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01-12-2021 | Positron Emission Tomography | Review

Clinical results of fibroblast activation protein (FAP) specific PET for non-malignant indications: systematic review

Authors: Paul Windisch, Daniel R. Zwahlen, Frederik L. Giesel, Eberhard Scholz, Patrick Lugenbiel, Jürgen Debus, Uwe Haberkorn, Sebastian Adeberg

Published in: EJNMMI Research | Issue 1/2021

Abstract

Purpose

Small molecules targeting fibroblast activation protein (FAP) have emerged as a new group of tracers for positron emission tomography (PET) in 2018. While most of the existing literature has been focussed on the application of FAP-specific PET in various kinds of cancers, some researchers have, both intentionally or unintentionally, used FAP-specific PET in patients with non-cancerous diseases. The purpose of this systematic review is therefore to summarize the available evidence of FAP-specific PET for non-malignant indications.

Methods

The MEDLINE database was searched for studies presenting the clinical use of FAP-specific PET, the records were screened according to PRISMA guidelines and articles containing patients suffering from non-malignant diseases were included.

Results

Sixteen studies with 303 patients were included. FAP-specific PET has been used in cardiac imaging, IgG₄-related disease, benign tumors as well as various kinds of inflammation. Two prospective studies on FAP-specific PET for IgG₄-related disease show its potential to differentiate inflammatory from fibrotic lesions, which could be used to determine the management of these patients.

Conclusion

While publications on FAP-specific PET for non-malignant indications are mostly limited to case reports and incidental findings, the first retrospective and prospective studies present promising results for IgG₄-related as well as cardiovascular disease that warrant further research. Several currently recruiting trials will add to the body evidence in the next few years.

Loktev A, Lindner T, Mier W, Debus J, Altmann A, Jäger D, et al. A Tumor-imaging method targeting cancer-associated fibroblasts. J Nucl Med. 2018;59:1423–9.PubMedPubMedCentralCrossRef

Lindner T, Loktev A, Altmann A, Giesel F, Kratochwil C, Debus J, et al. Development of quinoline-based theranostic ligands for the targeting of fibroblast activation protein. J Nucl Med. 2018;59:1415–22.PubMedCrossRef

Windisch P, Zwahlen DR, Koerber SA, Giesel FL, Debus J, Haberkorn U, et al. Clinical results of fibroblast activation protein (FAP) specific PET and implications for radiotherapy planning: systematic review. Cancers. 2020;12:2629.PubMedCentralCrossRef

Chen H, Zhao L, Ruan D, Pang Y, Hao B, Dai Y, et al. Usefulness of [68Ga]Ga-DOTA-FAPI-04 PET/CT in patients presenting with inconclusive [18F]FDG PET/CT findings. Eur J Nucl Med Mol Imaging. 2020. https://doi.org/10.1007/s00259-020-04940-6.CrossRefPubMedPubMedCentral

Heckmann MB, Reinhardt F, Finke D, Katus HA, Haberkorn U, Leuschner F, et al. Relationship between cardiac fibroblast activation protein activity by positron emission tomography and cardiovascular disease. Circ Cardiovasc Imaging. 2020;13:e010628.PubMedPubMedCentralCrossRef

Schmidkonz C, Rauber S, Atzinger A, Agarwal R, Götz TI, Soare A, et al. Disentangling inflammatory from fibrotic disease activity by fibroblast activation protein imaging. Ann Rheum Dis. 2020. https://doi.org/10.1136/annrheumdis-2020-217408.CrossRefPubMed

Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6:e1000097.PubMedPubMedCentralCrossRef

Pandya DN, Sinha A, Yuan H, Mutkus L, Stumpf K, Marini FC, et al. Imaging of fibroblast activation protein alpha expression in a preclinical mouse model of glioma using positron emission tomography. Molecules. 2020. https://doi.org/10.3390/molecules25163672.CrossRefPubMedPubMedCentral

Moon ES, Elvas F, Vliegen G, De Lombaerde S, Vangestel C, De Bruycker S, et al. Targeting fibroblast activation protein (FAP): next generation PET radiotracers using squaramide coupled bifunctional DOTA and DATA5m chelators. EJNMMI Radiopharm Chem. 2020;5:19.PubMedPubMedCentralCrossRef

10.

Hintz HM, Gallant JP, Vander Griend DJ, Coleman I, Nelson PS, LeBeau AM. Imaging fibroblast activation protein alpha improves diagnosis of metastatic prostate cancer with positron emission tomography. Clin Cancer Res. 2020. https://doi.org/10.1158/1078-0432.CCR-20-1358.CrossRefPubMedPubMedCentral

11.

