**Manuela A. Ho**ff**mann 1,2,\*, Hans-Georg Buchholz 2, Helmut J Wieler 3, Florian Rosar 2,4, Matthias Miederer 2, Nicolas Fischer <sup>5</sup> and Mathias Schreckenberger <sup>2</sup>**


Received: 2 September 2020; Accepted: 25 September 2020; Published: 28 September 2020

**Simple Summary:** Early diagnosis and tumor characterization of prostate cancer (PCa) are important for accurate treatment. [68Ga]Ga-PSMA-11 PET/CT turns out to constitute a major step toward improved diagnostic procedures to detect primary, recurrent, and metastatic PCa. The aim of our study is to evaluate the effect of a second imaging modality for the staging and restaging of PCa by possibly detecting additional PCa lesions due to the well-known increase of PSMA uptake over time. There was a significant increase in tracer uptake on delayed images in comparison to early [ 68Ga]Ga-PSMA-11 PET/CT in our study, but the lesion positivity rate was comparable. However, in a few individual cases, additional delayed scans provided an information advantage in PCa lesion detection. The findings of our study are likely to be of major interest to clinicians as well as to researchers defining the algorithms that are necessary to implement this promising method with its specific tracer into clinical routine.

**Abstract:** Routine [68Ga]Ga-PSMA-11 PET/CT (one hour post-injection) has been shown to accurately detect prostate cancer (PCa) lesions. The goal of this study is to evaluate the benefit of a dual-time point imaging modality for the staging and restaging of PCa patients. Biphasic [68Ga]Ga-PSMA-11 PET/CT of 233 patients, who underwent early and late scans (one/three hours post-injection), were retrospectively studied. Tumor uptake and biphasic lesion detection for 215 biochemically recurrent patients previously treated for localized PCa (prostatectomized patients (P-P)/irradiated patients (P-I) and 18 patients suspected of having primary PCa (P-T) were separately evaluated. Late [68Ga]Ga-PSMA-11 PET/CT imaging detected 554 PCa lesions in 114 P-P patients, 187 PCa lesions in 33 P-I patients, and 47 PCa lesions in 13 P-T patients. Most patients (106+32 P-P/P-I, 13 P-T) showed no additional PCa lesions. However, 11 PSMA-avid lesions were only detected in delayed images, and 33 lesions were confirmed as malignant by a SUVmax increase. The mean SUVmax of pelvic lymph node metastases was 25% higher (*p* < 0.001) comparing early and late PET/CT. High positivity rates from routine [68Ga]Ga-PSMA-11 PET/CT for the staging and restaging of PCa patients were demonstrated. There was no decisive influence of additional late imaging with PCa lesion detection on therapeutic decisions. However, in a few individual cases, additional delayed scans provided an information advantage in PCa lesion detection due to higher tracer uptake and improved contrast.

**Keywords:** [ 68Ga]Ga-PSMA PET/CT; prostate cancer; dual-time point imaging; delayed imaging; biphasic imaging; lesion positivity rate

#### **1. Introduction**

Prostate cancer (PCa) is the most commonly diagnosed cancer with an incidence of 1.276 million worldwide in 2018 [1]. Early diagnosis, accurate staging, and tumor characterization are critical for selection of optimal therapy. Molecular imaging with positron-emission tomography (PET) is regarded as a relevant diagnostic approach and has found its way into the guidelines of the European Association of Urology (EAU guidelines) on PCa [2,3]. The prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein that is significantly overexpressed in most prostate adenocarcinomas, compared with other PSMA-expressing tissues [4]. After many years of preclinical research on PSMA ligands, a breakthrough was achieved in 2011 with the clinical introduction of Glu-NH-CO-NH-Lys(Ahx)-{68Ga-(N,N- -bis-[2-hydroxy-5-(carboxyethyl)benzyl]ethylen-ediamine-N,N- -diacetic-acid)}([68Ga]Ga-HBED-CC-PSMA or [68Ga]Ga-PSMA-11) as a 68Gallium (68Ga)-labeled PSMA-targeted radioligand for PET/computed tomography (CT) [5,6]. PSMA PET/CT offers an appealing combination of PCa specificity and high sensitivity at low tumor volumes [7]. Sensitive and specific imaging is a fundamental requirement for the definition of the target volume in radiotherapy planning. One of the main limitations of both CT and magnetic resonance imaging (MRI) for lymph node (LN) staging is their limited capability to detect metastatic clusters in normal sized nodes; and microscopic LNM are often not enlarged [8,9]. The accurate assessment of locoregional LN metastases (LNM) is much more sensitive with PSMA PET/CT than with MRI [9]. Whereas PSMA PET/CT can detect an LNM of diameter of 3 mm, MRI can generally only identify pathological LN when they show aberrant anatomical characteristics such as a short-axis diameter >1 cm and/or non-oval shape. However, up to 80% of metastasis-involved nodes are smaller than this threshold limit that is typically used in clinical practice [10]. Meta-analytical data for the traditional CT and MRI imaging approaches suggest sensitivity of only 39–42% and specificity of 82% [10]. Since normal lymphatic or retroperitoneal fatty tissue does not demonstrate PSMA expression, metastatic LNs can be detected with a favorable lesion-to-background ratio. [68Ga]Ga-PSMA PET/CT imaging has been shown to accurately detect PCa lesions for LNM [11,12]. These characteristics have led to the evolution of PSMA PET/CT as an important diagnostic tool in nuclear medicine [7,9,13]. In 130 patients with intermediate to high-risk PCa, a sensitivity of 65.9% and a specificity of 98.9% for LN staging using [68Ga]Ga-PSMA-11 PET/CT was reported by Maurer et al. [12].

It has been described that PCa metastases demonstrate an increase of PSMA ligand uptake over time [5,14]. According to the Heidelberg group [5], 70% of PCa lesions have increased uptake and contrast three hours (h) post-injectionem (p.i.) compared to one h p.i. Clarification of the special situation of pelvic LNM and the possible impact of additional delayed imaging for salvage or primary therapy would be important for improved clinical decision making.

The goal of our study is to evaluate the effect of a second (late) imaging modality for the restaging and initial staging of patients with recurrent PCa, using additional findings in the abdominopelvic area based on the well-known increase of PSMA uptake over time.
