Diagnostic accuracy of ¹⁸F Prostate Specific Membrane Antigen (PSMA) PET-CT radiotracers in staging and restaging of high-risk prostate cancer patients and patients with biochemical recurrence: protocol for an overview of reviews

Introduction

Prostate cancer is the second most commonly diagnosed cancer and the fifth leading cause of cancer death among men worldwide¹. In Ireland, there are, on average, 3,474 new cases of prostate cancer per 100,000 people each year accounting for, on average, 29.2% of all invasive cancers diagnosed². The most appropriate treatment strategy for a given patient often depends on the stage of disease, and the risk factors such as prostate specific antigen (PSA) level and Gleason score^3–5. Evidence-based treatment strategies have been developed, and guidelines offer recommendations for specific sub-populations according to stage and risk^3,6. Accurate diagnosis, staging, and risk stratification are therefore essential in ensuring the optimal treatment strategies are offered and the best possible patient outcomes are achieved.

At present, prostate cancer may be detected by digital rectal examinations, PSA levels, and trans-rectal ultrasound (TRUS); histopathological confirmation is usually required to confirm a diagnosis as abnormal findings may be explained by other benign conditions⁵. However, histopathological confirmation is not always possible or appropriate especially in recurrent or metastatic disease, or populations such as older adults (≥85 years) and those with poor performance status. Metastatic spread to lymph nodes and distant organs is usually detected with ‘conventional imaging’ modalities, including a combination of computed tomography (CT), bone scintigraphy, and magnetic resonance imaging (MRI)⁵. The PROstate MRI Imaging Study (PROMIS) trial demonstrated that using MRI to triage patients with prostate cancer may allow 27% to avoid primary biopsy and result in an additional 18% clinically significant cancers being detected⁷.

However, there are a number of persisting limitations with the current reference standard of conventional imaging in the diagnosis and staging of prostate cancer. Despite improvements in the diagnosis and staging of disease with the addition of MRI, the false negative rate for MRI is estimated to be about 6.5% and sensitivity for lymph node imaging remains between 40–73%^8,9. Pooled data from a meta-analysis of patients imaged using MRI also showed a sensitivity of only 57%, 58% and 61% for extra-capsular extension, seminal vesicle involvement and overall stage T3 assessment, respectively¹⁰. Similarly, MRI has poor sensitivity in detecting bone metastases. While bone scintigraphy performs better it still has a low sensitivity of approximately 68% for bone metastases⁸. Hence, there has been a growing interest in radiotracers that may help improve the diagnosis and staging of prostate cancer.

A number of different prostate specific membrane antigen (PSMA)-targeted radiotracers are increasingly being applied in clinical practice in an attempt to improve diagnostic accuracy and the sensitivity and specificity of staging. A number of different manufacturers offer similar PSMA radiotracers that differ slightly in terms of the radioligand attached, the exact antigen, and their pharmacokinetic properties¹¹. In Ireland, ⁶⁸Ga PSMA is used as an alternative to conventional imaging investigations, where available. Such technology takes advantage of the fact that the PSMA protein is rarely expressed in normal prostate tissue, but is highly upregulated and overexpressed in prostate cancer cells and tumour vascular cells¹². While some national and international guidelines have adopted and recommended the use of PSMA positron emission tomography (PET) in combination with CT (PET-CT), others have not or have offered weak (as opposed to strong) recommendations^3,4,6,13. Most notably, the proPSMA trial found ⁶⁸Ga-PSMA PET-CT to be a suitable replacement for conventional imaging, providing superior accuracy to the combined findings of CT and bone scintigraphy¹⁴. One meta-analysis found ⁶⁸Ga-PSMA PET-CT to have a higher sensitivity and a comparable specificity for staging pre-operative lymph node metastases in intermediate- and high-risk prostate cancer compared with MRI¹⁵. On a per-patient-based analysis, the sensitivity and specificity of ⁶⁸Ga-PSMA PET-CT were 77% and 97%, respectively, after lymph node dissection at the time of prostatectomy. On a per-lesion based analysis, sensitivity and specificity were 75% and 99%, respectively¹⁶. Two retrospective studies also found that ⁶⁸Ga-PSMA PET-CT and PET-MRI demonstrated superiority to MRI alone in the staging of lymph nodes and other areas^17,18. However, the comparison of whole body MRI and PSMA PET-CT in detecting bone metastases has led to inconclusive and conflicting results in two small cohorts^15,19.