Roy J, Hettiarachchi SU, Kaake M, Mukkamala R, Low PS. Design and validation of fibroblast activation protein alpha targeted imaging and therapeutic agents. Theranostics. 2020;10:5778–89.PubMedPubMedCentralCrossRef

12.

Schröder MS, Harwardt M-L, Rahm JV, Li Y, Freund P, Dietz MS, et al. Imaging the fibroblast growth factor receptor network on the plasma membrane with DNA-assisted single-molecule super-resolution microscopy. Methods. 2020. https://doi.org/10.1016/j.ymeth.2020.05.004.CrossRefPubMed

13.

Xing J, Gong Q, Zou R, Li Z, Xia Y, Yu Z, et al. A novel fibroblast activation protein-targeted near-infrared fluorescent off-on probe for cancer cell detection, in vitro and in vivo imaging. J Mater Chem B Mater Biol Med. 2018;6:1449–51.PubMedCrossRef

14.

Arakawa A, Jakubowski N, Koellensperger G, Theiner S, Schweikert A, Flemig S, et al. Quantitative imaging of silver nanoparticles and essential elements in thin sections of fibroblast multicellular spheroids by high resolution laser ablation inductively coupled plasma time-of-flight mass spectrometry. Anal Chem. 2019a;91:10197–203.PubMedCrossRef

15.

Arakawa A, Jakubowski N, Koellensperger G, Theiner S, Schweikert A, Flemig S, et al. Imaging of Ag NP transport through collagen-rich microstructures in fibroblast multicellular spheroids by high-resolution laser ablation inductively coupled plasma time-of-flight mass spectrometry. Analyst. 2019b;144:4935–42.PubMedCrossRef

16.

van der Geest T, Roeleveld DM, Walgreen B, Helsen MM, Nayak TK, Klein C, et al. Imaging fibroblast activation protein to monitor therapeutic effects of neutralizing interleukin-22 in collagen-induced arthritis. Rheumatology. 2018;57:737–47.PubMedCrossRef

17.

Varasteh Z, Mohanta S, Robu S, Braeuer M, Li Y, Omidvari N, et al. Molecular imaging of fibroblast activity after myocardial infarction using a 68Ga-labeled fibroblast activation protein inhibitor, FAPI-04. J Nucl Med. 2019;60:1743–9.PubMedPubMedCentralCrossRef

18.

Röhrich M, Loi L, Floca R, Haberkorn U, Paech D. Dataset of voxelwise correlated signal values of ADC, rCBV and FAP-specific PET of 13 Glioblastoma patients. Data in Brief. 2020;31:105712.PubMedPubMedCentralCrossRef

19.

Calais J, Mona CE. Will FAPI PET/CT replace FDG PET/CT in the next decade?-Point: an important diagnostic, phenotypic and biomarker role. AJR Am J Roentgenol. 2020. https://doi.org/10.2214/AJR.20.24302.CrossRefPubMed

20.

Moradi F, Iagaru A. Will FAPI PET/CT Replace FDG PET/CT in the Next Decade?-Counterpoint: No, not so fast! AJR Am J Roentgenol. 2020. https://doi.org/10.2214/AJR.20.23794.CrossRefPubMed

21.

Thackeray JT. Sound and fibroblast activation protein inhibitor: imaging fibroblast activation in the heart. Circ Cardiovasc Imaging. 2020;13:e011603.PubMedCrossRef

22.

Chen H, Wu H. Reply: [68Ga]Ga-DOTA-FAPI-04 and [18F]FDG PET/CT for the diagnosis of primary and metastatic lesions in patients with hepatic cancer. Eur J Nucl Med Mol Imaging. 2020;47:2080–2.PubMedCrossRef

23.

Zheng J, Yao S. [68Ga]Ga-DOTA-FAPI-04 and [18F] FDG PET/CT for the diagnosis of primary and metastatic lesions in patients with hepatic cancer. Eur J Nucl Med Mol Imaging. 2020;47:2078–9.PubMedCrossRef

24.

Laffon E, Marthan R. Reversibility of 68Ga-FAPI-2 trapping might prove an asset for PET quantitative imaging. J Nucl Med. 2020;61:620.PubMed

25.

Pang Y, Zhao L, Chen H. 68Ga-FAPI outperforms 18F-FDG PET/CT in identifying bone metastasis and peritoneal carcinomatosis in a patient with metastatic breast cancer. Clin Nucl Med. 2020. https://doi.org/10.1097/RLU.0000000000003263.CrossRefPubMed

26.

