Context
Positron emission tomography (PET) of 68Ga-labelled prostate-specific membrane antigen (68Ga-PSMA) is an emerging imaging modality introduced to assess the burden of prostate cancer, typically in biochemically recurrent or advanced disease. 68Ga-PSMA PET provides the ability to selectively identify and localize metastatic prostate cancer cells and subsequently change patient management. Owing to its limited history, robust sensitivity and specificity data are not available for 68Ga-PSMA PET–positive scans.
Objective
A systematic review and meta-analysis of reported predictors of positive 68Ga-PSMA PET and corresponding sensitivity and specificity profiles.
Evidence acquisition
We performed critical reviews of MEDLINE, EMBASE, ScienceDirect, Cochrane Library, and Web of Science databases in April 2016 according to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) statement. Quality was assessed using the Quality Assessment if Diagnostic Accuracy Studies-2 tool. Meta-analysis and meta-regression of proportions were performed using a random-effects model with pre-PET prostate-specific antigen (PSA) levels as the dependent variable. Summary sensitivity and specificity values were obtained by fitting bivariate hierarchical regression models.
Evidence synthesis
Sixteen articles involving 1309 patients were analysed. The overall percentage of positive 68Ga-PSMA PET among patients was 40% (95% confidence interval [CI] 19–64%) for primary staging and 76% (95% CI 66–85%) for biochemical recurrence (BCR). Positive 68Ga-PSMA PET scans for BCR patients increased with pre-PET PSA. For the PSA categories 0–0.2, 0.2–1, 1–2, and >2 ng/ml, 42%, 58%, 76%, and 95% scans, respectively, were positive. Shorter PSA doubling time increased 68Ga-PSMA PET positivity. On per-patient analysis, the summary sensitivity and specificity were both 86%. On per-lesion analysis, the summary sensitivity and specificity were 80% and 97%, respectively.
Conclusions
In the setting of BCR prostate cancer, pre-PET PSA predicts the risk of positive 68Ga-PSMA PET. Pooled data indicate favourable sensitivity and specificity profiles compared to choline-based PET imaging techniques.
Patient summary
Positron emission tomography using 68Ga-labelled prostate-specific membrane antigen is an emerging radiological technique developed to improve the characterisation of metastatic prostate cancer. We summarised the data available to date and found that this new test provides excellent rates of detection of cancer spread in late-stage prostate cancer.
Prostate cancer is among the most prevalent cancers worldwide and is the third most common cause of cancer-associated mortality among men [1]
Prostate-specific membrane antigen (PSMA) is a transmembrane protein with a 707-amino-acid extracellular portion. The PSMA gene (FOLH1) is located on the short arm of chromosome 11. PSMA is expressed in the apical region of prostatic cells, the epithelium surrounding prostatic ducts [6]
To date, the use of 68Ga-PSMA has been well reported, with the compound Glu-NH-CO-NH-Lys-(Ahx)-[68Ga]-HBED (68Ga-PSMA-11) developed by the Heidelberg group in Germany. Initial series revealed superior sensitivity and specificity profiles compared to conventional choline-based tracers [19]
A systematic review was performed in accordance with Cochrane Collaboration and Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) guidelines [20]
Studies evaluating the utility of 68Ga-PSMA PET in detection of metastatic disease in advanced prostate cancer were included for analysis. Study designs considered for inclusion were clinical trials, prospective studies, and retrospective cohorts or comparative series. Studies assessing the diagnostic utility of 68Ga-PSMA PET in prostate cancer staging (before definitive treatment) or staging for recurrent disease (following therapy) were included for assessment. Studies were excluded if 68Ga-PSMA PET was used in assessing primary (prostatic) disease only or a specific visceral metastatic deposit (eg, pulmonary or cerebral metastases). In the current analysis, only studies using the 68Ga-PSMA-11 PSMA surface antigen HBED-CC (PSMA-11) were included for analysis provided the tracer was bound to 68Ga. Studies were excluded if alternative PSMA-bound radiotracers were used (eg, 18F or 99mTc tracers). No language or sample-size restrictions were used. Where duplicate study populations or analyses of repeated data were identified from the literature review, the publication reporting a larger sample size was used for analysis.
The primary outcome was to identify predictors of 68Ga-PSMA PET positivity. Studies that included only 68Ga-PSMA PET–positive studies were excluded, as predictive data were not available for analysis. The secondary outcome measure was the sensitivity and specificity of 68Ga-PSMA PET–positive lesions in advanced prostate cancer. For sensitivity and specificity analysis, only studies that included routine 68Ga-PSMA PET before preplanned lymph node dissection were included. Inclusion of series for which nodal biopsy was performed at the clinician's discretion does not provide meaningful false-negative data and thus does not provide accurate specificity values. An inadequate number of studies robustly assessed prostatic bed recurrence or suspicious bony metastatic disease in the manner outlined above. Therefore, we only assessed sensitivity and specificity values for 68Ga-PSMA PET in lymph nodes.
Studies were assessed for quality using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool [22]
The following information was extracted from each study: sample size, age, indication for PET (primary staging or recurrent disease staging), PSA, previous therapies, initial cancer stage, 68Ga-PSMA PET characteristics, rates of positive PET, and histopathologic correlation data. Rates of 68Ga-PSMA PET positivity were collected and stratified by pre-PET PSA and PSA doubling time (PSAdt) when possible. When histopathologic correlation data were available, numbers of true positives, false positives, true negatives, and false negatives were collected, as appropriate. For studies that included 68Ga-PSMA PET for both primary staging and recurrent cancer staging, the extracted data are displayed separately when available.
Extracted data were collated in Excel 2007 (Microsoft Corporation, Redmond, CA, USA) and analysis was performed using Stata v.12.0SE (College Station, TX, USA). Meta-analysis of proportions was performed using the metaprop command in Stata [23]
In patients undergoing a scan for disease recurrence, we performed a PSA level analysis. Note that for the cohort used by Afshar-Oromieh et al [14]
Random-effects meta-regression with Freeman-Tukey transformation was performed for study-defined PSA categories where the reference point was <2 ng/ml. We could not assign a valid reference point for categories greater than this as the reporting of PSA means, medians, and ranges was heterogeneous. Values were back-transformed using the equation described by Miller [26]
Summary sensitivity, specificity, and hierarchical receiver operating characteristic curves were created using the midas command [27]
Using the systematic search strategy outlined in the Supplementary material, 1895 articles were identified, of which 189 were duplicate records and excluded. Of the remaining 1706 records, 1470 were not relevant to the research question. A further 202 were conference abstracts, reviews, letters, and editorials that could not be quality assessed, and thus were excluded. From the remaining 34 articles, 11 were excluded as they did not contain relevant results and five contained duplicate data. One additional study was excluded as patients were enrolled following negative choline-based PET, and thus provided a skewed patient population [28]
Of the 16 studies relevant to the meta-analysis, one was prospective and 15 were retrospective in nature. Two studies included outcomes for 68Ga-PSMA PET performed before definitive therapy (primary staging), eight reported outcomes for biochemical recurrence or disease progression staging (secondary staging), and six included mixed groups. Basic details for the studies included are listed in Table 1.
Characteristics of the studies included
a The tracer used in all cases was 68Ga-PSMA-11.
b PET was used for 95 patients and magnetic resonance imaging for all 130 patients.
c Mean.
ADT = androgen deprivation therapy; ARTx = adjuvant radiotherapy; BCR = biochemical recurrence; CE = contrast-enhanced; CT = computerised tomography; CTx = chemotherapy; HIFU = high-intensity focused ultrasound; HR = high resolution;, LND = lymph node dissection, LNM = lymph node metastases; NCE = non–contrast-enhanced; NR = not reported; PCa = Prostate cancer; PET = positron emission tomography; PSMA = prostate-specific membrane antigen; RP = radical prostatectomy; RTx = primary radiotherapy; SRP = salvage prostatectomy.
While patient selection was generally acceptable in the studies included, a few studies did not clearly report the inclusion criteria. Furthermore, several studies included mixed patient populations including primary and secondary staging groups, raising concerns regarding applicability. All the studies clearly reported methodology for the index test and were thus not considered a significant source of potential bias. Of the studies included, 11 involved a reference test: histopathologic correlation of 68Ga-PSMA PET–positive lesions. However, in terms of flow and timing, multiple studies were at risk of bias, as many included targeted biopsies of suspicious lesions only. Such articles were excluded from sensitivity and specificity analyses because the false-negative data are not accurate. In total, five studies performed 68Ga-PSMA PET before planned lymph node sampling. Summary findings for the QUADAS-2 appraisal are illustrated in Figure 2.
(A) Appraisal of the quality of the studies included according to the Quality Assessment for Diagnostic Studies-2 (QUADAS-2) tool [22]
In total, we analysed 16 studies involving 1309 patients who underwent a 68Ga-PSMA PET scan, of which 926 (70.7%) were positive. In an overall meta-analysis by cohort type, 40% (95% CI 19–64%) of scans were positive for patients undergoing primary staging and 76% (95% CI 66–85%) for those undergoing secondary staging (Fig. 3). There was high heterogeneity between groups and within all subgroups (I2 > 70%). Egger's test for small-study effects did not reach significance (p > 0.10; Supplementary Figs. 1 and 2).
Forest plot of the proportion of 68Ga–prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET) positivity by patient cohort type. ES = effect size; CI = confidence interval. Reference numbers for the studies are as in Table 1.
In assessing disease recurrence, PSMA PET positivity increased with the PSA category (Fig. 4). For patients with PSA <0.2 ng/ml, the pooled estimate was 42%, which increased to 58%, 76%, and 95% for the 0.2–0.99, 1.00–1.99, and >2.00 ng/ml PSA subgroups, respectively. There was high heterogeneity within the <0.2 and 1.00–1.99 ng/ml subgroups and very high heterogeneity between subgroups (I2 = 97.4%); the test for small-study effects did not reach significance (Supplementary Fig. 3). In meta-regression analysis (Fig. 5), the predicted positivity was 48% (95% CI 38–57%) for PSA of 0.2 ng/ml, 56% (95% CI 49–64%) for 0.5 ng/ml, and 70% (95% CI 63–76%) for 1.0 ng/ml.
Forest plot of the proportion of 68Ga–prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET) positivity by PSA category. ES = effect size; CI = confidence interval. Reference numbers for the studies are as in Table 1.
Scatterplot of prostate specific antigen (PSA) level versus the proportion of 68Ga–prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET) positivity. The blue line is the meta-regression prediction and shading shows the 95% confidence interval. The size of the circles is related to the inverse of the variance.
A similar finding was observed for PSAdt: the pooled PSMA positivity was 64% for PSAdt ≥6 mo and 92% for PSAdt <6 mo (Fig. 6). There was high heterogeneity between the subgroups (I2 = 84.2%) and evidence of a small-study effect in the long PSAdt subgroup (Supplementary Fig. 4).
Forest plot of the proportion of 68Ga–prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET) positivity by prostate-specific antigen doubling time (PSA-dt) category. ES = effect size; CI = confidence interval.
As a sensitivity analysis, we excluded subpopulations with a sample size of less than ten and repeated the meta-analyses. This decreased the point estimate for 68Ga-PSMA PET positivity in the primary staging cohort to 27% (95% CI 15–42%). All other effects were negligible, with differences of ≤2% in the point estimates and CI boundaries for overall positivity and two PSA category proportions.
Of the studies included, 11 reported histopathologic correlation with 68Ga-PSMA PET; however, only five met the aforementioned inclusion criteria (summarised in Table 2). Of the five studies reporting the predictive ability of 68Ga-PSMA PET imaging with respect to histology-proven disease, per-patient and per-lesion analyses were possible for four studies each (Fig. 7). For per-lesion analysis, the summary sensitivity is 80% and specificity is 97%. For per-patient analysis, the summary sensitivity and specificity are both 86%, although the confidence intervals are especially wide because of the low patient numbers.
Studies with histopathologic correlation data for 68Ga PSMA PET–positive lesions included in pooled analysis
a Not included in the pooled analysis as data points did not meet the inclusion criteria.
HP = histopathology; LND = lymph node dissection; SS = sensitivity; SP = specificity.
68Ga-PSMA PET is a novel targeted imaging modality that may improve the identification of metastatic prostate cancer. Our meta-analysis results identified indication, PSA, and PSA-based kinetics as risk factors for positive imaging. Furthermore, pooled sensitivity and specificity for the available data appear promising compared to alternative imaging modalities for metastatic prostate cancer.
