State-of-the-art of FAPI-PET imaging: a systematic review and meta-analysis

Introduction Fibroblast activation protein-alpha (FAP alpha) is overexpressed on cancer-associated fibroblasts in approximately 90% of epithelial neoplasms, representing an appealing target for therapeutic and molecular imaging applications. [(68) Ga]Ga-labelled radiopharmaceuticals-FAP-inhibitors (FAPI)-have been developed for PET. We systematically reviewed and meta-analysed published literature to provide an overview of its clinical role. Materials and methods The search, limited to January 1st, 2018-March 31st, 2021, was performed on MedLine and Embase databases using all the possible combinations of terms "FAP", "FAPI", "PET/CT", "positron emission tomography", "fibroblast", "cancer-associated fibroblasts", "CAF", "molecular imaging", and "fibroblast imaging". Study quality was assessed using the QUADAS-2 criteria. Patient-based and lesion-based pooled sensitivities/specificities of FAPI PET were computed using a random-effects model directly from the STATA "metaprop" command. Between-study statistical heterogeneity was tested (I-2-statistics). Results Twenty-three studies were selected for systematic review. Investigations on staging or restaging head and neck cancer (n = 2, 29 patients), abdominal malignancies (n = 6, 171 patients), various cancers (n = 2, 143 patients), and radiation treatment planning (n = 4, 56 patients) were included in the meta-analysis. On patient-based analysis, pooled sensitivity was 0.99 (95% CI 0.97-1.00) with negligible heterogeneity; pooled specificity was 0.87 (95% CI 0.62-1.00), with negligible heterogeneity. On lesion-based analysis, sensitivity and specificity had high heterogeneity (I-2 = 88.56% and I-2 = 97.20%, respectively). Pooled sensitivity for the primary tumour was 1.00 (95% CI 0.98-1.00) with negligible heterogeneity. Pooled sensitivity/specificity of nodal metastases had high heterogeneity (I-2 = 89.18% and I-2 = 95.74%, respectively). Pooled sensitivity in distant metastases was good (0.93 with 95% CI 0.88-0.97) with negligible heterogeneity. Conclusions FAPI-PET appears promising, especially in imaging cancers unsuitable for [F-18]FDG imaging, particularly primary lesions and distant metastases. However, high-level evidence is needed to define its role, specifically to identify cancer types, non-oncological diseases, and clinical settings for its applications.