Detection Rate of 18F-Labeled PSMA PET/CT in Biochemical Recurrent Prostate Cancer: A Systematic Review and a Meta-Analysis

cancers Review Detection Rate of 18F-Labeled PSMA PET/CT in Biochemical Recurrent Prostate Cancer: A Systematic Review and a Meta-Analysis Giorgio Treglia 1,2,3, * , Salvatore Annunziata 4 , Daniele A. Pizzuto 5 , Luca Giovanella 1,5 , John O. Prior 3 and Luca Ceriani 1,5 1 2 3 4 5 * Clinic of Nuclear Medicine and Molecular Imaging, Imaging Institute of Southern Switzerland, CH-6500 Bellinzona, Switzerland; (L.G.); (L.C.) Health Technology Assessment Unit, Ente Ospedaliero Cantonale, CH-6500 Bellinzona, Switzerland Department of Nuclear Medicine and Molecular Imaging, Lausanne University Hospital and University of Lausanne, CH-1011 Lausanne, Switzerland; Nuclear Medicine Unit, IFO Regina Elena National Cancer Institute, IT-00144 Rome, Italy; Department of Nuclear Medicine, University Hospital of Zürich, CH-8091 Zürich, Switzerland; Correspondence: ; Tel.: +41-91-811-8919 Received: 1 May 2019; Accepted: 22 May 2019; Published: 23 May 2019



 Abstract: Background: The use of radiolabeled prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA PET/CT) for biochemical recurrent prostate cancer (BRPCa) is increasing worldwide. Recently, 18 F-labeled PSMA agents have become available. We performed a systematic review and meta-analysis regarding the detection rate (DR) of 18 F-labeled PSMA PET/CT in BRPCa to provide evidence-based data in this setting. Methods: A comprehensive literature search of PubMed/MEDLINE, EMBASE, and Cochrane Library databases through 23 April 2019 was performed. Pooled DR was calculated on a per-patient basis, with pooled proportion and 95% confidence interval (95% CI). Furthermore, pooled DR of 18 F-PSMA PET/CT using different cut-off values of prostate-specific antigen (PSA) was obtained. Results: Six articles (645 patients) were included in the meta-analysis. The pooled DR of 18 F-labeled PSMA PET/CT in BRPCa was 81% (95% CI: 71–88%). The pooled DR was 86% for PSA ≥ 0.5 ng/mL (95% CI: 78–93%) and 49% for PSA < 0.5 ng/mL (95% CI: 23–74%). Statistical heterogeneity was found. Conclusions: 18 F-labeled PSMA PET/CT demonstrated a good DR in BRPCa. DR of 18 F-labeled PSMA PET/CT is related to PSA values with significant lower DR in patients with PSA < 0.5 ng/mL. Prospective multicentric trials are needed to confirm these findings. Keywords: PET; PSMA; prostate; DCFPyL; DCFBC; PSMA-1007 1. Introduction The recent development of metabolic imaging methods has been aimed at improving diagnosis of prostate cancer (PCa), both at staging and in biochemical recurrent prostate cancer (BRPCa) when an increase of prostate-specific antigen (PSA) serum values is detected following curative primary treatments as radical prostatectomy or radiation therapy [1,2]. In patients with low but rising PSA serum values after definitive local therapy, it is important to identify the sites of recurrence early to maximize the effects of treatment; localizing the PCa recurrence can impact treatment decisions as local recurrence can be treated with focal radiation therapy, whereas distant metastases require more systemic therapies [1]. To this regard, radiolabeled prostate-specific membrane antigen (PSMA) Cancers 2019, 11, 710; doi:10.3390/cancers11050710 www.mdpi.com/journal/cancers Cancers 2019, 11, 710 2 of 14 positron emission tomography/computed tomography (PET/CT) is emerging as a very useful imaging method for detecting tumor lesions in BRPCa patients, with higher DR compared to other imaging modalities [1–5]. The PSMA is overexpressed in the majority of PCa cells but its overexpression has not been found in benign prostatic diseases; however, PSMA is not prostate specific and this protein may be expressed in other tissues and tumors beyond PCa [3–5]. Several PSMA ligands, differing slightly in chemical structure, are commercially available and they may be radiolabeled with different positron-emitters isotopes as Gallium-68 (68 Ga), Fluorine-18 (18 F), or Copper-64 (64 Cu) to obtain PET radiopharmaceuticals which could be used in clinical practice [4–8]. 68 Ga-labeled PSMA tracers are currently the most used PSMA agents for PET imaging of BRPCa patients. More recently, PSMA ligands had been labeled with other isotopes with more favorable physical characteristics, such as 18 F or 64 Cu [6–8]. Several 18 F-labeled PSMA agents have become available (18 F-PSMA-1007, 18 F-DCFPyL, and 18 F-DCFBC). Labeling of PSMA agents with 18 F may offer numerous advantages, including longer half-life and improved image resolution. Due to the lower positron energy, the theoretical achievable resolution of 18 F is slightly better in comparison to 68 Ga [7,8]. To date, several evidence-based articles evaluated the detection rate (DR) of 68 Ga-labeled PSMA PET/CT in BRPCa patients [9–15]. Conversely, we aimed to perform a meta-analysis about the DR of 18 F-labeled PSMA PET/CT in BRPCa patients to add evidence-based data in this setting. 2. Methods Reporting of this systematic review and meta-analysis conforms to the “Preferred Reporting Items for a Systematic Review and Meta-Analysis of Diagnostic Test Accuracy Studies” (PRISMA-DTA statement) which describes an evidence-based minimum set of items for reporting in systematic reviews and meta-analyses of diagnostic studies [16,17]. 2.1. Search Strategy Three authors (G.T., S.A., D.A.P.) performed a comprehensive computer literature search of PubMed/MEDLINE, EMBASE and Cochrane library databases to find relevant published articles on the DR of PET/CT using 18 F-labeled PSMA-agents in patients with BRPCa. A search algorithm based on a combination of these terms was used: (A) “PSMA” AND (B) “DCFPyL” OR “DCFBC” OR “1007”. No beginning date limit and language restrictions were used, and the literature search was updated until 23 April 2019. To expand our search, references of the retrieved articles were also screened for additional studies. 2.2. Study Selection Studies or subsets of studies investigating the DR of 18 F-labeled PSMA PET/CT in patients with BRPCa were eligible for inclusion in the qualitative (systematic review) and quantitative analysis (meta-analysis). The exclusion criteria for the systematic review were: (a) articles not within the field of interest of this review; (b) review articles, editorials or letters, comments, conference proceedings; (c) case reports or small case series. For the meta-analysis, articles with possible patient data overlap were excluded; in this case, articles with more complete information were included in the meta-analysis. Titles and abstracts were independently reviewed by three researchers applying the selected inclusion and exclusion criteria. Disagreements were solved in a consensus meeting. 2.3. Data Extraction For each eligible article, information was collected concerning basic study (authors, year of publication, country of origin, study design), patient characteristics (type and number of patients evaluated, mean age, Gleason score, (...truncated)