The current study highlights the growing body of evidence supporting the use of 68Ga-PSMA PET for primary staging. In this setting, groups have reported pooled positivity of 40%. Given that the risk of metastatic spread is unlikely in low-risk disease, a majority of the studies included patients with intermediate- and high-risk prostate cancer in accordance with the D’Amico classification [47]
To date, the majority of data outlining the utility of 68Ga-PSMA PET are in the setting of secondary staging for biochemical recurrence after definitive therapy. In clinical practice, early detection and highly accurate localisation of disease recurrence are critical, as these may facilitate initiation of subsequent therapies, such as radiotherapy [54]
Pooled data from the current study highlight the promising detection rates for 68Ga-PSMA PET in prostate cancer with low PSA or PSAdt. Despite advances in bone scintigraphy and CT imaging, detection of locoregional or distant recurrence with low PSA has been problematic. Therefore, most guidelines recommend imaging when patients are symptomatic or PSA levels are >10 ng/ml [4]
An increasing number of centres are reporting early outcomes for 68Ga-PSMA PET, particularly in Germany and Australia, with results for many series yet to be published [59]
There are several limitations to the current study. First, a majority of the series used for meta-analysis were derived from small, retrospective, single-institutional studies. In addition, the heterogeneous nature of the patient cohorts, treatment protocols, and study designs included represents a potential limitation of the data available for analysis. Second, of the studies used for pooled sensitivity and specificity data, the majority had a small sample size and assessed patients in the primary staging setting. Additional data in the future will undoubtedly be of benefit for such analyses.
The absence of accurate imaging for detection of small-volume metastases in advanced prostate cancer has prompted the introduction of 68Ga-PSMA PET. The results of the current study suggest that PSA and associated kinetics predict the risk of metastatic disease diagnosed by 68Ga-PSMA PET. This novel imaging modality appears to provide superior sensitivity and specificity compared to alternative techniques. These promising early results for 68Ga-PSMA PET indicate a significant need for further clinical data.
Author contributions: Nathan Lawrentschuk had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Lawrentschuk, Perera, Papa.
Acquisition of data: Perera, Papa, Christidis, Wetherell.
Analysis and interpretation of data: Papa, Perera, Hofman.
Drafting of the manuscript: Perera, Papa, Hofman, Murphy, Bolton.
Critical revision of the manuscript for important intellectual content: Murphy, Bolton, Hofman, Lawrentschuk.
Statistical analysis: Papa.
Obtaining funding: None.
Administrative, technical, or material support: None.
Supervision: Bolton, Lawrentschuk, Murphy, Hofman.
Other: None.
Financial disclosures: Nathan Lawrentschuk certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None.
Funding/Support and role of the sponsor: None.
Acknowledgments: Marlon Perera is supported by a Royal Australasian College of Surgeons scholarship.
Prostate cancer is among the most prevalent cancers worldwide and is the third most common cause of cancer-associated mortality among men [1]
Prostate-specific membrane antigen (PSMA) is a transmembrane protein with a 707-amino-acid extracellular portion. The PSMA gene (FOLH1) is located on the short arm of chromosome 11. PSMA is expressed in the apical region of prostatic cells, the epithelium surrounding prostatic ducts [6]
To date, the use of 68Ga-PSMA has been well reported, with the compound Glu-NH-CO-NH-Lys-(Ahx)-[68Ga]-HBED (68Ga-PSMA-11) developed by the Heidelberg group in Germany. Initial series revealed superior sensitivity and specificity profiles compared to conventional choline-based tracers [19]
A systematic review was performed in accordance with Cochrane Collaboration and Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) guidelines [20]
Studies evaluating the utility of 68Ga-PSMA PET in detection of metastatic disease in advanced prostate cancer were included for analysis. Study designs considered for inclusion were clinical trials, prospective studies, and retrospective cohorts or comparative series. Studies assessing the diagnostic utility of 68Ga-PSMA PET in prostate cancer staging (before definitive treatment) or staging for recurrent disease (following therapy) were included for assessment. Studies were excluded if 68Ga-PSMA PET was used in assessing primary (prostatic) disease only or a specific visceral metastatic deposit (eg, pulmonary or cerebral metastases). In the current analysis, only studies using the 68Ga-PSMA-11 PSMA surface antigen HBED-CC (PSMA-11) were included for analysis provided the tracer was bound to 68Ga. Studies were excluded if alternative PSMA-bound radiotracers were used (eg, 18F or 99mTc tracers). No language or sample-size restrictions were used. Where duplicate study populations or analyses of repeated data were identified from the literature review, the publication reporting a larger sample size was used for analysis.
The primary outcome was to identify predictors of 68Ga-PSMA PET positivity. Studies that included only 68Ga-PSMA PET–positive studies were excluded, as predictive data were not available for analysis. The secondary outcome measure was the sensitivity and specificity of 68Ga-PSMA PET–positive lesions in advanced prostate cancer. For sensitivity and specificity analysis, only studies that included routine 68Ga-PSMA PET before preplanned lymph node dissection were included. Inclusion of series for which nodal biopsy was performed at the clinician's discretion does not provide meaningful false-negative data and thus does not provide accurate specificity values. An inadequate number of studies robustly assessed prostatic bed recurrence or suspicious bony metastatic disease in the manner outlined above. Therefore, we only assessed sensitivity and specificity values for 68Ga-PSMA PET in lymph nodes.
Studies were assessed for quality using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool [22]
The following information was extracted from each study: sample size, age, indication for PET (primary staging or recurrent disease staging), PSA, previous therapies, initial cancer stage, 68Ga-PSMA PET characteristics, rates of positive PET, and histopathologic correlation data. Rates of 68Ga-PSMA PET positivity were collected and stratified by pre-PET PSA and PSA doubling time (PSAdt) when possible. When histopathologic correlation data were available, numbers of true positives, false positives, true negatives, and false negatives were collected, as appropriate. For studies that included 68Ga-PSMA PET for both primary staging and recurrent cancer staging, the extracted data are displayed separately when available.
Extracted data were collated in Excel 2007 (Microsoft Corporation, Redmond, CA, USA) and analysis was performed using Stata v.12.0SE (College Station, TX, USA). Meta-analysis of proportions was performed using the metaprop command in Stata [23]
In patients undergoing a scan for disease recurrence, we performed a PSA level analysis. Note that for the cohort used by Afshar-Oromieh et al [14]
Random-effects meta-regression with Freeman-Tukey transformation was performed for study-defined PSA categories where the reference point was <2 ng/ml. We could not assign a valid reference point for categories greater than this as the reporting of PSA means, medians, and ranges was heterogeneous. Values were back-transformed using the equation described by Miller [26]
Summary sensitivity, specificity, and hierarchical receiver operating characteristic curves were created using the midas command [27]
Using the systematic search strategy outlined in the Supplementary material, 1895 articles were identified, of which 189 were duplicate records and excluded. Of the remaining 1706 records, 1470 were not relevant to the research question. A further 202 were conference abstracts, reviews, letters, and editorials that could not be quality assessed, and thus were excluded. From the remaining 34 articles, 11 were excluded as they did not contain relevant results and five contained duplicate data. One additional study was excluded as patients were enrolled following negative choline-based PET, and thus provided a skewed patient population [28]
Of the 16 studies relevant to the meta-analysis, one was prospective and 15 were retrospective in nature. Two studies included outcomes for 68Ga-PSMA PET performed before definitive therapy (primary staging), eight reported outcomes for biochemical recurrence or disease progression staging (secondary staging), and six included mixed groups. Basic details for the studies included are listed in Table 1.
Characteristics of the studies included
a The tracer used in all cases was 68Ga-PSMA-11.
b PET was used for 95 patients and magnetic resonance imaging for all 130 patients.
c Mean.
ADT = androgen deprivation therapy; ARTx = adjuvant radiotherapy; BCR = biochemical recurrence; CE = contrast-enhanced; CT = computerised tomography; CTx = chemotherapy; HIFU = high-intensity focused ultrasound; HR = high resolution;, LND = lymph node dissection, LNM = lymph node metastases; NCE = non–contrast-enhanced; NR = not reported; PCa = Prostate cancer; PET = positron emission tomography; PSMA = prostate-specific membrane antigen; RP = radical prostatectomy; RTx = primary radiotherapy; SRP = salvage prostatectomy.
While patient selection was generally acceptable in the studies included, a few studies did not clearly report the inclusion criteria. Furthermore, several studies included mixed patient populations including primary and secondary staging groups, raising concerns regarding applicability. All the studies clearly reported methodology for the index test and were thus not considered a significant source of potential bias. Of the studies included, 11 involved a reference test: histopathologic correlation of 68Ga-PSMA PET–positive lesions. However, in terms of flow and timing, multiple studies were at risk of bias, as many included targeted biopsies of suspicious lesions only. Such articles were excluded from sensitivity and specificity analyses because the false-negative data are not accurate. In total, five studies performed 68Ga-PSMA PET before planned lymph node sampling. Summary findings for the QUADAS-2 appraisal are illustrated in Figure 2.
(A) Appraisal of the quality of the studies included according to the Quality Assessment for Diagnostic Studies-2 (QUADAS-2) tool [22]
In total, we analysed 16 studies involving 1309 patients who underwent a 68Ga-PSMA PET scan, of which 926 (70.7%) were positive. In an overall meta-analysis by cohort type, 40% (95% CI 19–64%) of scans were positive for patients undergoing primary staging and 76% (95% CI 66–85%) for those undergoing secondary staging (Fig. 3). There was high heterogeneity between groups and within all subgroups (I2 > 70%). Egger's test for small-study effects did not reach significance (p > 0.10; Supplementary Figs. 1 and 2).
Forest plot of the proportion of 68Ga–prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET) positivity by patient cohort type. ES = effect size; CI = confidence interval. Reference numbers for the studies are as in Table 1.
In assessing disease recurrence, PSMA PET positivity increased with the PSA category (Fig. 4). For patients with PSA <0.2 ng/ml, the pooled estimate was 42%, which increased to 58%, 76%, and 95% for the 0.2–0.99, 1.00–1.99, and >2.00 ng/ml PSA subgroups, respectively. There was high heterogeneity within the <0.2 and 1.00–1.99 ng/ml subgroups and very high heterogeneity between subgroups (I2 = 97.4%); the test for small-study effects did not reach significance (Supplementary Fig. 3). In meta-regression analysis (Fig. 5), the predicted positivity was 48% (95% CI 38–57%) for PSA of 0.2 ng/ml, 56% (95% CI 49–64%) for 0.5 ng/ml, and 70% (95% CI 63–76%) for 1.0 ng/ml.
Forest plot of the proportion of 68Ga–prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET) positivity by PSA category. ES = effect size; CI = confidence interval. Reference numbers for the studies are as in Table 1.
Scatterplot of prostate specific antigen (PSA) level versus the proportion of 68Ga–prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET) positivity. The blue line is the meta-regression prediction and shading shows the 95% confidence interval. The size of the circles is related to the inverse of the variance.
A similar finding was observed for PSAdt: the pooled PSMA positivity was 64% for PSAdt ≥6 mo and 92% for PSAdt <6 mo (Fig. 6). There was high heterogeneity between the subgroups (I2 = 84.2%) and evidence of a small-study effect in the long PSAdt subgroup (Supplementary Fig. 4).
Forest plot of the proportion of 68Ga–prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET) positivity by prostate-specific antigen doubling time (PSA-dt) category. ES = effect size; CI = confidence interval.
As a sensitivity analysis, we excluded subpopulations with a sample size of less than ten and repeated the meta-analyses. This decreased the point estimate for 68Ga-PSMA PET positivity in the primary staging cohort to 27% (95% CI 15–42%). All other effects were negligible, with differences of ≤2% in the point estimates and CI boundaries for overall positivity and two PSA category proportions.
Of the studies included, 11 reported histopathologic correlation with 68Ga-PSMA PET; however, only five met the aforementioned inclusion criteria (summarised in Table 2). Of the five studies reporting the predictive ability of 68Ga-PSMA PET imaging with respect to histology-proven disease, per-patient and per-lesion analyses were possible for four studies each (Fig. 7). For per-lesion analysis, the summary sensitivity is 80% and specificity is 97%. For per-patient analysis, the summary sensitivity and specificity are both 86%, although the confidence intervals are especially wide because of the low patient numbers.
