roselt PJ, Kallur KG, Tothill RW, Mileshkin L. FAPI PET/CT: will it end the hegemony of 18F-FDG in oncology? J Nucl Med 2021;62(3):296–302. Crossref, Medline, Google Scholar5. Loktev A, Lindner T, Mier W, et al. A tumor-imaging method targeting cancer-associated fibroblasts. J Nucl Med 2018;59(9):1423–1429. Crossref, Medline, Google Scholar6. Syed M, Flechsig P, Liermann J, et al. Fibroblast activation protein inhibitor (FAPI) PET for diagnostics and advanced targeted radiotherapy in head and neck cancers. Eur J Nucl Med Mol Imaging 2020;47(12):2836–2845. Crossref, Medline, Google Scholar7. Watabe T, Liu Y, Kaneda-Nakashima K, et al. Theranostics targeting fibroblast activation protein in the tumor stroma: 64Cu- and 225Ac-Labeled FAPI-04 in pancreatic cancer xenograft mouse models. J Nucl Med 2020;61(4):563–569. Crossref, Medline, Google Scholar8. Lindner T, Loktev A, Altmann A, et al. Development of quinoline-based theranostic ligands for the targeting of fibroblast activation protein. J Nucl Med 2018;59(9):1415–1422. Crossref, Medline, Google ScholarArticle HistoryReceived: Nov 11 2021Revision requested: Nov 17 2021Revision received: Dec 2 2021Accepted: Dec 7 2021Published online: Jan 04 2022Published in print: Apr 2022 FiguresReferencesRelatedDetailsCited ByDifferent uptake patterns of 68Ga-FAPI in aseptic loosening and periprosthetic joint infection of hip arthroplasty: A case series and literature reviewYiqunWang, RuiminWang, LeiGeng, QingxiaoLi, ErpengQi, YuanyuanShi, YanmeiWang, QingyuanZheng, GuoqiangZhang, JiyingChen, JiaheTian2022 | Frontiers in Medicine, Vol. 9Accompanying This ArticleComparison of 68Ga-FAPI and 18F-FDG PET/CT in the Evaluation of Advanced Lung CancerJan 4 2022RadiologyRecommended Articles Comparison of 68Ga-FAPI and 18F-FDG PET/CT in the Evaluation of Advanced Lung CancerRadiology2022Volume: 303Issue: 1pp. 191-199Low-Dose Chest CT to Predict Disease-Free Survival for Early-Stage Node-Negative Centrally Located Lung AdenocarcinomaRadiology2021Volume: 299Issue: 2pp. 448-449Over- and Underdiagnosis in Lung Cancer: Searching for a “Solid” DiagnosisRadiology2016Volume: 280Issue: 3pp. 655-658Low-Dose CT Screening for Lung Cancer: Evidence from 2 Decades of StudyRadiology: Imaging Cancer2020Volume: 2Issue: 2Revisions to the TNM Staging of Lung Cancer: Rationale, Significance, and Clinical ApplicationRadioGraphics2018Volume: 38Issue: 2pp. 374-391See More RSNA Education Exhibits Management of Solitary Pulmonary Nodules: Pushing the Limits Beyond the GuidelinesDigital Posters2019Challenges and Pitfalls in Lung Cancer ScreeningDigital Posters2022Multifocal Lung Adenocarcinomas: Comprehensive Review and the Current Management StrategyDigital Posters2019 RSNA Case Collection Thoracic splenosisRSNA Case Collection2020Diffuse idiopathic pulmonary neuroendocrine cell hyperplasiaRSNA Case Collection2020Solitary intracranial metastasis RSNA Case Collection2020 Vol. 303, No. 1 Metrics Altmetric Score PDF download