The evolving role of FAPI-PET in assessing patients with various malignancies and its potential superiority over FDG-PET in this setting

Introduction: Fibroblast activation protein (FAP) is overexpressed in cancer-associated fibroblasts (CAFs) of many human epithelial cancers and more in tumors with high grades of desmoplasia. Higher expression of FAP on CAFs is a marker of aggressive tumor behavior and poor prognosis. Molecular PET/CT imaging with radiolabeled FAP inhibitors (FAPI) has been investigated in several cancers. Through literature review, we aim to identify the potential applications of fibroblast activation protein inhibitors (FAPI) PET/CT in malignant disorders, compare the performance of FAPI PET/CT vs. 18F-fluorodeoxyglucose (18F-FDG) PET/CT, discuss the usefulness in adopting FAPI PET/CT in domains where 18F-FDG PET/CT has been found to have a limited role.

Methods: We searched the literature via Google Scholar and PubMed to compile the existing articles describing the data generated by FAPI PET/CT and compared the results to 18F-FDG PET/CT in various primary and metastatic tumors. We selected papers that were highly cited. We carefully compared the pros and cons of the approach. We determined the advantages, limitations, and other shortcomings of both techniques.

Results: 68Ga-FAPI has shown a relatively higher uptake than 18F-FDG in several cancers, with some of the highest uptake found in sarcoma, esophageal, breast, cholangiocarcinoma, and lung cancer. Most studies have been performed in a mixed population of different cancers, but recently more studies for specific cancers have been published. Furthermore, FAPI PET/CT has shown better sensitivity in detecting lymph nodes, bone, and visceral metastases, especially in identifying liver metastases, peritoneal carcinomatosis, and brain tumors. In addition to this, in patients undergoing oncological evaluation with inconclusive 18F-FDG PET/CT findings, FAPI PET/CT may have a complementary role in discriminating mass lesions on conventional imaging, locating the primary site of unknown malignancy, modifying tumor staging, and detecting suspected disease recurrence. Because of its low expression in normal organs, FAP is also a promising target for theranostics. A proof-of-concept study in mice with human pancreatic cancer xenografts used FAPI labeled with radionuclides with a relatively long half-life, 64Cu (half-life, 12.7 h) for PET imaging and 225Ac (half-life, 10 d) for radionuclide therapy, showed significant tumor growth suppression compared to controls. α-therapy targeting FAP in the cancer stroma is effective and believed to contribute to developing a new treatment strategy in cancers with high expression of FAP and in cancers with few treatment options. Normal fibroblasts have a minimal expression of FAP, resulting in low or no uptake in normal adult human tissue. Tumor-to-background contrast ratios are equal to or even better than 18F-FDG due to high uptake, rapid clearance from circulation, and low uptake in normal tissue. In contrast to 18F-FDG, no diet or fasting in preparation for the examination is necessary, and because of the high contrast, image acquisition can be performed as soon as 10 minutes after FAPI administration. Several 68Ga-FAPIs have already been proposed as promising PET tracers. However, the relatively short half-life of 68Ga (1.90-MeV positron energy) poses some disadvantages concerning production capacity and nuclear decay properties resulting in problems with manufacture and delivery. Labeling with 18F (half-life, 110 min, 0.65-MeV positron energy) would solve these issues. Moreover, recent developments toward an improved compound for therapeutic application have identified 68Ga -FAPI-46 as a promising agent because of an increased tumor retention time compared to other 68Ga labeled FAPI tracers.

Conclusions: Although available data are limited, FAPI PET/CT seems to be a promising molecular imaging tool for cancer imaging. It can be used for imaging different types of cancers and outperforms 18F-FDG PET/CT in some of these. Its potential as a theragnostic tool warrants special attention.