Studies with histopathologic correlation data for 68Ga PSMA PET–positive lesions included in pooled analysis
a Not included in the pooled analysis as data points did not meet the inclusion criteria.
HP = histopathology; LND = lymph node dissection; SS = sensitivity; SP = specificity.
68Ga-PSMA PET is a novel targeted imaging modality that may improve the identification of metastatic prostate cancer. Our meta-analysis results identified indication, PSA, and PSA-based kinetics as risk factors for positive imaging. Furthermore, pooled sensitivity and specificity for the available data appear promising compared to alternative imaging modalities for metastatic prostate cancer.
The current study highlights the growing body of evidence supporting the use of 68Ga-PSMA PET for primary staging. In this setting, groups have reported pooled positivity of 40%. Given that the risk of metastatic spread is unlikely in low-risk disease, a majority of the studies included patients with intermediate- and high-risk prostate cancer in accordance with the D’Amico classification [47]
To date, the majority of data outlining the utility of 68Ga-PSMA PET are in the setting of secondary staging for biochemical recurrence after definitive therapy. In clinical practice, early detection and highly accurate localisation of disease recurrence are critical, as these may facilitate initiation of subsequent therapies, such as radiotherapy [54]
Pooled data from the current study highlight the promising detection rates for 68Ga-PSMA PET in prostate cancer with low PSA or PSAdt. Despite advances in bone scintigraphy and CT imaging, detection of locoregional or distant recurrence with low PSA has been problematic. Therefore, most guidelines recommend imaging when patients are symptomatic or PSA levels are >10 ng/ml [4]
An increasing number of centres are reporting early outcomes for 68Ga-PSMA PET, particularly in Germany and Australia, with results for many series yet to be published [59]
There are several limitations to the current study. First, a majority of the series used for meta-analysis were derived from small, retrospective, single-institutional studies. In addition, the heterogeneous nature of the patient cohorts, treatment protocols, and study designs included represents a potential limitation of the data available for analysis. Second, of the studies used for pooled sensitivity and specificity data, the majority had a small sample size and assessed patients in the primary staging setting. Additional data in the future will undoubtedly be of benefit for such analyses.
The absence of accurate imaging for detection of small-volume metastases in advanced prostate cancer has prompted the introduction of 68Ga-PSMA PET. The results of the current study suggest that PSA and associated kinetics predict the risk of metastatic disease diagnosed by 68Ga-PSMA PET. This novel imaging modality appears to provide superior sensitivity and specificity compared to alternative techniques. These promising early results for 68Ga-PSMA PET indicate a significant need for further clinical data.
Author contributions: Nathan Lawrentschuk had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Lawrentschuk, Perera, Papa.
Acquisition of data: Perera, Papa, Christidis, Wetherell.
Analysis and interpretation of data: Papa, Perera, Hofman.
Drafting of the manuscript: Perera, Papa, Hofman, Murphy, Bolton.
Critical revision of the manuscript for important intellectual content: Murphy, Bolton, Hofman, Lawrentschuk.
Statistical analysis: Papa.
Obtaining funding: None.
Administrative, technical, or material support: None.
Supervision: Bolton, Lawrentschuk, Murphy, Hofman.
Other: None.
Financial disclosures: Nathan Lawrentschuk certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None.
Funding/Support and role of the sponsor: None.
Acknowledgments: Marlon Perera is supported by a Royal Australasian College of Surgeons scholarship.
Prostate cancer is among the most prevalent cancers worldwide and is the third most common cause of cancer-associated mortality among men [1]
Prostate-specific membrane antigen (PSMA) is a transmembrane protein with a 707-amino-acid extracellular portion. The PSMA gene (FOLH1) is located on the short arm of chromosome 11. PSMA is expressed in the apical region of prostatic cells, the epithelium surrounding prostatic ducts [6]
To date, the use of 68Ga-PSMA has been well reported, with the compound Glu-NH-CO-NH-Lys-(Ahx)-[68Ga]-HBED (68Ga-PSMA-11) developed by the Heidelberg group in Germany. Initial series revealed superior sensitivity and specificity profiles compared to conventional choline-based tracers [19]
A systematic review was performed in accordance with Cochrane Collaboration and Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) guidelines [20]
Studies evaluating the utility of 68Ga-PSMA PET in detection of metastatic disease in advanced prostate cancer were included for analysis. Study designs considered for inclusion were clinical trials, prospective studies, and retrospective cohorts or comparative series. Studies assessing the diagnostic utility of 68Ga-PSMA PET in prostate cancer staging (before definitive treatment) or staging for recurrent disease (following therapy) were included for assessment. Studies were excluded if 68Ga-PSMA PET was used in assessing primary (prostatic) disease only or a specific visceral metastatic deposit (eg, pulmonary or cerebral metastases). In the current analysis, only studies using the 68Ga-PSMA-11 PSMA surface antigen HBED-CC (PSMA-11) were included for analysis provided the tracer was bound to 68Ga. Studies were excluded if alternative PSMA-bound radiotracers were used (eg, 18F or 99mTc tracers). No language or sample-size restrictions were used. Where duplicate study populations or analyses of repeated data were identified from the literature review, the publication reporting a larger sample size was used for analysis.
The primary outcome was to identify predictors of 68Ga-PSMA PET positivity. Studies that included only 68Ga-PSMA PET–positive studies were excluded, as predictive data were not available for analysis. The secondary outcome measure was the sensitivity and specificity of 68Ga-PSMA PET–positive lesions in advanced prostate cancer. For sensitivity and specificity analysis, only studies that included routine 68Ga-PSMA PET before preplanned lymph node dissection were included. Inclusion of series for which nodal biopsy was performed at the clinician's discretion does not provide meaningful false-negative data and thus does not provide accurate specificity values. An inadequate number of studies robustly assessed prostatic bed recurrence or suspicious bony metastatic disease in the manner outlined above. Therefore, we only assessed sensitivity and specificity values for 68Ga-PSMA PET in lymph nodes.
Studies were assessed for quality using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool [22]
The following information was extracted from each study: sample size, age, indication for PET (primary staging or recurrent disease staging), PSA, previous therapies, initial cancer stage, 68Ga-PSMA PET characteristics, rates of positive PET, and histopathologic correlation data. Rates of 68Ga-PSMA PET positivity were collected and stratified by pre-PET PSA and PSA doubling time (PSAdt) when possible. When histopathologic correlation data were available, numbers of true positives, false positives, true negatives, and false negatives were collected, as appropriate. For studies that included 68Ga-PSMA PET for both primary staging and recurrent cancer staging, the extracted data are displayed separately when available.
Extracted data were collated in Excel 2007 (Microsoft Corporation, Redmond, CA, USA) and analysis was performed using Stata v.12.0SE (College Station, TX, USA). Meta-analysis of proportions was performed using the metaprop command in Stata [23]
In patients undergoing a scan for disease recurrence, we performed a PSA level analysis. Note that for the cohort used by Afshar-Oromieh et al [14]
Random-effects meta-regression with Freeman-Tukey transformation was performed for study-defined PSA categories where the reference point was <2 ng/ml. We could not assign a valid reference point for categories greater than this as the reporting of PSA means, medians, and ranges was heterogeneous. Values were back-transformed using the equation described by Miller [26]
Summary sensitivity, specificity, and hierarchical receiver operating characteristic curves were created using the midas command [27]
Using the systematic search strategy outlined in the Supplementary material, 1895 articles were identified, of which 189 were duplicate records and excluded. Of the remaining 1706 records, 1470 were not relevant to the research question. A further 202 were conference abstracts, reviews, letters, and editorials that could not be quality assessed, and thus were excluded. From the remaining 34 articles, 11 were excluded as they did not contain relevant results and five contained duplicate data. One additional study was excluded as patients were enrolled following negative choline-based PET, and thus provided a skewed patient population [28]
Of the 16 studies relevant to the meta-analysis, one was prospective and 15 were retrospective in nature. Two studies included outcomes for 68Ga-PSMA PET performed before definitive therapy (primary staging), eight reported outcomes for biochemical recurrence or disease progression staging (secondary staging), and six included mixed groups. Basic details for the studies included are listed in Table 1.
Characteristics of the studies included
a The tracer used in all cases was 68Ga-PSMA-11.
b PET was used for 95 patients and magnetic resonance imaging for all 130 patients.
c Mean.
ADT = androgen deprivation therapy; ARTx = adjuvant radiotherapy; BCR = biochemical recurrence; CE = contrast-enhanced; CT = computerised tomography; CTx = chemotherapy; HIFU = high-intensity focused ultrasound; HR = high resolution;, LND = lymph node dissection, LNM = lymph node metastases; NCE = non–contrast-enhanced; NR = not reported; PCa = Prostate cancer; PET = positron emission tomography; PSMA = prostate-specific membrane antigen; RP = radical prostatectomy; RTx = primary radiotherapy; SRP = salvage prostatectomy.
While patient selection was generally acceptable in the studies included, a few studies did not clearly report the inclusion criteria. Furthermore, several studies included mixed patient populations including primary and secondary staging groups, raising concerns regarding applicability. All the studies clearly reported methodology for the index test and were thus not considered a significant source of potential bias. Of the studies included, 11 involved a reference test: histopathologic correlation of 68Ga-PSMA PET–positive lesions. However, in terms of flow and timing, multiple studies were at risk of bias, as many included targeted biopsies of suspicious lesions only. Such articles were excluded from sensitivity and specificity analyses because the false-negative data are not accurate. In total, five studies performed 68Ga-PSMA PET before planned lymph node sampling. Summary findings for the QUADAS-2 appraisal are illustrated in Figure 2.
(A) Appraisal of the quality of the studies included according to the Quality Assessment for Diagnostic Studies-2 (QUADAS-2) tool [22]
In total, we analysed 16 studies involving 1309 patients who underwent a 68Ga-PSMA PET scan, of which 926 (70.7%) were positive. In an overall meta-analysis by cohort type, 40% (95% CI 19–64%) of scans were positive for patients undergoing primary staging and 76% (95% CI 66–85%) for those undergoing secondary staging (Fig. 3). There was high heterogeneity between groups and within all subgroups (I2 > 70%). Egger's test for small-study effects did not reach significance (p > 0.10; Supplementary Figs. 1 and 2).
Forest plot of the proportion of 68Ga–prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET) positivity by patient cohort type. ES = effect size; CI = confidence interval. Reference numbers for the studies are as in Table 1.
In assessing disease recurrence, PSMA PET positivity increased with the PSA category (Fig. 4). For patients with PSA <0.2 ng/ml, the pooled estimate was 42%, which increased to 58%, 76%, and 95% for the 0.2–0.99, 1.00–1.99, and >2.00 ng/ml PSA subgroups, respectively. There was high heterogeneity within the <0.2 and 1.00–1.99 ng/ml subgroups and very high heterogeneity between subgroups (I2 = 97.4%); the test for small-study effects did not reach significance (Supplementary Fig. 3). In meta-regression analysis (Fig. 5), the predicted positivity was 48% (95% CI 38–57%) for PSA of 0.2 ng/ml, 56% (95% CI 49–64%) for 0.5 ng/ml, and 70% (95% CI 63–76%) for 1.0 ng/ml.
Forest plot of the proportion of 68Ga–prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET) positivity by PSA category. ES = effect size; CI = confidence interval. Reference numbers for the studies are as in Table 1.
Scatterplot of prostate specific antigen (PSA) level versus the proportion of 68Ga–prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET) positivity. The blue line is the meta-regression prediction and shading shows the 95% confidence interval. The size of the circles is related to the inverse of the variance.
A similar finding was observed for PSAdt: the pooled PSMA positivity was 64% for PSAdt ≥6 mo and 92% for PSAdt <6 mo (Fig. 6). There was high heterogeneity between the subgroups (I2 = 84.2%) and evidence of a small-study effect in the long PSAdt subgroup (Supplementary Fig. 4).
Forest plot of the proportion of 68Ga–prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET) positivity by prostate-specific antigen doubling time (PSA-dt) category. ES = effect size; CI = confidence interval.
As a sensitivity analysis, we excluded subpopulations with a sample size of less than ten and repeated the meta-analyses. This decreased the point estimate for 68Ga-PSMA PET positivity in the primary staging cohort to 27% (95% CI 15–42%). All other effects were negligible, with differences of ≤2% in the point estimates and CI boundaries for overall positivity and two PSA category proportions.