Liu Q, Shi S, Xu X, Yu X, Song S. The superiority of [68Ga]-FAPI-04 over [18F]-FDG PET/CT in imaging metastatic esophageal squamous cell carcinoma. Eur J Nucl Med Mol Imaging. 2020. https://doi.org/10.1007/s00259-020-04997-3.CrossRefPubMedPubMedCentral

27.

Fan C, Guo W, Su G, Chen B, Chen H. Widespread metastatic gastric signet-ring cell carcinoma shown by 68Ga-FAPI PET/CT. Clin Nucl Med. 2020. https://doi.org/10.1097/RLU.0000000000003245.CrossRefPubMed

28.

Hao B, Wu J, Pang Y, Sun L, Chen H. 68Ga-FAPI PET/CT in Assessment of leptomeningeal metastases in a patient with lung adenocarcinoma. Clin Nucl Med. 2020;45:784–6.PubMedCrossRef

29.

Wang G, Jin X, Zhu H, Wang S, Ding J, Zhang Y, et al. 68Ga-NOTA-FAPI-04 PET/CT in a patient with primary gastric diffuse large B cell lymphoma: comparisons with [18F] FDG PET/CT. Eur J Nucl Med Mol Imaging. 2020. https://doi.org/10.1007/s00259-020-04946-0.CrossRefPubMedPubMedCentral

30.

Windisch P, Röhrich M, Regnery S, Tonndorf-Martini E, Held T, Lang K, et al. Fibroblast activation protein (FAP) specific PET for advanced target volume delineation in glioblastoma. Radiother Oncol. 2020;150:159–63.PubMedCrossRef

31.

Röhrich M, Floca R, Loi L, Adeberg S, Windisch P, Giesel FL, et al. FAP-specific PET signaling shows a moderately positive correlation with relative CBV and no correlation with ADC in 13 IDH wildtype glioblastomas. Eur J Radiol. 2020;127:109021.PubMedCrossRef

32.

Röhrich M, Loktev A, Wefers AK, Altmann A, Paech D, Adeberg S, et al. IDH-wildtype glioblastomas and grade III/IV IDH-mutant gliomas show elevated tracer uptake in fibroblast activation protein-specific PET/CT. Eur J Nucl Med Mol Imaging. 2019. https://doi.org/10.1007/s00259-019-04444-y.CrossRefPubMed

33.

Syed M, Flechsig P, Liermann J, Windisch P, Haberkorn U, Debus J, et al. Fibroblast activation protein (FAPI) specific PET for advanced target volume delineation in head and neck cancer. Int J Radiat Oncol Biol Phys. 2019;105:383.CrossRef

34.

Pang Y, Hao B, Shang Q, Sun L, Chen H. Comparison of 68Ga-FAPI and 18F-FDG PET/CT in a patient with cholangiocellular carcinoma: a case report. Clin Nucl Med. 2020;45:566–7.PubMedCrossRef

35.

Chen H, Pang Y, Wu J, Zhao L, Hao B, Wu J, et al. Comparison of [68Ga]Ga-DOTA-FAPI-04 and [18F] FDG PET/CT for the diagnosis of primary and metastatic lesions in patients with various types of cancer. Eur J Nucl Med Mol Imaging. 2020;47:1820–32.PubMedCrossRef

36.

Meyer C, Dahlbom M, Lindner T, Vauclin S, Mona C, Slavik R, et al. Radiation dosimetry and biodistribution of 68Ga-FAPI-46 PET imaging in cancer patients. J Nucl Med. 2019. https://doi.org/10.2967/jnumed.119.236786.CrossRefPubMedPubMedCentral

37.

Koerber SA, Staudinger F, Kratochwil C, Adeberg S, Haefner MF, Ungerechts G, et al. The role of FAPI-PET/CT for patients with malignancies of the lower gastrointestinal tract - first clinical experience. J Nucl Med. 2020. https://doi.org/10.2967/jnumed.119.237016.CrossRefPubMedPubMedCentral

38.

Giesel F, Adeberg S, Syed M, Lindner T, Jimenez LD, Mavriopoulou E, et al. FAPI-74 PET/CT using either 18F-AlF or cold-kit 68Ga-labeling: biodistribution, radiation dosimetry and tumor delineation in lung cancer patients. J Nucl Med. 2020. https://doi.org/10.2967/jnumed.120.245084.CrossRefPubMedPubMedCentral

39.

Khreish F, Rosar F, Kratochwil C, Giesel FL, Haberkorn U, Ezziddin S. Positive FAPI-PET/CT in a metastatic castration-resistant prostate cancer patient with PSMA-negative/FDG-positive disease. Eur J Nucl Med Mol Imaging. 2020;47:2040–1.PubMedCrossRef

40.