Radiolabelling PSMA-targeted agents with ¹⁸F instead of ⁶⁸Ga may provide several advantages, including improved image resolution and a longer half-life, which may enable better transportation logistics and access to the radiopharmaceutical^20–23. Research into ¹⁸F-PSMA has accelerated over recent years, yet high quality randomised control trials are lacking. Preliminary scoping of this topic identified a number of relevant systematic reviews and meta-analyses, however individually these each appear to be limited in the scope of their assessment. While some focus on diagnosis, others focus on detection rate, per patient or per lesion sensitivity, and consider a different array of comparators or populations (e.g., high-risk patients versus those with biochemical recurrence, that is, those with a rising PSA after definitive treatment with surgery or radiotherapy). Overviews of reviews use explicit and systematic methods to search for, identify and appraise multiple systematic reviews on related research questions in the same topic area for the purpose of extracting and analysing their results across important outcomes. Thus, the unit of searching, inclusion and data analysis is the systematic review. Overviews often address research questions that are broader in scope than those examined in individual systematic reviews.

We present a protocol for an overview of reviews that aims to collate existing evidence syntheses on a range of diagnostic accuracy measures exploring the use ¹⁸F-PSMA PET-CT in prostate cancer, using a range of comparators, in distinctly different populations. This overview focuses on high-risk patients and those with biochemical recurrence as these cohorts are most at risk for metastatic disease. In Ireland, these patients currently undergo conventional imaging or where available, ⁶⁸Ga-PSMA PET-CT. ¹⁸F-PSMA imaging is suggested as a replacement for ⁶⁸Ga-PSMA imaging. While individual systematic reviews may focus on one or more aspects of Tumour, Node, Metastasis (TNM) staging, this overview aims to provide a more comprehensive picture of the evidence for ¹⁸F-PSMA PET-CT in prostate cancer staging and restaging. It also aims to highlight where evidence gaps exist. This work will help inform the generic justification of this practice in Ireland, and is being carried out by the Health Information and Quality Authority (HIQA).

Study aims and research questions

This protocol has been registered on the Open Science Framework (September 7, 2023) and developed in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for systematic review protocols (PRISMA-P)^24,25. The completed PRISMA-P checklist is available from the registration site. The inclusion and exclusion criteria will follow a Population, Intervention, Comparator and Outcome (PICO) approach.

Search strategy

Electronic searches will be conducted in Medline (EBSCO), Embase (Ovid), Google Scholar and the Cochrane Database for Systematic Reviews, supplemented by a grey literature search. No language or date restrictions will be applied to the eligibility criteria or the search strategy. The full search strategy can be found on Zenodo as Extended data²⁶.

A list of sites included in the grey literature search are given on Open Science Framework as Extended data²⁴. Forward citation searching and searching reference lists of included reviews will be conducted to identify other possibly relevant reviews. European Public Assessment Reports (EPARs) for authorised forms of the radiotracer will also be reviewed with a particular focus on identifying possible adverse events not reported within the peer-reviewed literature²⁷.

Data collection and analysis

Deviations from the protocol

Amendments to the protocol prior to and during the conduct of the review will be documented by tabulating version history and important changes in the protocol. Any such deviations will be described in the final report.

Discussion

This protocol describes each of the steps that will be undertaken as part of this overview of reviews. The proposed overview aims to consolidate existing evidence syntheses that assess different aspects of prostate cancer staging and restaging using ¹⁸F-PSMA PET-CT to provide a comprehensive overview of the existing evidence, the certainty of the evidence, and the gaps in the evidence at present. We anticipate that the evidence from this overview will be of interest to healthcare professionals, academics and other health policy decision-makers.

HIQA is the competent authority for medical exposures to ionising radiation in Ireland. Part of HIQA’s remit is the justification of new practices before they are generally adopted (also known as Level Two or ‘generic justification’). Generic justification considers whether the benefits of a new practice outweigh the risks, at a population level. In accordance with HIQA’s methods for generic justification, the findings from this overview of reviews will inform HIQA’s decision on whether the practice of ¹⁸F-PSMA PET-CT should be generically justified⁴¹.

Study status

This study is complete, the published overview of reviews is available under open access from Seminars in Nuclear Medicine⁴².