Of the studies included, 11 reported histopathologic correlation with 68Ga-PSMA PET; however, only five met the aforementioned inclusion criteria (summarised in Table 2). Of the five studies reporting the predictive ability of 68Ga-PSMA PET imaging with respect to histology-proven disease, per-patient and per-lesion analyses were possible for four studies each (Fig. 7). For per-lesion analysis, the summary sensitivity is 80% and specificity is 97%. For per-patient analysis, the summary sensitivity and specificity are both 86%, although the confidence intervals are especially wide because of the low patient numbers.
Studies with histopathologic correlation data for 68Ga PSMA PET–positive lesions included in pooled analysis
a Not included in the pooled analysis as data points did not meet the inclusion criteria.
HP = histopathology; LND = lymph node dissection; SS = sensitivity; SP = specificity.
68Ga-PSMA PET is a novel targeted imaging modality that may improve the identification of metastatic prostate cancer. Our meta-analysis results identified indication, PSA, and PSA-based kinetics as risk factors for positive imaging. Furthermore, pooled sensitivity and specificity for the available data appear promising compared to alternative imaging modalities for metastatic prostate cancer.
The current study highlights the growing body of evidence supporting the use of 68Ga-PSMA PET for primary staging. In this setting, groups have reported pooled positivity of 40%. Given that the risk of metastatic spread is unlikely in low-risk disease, a majority of the studies included patients with intermediate- and high-risk prostate cancer in accordance with the D’Amico classification [47]
To date, the majority of data outlining the utility of 68Ga-PSMA PET are in the setting of secondary staging for biochemical recurrence after definitive therapy. In clinical practice, early detection and highly accurate localisation of disease recurrence are critical, as these may facilitate initiation of subsequent therapies, such as radiotherapy [54]
Pooled data from the current study highlight the promising detection rates for 68Ga-PSMA PET in prostate cancer with low PSA or PSAdt. Despite advances in bone scintigraphy and CT imaging, detection of locoregional or distant recurrence with low PSA has been problematic. Therefore, most guidelines recommend imaging when patients are symptomatic or PSA levels are >10 ng/ml [4]
An increasing number of centres are reporting early outcomes for 68Ga-PSMA PET, particularly in Germany and Australia, with results for many series yet to be published [59]
There are several limitations to the current study. First, a majority of the series used for meta-analysis were derived from small, retrospective, single-institutional studies. In addition, the heterogeneous nature of the patient cohorts, treatment protocols, and study designs included represents a potential limitation of the data available for analysis. Second, of the studies used for pooled sensitivity and specificity data, the majority had a small sample size and assessed patients in the primary staging setting. Additional data in the future will undoubtedly be of benefit for such analyses.
The absence of accurate imaging for detection of small-volume metastases in advanced prostate cancer has prompted the introduction of 68Ga-PSMA PET. The results of the current study suggest that PSA and associated kinetics predict the risk of metastatic disease diagnosed by 68Ga-PSMA PET. This novel imaging modality appears to provide superior sensitivity and specificity compared to alternative techniques. These promising early results for 68Ga-PSMA PET indicate a significant need for further clinical data.
Author contributions: Nathan Lawrentschuk had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Lawrentschuk, Perera, Papa.
Acquisition of data: Perera, Papa, Christidis, Wetherell.
Analysis and interpretation of data: Papa, Perera, Hofman.
Drafting of the manuscript: Perera, Papa, Hofman, Murphy, Bolton.
Critical revision of the manuscript for important intellectual content: Murphy, Bolton, Hofman, Lawrentschuk.
Statistical analysis: Papa.
Obtaining funding: None.
Administrative, technical, or material support: None.
Supervision: Bolton, Lawrentschuk, Murphy, Hofman.
Other: None.
Financial disclosures: Nathan Lawrentschuk certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None.
Funding/Support and role of the sponsor: None.
Acknowledgments: Marlon Perera is supported by a Royal Australasian College of Surgeons scholarship.
Prostate cancer is among the most prevalent cancers worldwide and is the third most common cause of cancer-associated mortality among men [1]
Prostate-specific membrane antigen (PSMA) is a transmembrane protein with a 707-amino-acid extracellular portion. The PSMA gene (FOLH1) is located on the short arm of chromosome 11. PSMA is expressed in the apical region of prostatic cells, the epithelium surrounding prostatic ducts [6]
To date, the use of 68Ga-PSMA has been well reported, with the compound Glu-NH-CO-NH-Lys-(Ahx)-[68Ga]-HBED (68Ga-PSMA-11) developed by the Heidelberg group in Germany. Initial series revealed superior sensitivity and specificity profiles compared to conventional choline-based tracers [19]
A systematic review was performed in accordance with Cochrane Collaboration and Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) guidelines [20]
Studies evaluating the utility of 68Ga-PSMA PET in detection of metastatic disease in advanced prostate cancer were included for analysis. Study designs considered for inclusion were clinical trials, prospective studies, and retrospective cohorts or comparative series. Studies assessing the diagnostic utility of 68Ga-PSMA PET in prostate cancer staging (before definitive treatment) or staging for recurrent disease (following therapy) were included for assessment. Studies were excluded if 68Ga-PSMA PET was used in assessing primary (prostatic) disease only or a specific visceral metastatic deposit (eg, pulmonary or cerebral metastases). In the current analysis, only studies using the 68Ga-PSMA-11 PSMA surface antigen HBED-CC (PSMA-11) were included for analysis provided the tracer was bound to 68Ga. Studies were excluded if alternative PSMA-bound radiotracers were used (eg, 18F or 99mTc tracers). No language or sample-size restrictions were used. Where duplicate study populations or analyses of repeated data were identified from the literature review, the publication reporting a larger sample size was used for analysis.
The primary outcome was to identify predictors of 68Ga-PSMA PET positivity. Studies that included only 68Ga-PSMA PET–positive studies were excluded, as predictive data were not available for analysis. The secondary outcome measure was the sensitivity and specificity of 68Ga-PSMA PET–positive lesions in advanced prostate cancer. For sensitivity and specificity analysis, only studies that included routine 68Ga-PSMA PET before preplanned lymph node dissection were included. Inclusion of series for which nodal biopsy was performed at the clinician's discretion does not provide meaningful false-negative data and thus does not provide accurate specificity values. An inadequate number of studies robustly assessed prostatic bed recurrence or suspicious bony metastatic disease in the manner outlined above. Therefore, we only assessed sensitivity and specificity values for 68Ga-PSMA PET in lymph nodes.
Studies were assessed for quality using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool [22]
The following information was extracted from each study: sample size, age, indication for PET (primary staging or recurrent disease staging), PSA, previous therapies, initial cancer stage, 68Ga-PSMA PET characteristics, rates of positive PET, and histopathologic correlation data. Rates of 68Ga-PSMA PET positivity were collected and stratified by pre-PET PSA and PSA doubling time (PSAdt) when possible. When histopathologic correlation data were available, numbers of true positives, false positives, true negatives, and false negatives were collected, as appropriate. For studies that included 68Ga-PSMA PET for both primary staging and recurrent cancer staging, the extracted data are displayed separately when available.
Extracted data were collated in Excel 2007 (Microsoft Corporation, Redmond, CA, USA) and analysis was performed using Stata v.12.0SE (College Station, TX, USA). Meta-analysis of proportions was performed using the metaprop command in Stata [23]
In patients undergoing a scan for disease recurrence, we performed a PSA level analysis. Note that for the cohort used by Afshar-Oromieh et al [14]
Random-effects meta-regression with Freeman-Tukey transformation was performed for study-defined PSA categories where the reference point was <2 ng/ml. We could not assign a valid reference point for categories greater than this as the reporting of PSA means, medians, and ranges was heterogeneous. Values were back-transformed using the equation described by Miller [26]
Summary sensitivity, specificity, and hierarchical receiver operating characteristic curves were created using the midas command [27]
Using the systematic search strategy outlined in the Supplementary material, 1895 articles were identified, of which 189 were duplicate records and excluded. Of the remaining 1706 records, 1470 were not relevant to the research question. A further 202 were conference abstracts, reviews, letters, and editorials that could not be quality assessed, and thus were excluded. From the remaining 34 articles, 11 were excluded as they did not contain relevant results and five contained duplicate data. One additional study was excluded as patients were enrolled following negative choline-based PET, and thus provided a skewed patient population [28]
Of the 16 studies relevant to the meta-analysis, one was prospective and 15 were retrospective in nature. Two studies included outcomes for 68Ga-PSMA PET performed before definitive therapy (primary staging), eight reported outcomes for biochemical recurrence or disease progression staging (secondary staging), and six included mixed groups. Basic details for the studies included are listed in Table 1.
Characteristics of the studies included
a The tracer used in all cases was 68Ga-PSMA-11.
b PET was used for 95 patients and magnetic resonance imaging for all 130 patients.
c Mean.
ADT = androgen deprivation therapy; ARTx = adjuvant radiotherapy; BCR = biochemical recurrence; CE = contrast-enhanced; CT = computerised tomography; CTx = chemotherapy; HIFU = high-intensity focused ultrasound; HR = high resolution;, LND = lymph node dissection, LNM = lymph node metastases; NCE = non–contrast-enhanced; NR = not reported; PCa = Prostate cancer; PET = positron emission tomography; PSMA = prostate-specific membrane antigen; RP = radical prostatectomy; RTx = primary radiotherapy; SRP = salvage prostatectomy.
While patient selection was generally acceptable in the studies included, a few studies did not clearly report the inclusion criteria. Furthermore, several studies included mixed patient populations including primary and secondary staging groups, raising concerns regarding applicability. All the studies clearly reported methodology for the index test and were thus not considered a significant source of potential bias. Of the studies included, 11 involved a reference test: histopathologic correlation of 68Ga-PSMA PET–positive lesions. However, in terms of flow and timing, multiple studies were at risk of bias, as many included targeted biopsies of suspicious lesions only. Such articles were excluded from sensitivity and specificity analyses because the false-negative data are not accurate. In total, five studies performed 68Ga-PSMA PET before planned lymph node sampling. Summary findings for the QUADAS-2 appraisal are illustrated in Figure 2.
(A) Appraisal of the quality of the studies included according to the Quality Assessment for Diagnostic Studies-2 (QUADAS-2) tool [22]
In total, we analysed 16 studies involving 1309 patients who underwent a 68Ga-PSMA PET scan, of which 926 (70.7%) were positive. In an overall meta-analysis by cohort type, 40% (95% CI 19–64%) of scans were positive for patients undergoing primary staging and 76% (95% CI 66–85%) for those undergoing secondary staging (Fig. 3). There was high heterogeneity between groups and within all subgroups (I2 > 70%). Egger's test for small-study effects did not reach significance (p > 0.10; Supplementary Figs. 1 and 2).
Forest plot of the proportion of 68Ga–prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET) positivity by patient cohort type. ES = effect size; CI = confidence interval. Reference numbers for the studies are as in Table 1.
In assessing disease recurrence, PSMA PET positivity increased with the PSA category (Fig. 4). For patients with PSA <0.2 ng/ml, the pooled estimate was 42%, which increased to 58%, 76%, and 95% for the 0.2–0.99, 1.00–1.99, and >2.00 ng/ml PSA subgroups, respectively. There was high heterogeneity within the <0.2 and 1.00–1.99 ng/ml subgroups and very high heterogeneity between subgroups (I2 = 97.4%); the test for small-study effects did not reach significance (Supplementary Fig. 3). In meta-regression analysis (Fig. 5), the predicted positivity was 48% (95% CI 38–57%) for PSA of 0.2 ng/ml, 56% (95% CI 49–64%) for 0.5 ng/ml, and 70% (95% CI 63–76%) for 1.0 ng/ml.
Forest plot of the proportion of 68Ga–prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET) positivity by PSA category. ES = effect size; CI = confidence interval. Reference numbers for the studies are as in Table 1.
Scatterplot of prostate specific antigen (PSA) level versus the proportion of 68Ga–prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET) positivity. The blue line is the meta-regression prediction and shading shows the 95% confidence interval. The size of the circles is related to the inverse of the variance.
A similar finding was observed for PSAdt: the pooled PSMA positivity was 64% for PSAdt ≥6 mo and 92% for PSAdt <6 mo (Fig. 6). There was high heterogeneity between the subgroups (I2 = 84.2%) and evidence of a small-study effect in the long PSAdt subgroup (Supplementary Fig. 4).
Forest plot of the proportion of 68Ga–prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET) positivity by prostate-specific antigen doubling time (PSA-dt) category. ES = effect size; CI = confidence interval.
