[18F] AlF‑NOTA‑FAPI‑04 PET/CT as a promising tool for imaging fibroblast activation protein in gastrointestinal system cancers: a prospective investigation of comparative analysis with 18F-FDG

European Journal of Nuclear Medicine and Molecular Imaging https://doi.org/10.1007/s00259-023-06351-9 ORIGINAL ARTICLE [18F] AlF‑NOTA‑FAPI‑04 PET/CT as a promising tool for imaging fibroblast activation protein in gastrointestinal system cancers: a prospective investigation of comparative analysis with 18F‑FDG Liping Yang1 · Shichuan Xu2 · Liang Cheng1 · Chao Gao3 · Shaodong Cao3 · Zhengsong Chang4 · Kezheng Wang1 Received: 6 April 2023 / Accepted: 20 July 2023 © The Author(s) 2023 Abstract Purpose The radiopharmaceutical [18F]AlF-NOTA-FAPI-04 presents a promising alternative to 68 Ga-FAPI owing to its relatively longer half-life. This study aimed to evaluate the clinical usefulness of [ 18F]AlF-NOTA-FAPI-04 PET/CT for the diagnosis of primary and metastatic lesions in various types of gastrointestinal system cancers, compared with 18F-FDG PET/CT. Methods Patients diagnosed with gastrointestinal system malignancies were prospectively enrolled. All patients underwent both 18F-FDG and 18F-FAPI-04 PET/CT scans within one week, with 44 (73.3%) for cancer staging and 16 (26.7%) for tumor restaging. Diagnostic efficacy of the primary tumor, as well as the presence and number of lymph nodes and distant metastases, were assessed. Tumor uptake was quantified by the maximum standard uptake value (SUVmax). Results For detection of primary tumor, the diagnostic sensitivity of 18F-FDG PET/CT was 72.7%, while it was 97.7% for 18 F-FAPI-04 PET/CT. Based on per-lymph node analysis, the sensitivity, specificity, and accuracy of 18F-FAPI-04 PET/CT in diagnosing metastatic lymph nodes were 91.89%, 92.00%, and 91.96%, respectively. These values were notably higher than those 18F-FDG PET/CT (79.72%, 81.33% and 80.80%, respectively). The 18F-FAPI-04 PET/CT surpassed 18F-FDG PET/ CT in detecting suspected metastases in the brain (7 vs. 3), liver (39 vs. 20), bone (79 vs. 51), lung (11 vs. 4), and peritoneal carcinoma (48 vs. 22). Based on per-patient analysis, differential diagnostic accuracies (18F-FAPI-04 vs. 18F-FDG PET/CT) were observed in all patients (91.7% vs. 76.7%), the initial staging group (90.9% vs. 79.5%), and the re-staging group (93.8% vs. 68.7%). Additionally, 18F-FAPI-04 PET/CT revised final diagnosis in 31.7% of patients, contrasting with 18F-FDG PET/ CT, and prompted changes in clinical management for 21.7% of the patients. Conclusion 18F-FAPI-04 PET/CT outperforms 18F-FDG PET/CT in delineating the primary gastrointestinal tumors and detecting suspected metastatic lesions due to a higher target-to-background ratio (TBR). Moreover, 18F-FAPI-04 PET/CT could provide valuable guidance for tumor staging, thereby having a potential impact on patient management. Keywords Gastrointestinal system cancers · FAPI PET/CT · FDG PET/CT · Cancer-associated fibroblast · Clinical management Zhengsong Chang and Kezheng Wang contributed equally to this work. * Zhengsong Chang 2 Department of Medical Instruments, Second Hospital of Harbin, Harbin, China * Kezheng Wang 3 Department of Medical Imaging, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, China 4 Department of Pathology, Harbin Medical University Cancer Hospital, Harbin, China 1 Department of PET‑CT, Harbin Medical University Cancer Hospital, Harbin, China 13 Vol.:(0123456789) European Journal of Nuclear Medicine and Molecular Imaging Introduction Alterations in metabolism are among the hallmarks of malignant tumors. The transition to increased glucose metabolism, characteristic of cancerous cells, was first observed since the 1980s through fluorine-18 fluorodeoxyglucose (18F-FDG) PET/CT imaging [1]. Consequently, 18 F-FDG uptake is linked to glucose metabolism levels and is frequently employed as a diagnostic radiotracer for oncological PET imaging. Despite consensus on the significant contributions of 18F-FDG PET/CT to tumor staging, therapeutic efficacy assessment, and recurrence monitoring in gastrointestinal system cancers, its limitations cannot be overlooked [2]. A decreased sensitivity in detecting early-stage or specific subtypes of gastrointestinal system malignancies has been reported, attributed to the slow proliferation of these tumor cells. In addition, the ability of 18F-FDG PET/CT to detect regional lymph node metastasis is suboptimal, with a sensitivity of only 55%, leading to subpar treatment and poor survival outcomes [3]. Thus, there is an urgent need to develop an effective PET radiotracer to facilitate accurate tumor characterization and personalized patient management. It's well-established that the tumor microenvironment has an indispensable role in fostering neoplasia development. Cancer-associated fibroblasts (CAFs) are the dominant components of the tumor microenvironment. Research has shown that CAFs are critical catalysts for tumor growth, invasion, metastatic spread, and they're closely linked with treatment resistance and poor survival prognosis [4]. Fibroblast activation protein (FAP), a type II transmembrane serine protease, is scarcely found in normal tissues and organs, but is overexpressed in CAFs in various epithelial carcinomas. CAFs enable promote tumor cell migration, invasion, angiogenesis, and metastasis by activating corresponding signaling pathways [5]. Given these properties, Gallium-68-labeled fibroblast activation protein inhibitor (68Ga-FAPI) has emerged as a novel FAP-targeting radiotracer for PET cancer imaging, promising in vivo visualization of tumor stroma. Among these FAPIs, FAPI-04 stands out due to its enhanced FAP binding capacity and favorable pharmacokinetics, making it ideal for contrast and visibility [6]. This led to the development of 68Ga-DOTA-FAPI-04 PET/CT for fast imaging of a wide range of tumors. Current research on molecular imaging probes targeting FAP commonly uses 68Ga-FAPI-04 for PET imaging. Despite the unprecedented success of 68Ga-FAPI-04 PET/CT in detecting primary tumors, it has its drawbacks. The broad application of 68Ga-labeled FAPI in clinical practice is limited due to the short half-life of 68Ga, high costs, and insufficient availability of radionuclides from 13 the 68 Ge/ 68 Ga generator. Conversely, 18 F is the most widely used radionuclide in PET imaging, as it can be mass-produced via a cyclotron and transported over long distances [7]. Consequently, 18F-FAPI-04 emerges as an ideal alternative to 68Ga-FAPI-04. Preclinical evaluations of 18F-FAPI-04 PET/CT have demonstrated promising results in cancer imaging of FAP expression in mice [8], proving its safety and feasibility for further clinical translation. However, a paucity of studies directly comparing these two PET radiotracers ( 18F-FAPI-04 and 18F-FDG) in characterizing primary tumors and metastatic lesions can be noted in current literature. Therefore, our study aims to conduct a prospective, head-to-head comparison of 18F-FAPI-04 to 18F-FDG in patients with various gastrointestinal system cancers to establish generalizable differences between the (...truncated)