Giesel FL, Heussel CP, Lindner T, Röhrich M, Rathke H, Kauczor H-U, et al. FAPI-PET/CT improves staging in a lung cancer patient with cerebral metastasis. Eur J Nucl Med Mol Imaging. 2019;46:1754–5.PubMedCrossRef

41.

Kratochwil C, Flechsig P, Lindner T, Abderrahim L, Altmann A, Mier W, et al. 68Ga-FAPI PET/CT: tracer uptake in 28 different kinds of cancer. J Nucl Med. 2019;60:801–5.PubMedPubMedCentralCrossRef

42.

Giesel F, Kratochwil C, Lindner T, Marschalek M, Loktev A, Lehnert W, et al. FAPI-PET/CT: biodistribution and preliminary dosimetry estimate of two DOTA-containing FAP-targeting agents in patients with various cancers. J Nucl Med. 2018. https://doi.org/10.2967/jnumed.118.215913.CrossRefPubMedPubMedCentral

43.

Xu T, Zhao Y, Ding H, Cai L, Zhou Z, Song Z, et al. [68Ga]Ga-DOTA-FAPI-04 PET/CT imaging in a case of prostate cancer with shoulder arthritis. Eur J Nucl Med Mol Imaging. 2020. https://doi.org/10.1007/s00259-020-05028-x.CrossRefPubMedPubMedCentral

44.

Shi X, Lin X, Huo L, Li X. Cardiac fibroblast activation in dilated cardiomyopathy detected by positron emission tomography. J Nucl Cardiol. 2020. https://doi.org/10.1007/s12350-020-02315-w.CrossRefPubMed

45.

Hayrapetian A, Girgis MD, Yanagawa J, French SW, Schelbert HR, Auerbach MS, et al. Incidental detection of elastofibroma dorsi with 68Ga-FAPI-46 and 18F-FDG PET/CT in a patient with esophageal cancer. Clin Nucl Med. 2020. https://doi.org/10.1097/RLU.0000000000003218.CrossRef

46.

Hao B, Wu X, Pang Y, Sun L, Wu H, Huang W, et al. [18F]FDG and [68Ga]Ga-DOTA-FAPI-04 PET/CT in the evaluation of tuberculous lesions. Eur J Nucl Med Mol Imaging. 2020. https://doi.org/10.1007/s00259-020-04941-5.CrossRefPubMed

47.

Luo Y, Pan Q, Yang H, Peng L, Zhang W, Li F. Fibroblast activation protein targeted PET/CT with 68Ga-FAPI for imaging IgG4-related disease: comparison to 18F-FDG PET/CT. J Nucl Med. 2020. https://doi.org/10.2967/jnumed.120.244723.CrossRefPubMedPubMedCentral

48.

Shi X, Xing H, Yang X, Li F, Yao S, Zhang H, et al. Fibroblast imaging of hepatic carcinoma with 68Ga-FAPI-04 PET/CT: a pilot study in patients with suspected hepatic nodules. Eur J Nucl Med Mol Imaging. 2020. https://doi.org/10.1007/s00259-020-04882-z.CrossRefPubMedPubMedCentral

49.

Pang Y, Huang H, Fu L, Zhao L, Chen H. 68Ga-FAPI PET/CT detects gastric signet-ring cell carcinoma in a patient previously treated for prostate cancer. Clin Nucl Med. 2020;45:632–5.PubMedCrossRef

50.

Zhao L, Gu J, Fu K, Lin Q, Chen H. 68Ga-FAPI PET/CT in assessment of liver nodules in a cirrhotic patient. Clin Nucl Med. 2020. https://doi.org/10.1097/RLU.0000000000003015.CrossRefPubMed

51.

Chen H, Zhao L, Ruan D, Sun L, Lin Q. 68Ga-FAPI PET/CT improves therapeutic strategy by detecting a second primary malignancy in a patient with rectal cancer. Clin Nucl Med. 2020;45:468–70.PubMedCrossRef

52.

Pan Q, Luo Y, Zhang W. Recurrent immunoglobulin G4-related disease shown on 18F-FDG and 68Ga-FAPI PET/CT. Clin Nucl Med. 2020;45:312–3.PubMedCrossRef

53.

Luo Y, Pan Q, Zhang W, Li F. Intense FAPI uptake in inflammation may mask the tumor activity of pancreatic cancer in 68Ga-FAPI PET/CT. Clin Nucl Med. 2020;45:310–1.PubMedCrossRef

54.

Totzeck M, Siebermair J, Rassaf T, Rischpler C. Cardiac fibroblast activation detected by positron emission tomography/computed tomography as a possible sign of cardiotoxicity. Eur Heart J. 2020;41:1060.PubMed

55.