As a sensitivity analysis, we excluded subpopulations with a sample size of less than ten and repeated the meta-analyses. This decreased the point estimate for 68Ga-PSMA PET positivity in the primary staging cohort to 27% (95% CI 15–42%). All other effects were negligible, with differences of ≤2% in the point estimates and CI boundaries for overall positivity and two PSA category proportions.
Of the studies included, 11 reported histopathologic correlation with 68Ga-PSMA PET; however, only five met the aforementioned inclusion criteria (summarised in Table 2). Of the five studies reporting the predictive ability of 68Ga-PSMA PET imaging with respect to histology-proven disease, per-patient and per-lesion analyses were possible for four studies each (Fig. 7). For per-lesion analysis, the summary sensitivity is 80% and specificity is 97%. For per-patient analysis, the summary sensitivity and specificity are both 86%, although the confidence intervals are especially wide because of the low patient numbers.
Studies with histopathologic correlation data for 68Ga PSMA PET–positive lesions included in pooled analysis
a Not included in the pooled analysis as data points did not meet the inclusion criteria.
HP = histopathology; LND = lymph node dissection; SS = sensitivity; SP = specificity.
68Ga-PSMA PET is a novel targeted imaging modality that may improve the identification of metastatic prostate cancer. Our meta-analysis results identified indication, PSA, and PSA-based kinetics as risk factors for positive imaging. Furthermore, pooled sensitivity and specificity for the available data appear promising compared to alternative imaging modalities for metastatic prostate cancer.
The current study highlights the growing body of evidence supporting the use of 68Ga-PSMA PET for primary staging. In this setting, groups have reported pooled positivity of 40%. Given that the risk of metastatic spread is unlikely in low-risk disease, a majority of the studies included patients with intermediate- and high-risk prostate cancer in accordance with the D’Amico classification [47]
To date, the majority of data outlining the utility of 68Ga-PSMA PET are in the setting of secondary staging for biochemical recurrence after definitive therapy. In clinical practice, early detection and highly accurate localisation of disease recurrence are critical, as these may facilitate initiation of subsequent therapies, such as radiotherapy [54]
Pooled data from the current study highlight the promising detection rates for 68Ga-PSMA PET in prostate cancer with low PSA or PSAdt. Despite advances in bone scintigraphy and CT imaging, detection of locoregional or distant recurrence with low PSA has been problematic. Therefore, most guidelines recommend imaging when patients are symptomatic or PSA levels are >10 ng/ml [4]
An increasing number of centres are reporting early outcomes for 68Ga-PSMA PET, particularly in Germany and Australia, with results for many series yet to be published [59]
There are several limitations to the current study. First, a majority of the series used for meta-analysis were derived from small, retrospective, single-institutional studies. In addition, the heterogeneous nature of the patient cohorts, treatment protocols, and study designs included represents a potential limitation of the data available for analysis. Second, of the studies used for pooled sensitivity and specificity data, the majority had a small sample size and assessed patients in the primary staging setting. Additional data in the future will undoubtedly be of benefit for such analyses.
The absence of accurate imaging for detection of small-volume metastases in advanced prostate cancer has prompted the introduction of 68Ga-PSMA PET. The results of the current study suggest that PSA and associated kinetics predict the risk of metastatic disease diagnosed by 68Ga-PSMA PET. This novel imaging modality appears to provide superior sensitivity and specificity compared to alternative techniques. These promising early results for 68Ga-PSMA PET indicate a significant need for further clinical data.
Author contributions: Nathan Lawrentschuk had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Lawrentschuk, Perera, Papa.
Acquisition of data: Perera, Papa, Christidis, Wetherell.
Analysis and interpretation of data: Papa, Perera, Hofman.
Drafting of the manuscript: Perera, Papa, Hofman, Murphy, Bolton.
Critical revision of the manuscript for important intellectual content: Murphy, Bolton, Hofman, Lawrentschuk.
Statistical analysis: Papa.
Obtaining funding: None.
Administrative, technical, or material support: None.
Supervision: Bolton, Lawrentschuk, Murphy, Hofman.
Other: None.
Financial disclosures: Nathan Lawrentschuk certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None.
Funding/Support and role of the sponsor: None.
Acknowledgments: Marlon Perera is supported by a Royal Australasian College of Surgeons scholarship.
Prostate cancer is among the most prevalent cancers worldwide and is the third most common cause of cancer-associated mortality among men [1]
Prostate-specific membrane antigen (PSMA) is a transmembrane protein with a 707-amino-acid extracellular portion. The PSMA gene (FOLH1) is located on the short arm of chromosome 11. PSMA is expressed in the apical region of prostatic cells, the epithelium surrounding prostatic ducts [6]
To date, the use of 68Ga-PSMA has been well reported, with the compound Glu-NH-CO-NH-Lys-(Ahx)-[68Ga]-HBED (68Ga-PSMA-11) developed by the Heidelberg group in Germany. Initial series revealed superior sensitivity and specificity profiles compared to conventional choline-based tracers [19]
A systematic review was performed in accordance with Cochrane Collaboration and Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) guidelines [20]
Studies evaluating the utility of 68Ga-PSMA PET in detection of metastatic disease in advanced prostate cancer were included for analysis. Study designs considered for inclusion were clinical trials, prospective studies, and retrospective cohorts or comparative series. Studies assessing the diagnostic utility of 68Ga-PSMA PET in prostate cancer staging (before definitive treatment) or staging for recurrent disease (following therapy) were included for assessment. Studies were excluded if 68Ga-PSMA PET was used in assessing primary (prostatic) disease only or a specific visceral metastatic deposit (eg, pulmonary or cerebral metastases). In the current analysis, only studies using the 68Ga-PSMA-11 PSMA surface antigen HBED-CC (PSMA-11) were included for analysis provided the tracer was bound to 68Ga. Studies were excluded if alternative PSMA-bound radiotracers were used (eg, 18F or 99mTc tracers). No language or sample-size restrictions were used. Where duplicate study populations or analyses of repeated data were identified from the literature review, the publication reporting a larger sample size was used for analysis.
The primary outcome was to identify predictors of 68Ga-PSMA PET positivity. Studies that included only 68Ga-PSMA PET–positive studies were excluded, as predictive data were not available for analysis. The secondary outcome measure was the sensitivity and specificity of 68Ga-PSMA PET–positive lesions in advanced prostate cancer. For sensitivity and specificity analysis, only studies that included routine 68Ga-PSMA PET before preplanned lymph node dissection were included. Inclusion of series for which nodal biopsy was performed at the clinician's discretion does not provide meaningful false-negative data and thus does not provide accurate specificity values. An inadequate number of studies robustly assessed prostatic bed recurrence or suspicious bony metastatic disease in the manner outlined above. Therefore, we only assessed sensitivity and specificity values for 68Ga-PSMA PET in lymph nodes.
Studies were assessed for quality using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool [22]
The following information was extracted from each study: sample size, age, indication for PET (primary staging or recurrent disease staging), PSA, previous therapies, initial cancer stage, 68Ga-PSMA PET characteristics, rates of positive PET, and histopathologic correlation data. Rates of 68Ga-PSMA PET positivity were collected and stratified by pre-PET PSA and PSA doubling time (PSAdt) when possible. When histopathologic correlation data were available, numbers of true positives, false positives, true negatives, and false negatives were collected, as appropriate. For studies that included 68Ga-PSMA PET for both primary staging and recurrent cancer staging, the extracted data are displayed separately when available.
Extracted data were collated in Excel 2007 (Microsoft Corporation, Redmond, CA, USA) and analysis was performed using Stata v.12.0SE (College Station, TX, USA). Meta-analysis of proportions was performed using the metaprop command in Stata [23]
In patients undergoing a scan for disease recurrence, we performed a PSA level analysis. Note that for the cohort used by Afshar-Oromieh et al [14]
Random-effects meta-regression with Freeman-Tukey transformation was performed for study-defined PSA categories where the reference point was <2 ng/ml. We could not assign a valid reference point for categories greater than this as the reporting of PSA means, medians, and ranges was heterogeneous. Values were back-transformed using the equation described by Miller [26]
Summary sensitivity, specificity, and hierarchical receiver operating characteristic curves were created using the midas command [27]
Using the systematic search strategy outlined in the Supplementary material, 1895 articles were identified, of which 189 were duplicate records and excluded. Of the remaining 1706 records, 1470 were not relevant to the research question. A further 202 were conference abstracts, reviews, letters, and editorials that could not be quality assessed, and thus were excluded. From the remaining 34 articles, 11 were excluded as they did not contain relevant results and five contained duplicate data. One additional study was excluded as patients were enrolled following negative choline-based PET, and thus provided a skewed patient population [28]
Of the 16 studies relevant to the meta-analysis, one was prospective and 15 were retrospective in nature. Two studies included outcomes for 68Ga-PSMA PET performed before definitive therapy (primary staging), eight reported outcomes for biochemical recurrence or disease progression staging (secondary staging), and six included mixed groups. Basic details for the studies included are listed in Table 1.
Characteristics of the studies included
a The tracer used in all cases was 68Ga-PSMA-11.
b PET was used for 95 patients and magnetic resonance imaging for all 130 patients.
c Mean.
ADT = androgen deprivation therapy; ARTx = adjuvant radiotherapy; BCR = biochemical recurrence; CE = contrast-enhanced; CT = computerised tomography; CTx = chemotherapy; HIFU = high-intensity focused ultrasound; HR = high resolution;, LND = lymph node dissection, LNM = lymph node metastases; NCE = non–contrast-enhanced; NR = not reported; PCa = Prostate cancer; PET = positron emission tomography; PSMA = prostate-specific membrane antigen; RP = radical prostatectomy; RTx = primary radiotherapy; SRP = salvage prostatectomy.
While patient selection was generally acceptable in the studies included, a few studies did not clearly report the inclusion criteria. Furthermore, several studies included mixed patient populations including primary and secondary staging groups, raising concerns regarding applicability. All the studies clearly reported methodology for the index test and were thus not considered a significant source of potential bias. Of the studies included, 11 involved a reference test: histopathologic correlation of 68Ga-PSMA PET–positive lesions. However, in terms of flow and timing, multiple studies were at risk of bias, as many included targeted biopsies of suspicious lesions only. Such articles were excluded from sensitivity and specificity analyses because the false-negative data are not accurate. In total, five studies performed 68Ga-PSMA PET before planned lymph node sampling. Summary findings for the QUADAS-2 appraisal are illustrated in Figure 2.
(A) Appraisal of the quality of the studies included according to the Quality Assessment for Diagnostic Studies-2 (QUADAS-2) tool [22]
In total, we analysed 16 studies involving 1309 patients who underwent a 68Ga-PSMA PET scan, of which 926 (70.7%) were positive. In an overall meta-analysis by cohort type, 40% (95% CI 19–64%) of scans were positive for patients undergoing primary staging and 76% (95% CI 66–85%) for those undergoing secondary staging (Fig. 3). There was high heterogeneity between groups and within all subgroups (I2 > 70%). Egger's test for small-study effects did not reach significance (p > 0.10; Supplementary Figs. 1 and 2).
Forest plot of the proportion of 68Ga–prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET) positivity by patient cohort type. ES = effect size; CI = confidence interval. Reference numbers for the studies are as in Table 1.
In assessing disease recurrence, PSMA PET positivity increased with the PSA category (Fig. 4). For patients with PSA <0.2 ng/ml, the pooled estimate was 42%, which increased to 58%, 76%, and 95% for the 0.2–0.99, 1.00–1.99, and >2.00 ng/ml PSA subgroups, respectively. There was high heterogeneity within the <0.2 and 1.00–1.99 ng/ml subgroups and very high heterogeneity between subgroups (I2 = 97.4%); the test for small-study effects did not reach significance (Supplementary Fig. 3). In meta-regression analysis (Fig. 5), the predicted positivity was 48% (95% CI 38–57%) for PSA of 0.2 ng/ml, 56% (95% CI 49–64%) for 0.5 ng/ml, and 70% (95% CI 63–76%) for 1.0 ng/ml.
Forest plot of the proportion of 68Ga–prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET) positivity by PSA category. ES = effect size; CI = confidence interval. Reference numbers for the studies are as in Table 1.
Scatterplot of prostate specific antigen (PSA) level versus the proportion of 68Ga–prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET) positivity. The blue line is the meta-regression prediction and shading shows the 95% confidence interval. The size of the circles is related to the inverse of the variance.
