18F-PSMA-11 Versus 68Ga-PSMA-11 Positron Emission Tomography/Computed Tomography for Staging and Biochemical Recurrence of Prostate Cancer: A Prospective Double-blind Randomised Cross-over Trial

doi:10.1016/j.eururo.2022.05.010

European Urology

Volume 82, Issue 5, November 2022, Pages 501-509

https://doi.org/10.1016/j.eururo.2022.05.010 Get rights and content

Abstract

Background

Fluorine-18 (¹⁸F)-labelled prostate-specific membrane antigen (PSMA) offers several advantages over gallium-68 (⁶⁸Ga) in terms of costs, yield, transport/distribution, and image resolution.

Objective

This trial investigates the new radiotracer ¹⁸F-PSMA-11 via a prospective, intraindividual crossover design. The trial was powered for noninferiority of ¹⁸F-PSMA-11 over ⁶⁸Ga-PSMA-11 positron emission tomography (PET)/computed tomography (CT) in terms of the number of positive PET scans. Secondary endpoints were as follows: (1) superiority of ¹⁸F-PSMA-11 over ⁶⁸Ga-PSMA-11 with respect to the number of positive PET scans, the total number of suspicious prostate cancer lesions, and the miPSMA expression score of corresponding lesions; (2) correlation of the PET/CT images with available follow-up data for ¹⁸F-PSMA-11 and ⁶⁸Ga-PSMA-11; and (3) assessment of the interobserver variability.

Design, setting, and participants

Prostate cancer patients (primary or biochemical recurrence) were randomised in a double-blind crossover design whereby each patient received both ¹⁸F-PSMA-11 and ⁶⁸Ga-PSMA-11 PET/CT.

Outcome measurements and statistical analysis

All scans were reviewed and scored by three independent experienced nuclear physicians following the proposed guideline for the interpretation of PSMA-ligand PET/CT, as described by Eiber et al.

Results and limitations

In total, 82 patients were included for scan analyses. The primary endpoint was met: per patient, the proportions of positive scans rated by the three readers were 67%/67%, 65%/65%, and 73%/70% for ¹⁸F-PSMA-11/⁶⁸Ga-PSMA-11 PET/CT. The miPSMA expression score was higher for ¹⁸F-PSMA-11 than for ⁶⁸Ga-PSMA-11 for the reference reader. Follow-up data showed identical estimated sensitivity for both the ¹⁸F-PSMA-11 and the ⁶⁸Ga-PSMA-11 scan (0.92, 0.83, and 0.92 for the three readers). A fair to good agreement among readers (at patient level) was obtained, which was demonstrated by a Light’s kappa value of 0.59 for both tracers.

Conclusions

The tracer ¹⁸F-PSMA-11 is noninferior to ⁶⁸Ga-PSMA-11. Superiority of ¹⁸F-PSMA-11 was limited to the miPSMA expression score, given by the reference reader. Inter-rater agreement was fair to good, and equal for both radiotracers.

Patient summary

In this study, we compared two radiotracers: ¹⁸F-PSMA-11 and ⁶⁸Ga-PSMA-11. We proved that ¹⁸F-PSMA-11 is not inferior to ⁶⁸Ga-PSMA-11 for detecting prostate cancer and thus can be used as an alternative. Possible superiority of this tracer should be further investigated in specific subpopulations.

Introduction

The use of prostate-specific membrane antigen (PSMA) positron emission tomography (PET)/computed tomography (CT) for biochemical recurrence and even for staging prostate cancer is increasing worldwide due to the higher accuracy of PSMA PET/CT than conventional imaging and choline PET/CT [1], [2], [3], [4], [5], [6]. According to initial protocols, PSMA-11 is labelled with gallium-68. However, the cost and limited yield of a ⁶⁸Ge/⁶⁸Ga generator in combination with transport limitations due to the relatively short half-life of this radioisotope (68 min) fuel the search for alternative radioisotopes. Fluorine-18 radiotracers offer several advantages including a longer half-life, a higher positron yield, and the possibility to use higher starting activities, making large batch production, delayed imaging, distribution to other centres, and cost savings possible. Additionally, F-18 has lower positron energy than Ga-68, leading to images with a higher spatial resolution. This could be beneficial for detecting small lesions expected in case of low prostate-specific antigen (PSA) values [7].

Our research centre contributed to this evolution by developing ¹⁸F-PSMA-11. A phase 1 trial demonstrated the safety of this tracer and calculated a radiation dose similar to other radiotracers aimed at PSMA. A phase 2 trial optimised the PET protocol [8], [9].

