Head-to-head Intra-individual Comparison of [68Ga]-FAPI and [18F]-FDG PET/CT in Patients with Bladder Cancer

Molecular Imaging and Biology DOI 10.1007/s11307-022-01715-3 © The Author(s), 2022 RESEARCH ARTICLE Head‑to‑head Intra‑individual Comparison of [68Ga]‑FAPI and [18F]‑FDG PET/CT in Patients with Bladder Cancer E. Novruzov1, K. Dendl1,2, H. Ndlovu3, P. L. Choyke4, M. Dabir1, M. Beu1, F. Novruzov5, E. Mehdi5, F. Guliyev6, S. A. Koerber7, I. Lawal4, G. Niegisch8, J. Debus7, U. Haberkorn2, M. Sathekge3, and F. L. Giesel1,2 1Department of Nuclear Medicine, Medical Faculty, Heinrich-Heine-University, University Hospital Dusseldorf, Dusseldorf, Germany 2 Department of Nuclear Medicine, University Hospital Heidelberg, Heidelberg, Germany 3 Department of Nuclear Medicine, University of Pretoria & Steve Biko Academic Hospital, Pretoria, South Africa 4 Molecular Imaging Branch, National Cancer Institute, Bethesda, MD, USA 5 Nuclear Medicine Department, National Centre of Oncology, Baku, Azerbaijan 6 Department of Uro‑Oncology, National Centre of Oncology, Baku, Azerbaijan 7 Department of Radiation Oncology, Heidelberg University Hospital, Heidelberg, Germany 8 Department of Urology, University Hospital Duesseldorf, Duesseldorf, Germany 2022 Abstract Aim/Purpose: Fibroblast activation protein-(FAP)-ligands, a novel class of tracers for PET/CT imaging, demonstrated promising results in previous studies in various malignancies compared to standard [18F]FDG PET/CT. 68Ga-labeled fibroblast activation protein inhibitor-([68Ga]Ga-DOTA-FAPI)-PET/CT impresses with sharp contrasts in terms of high tumor uptake and low background noise leading to clear delineation. [18F]FDG PET/CT has limited accuracy in bladder cancer due to high background signal. Therefore, we sought to evaluate the diagnostic potential of [ 68Ga]FAPI in patients with bladder cancer. Material and Methods: This retrospective analysis consisted of 8 patients (median age 66), 7 of whom underwent both [68Ga]FAPI and [18F]FDG PET/CT scans with a median time interval of 5 days (range 1–20 days). Quantification of tracer uptake was determined with SUVmax and SUVmean. Furthermore, the tumor-to-background ratio (TBR) was derived by dividing the SUVmax of tumor lesions by the SUVmax of adipose tissue, skeletal muscle, and blood pool. Results: Overall, 31 metastases were detected in five patients including lymph node metastases (n = 23), bone metastases (n = 4), lung metastases (n = 3), and a peritoneal metastasis (n = 1). In one patient, [68Ga]FAPI demonstrated significant uptake in the primary tumor located in the bladder wall. [ 68Ga] FAPI-PET/CT demonstrated significantly higher uptake compared to [ 18F]FDG PET/CT with higher mean SUVmax (8.2 vs. 4.6; p = 0.01). Furthermore, [68Ga]FAPI detected additional 30% (n = 9) lesions, missed by [18F]FDG. TBR demonstrated favorable uptake for [ 68Ga]FAPI in comparison to [ 18F]FDG. Significant differences were determined with regard to metastasis/blood pool ([68Ga]FAPI 5.3 vs [ 18F]FDG 1.9; p = 0.001). Conclusion: [68Ga]FAPI-PET/CT is a promising diagnostic radioligand for patients with bladder cancer. This first described analysis of FAP-ligand in bladder cancer revealed superiority over [18F]FDG in a small patient cohort. Thus, this so far assumed potential has to be confirmed and extended by larger and prospective studies. Correspondence to: F. L. Giesel; e-mail: Vol.:(0123456789) Giesel et al.: Head‑to‑head Intra‑individual Comparison of [68Ga]‑FAPI and [18F]‑FDG PET/CT in Patients Keywords FAPI · PET · Bladder cancer · Fibroblast activation protein · Urothelial carcinoma Introduction Urothelial carcinoma is the most common (> 90%) cell type of bladder cancer associated with worldwide highly varying incidence and prevalence rates mainly depending on environmental factors [1–4]. While bladder cancer in its early clinical stages (non-muscle-invasive bladder cancer, NMIBC ≤ T1) has an overall good prognosis, it nevertheless is associated with high recurrence rates (40–70% rate within 5 years). The prognosis in advanced clinical stage disease (muscle-invasive bladder cancer; MIBC ≥ T2) is poor due to the early development of distant metastases. Accurate staging plays a crucial role for proper patient stratification and therapy management [5, 6]. Besides T-stage, nodal status is the most important prognostic factor that correlates with 5-year disease-free survival. Furthermore, the extent of nodal metastasis shows a direct correlation with T-status at the time of initial presentation which reveals a lymph node involvement of approximately 30% in T2 and up to 60% in ≥ T3 cancers [7]. The imaging modalities of computed tomography urography (CTU) and multiparametric magnetic resonance imaging (mpMRI) along with the urological examination methods provide a clinically acceptable diagnostic performance in patients with early clinical stages (NMIBC), whereas the diagnostic performance of the conventional imaging modalities for initial tumor staging has been disappointing due to their low sensitivity for lymph node involvement (≤ 50%) in patients with advanced clinical stages (MIBC) (7–9). Although 2-deoxy-2-[18F] fluoro-D-glucose positron emission tomography/computed tomography ([18F]FDG PET/CT) is substantially better than conventional imaging modalities in tumor surveillance and therapy response monitoring, its diagnostic performance in detection of lymph node involvement for initial tumor staging in advanced clinical stages is only slightly better than conventional imaging (up to 56%) [7, 8]. The renal clearance and high tracer accumulation in the urinary bladder are further limiting factors for the use of [18F]FDG PET/CT in primary tumor detection despite techniques such as urinary catheterization and administration of diuretics to reduce bladder activity [9–11]. Cancer-associated fibroblasts (CAFs) in the tumor microenvironment enhance pro-tumorigenic effects in many cancers including bladder cancer, which influences as a part of supportive tumor stroma various aspects of tumor development and progression as well as therapeutic response. CAFs promote tumorigenesis in urothelial bladder carcinoma via multiple markers including alpha smooth muscle actin (ASMA), CD90/Thy-1, fibroblast activation protein (FAP), platelet derived growth factor receptor-alpha and -beta (PDGFR-α/-β) and especially in advanced stages significantly increased FAP-expression [12, 13]. FAP is a type II transmembrane serine protease with post proline dipeptidyl peptidase as well as endopeptidase activity and its increased expression appears to be an independent adverse prognostic factor in urothelial bladder cancer [13]. Similar correlations are observed in breast cancer, colorectal cancer, ovarian cancer, and pancreatic ductal adenocarcinoma. FAP-expression is also observed in chronic inflammation and fibrotic diseases [14, 15]. Thus, [68Ga]FAPI, a novel, recently developed tracer family targeting FAP shows a favorable tumor-to-background ratio and some important practical advantages regarding the scan prepara (...truncated)