A similar finding was observed for PSAdt: the pooled PSMA positivity was 64% for PSAdt ≥6 mo and 92% for PSAdt <6 mo (Fig. 6). There was high heterogeneity between the subgroups (I2 = 84.2%) and evidence of a small-study effect in the long PSAdt subgroup (Supplementary Fig. 4).
Forest plot of the proportion of 68Ga–prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET) positivity by prostate-specific antigen doubling time (PSA-dt) category. ES = effect size; CI = confidence interval.
As a sensitivity analysis, we excluded subpopulations with a sample size of less than ten and repeated the meta-analyses. This decreased the point estimate for 68Ga-PSMA PET positivity in the primary staging cohort to 27% (95% CI 15–42%). All other effects were negligible, with differences of ≤2% in the point estimates and CI boundaries for overall positivity and two PSA category proportions.
Of the studies included, 11 reported histopathologic correlation with 68Ga-PSMA PET; however, only five met the aforementioned inclusion criteria (summarised in Table 2). Of the five studies reporting the predictive ability of 68Ga-PSMA PET imaging with respect to histology-proven disease, per-patient and per-lesion analyses were possible for four studies each (Fig. 7). For per-lesion analysis, the summary sensitivity is 80% and specificity is 97%. For per-patient analysis, the summary sensitivity and specificity are both 86%, although the confidence intervals are especially wide because of the low patient numbers.
Studies with histopathologic correlation data for 68Ga PSMA PET–positive lesions included in pooled analysis
a Not included in the pooled analysis as data points did not meet the inclusion criteria.
HP = histopathology; LND = lymph node dissection; SS = sensitivity; SP = specificity.
68Ga-PSMA PET is a novel targeted imaging modality that may improve the identification of metastatic prostate cancer. Our meta-analysis results identified indication, PSA, and PSA-based kinetics as risk factors for positive imaging. Furthermore, pooled sensitivity and specificity for the available data appear promising compared to alternative imaging modalities for metastatic prostate cancer.
The current study highlights the growing body of evidence supporting the use of 68Ga-PSMA PET for primary staging. In this setting, groups have reported pooled positivity of 40%. Given that the risk of metastatic spread is unlikely in low-risk disease, a majority of the studies included patients with intermediate- and high-risk prostate cancer in accordance with the D’Amico classification [47]
To date, the majority of data outlining the utility of 68Ga-PSMA PET are in the setting of secondary staging for biochemical recurrence after definitive therapy. In clinical practice, early detection and highly accurate localisation of disease recurrence are critical, as these may facilitate initiation of subsequent therapies, such as radiotherapy [54]
Pooled data from the current study highlight the promising detection rates for 68Ga-PSMA PET in prostate cancer with low PSA or PSAdt. Despite advances in bone scintigraphy and CT imaging, detection of locoregional or distant recurrence with low PSA has been problematic. Therefore, most guidelines recommend imaging when patients are symptomatic or PSA levels are >10 ng/ml [4]
An increasing number of centres are reporting early outcomes for 68Ga-PSMA PET, particularly in Germany and Australia, with results for many series yet to be published [59]
There are several limitations to the current study. First, a majority of the series used for meta-analysis were derived from small, retrospective, single-institutional studies. In addition, the heterogeneous nature of the patient cohorts, treatment protocols, and study designs included represents a potential limitation of the data available for analysis. Second, of the studies used for pooled sensitivity and specificity data, the majority had a small sample size and assessed patients in the primary staging setting. Additional data in the future will undoubtedly be of benefit for such analyses.
The absence of accurate imaging for detection of small-volume metastases in advanced prostate cancer has prompted the introduction of 68Ga-PSMA PET. The results of the current study suggest that PSA and associated kinetics predict the risk of metastatic disease diagnosed by 68Ga-PSMA PET. This novel imaging modality appears to provide superior sensitivity and specificity compared to alternative techniques. These promising early results for 68Ga-PSMA PET indicate a significant need for further clinical data.
Author contributions: Nathan Lawrentschuk had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Lawrentschuk, Perera, Papa.
Acquisition of data: Perera, Papa, Christidis, Wetherell.
Analysis and interpretation of data: Papa, Perera, Hofman.
Drafting of the manuscript: Perera, Papa, Hofman, Murphy, Bolton.
Critical revision of the manuscript for important intellectual content: Murphy, Bolton, Hofman, Lawrentschuk.
Statistical analysis: Papa.
Obtaining funding: None.
Administrative, technical, or material support: None.
Supervision: Bolton, Lawrentschuk, Murphy, Hofman.
Other: None.
Financial disclosures: Nathan Lawrentschuk certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None.
Funding/Support and role of the sponsor: None.
Acknowledgments: Marlon Perera is supported by a Royal Australasian College of Surgeons scholarship.
Prostate cancer is among the most prevalent cancers worldwide and is the third most common cause of cancer-associated mortality among men [1]
Prostate-specific membrane antigen (PSMA) is a transmembrane protein with a 707-amino-acid extracellular portion. The PSMA gene (FOLH1) is located on the short arm of chromosome 11. PSMA is expressed in the apical region of prostatic cells, the epithelium surrounding prostatic ducts [6]
To date, the use of 68Ga-PSMA has been well reported, with the compound Glu-NH-CO-NH-Lys-(Ahx)-[68Ga]-HBED (68Ga-PSMA-11) developed by the Heidelberg group in Germany. Initial series revealed superior sensitivity and specificity profiles compared to conventional choline-based tracers [19]
A systematic review was performed in accordance with Cochrane Collaboration and Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) guidelines [20]
Studies evaluating the utility of 68Ga-PSMA PET in detection of metastatic disease in advanced prostate cancer were included for analysis. Study designs considered for inclusion were clinical trials, prospective studies, and retrospective cohorts or comparative series. Studies assessing the diagnostic utility of 68Ga-PSMA PET in prostate cancer staging (before definitive treatment) or staging for recurrent disease (following therapy) were included for assessment. Studies were excluded if 68Ga-PSMA PET was used in assessing primary (prostatic) disease only or a specific visceral metastatic deposit (eg, pulmonary or cerebral metastases). In the current analysis, only studies using the 68Ga-PSMA-11 PSMA surface antigen HBED-CC (PSMA-11) were included for analysis provided the tracer was bound to 68Ga. Studies were excluded if alternative PSMA-bound radiotracers were used (eg, 18F or 99mTc tracers). No language or sample-size restrictions were used. Where duplicate study populations or analyses of repeated data were identified from the literature review, the publication reporting a larger sample size was used for analysis.
The primary outcome was to identify predictors of 68Ga-PSMA PET positivity. Studies that included only 68Ga-PSMA PET–positive studies were excluded, as predictive data were not available for analysis. The secondary outcome measure was the sensitivity and specificity of 68Ga-PSMA PET–positive lesions in advanced prostate cancer. For sensitivity and specificity analysis, only studies that included routine 68Ga-PSMA PET before preplanned lymph node dissection were included. Inclusion of series for which nodal biopsy was performed at the clinician's discretion does not provide meaningful false-negative data and thus does not provide accurate specificity values. An inadequate number of studies robustly assessed prostatic bed recurrence or suspicious bony metastatic disease in the manner outlined above. Therefore, we only assessed sensitivity and specificity values for 68Ga-PSMA PET in lymph nodes.
Studies were assessed for quality using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool [22]
The following information was extracted from each study: sample size, age, indication for PET (primary staging or recurrent disease staging), PSA, previous therapies, initial cancer stage, 68Ga-PSMA PET characteristics, rates of positive PET, and histopathologic correlation data. Rates of 68Ga-PSMA PET positivity were collected and stratified by pre-PET PSA and PSA doubling time (PSAdt) when possible. When histopathologic correlation data were available, numbers of true positives, false positives, true negatives, and false negatives were collected, as appropriate. For studies that included 68Ga-PSMA PET for both primary staging and recurrent cancer staging, the extracted data are displayed separately when available.
Extracted data were collated in Excel 2007 (Microsoft Corporation, Redmond, CA, USA) and analysis was performed using Stata v.12.0SE (College Station, TX, USA). Meta-analysis of proportions was performed using the metaprop command in Stata [23]
In patients undergoing a scan for disease recurrence, we performed a PSA level analysis. Note that for the cohort used by Afshar-Oromieh et al [14]
Random-effects meta-regression with Freeman-Tukey transformation was performed for study-defined PSA categories where the reference point was <2 ng/ml. We could not assign a valid reference point for categories greater than this as the reporting of PSA means, medians, and ranges was heterogeneous. Values were back-transformed using the equation described by Miller [26]
Summary sensitivity, specificity, and hierarchical receiver operating characteristic curves were created using the midas command [27]
Using the systematic search strategy outlined in the Supplementary material, 1895 articles were identified, of which 189 were duplicate records and excluded. Of the remaining 1706 records, 1470 were not relevant to the research question. A further 202 were conference abstracts, reviews, letters, and editorials that could not be quality assessed, and thus were excluded. From the remaining 34 articles, 11 were excluded as they did not contain relevant results and five contained duplicate data. One additional study was excluded as patients were enrolled following negative choline-based PET, and thus provided a skewed patient population [28]
Of the 16 studies relevant to the meta-analysis, one was prospective and 15 were retrospective in nature. Two studies included outcomes for 68Ga-PSMA PET performed before definitive therapy (primary staging), eight reported outcomes for biochemical recurrence or disease progression staging (secondary staging), and six included mixed groups. Basic details for the studies included are listed in Table 1.
Characteristics of the studies included
a The tracer used in all cases was 68Ga-PSMA-11.
b PET was used for 95 patients and magnetic resonance imaging for all 130 patients.
c Mean.
ADT = androgen deprivation therapy; ARTx = adjuvant radiotherapy; BCR = biochemical recurrence; CE = contrast-enhanced; CT = computerised tomography; CTx = chemotherapy; HIFU = high-intensity focused ultrasound; HR = high resolution;, LND = lymph node dissection, LNM = lymph node metastases; NCE = non–contrast-enhanced; NR = not reported; PCa = Prostate cancer; PET = positron emission tomography; PSMA = prostate-specific membrane antigen; RP = radical prostatectomy; RTx = primary radiotherapy; SRP = salvage prostatectomy.
While patient selection was generally acceptable in the studies included, a few studies did not clearly report the inclusion criteria. Furthermore, several studies included mixed patient populations including primary and secondary staging groups, raising concerns regarding applicability. All the studies clearly reported methodology for the index test and were thus not considered a significant source of potential bias. Of the studies included, 11 involved a reference test: histopathologic correlation of 68Ga-PSMA PET–positive lesions. However, in terms of flow and timing, multiple studies were at risk of bias, as many included targeted biopsies of suspicious lesions only. Such articles were excluded from sensitivity and specificity analyses because the false-negative data are not accurate. In total, five studies performed 68Ga-PSMA PET before planned lymph node sampling. Summary findings for the QUADAS-2 appraisal are illustrated in Figure 2.
(A) Appraisal of the quality of the studies included according to the Quality Assessment for Diagnostic Studies-2 (QUADAS-2) tool [22]
In total, we analysed 16 studies involving 1309 patients who underwent a 68Ga-PSMA PET scan, of which 926 (70.7%) were positive. In an overall meta-analysis by cohort type, 40% (95% CI 19–64%) of scans were positive for patients undergoing primary staging and 76% (95% CI 66–85%) for those undergoing secondary staging (Fig. 3). There was high heterogeneity between groups and within all subgroups (I2 > 70%). Egger's test for small-study effects did not reach significance (p > 0.10; Supplementary Figs. 1 and 2).
Forest plot of the proportion of 68Ga–prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET) positivity by patient cohort type. ES = effect size; CI = confidence interval. Reference numbers for the studies are as in Table 1.
In assessing disease recurrence, PSMA PET positivity increased with the PSA category (Fig. 4). For patients with PSA <0.2 ng/ml, the pooled estimate was 42%, which increased to 58%, 76%, and 95% for the 0.2–0.99, 1.00–1.99, and >2.00 ng/ml PSA subgroups, respectively. There was high heterogeneity within the <0.2 and 1.00–1.99 ng/ml subgroups and very high heterogeneity between subgroups (I2 = 97.4%); the test for small-study effects did not reach significance (Supplementary Fig. 3). In meta-regression analysis (Fig. 5), the predicted positivity was 48% (95% CI 38–57%) for PSA of 0.2 ng/ml, 56% (95% CI 49–64%) for 0.5 ng/ml, and 70% (95% CI 63–76%) for 1.0 ng/ml.