In this phase 3 trial, we present a prospective intraindividual comparison between ¹⁸F-PSMA-11 and ⁶⁸Ga-PSMA-11 PET/CT in prostate cancer patients at primary diagnosis or biochemical recurrence, aiming to prove noninferiority of ¹⁸F-PSMA-11 at patient level.

Section snippets

Patients and methods

All procedures were in accordance with the ethical standards of the Ethics Committee of the Ghent University Hospital (2019/0159), and with the 1964 Helsinki declaration and its amendments or comparable ethical standards (EudraCT nr: 2018-003168-29). The study was supported by the Flemish foundation FWO/TBM (T001517).

Results

Between April 2019 and March 2020, 96 patients were enrolled. Eighty-five patients completed the entire protocol. The examinations were well tolerated, and no drug-related adverse events were reported. Three patients were excluded from the analysis due to technical complications during scanning, resulting in 82 included patients (Fig. 3).

The clinical characteristics and prior treatments of these 85 patients can be found in Table 2.

The median administered activity (Q1-Q3) of ¹⁸F-PSMA-11 and ⁶⁸

Discussion

While multiple F-18 radiotracers aimed at PSMA have been developed, this is the largest prospective phase 3 clinical trial that intraindividually compares an F-18–based radiotracer with ⁶⁸Ga-PSMA-11 [13], [14], [15], [16].

With regard to ¹⁸F-PSMA-11, a smaller prospective head-to-head study in 37 prostate cancer patients with biochemical relapse after initial treatment has been performed with similar diagnostic values for ⁶⁸Ga-PSMA-11 and ¹⁸F-PSMA-11 [17]. In the current phase 3 clinical trial,

Conclusions

To date, the results of this largest prospective clinical trial comparing ¹⁸F-PSMA-11 with ⁶⁸Ga-PSMA-11 indicate that ¹⁸F-PSMA-11 is a good and cost-efficient alternative in the detection and staging of prostate cancer. The trial demonstrated noninferiority of ¹⁸F-PSMA-11 by all readers, as well as superiority of ¹⁸F-PSMA-11 with regard to the miPSMA expression score by the reference reader. Additional research in specific subpopulations is required to further explore superiority. Although,