Luo Y, Pan Q, Zhang W. IgG4-related disease revealed by 68Ga-FAPI and 18F-FDG PET/CT. Eur J Nucl Med Mol Imaging. 2019;46:2625–6.PubMedCrossRef

56.

Ankrah AO, Lawal IO, Boshomane TMG, Klein HC, Ebenhan T, Dierckx RAJO, et al. Comparison of fluorine(18)-fluorodeoxyglucose and Gallium(68)-citrate PET/CT in patients with tuberculosis. Nuklearmedizin. 2019;58:371–8.PubMedCrossRef

57.

Siebermair J, Köhler MI, Kupusovic J, Nekolla SG, Kessler L, Ferdinandus J, et al. Cardiac fibroblast activation detected by Ga-68 FAPI PET imaging as a potential novel biomarker of cardiac injury/remodeling. J Nucl Cardiol. 2020. https://doi.org/10.1007/s12350-020-02307-w.CrossRefPubMedPubMedCentral

58.

Tillmanns J, Hoffmann D, Habbaba Y, Schmitto JD, Sedding D, Fraccarollo D, et al. Fibroblast activation protein alpha expression identifies activated fibroblasts after myocardial infarction. J Mol Cell Cardiol. 2015;87:194–203.PubMedCrossRef

59.

Kaur H, Takefuji M, Ngai CY, Carvalho J, Bayer J, Wietelmann A, et al. Targeted ablation of periostin-expressing activated fibroblasts prevents adverse cardiac remodeling in mice. Circ Res. 2016;118:1906–17.PubMedCrossRef

60.

Lapa C, Reiter T, Werner RA, Ertl G, Wester H-J, Buck AK, et al. [68Ga]Pentixafor-PET/CT for imaging of chemokine receptor 4 expression after myocardial infarction. JACC Cardiovasc Imaging. 2015;8:1466–8.PubMedCrossRef

61.

Reiter T, Kircher M, Schirbel A, Werner RA, Kropf S, Ertl G, et al. Imaging of C-X-C motif chemokine receptor CXCR4 expression after myocardial infarction with [68Ga]Pentixafor-PET/CT in correlation with cardiac MRI. JACC Cardiovasc Imaging. 2018;11:1541–3.PubMedCrossRef

62.

Thackeray JT, Derlin T, Haghikia A, Napp LC, Wang Y, Ross TL, et al. Molecular imaging of the chemokine receptor CXCR4 after acute myocardial infarction. JACC Cardiovasc Imaging. 2015;8:1417–26.PubMedCrossRef

63.

Darby SC, Cutter DJ, Boerma M, Constine LS, Fajardo LF, Kodama K, et al. Radiation-related heart disease: current knowledge and future prospects. Int J Radiat Oncol Biol Phys. 2010;76:656–65.PubMedPubMedCentralCrossRef

64.

Alarid-Escudero F, Blaes AH, Kuntz KM. Trade-offs between efficacy and cardiac toxicity of adjuvant chemotherapy in early-stage breast cancer patients: do competing risks matter? Breast J. 2017;23:401–9.PubMedCrossRef

65.

Gomez DR, Tang C, Zhang J, Blumenschein GR Jr, Hernandez M, Lee JJ, et al. Local consolidative therapy vs maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer: long-term results of a multi-institutional, phase II randomized study. J Clin Oncol. 2019;37:1558.PubMedPubMedCentralCrossRef

66.

Sonni I, Lee-Felker S, Memarzadeh S, Quinn MM, Mona CE, Lückerath K, et al. 68Ga-FAPi-46 diffuse bilateral breast uptake in a patient with cervical cancer after hormonal stimulation. Eur J Nucl Med Mol Imaging. 2020. https://doi.org/10.1007/s00259-020-04947-z.CrossRefPubMed

Title: Clinical results of fibroblast activation protein (FAP) specific PET for non-malignant indications: systematic review
Authors: Paul Windisch
Daniel R. Zwahlen
Frederik L. Giesel
Eberhard Scholz
Patrick Lugenbiel
Jürgen Debus
Uwe Haberkorn
Sebastian Adeberg
Publication date: 01-12-2021
Publisher: Springer Berlin Heidelberg
Keyword: Positron Emission Tomography
Published in: EJNMMI Research / Issue 1/2021
Electronic ISSN: 2191-219X
DOI: https://doi.org/10.1186/s13550-021-00761-2

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Clinical results of fibroblast activation protein (FAP) specific PET for non-malignant indications: systematic review

Abstract

Purpose

Methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusion

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