Forest plot of the proportion of 68Ga–prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET) positivity by PSA category. ES = effect size; CI = confidence interval. Reference numbers for the studies are as in Table 1.
Scatterplot of prostate specific antigen (PSA) level versus the proportion of 68Ga–prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET) positivity. The blue line is the meta-regression prediction and shading shows the 95% confidence interval. The size of the circles is related to the inverse of the variance.
A similar finding was observed for PSAdt: the pooled PSMA positivity was 64% for PSAdt ≥6 mo and 92% for PSAdt <6 mo (Fig. 6). There was high heterogeneity between the subgroups (I2 = 84.2%) and evidence of a small-study effect in the long PSAdt subgroup (Supplementary Fig. 4).
Forest plot of the proportion of 68Ga–prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET) positivity by prostate-specific antigen doubling time (PSA-dt) category. ES = effect size; CI = confidence interval.
As a sensitivity analysis, we excluded subpopulations with a sample size of less than ten and repeated the meta-analyses. This decreased the point estimate for 68Ga-PSMA PET positivity in the primary staging cohort to 27% (95% CI 15–42%). All other effects were negligible, with differences of ≤2% in the point estimates and CI boundaries for overall positivity and two PSA category proportions.
Of the studies included, 11 reported histopathologic correlation with 68Ga-PSMA PET; however, only five met the aforementioned inclusion criteria (summarised in Table 2). Of the five studies reporting the predictive ability of 68Ga-PSMA PET imaging with respect to histology-proven disease, per-patient and per-lesion analyses were possible for four studies each (Fig. 7). For per-lesion analysis, the summary sensitivity is 80% and specificity is 97%. For per-patient analysis, the summary sensitivity and specificity are both 86%, although the confidence intervals are especially wide because of the low patient numbers.
Studies with histopathologic correlation data for 68Ga PSMA PET–positive lesions included in pooled analysis
a Not included in the pooled analysis as data points did not meet the inclusion criteria.
HP = histopathology; LND = lymph node dissection; SS = sensitivity; SP = specificity.
68Ga-PSMA PET is a novel targeted imaging modality that may improve the identification of metastatic prostate cancer. Our meta-analysis results identified indication, PSA, and PSA-based kinetics as risk factors for positive imaging. Furthermore, pooled sensitivity and specificity for the available data appear promising compared to alternative imaging modalities for metastatic prostate cancer.
The current study highlights the growing body of evidence supporting the use of 68Ga-PSMA PET for primary staging. In this setting, groups have reported pooled positivity of 40%. Given that the risk of metastatic spread is unlikely in low-risk disease, a majority of the studies included patients with intermediate- and high-risk prostate cancer in accordance with the D’Amico classification [47]
To date, the majority of data outlining the utility of 68Ga-PSMA PET are in the setting of secondary staging for biochemical recurrence after definitive therapy. In clinical practice, early detection and highly accurate localisation of disease recurrence are critical, as these may facilitate initiation of subsequent therapies, such as radiotherapy [54]
Pooled data from the current study highlight the promising detection rates for 68Ga-PSMA PET in prostate cancer with low PSA or PSAdt. Despite advances in bone scintigraphy and CT imaging, detection of locoregional or distant recurrence with low PSA has been problematic. Therefore, most guidelines recommend imaging when patients are symptomatic or PSA levels are >10 ng/ml [4]
An increasing number of centres are reporting early outcomes for 68Ga-PSMA PET, particularly in Germany and Australia, with results for many series yet to be published [59]
There are several limitations to the current study. First, a majority of the series used for meta-analysis were derived from small, retrospective, single-institutional studies. In addition, the heterogeneous nature of the patient cohorts, treatment protocols, and study designs included represents a potential limitation of the data available for analysis. Second, of the studies used for pooled sensitivity and specificity data, the majority had a small sample size and assessed patients in the primary staging setting. Additional data in the future will undoubtedly be of benefit for such analyses.
The absence of accurate imaging for detection of small-volume metastases in advanced prostate cancer has prompted the introduction of 68Ga-PSMA PET. The results of the current study suggest that PSA and associated kinetics predict the risk of metastatic disease diagnosed by 68Ga-PSMA PET. This novel imaging modality appears to provide superior sensitivity and specificity compared to alternative techniques. These promising early results for 68Ga-PSMA PET indicate a significant need for further clinical data.
Author contributions: Nathan Lawrentschuk had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Lawrentschuk, Perera, Papa.
Acquisition of data: Perera, Papa, Christidis, Wetherell.
Analysis and interpretation of data: Papa, Perera, Hofman.
Drafting of the manuscript: Perera, Papa, Hofman, Murphy, Bolton.
Critical revision of the manuscript for important intellectual content: Murphy, Bolton, Hofman, Lawrentschuk.
Statistical analysis: Papa.
Obtaining funding: None.
Administrative, technical, or material support: None.
Supervision: Bolton, Lawrentschuk, Murphy, Hofman.
Other: None.
Financial disclosures: Nathan Lawrentschuk certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None.
Funding/Support and role of the sponsor: None.
Acknowledgments: Marlon Perera is supported by a Royal Australasian College of Surgeons scholarship.
Prostate cancer is among the most prevalent cancers worldwide and is the third most common cause of cancer-associated mortality among men [1]
Prostate-specific membrane antigen (PSMA) is a transmembrane protein with a 707-amino-acid extracellular portion. The PSMA gene (FOLH1) is located on the short arm of chromosome 11. PSMA is expressed in the apical region of prostatic cells, the epithelium surrounding prostatic ducts [6]
To date, the use of 68Ga-PSMA has been well reported, with the compound Glu-NH-CO-NH-Lys-(Ahx)-[68Ga]-HBED (68Ga-PSMA-11) developed by the Heidelberg group in Germany. Initial series revealed superior sensitivity and specificity profiles compared to conventional choline-based tracers [19]
A systematic review was performed in accordance with Cochrane Collaboration and Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) guidelines [20]
Studies evaluating the utility of 68Ga-PSMA PET in detection of metastatic disease in advanced prostate cancer were included for analysis. Study designs considered for inclusion were clinical trials, prospective studies, and retrospective cohorts or comparative series. Studies assessing the diagnostic utility of 68Ga-PSMA PET in prostate cancer staging (before definitive treatment) or staging for recurrent disease (following therapy) were included for assessment. Studies were excluded if 68Ga-PSMA PET was used in assessing primary (prostatic) disease only or a specific visceral metastatic deposit (eg, pulmonary or cerebral metastases). In the current analysis, only studies using the 68Ga-PSMA-11 PSMA surface antigen HBED-CC (PSMA-11) were included for analysis provided the tracer was bound to 68Ga. Studies were excluded if alternative PSMA-bound radiotracers were used (eg, 18F or 99mTc tracers). No language or sample-size restrictions were used. Where duplicate study populations or analyses of repeated data were identified from the literature review, the publication reporting a larger sample size was used for analysis.
The primary outcome was to identify predictors of 68Ga-PSMA PET positivity. Studies that included only 68Ga-PSMA PET–positive studies were excluded, as predictive data were not available for analysis. The secondary outcome measure was the sensitivity and specificity of 68Ga-PSMA PET–positive lesions in advanced prostate cancer. For sensitivity and specificity analysis, only studies that included routine 68Ga-PSMA PET before preplanned lymph node dissection were included. Inclusion of series for which nodal biopsy was performed at the clinician's discretion does not provide meaningful false-negative data and thus does not provide accurate specificity values. An inadequate number of studies robustly assessed prostatic bed recurrence or suspicious bony metastatic disease in the manner outlined above. Therefore, we only assessed sensitivity and specificity values for 68Ga-PSMA PET in lymph nodes.
Studies were assessed for quality using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool [22]
The following information was extracted from each study: sample size, age, indication for PET (primary staging or recurrent disease staging), PSA, previous therapies, initial cancer stage, 68Ga-PSMA PET characteristics, rates of positive PET, and histopathologic correlation data. Rates of 68Ga-PSMA PET positivity were collected and stratified by pre-PET PSA and PSA doubling time (PSAdt) when possible. When histopathologic correlation data were available, numbers of true positives, false positives, true negatives, and false negatives were collected, as appropriate. For studies that included 68Ga-PSMA PET for both primary staging and recurrent cancer staging, the extracted data are displayed separately when available.
Extracted data were collated in Excel 2007 (Microsoft Corporation, Redmond, CA, USA) and analysis was performed using Stata v.12.0SE (College Station, TX, USA). Meta-analysis of proportions was performed using the metaprop command in Stata [23]
In patients undergoing a scan for disease recurrence, we performed a PSA level analysis. Note that for the cohort used by Afshar-Oromieh et al [14]
Random-effects meta-regression with Freeman-Tukey transformation was performed for study-defined PSA categories where the reference point was <2 ng/ml. We could not assign a valid reference point for categories greater than this as the reporting of PSA means, medians, and ranges was heterogeneous. Values were back-transformed using the equation described by Miller [26]
Summary sensitivity, specificity, and hierarchical receiver operating characteristic curves were created using the midas command [27]
Using the systematic search strategy outlined in the Supplementary material, 1895 articles were identified, of which 189 were duplicate records and excluded. Of the remaining 1706 records, 1470 were not relevant to the research question. A further 202 were conference abstracts, reviews, letters, and editorials that could not be quality assessed, and thus were excluded. From the remaining 34 articles, 11 were excluded as they did not contain relevant results and five contained duplicate data. One additional study was excluded as patients were enrolled following negative choline-based PET, and thus provided a skewed patient population [28]
Of the 16 studies relevant to the meta-analysis, one was prospective and 15 were retrospective in nature. Two studies included outcomes for 68Ga-PSMA PET performed before definitive therapy (primary staging), eight reported outcomes for biochemical recurrence or disease progression staging (secondary staging), and six included mixed groups. Basic details for the studies included are listed in Table 1.
Characteristics of the studies included
a The tracer used in all cases was 68Ga-PSMA-11.
b PET was used for 95 patients and magnetic resonance imaging for all 130 patients.
c Mean.
ADT = androgen deprivation therapy; ARTx = adjuvant radiotherapy; BCR = biochemical recurrence; CE = contrast-enhanced; CT = computerised tomography; CTx = chemotherapy; HIFU = high-intensity focused ultrasound; HR = high resolution;, LND = lymph node dissection, LNM = lymph node metastases; NCE = non–contrast-enhanced; NR = not reported; PCa = Prostate cancer; PET = positron emission tomography; PSMA = prostate-specific membrane antigen; RP = radical prostatectomy; RTx = primary radiotherapy; SRP = salvage prostatectomy.
While patient selection was generally acceptable in the studies included, a few studies did not clearly report the inclusion criteria. Furthermore, several studies included mixed patient populations including primary and secondary staging groups, raising concerns regarding applicability. All the studies clearly reported methodology for the index test and were thus not considered a significant source of potential bias. Of the studies included, 11 involved a reference test: histopathologic correlation of 68Ga-PSMA PET–positive lesions. However, in terms of flow and timing, multiple studies were at risk of bias, as many included targeted biopsies of suspicious lesions only. Such articles were excluded from sensitivity and specificity analyses because the false-negative data are not accurate. In total, five studies performed 68Ga-PSMA PET before planned lymph node sampling. Summary findings for the QUADAS-2 appraisal are illustrated in Figure 2.
(A) Appraisal of the quality of the studies included according to the Quality Assessment for Diagnostic Studies-2 (QUADAS-2) tool [22]
In total, we analysed 16 studies involving 1309 patients who underwent a 68Ga-PSMA PET scan, of which 926 (70.7%) were positive. In an overall meta-analysis by cohort type, 40% (95% CI 19–64%) of scans were positive for patients undergoing primary staging and 76% (95% CI 66–85%) for those undergoing secondary staging (Fig. 3). There was high heterogeneity between groups and within all subgroups (I2 > 70%). Egger's test for small-study effects did not reach significance (p > 0.10; Supplementary Figs. 1 and 2).
Forest plot of the proportion of 68Ga–prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET) positivity by patient cohort type. ES = effect size; CI = confidence interval. Reference numbers for the studies are as in Table 1.