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Applications of Artificial Intelligence in PSMA PET/CT for Prostate Cancer Imaging
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Prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) has emerged as an important imaging technique for prostate cancer. The use of PSMA PET/CT is rapidly increasing, while the number of nuclear medicine physicians and radiologists to interpret these scans is limited. Additionally, there is variability in interpretation among readers. Artificial intelligence techniques, including traditional machine learning and deep learning algorithms, are being used to address these challenges and provide additional insights from the images. The aim of this scoping review was to summarize the available research on the development and applications of AI in PSMA PET/CT for prostate cancer imaging. A systematic literature search was performed in PubMed, Embase and Cinahl according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A total of 26 publications were included in the synthesis. The included studies focus on different aspects of artificial intelligence in PSMA PET/CT, including detection of primary tumor, local recurrence and metastatic lesions, lesion classification, tumor quantification and prediction/prognostication. Several studies show similar performances of artificial intelligence algorithms compared to human interpretation. Few artificial intelligence tools are approved for use in clinical practice. Major limitations include the lack of external validation and prospective design. Demonstrating the clinical impact and utility of artificial intelligence tools is crucial for their adoption in healthcare settings. To take the next step towards a clinically valuable artificial intelligence tool that provides quantitative data, independent validation studies are needed across institutions and equipment to ensure robustness.
Management of Patients with Advanced Prostate Cancer. Part I: Intermediate-/High-risk and Locally Advanced Disease, Biochemical Relapse, and Side Effects of Hormonal Treatment: Report of the Advanced Prostate Cancer Consensus Conference 2022
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Citation Excerpt :
Several PSMA ligands are currently available and are primarily radiolabelled with one of two positron-emitting isotopes: gallium-68 (68Ga) and fluorine-18 (18F) [28–31]. In Europe, initially, 68Ga-PSMA-11 was the most commonly used PSMA agent, but recently, 18F-PSMA ligands (eg, 18F-DCFPyL or 18F-PSMA-1007) have become more available and are frequently used instead [28–31]. Logistical superiority is the major differentiator between 18F PSMA ligands and 68Ga-PSMA ligand; 18F-PSMA ligands have a longer half-life (110 vs 68 min for 68Ga) and higher production yields (currently 100-fold higher), making them more accessible and economical (18F is a cyclotron product, while 68Ga is predominantly generator-based) [28].
Innovations in imaging and molecular characterisation and the evolution of new therapies have improved outcomes in advanced prostate cancer. Nonetheless, we continue to lack high-level evidence on a variety of clinical topics that greatly impact daily practice. To supplement evidence-based guidelines, the 2022 Advanced Prostate Cancer Consensus Conference (APCCC 2022) surveyed experts about key dilemmas in clinical management.
To present consensus voting results for select questions from APCCC 2022.
Before the conference, a panel of 117 international prostate cancer experts used a modified Delphi process to develop 198 multiple-choice consensus questions on (1) intermediate- and high-risk and locally advanced prostate cancer, (2) biochemical recurrence after local treatment, (3) side effects from hormonal therapies, (4) metastatic hormone-sensitive prostate cancer, (5) nonmetastatic castration-resistant prostate cancer, (6) metastatic castration-resistant prostate cancer, and (7) oligometastatic and oligoprogressive prostate cancer. Before the conference, these questions were administered via a web-based survey to the 105 physician panel members (“panellists”) who directly engage in prostate cancer treatment decision-making. Herein, we present results for the 82 questions on topics 1–3.
Consensus was defined as ≥75% agreement, with strong consensus defined as ≥90% agreement.
The voting results reveal varying degrees of consensus, as is discussed in this article and shown in the detailed results in the Supplementary material. The findings reflect the opinions of an international panel of experts and did not incorporate a formal literature review and meta-analysis.
These voting results by a panel of international experts in advanced prostate cancer can help physicians and patients navigate controversial areas of clinical management for which high-level evidence is scant or conflicting. The findings can also help funders and policymakers prioritise areas for future research. Diagnostic and treatment decisions should always be individualised based on patient and cancer characteristics (disease extent and location, treatment history, comorbidities, and patient preferences) and should incorporate current and emerging clinical evidence, therapeutic guidelines, and logistic and economic factors. Enrolment in clinical trials is always strongly encouraged. Importantly, APCCC 2022 once again identified important gaps (areas of nonconsensus) that merit evaluation in specifically designed trials.
The Advanced Prostate Cancer Consensus Conference (APCCC) provides a forum to discuss and debate current diagnostic and treatment options for patients with advanced prostate cancer. The conference aims to share the knowledge of international experts in prostate cancer with health care providers and patients worldwide. At each APCCC, a panel of physician experts vote in response to multiple-choice questions about their clinical opinions and approaches to managing advanced prostate cancer. This report presents voting results for the subset of questions pertaining to intermediate- and high-risk and locally advanced prostate cancer, biochemical relapse after definitive treatment, advanced (next-generation) imaging, and management of side effects caused by hormonal therapies. The results provide a practical guide to help clinicians and patients discuss treatment options as part of shared multidisciplinary decision-making. The findings may be especially useful when there is little or no high-level evidence to guide treatment decisions.
18F-PSMA-11 as an Attractive 68Ga-PSMA-11 Alternative for Prostate Cancer Imaging
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PSMA-targeted dendrimer as an efficient anticancer drug delivery vehicle for prostate cancer
2024, Nanoscale
First-in-human study of PSMA-targeting agent, [18F]AlF-P16-093: dosimetry and initial evaluation in prostate cancer patients
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Abstract

Background

Objective

Design, setting, and participants

Outcome measurements and statistical analysis

Results and limitations

Conclusions

Patient summary

Introduction

Section snippets

Patients and methods

Results

Discussion

Conclusions

Appl Radiat Isot

Lancet

Pract Radiat Oncol

Semin Nucl Med

PSMA ligands for PET imaging of prostate cancer

J Nucl Med

Diagnostic role of 18F-PSMA-1007 PET/CT in prostate cancer staging: a systematic review

Diagnostics

Detection rate of18 F-labeled PSMA PET/CT in biochemical recurrent prostate cancer: a systematic review and a meta-analysis

Cancers (Basel)

Prostate-specific membrane antigen PET in prostate cancer

Radiology

Radiolabelled choline versus PSMA PET/CT in prostate cancer restaging: a meta-analysis

Am J Nucl Med Mol Imaging

Prospective comparison of 18F-fluoromethylcholine Versus 68Ga-PSMA PET/CT in prostate cancer patients who have rising PSA after curative treatment and are being considered for targeted therapy

J Nucl Med

PSA-stratified performance of 18F-and 68Ga-PSMA PET in patients with biochemical recurrence of prostate cancer

J Nucl Med

Radiation dosimetry and biodistribution of 18F-PSMA-11 for PET imaging of prostate cancer

J Nucl Med