Prostate-specific membrane antigen positron emission tomography compared to multiparametric MRI for prostate cancer diagnosis: a protocol for a systematic review and meta-analysis

Introduction The introduction of multiparametric MRI (mpMRI) has improved almost every aspect of the prostate cancer diagnostic pathway. However, the novel imaging technique, prostate-specific membrane antigen positron emission tomography (PSMA PET) may have demonstrable accuracy in detecting and staging prostate cancer. Here, we describe a protocol for a systematic review and meta-analysis comparing mpMRI to PSMA PET for the diagnosis of suspected prostate cancer. Methods and analysis A systematic search of MEDLINE, EMBASE, PubMed and Cochrane databases will be conducted. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines will be followed for screening, data extraction, statistical analysis and reporting. Included papers will be full-text articles providing original data, written in English articles and comparing the use of PSMA PET with mpMRI in the diagnosis of prostate cancer. All studies published between July 1977 and March 2021 will be eligible for inclusion. Study bias and quality will be assessed using Quadas-2 score. To ensure the quality of the reporting of studies, this protocol is written following the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols 2015 checklist. Ethics and dissemination Ethical approval will not be required for this systematic review. Findings will be disseminated through peer-reviewed publications and presentations at both national and international conferences. PROSPERO registration number CRD42021239296.


GENERAL COMMENTS
My only concern is the (apparently) limited number of publications dealing with this subject. Usually reviews like the proposed are based on a large body of peer-reviewed publications. I am only aware of a few, but perhaps the authors have knowledge of others that may be relevant. PSMA is of utmost interest, so I endorse the concept!

Daan Nieboer
Erasmus MC, Department of Public Health REVIEW RETURNED 04-Oct-2021

GENERAL COMMENTS
The authors present a protocol for a systematic review and metaanalysis to compare the diagnostic accuracy of PSMA-PET and mpMRI for the diagnosis of prostate cancer. The protocol is well written and clear, however some methodological issues remain unadressed.
1. Sensitivty and specificity should be analyzed using a bivariate meta-analysis model rather than two univariate meta-analyses of sensitivity and specificity. The r-packages meta and metafor are unable to fit these models.
2. NPV and PPV are not only dependent on the test characteristics, but also on the prevalence of prostate cancer in the sample. Performing a meta-analysis of NPV and PPV is likely to introduce heterogeneity due to differences in prevalence of prostate cancer across studies. It may be better to perform a meta-analysis of sensitivity and specificity and subsequently calculate the PPV and NPV across a range of relevant prevalences.
3. Would the Quadas-2 not be more appropriate for a systematic review comparing the diagnostic accuracy of two tests rather than the newcastle-ottowa scale?
4. What is the reference test to which the PSMA-PET and mpMRI will be related?
5. Are there subgroup analyses/meta-regression planned to investigate possible sources of heterogeneity?

VERSION 1 -AUTHOR RESPONSE
Reviewer: 1 Dr. Leonard Marks, University of California Los Angeles David Geffen School of Medicine Comments to the Author: My only concern is the (apparently) limited number of publications dealing with this subject. Usually reviews like the proposed are based on a large body of peer-reviewed publications. I am only aware of a few, but perhaps the authors have knowledge of others that may be relevant. PSMA is of utmost interest, so I endorse the concept! Thank you Dr. Marks. Since the FDA approval of using Gallium 68 PSMA-11 (https://www.fda.gov/news-events/press-announcements/fda-approves-first-psma-targeted-petimaging-drug-men-prostate-cancer) many literature has been published comparing the diagnostic performance of PSMA PET and mpMRI. At the time of literature research (Feb 2020) we have eluded more than 10 papers matching the inclusion criteria for meta-analysis and we will continue to invite papers for our analysis.
Reviewer: 2 Dr. Daan Nieboer, Erasmus MC Comments to the Author: The authors present a protocol for a systematic review and meta-analysis to compare the diagnostic accuracy of PSMA-PET and mpMRI for the diagnosis of prostate cancer. The protocol is well written and clear, however some methodological issues remain unadressed.
1. Sensitivty and specificity should be analyzed using a bivariate meta-analysis model rather than two univariate meta-analyses of sensitivity and specificity. The r-packages meta and metafor are unable to fit these models.
We will be using ''mada'' for bivariate meta-analysis as stated in ''mvmeta''package for R (https://cran.r-project.org/web/packages/mvmeta/mvmeta.pdf). This is reflected the Meta Analysis section 2. NPV and PPV are not only dependent on the test characteristics, but also on the prevalence of prostate cancer in the sample. Performing a meta-analysis of NPV and PPV is likely to introduce heterogeneity due to differences in prevalence of prostate cancer across studies. It may be better to perform a meta-analysis of sensitivity and specificity and subsequently calculate the PPV and NPV across a range of relevant prevalences.
We will aim to calculate the pooled sensitivity and specificity across the studies using the relevant statistical packages and then calculate the PPV and NPV values. The correction is highlighted on the 1 st paragraph of METHODS and ANALYSIS 3. Would the Quadas-2 not be more appropriate for a systematic review comparing the diagnostic accuracy of two tests rather than the newcastle-ottowa scale?
We will be conducting Quadas-2 analysis for risk of bias. The correction is highlighted at the 'Risk of Bias in individual studies' section