JSUR Journal

Introduction

Traditional management of patients with Prostate Cancer (PCa) start with staging with conventional imaging such as ultrasound, CT, and bone scans and a systematic 12 needle diagnostic biopsy. For patients with localized cancer by conventional imaging, primary treatment with a curative intention included Radical Prostatectomy (RP) or External Beam Radiotherapy (EBRT), brachytherapy, or both. After RP, most patients have a fall of PSA to undetectable values, but it is a clinical challenge that a quarter of the responding patients relapse (Biochemical Recurrence (BCR)) [1]. Further, other patients had persisting measurable Prostate Specific Antigen (PSA). Half of the patients who died of PCa initially did not have metastases diagnosed by conventional staging [2]. It was hoped that PSMA PET meets the challenge. In patients with High-Risk PCa (HRPC), pretreatment [⁶⁸Ga]Ga-PSMA-PET/CT diagnosed metastases better than conventional imaging [3], and some countries recommended that HRPC patients were staged with pretreatment PSMA PET [4]. The Federal Drug Administration of the United States of America (FDA) approved [⁶⁸Ga]Ga PSMA [3], [¹⁸F]F-DCF Pyl PSMA [5], and [¹⁸F]F-rh-PSMA 7[6]. Today, half of HRPCa patients are staged with pretreatment PSMA PET [7], and the rate of the pretreatment staging increases.

However, oncologists and international guidelines disagreed on whether changes in the stage diagnosed with pretreatment PSMA PET needed to change the primary treatment [8-11]. Our Systematic Review and Meta-Analysis (SR and MA) aimed to summarize pretreatment PSMA PET for impact on the primary staging and treatment.

Methods

Publications

In August 2024 to January 2025, we undertook a SR according to the Preferred Reporting Items For Systematic Analysis (PRISMA) guidelines [12]. The Pubmed search used the search words ((cohorts) AND (prostate adenocarcinoma OR prostate cancer OR prostate malignancy OR prostate neoplasms) AND (diagnosis OR preoperative OR staging) AND (prostate specific membrane antigen OR PSMA) AND (¹⁸Fluoride OR ¹⁸FOR ⁶⁸Gallium OR ⁶⁸Ga) AND (positron emission tomography OR PET) NOT (abstracts OR case reports OR editorials OR proceedings OR number of patient less than 20 OR publications published before 2016 OR reviews) NOT (biochemical recurrence OR relapse OR restaging)). We searched for publications in Google Scholar and in reference lists of original research publications and reviews. The SR included original research publications reported in English between 2016 and January 2025 including at least 20 patients with localized PCa who had undergone pretreatment PSMA PET. The SR excluded publications that only reported patients with Low-Risk (LRPC) or Intermediate-Risk (IRPC) and Lymph Node Metastases (LNM).

The SR was registered in the INPLASY register (2024311004).

Definitions

PCa histology was redefined using the grading of the International Society of Urologic Pathology 2019 (ISUP) [13]. Prostatic lesions with the highest ISUP grade were defined as dominant intraprostatic lesions (DIL). It is the most common site of local failure after radiation therapy for local PCa [14]. Risk groups were defined according to the D’Amico classification [15]. Multiparametric MRI (mpMRI) was defined as the combination of T2-weighted imaging, diffusion-weighted imaging, and dynamic contrast-enhanced imaging. Prostate Imaging Reporting and DataSystem (PI-RADS) 4-5, defined as positive mpMRI, had a higher sensitivity and negative predictive value than PI-RADS 1-3, defined as negative or intermediate mpMRI [16].

Lesions diagnosed with conventional imaging in the prostate, lymph nodes, and bones were defined as cT1, cN1, and cM1, respectively. Positive sites on PSMA PET in the prostate, lymph nodes, and bones were defined as miT1, miN1, and miM1, respectively [17].

Activity of the pretreatment PSMA PET was defined as the activity of the PET tracer following intravenous injection. Uptake time of the PET tracer was defined as the interval between injection of the tracer and reading of the uptake. A site was defined as positive, if it had a higher uptake than the liver. The Prostate Cancer Molecular Imaging Standardized Evaluation Framework Including Response Evaluation second version (PROMISE v2) defined how best to perform and report PSMA PET [18].

Statistical Analyses

The findings were registered in an Excel database and transferred to STATA. Rates of findings were summarized in Forest plots by the method by Nyaga [19]. All statistical analyses were carried out in STATA version 14 with updates (Stata Corp., College Station, TX, USA). A p value <0.05 indicated statistical significance.

Results

Pretreatment PSMA PET

Figure 1 shows the selection of publications. (Tables 1A and 1B) summarize findings in 116 original research publications [3,5,20153]. They reported 19,717 patients. 105 publications reported both IRPC and HRPC patients whereas 11 studies only reported HRPC patients. 131 (1%) patients had LRPC, 5,895 (40%) had IRPC, and 7,247 (59%) patients had HRPC. Meijer [94] and Ingvar [60] found that HRPC patients had more true-positive metastatic sites than IRPC patients. Tables 2A and 2B show PSMA PET methods. Most publications used [⁶⁸Ga]-Ga-PSMA PET, and some used [¹⁸F]-F-PSMA PET. We based the diagnostic performance of pretreatment PSMA PET on publications that used ePLND and histologically confirmed LNM as the gold reference test, shown in Figure 2. Hoffmann [59] and Chandekar [42] found that [⁶⁸Ga]Ga PSMA PET and [¹⁸F]F-PSMA-1007 were equally effectively to diagnose sites as positive.

The follow-up of findings with [¹⁸F]F-PSMA-1007 in patients over time has clarified findings in scapula and in abdominal ganglions showing they are likely to be due to benign and malignant disorders thereby reducing the false-positive readings [154]. PSMA PET could also yield false-negative. For example, PSMA PET did not diagnose most small metastases with a diameter <4 mm, as shown in Figure 3. Patients with small cell and neuroendocrine PCa downregulated PSMA. These patients generally had false-negative PSMA PET. A high ISUP grade and LNM gave a high SUV_max on PSMA PET [152,155]. Baas [53] found that pretreatment PSMA PET before RP predicted PSA persistence and BCR. Patients with a negative PSMA PET with no LNM (miN0 pN0) had the lowest rates of PSA persistence and BCR, whereas patients with a positive PSMA PET with LNM (miN1 pN1) had the highest rates.