In assessing disease recurrence, PSMA PET positivity increased with the PSA category (Fig. 4). For patients with PSA <0.2 ng/ml, the pooled estimate was 42%, which increased to 58%, 76%, and 95% for the 0.2–0.99, 1.00–1.99, and >2.00 ng/ml PSA subgroups, respectively. There was high heterogeneity within the <0.2 and 1.00–1.99 ng/ml subgroups and very high heterogeneity between subgroups (I2 = 97.4%); the test for small-study effects did not reach significance (Supplementary Fig. 3). In meta-regression analysis (Fig. 5), the predicted positivity was 48% (95% CI 38–57%) for PSA of 0.2 ng/ml, 56% (95% CI 49–64%) for 0.5 ng/ml, and 70% (95% CI 63–76%) for 1.0 ng/ml.
Forest plot of the proportion of 68Ga–prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET) positivity by PSA category. ES = effect size; CI = confidence interval. Reference numbers for the studies are as in Table 1.
Scatterplot of prostate specific antigen (PSA) level versus the proportion of 68Ga–prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET) positivity. The blue line is the meta-regression prediction and shading shows the 95% confidence interval. The size of the circles is related to the inverse of the variance.
A similar finding was observed for PSAdt: the pooled PSMA positivity was 64% for PSAdt ≥6 mo and 92% for PSAdt <6 mo (Fig. 6). There was high heterogeneity between the subgroups (I2 = 84.2%) and evidence of a small-study effect in the long PSAdt subgroup (Supplementary Fig. 4).
Forest plot of the proportion of 68Ga–prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET) positivity by prostate-specific antigen doubling time (PSA-dt) category. ES = effect size; CI = confidence interval.
As a sensitivity analysis, we excluded subpopulations with a sample size of less than ten and repeated the meta-analyses. This decreased the point estimate for 68Ga-PSMA PET positivity in the primary staging cohort to 27% (95% CI 15–42%). All other effects were negligible, with differences of ≤2% in the point estimates and CI boundaries for overall positivity and two PSA category proportions.
Of the studies included, 11 reported histopathologic correlation with 68Ga-PSMA PET; however, only five met the aforementioned inclusion criteria (summarised in Table 2). Of the five studies reporting the predictive ability of 68Ga-PSMA PET imaging with respect to histology-proven disease, per-patient and per-lesion analyses were possible for four studies each (Fig. 7). For per-lesion analysis, the summary sensitivity is 80% and specificity is 97%. For per-patient analysis, the summary sensitivity and specificity are both 86%, although the confidence intervals are especially wide because of the low patient numbers.
Studies with histopathologic correlation data for 68Ga PSMA PET–positive lesions included in pooled analysis
a Not included in the pooled analysis as data points did not meet the inclusion criteria.
HP = histopathology; LND = lymph node dissection; SS = sensitivity; SP = specificity.
68Ga-PSMA PET is a novel targeted imaging modality that may improve the identification of metastatic prostate cancer. Our meta-analysis results identified indication, PSA, and PSA-based kinetics as risk factors for positive imaging. Furthermore, pooled sensitivity and specificity for the available data appear promising compared to alternative imaging modalities for metastatic prostate cancer.
The current study highlights the growing body of evidence supporting the use of 68Ga-PSMA PET for primary staging. In this setting, groups have reported pooled positivity of 40%. Given that the risk of metastatic spread is unlikely in low-risk disease, a majority of the studies included patients with intermediate- and high-risk prostate cancer in accordance with the D’Amico classification [47]
To date, the majority of data outlining the utility of 68Ga-PSMA PET are in the setting of secondary staging for biochemical recurrence after definitive therapy. In clinical practice, early detection and highly accurate localisation of disease recurrence are critical, as these may facilitate initiation of subsequent therapies, such as radiotherapy [54]
Pooled data from the current study highlight the promising detection rates for 68Ga-PSMA PET in prostate cancer with low PSA or PSAdt. Despite advances in bone scintigraphy and CT imaging, detection of locoregional or distant recurrence with low PSA has been problematic. Therefore, most guidelines recommend imaging when patients are symptomatic or PSA levels are >10 ng/ml [4]
An increasing number of centres are reporting early outcomes for 68Ga-PSMA PET, particularly in Germany and Australia, with results for many series yet to be published [59]
There are several limitations to the current study. First, a majority of the series used for meta-analysis were derived from small, retrospective, single-institutional studies. In addition, the heterogeneous nature of the patient cohorts, treatment protocols, and study designs included represents a potential limitation of the data available for analysis. Second, of the studies used for pooled sensitivity and specificity data, the majority had a small sample size and assessed patients in the primary staging setting. Additional data in the future will undoubtedly be of benefit for such analyses.
The absence of accurate imaging for detection of small-volume metastases in advanced prostate cancer has prompted the introduction of 68Ga-PSMA PET. The results of the current study suggest that PSA and associated kinetics predict the risk of metastatic disease diagnosed by 68Ga-PSMA PET. This novel imaging modality appears to provide superior sensitivity and specificity compared to alternative techniques. These promising early results for 68Ga-PSMA PET indicate a significant need for further clinical data.
Author contributions: Nathan Lawrentschuk had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Lawrentschuk, Perera, Papa.
Acquisition of data: Perera, Papa, Christidis, Wetherell.
Analysis and interpretation of data: Papa, Perera, Hofman.
Drafting of the manuscript: Perera, Papa, Hofman, Murphy, Bolton.
Critical revision of the manuscript for important intellectual content: Murphy, Bolton, Hofman, Lawrentschuk.
Statistical analysis: Papa.
Obtaining funding: None.
Administrative, technical, or material support: None.
Supervision: Bolton, Lawrentschuk, Murphy, Hofman.
Other: None.
Financial disclosures: Nathan Lawrentschuk certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None.
Funding/Support and role of the sponsor: None.
Acknowledgments: Marlon Perera is supported by a Royal Australasian College of Surgeons scholarship.
Prostate cancer is among the most prevalent cancers worldwide and is the third most common cause of cancer-associated mortality among men [1]
Prostate-specific membrane antigen (PSMA) is a transmembrane protein with a 707-amino-acid extracellular portion. The PSMA gene (FOLH1) is located on the short arm of chromosome 11. PSMA is expressed in the apical region of prostatic cells, the epithelium surrounding prostatic ducts [6]
To date, the use of 68Ga-PSMA has been well reported, with the compound Glu-NH-CO-NH-Lys-(Ahx)-[68Ga]-HBED (68Ga-PSMA-11) developed by the Heidelberg group in Germany. Initial series revealed superior sensitivity and specificity profiles compared to conventional choline-based tracers [19]
A systematic review was performed in accordance with Cochrane Collaboration and Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) guidelines [20]
Studies evaluating the utility of 68Ga-PSMA PET in detection of metastatic disease in advanced prostate cancer were included for analysis. Study designs considered for inclusion were clinical trials, prospective studies, and retrospective cohorts or comparative series. Studies assessing the diagnostic utility of 68Ga-PSMA PET in prostate cancer staging (before definitive treatment) or staging for recurrent disease (following therapy) were included for assessment. Studies were excluded if 68Ga-PSMA PET was used in assessing primary (prostatic) disease only or a specific visceral metastatic deposit (eg, pulmonary or cerebral metastases). In the current analysis, only studies using the 68Ga-PSMA-11 PSMA surface antigen HBED-CC (PSMA-11) were included for analysis provided the tracer was bound to 68Ga. Studies were excluded if alternative PSMA-bound radiotracers were used (eg, 18F or 99mTc tracers). No language or sample-size restrictions were used. Where duplicate study populations or analyses of repeated data were identified from the literature review, the publication reporting a larger sample size was used for analysis.
The primary outcome was to identify predictors of 68Ga-PSMA PET positivity. Studies that included only 68Ga-PSMA PET–positive studies were excluded, as predictive data were not available for analysis. The secondary outcome measure was the sensitivity and specificity of 68Ga-PSMA PET–positive lesions in advanced prostate cancer. For sensitivity and specificity analysis, only studies that included routine 68Ga-PSMA PET before preplanned lymph node dissection were included. Inclusion of series for which nodal biopsy was performed at the clinician's discretion does not provide meaningful false-negative data and thus does not provide accurate specificity values. An inadequate number of studies robustly assessed prostatic bed recurrence or suspicious bony metastatic disease in the manner outlined above. Therefore, we only assessed sensitivity and specificity values for 68Ga-PSMA PET in lymph nodes.
Studies were assessed for quality using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool [22]
The following information was extracted from each study: sample size, age, indication for PET (primary staging or recurrent disease staging), PSA, previous therapies, initial cancer stage, 68Ga-PSMA PET characteristics, rates of positive PET, and histopathologic correlation data. Rates of 68Ga-PSMA PET positivity were collected and stratified by pre-PET PSA and PSA doubling time (PSAdt) when possible. When histopathologic correlation data were available, numbers of true positives, false positives, true negatives, and false negatives were collected, as appropriate. For studies that included 68Ga-PSMA PET for both primary staging and recurrent cancer staging, the extracted data are displayed separately when available.
Extracted data were collated in Excel 2007 (Microsoft Corporation, Redmond, CA, USA) and analysis was performed using Stata v.12.0SE (College Station, TX, USA). Meta-analysis of proportions was performed using the metaprop command in Stata [23]
In patients undergoing a scan for disease recurrence, we performed a PSA level analysis. Note that for the cohort used by Afshar-Oromieh et al [14]
Random-effects meta-regression with Freeman-Tukey transformation was performed for study-defined PSA categories where the reference point was <2 ng/ml. We could not assign a valid reference point for categories greater than this as the reporting of PSA means, medians, and ranges was heterogeneous. Values were back-transformed using the equation described by Miller [26]
Summary sensitivity, specificity, and hierarchical receiver operating characteristic curves were created using the midas command [27]
Using the systematic search strategy outlined in the Supplementary material, 1895 articles were identified, of which 189 were duplicate records and excluded. Of the remaining 1706 records, 1470 were not relevant to the research question. A further 202 were conference abstracts, reviews, letters, and editorials that could not be quality assessed, and thus were excluded. From the remaining 34 articles, 11 were excluded as they did not contain relevant results and five contained duplicate data. One additional study was excluded as patients were enrolled following negative choline-based PET, and thus provided a skewed patient population [28]
Of the 16 studies relevant to the meta-analysis, one was prospective and 15 were retrospective in nature. Two studies included outcomes for 68Ga-PSMA PET performed before definitive therapy (primary staging), eight reported outcomes for biochemical recurrence or disease progression staging (secondary staging), and six included mixed groups. Basic details for the studies included are listed in Table 1.
Characteristics of the studies included
a The tracer used in all cases was 68Ga-PSMA-11.
b PET was used for 95 patients and magnetic resonance imaging for all 130 patients.
c Mean.
ADT = androgen deprivation therapy; ARTx = adjuvant radiotherapy; BCR = biochemical recurrence; CE = contrast-enhanced; CT = computerised tomography; CTx = chemotherapy; HIFU = high-intensity focused ultrasound; HR = high resolution;, LND = lymph node dissection, LNM = lymph node metastases; NCE = non–contrast-enhanced; NR = not reported; PCa = Prostate cancer; PET = positron emission tomography; PSMA = prostate-specific membrane antigen; RP = radical prostatectomy; RTx = primary radiotherapy; SRP = salvage prostatectomy.
While patient selection was generally acceptable in the studies included, a few studies did not clearly report the inclusion criteria. Furthermore, several studies included mixed patient populations including primary and secondary staging groups, raising concerns regarding applicability. All the studies clearly reported methodology for the index test and were thus not considered a significant source of potential bias. Of the studies included, 11 involved a reference test: histopathologic correlation of 68Ga-PSMA PET–positive lesions. However, in terms of flow and timing, multiple studies were at risk of bias, as many included targeted biopsies of suspicious lesions only. Such articles were excluded from sensitivity and specificity analyses because the false-negative data are not accurate. In total, five studies performed 68Ga-PSMA PET before planned lymph node sampling. Summary findings for the QUADAS-2 appraisal are illustrated in Figure 2.
(A) Appraisal of the quality of the studies included according to the Quality Assessment for Diagnostic Studies-2 (QUADAS-2) tool [22]
In total, we analysed 16 studies involving 1309 patients who underwent a 68Ga-PSMA PET scan, of which 926 (70.7%) were positive. In an overall meta-analysis by cohort type, 40% (95% CI 19–64%) of scans were positive for patients undergoing primary staging and 76% (95% CI 66–85%) for those undergoing secondary staging (Fig. 3). There was high heterogeneity between groups and within all subgroups (I2 > 70%). Egger's test for small-study effects did not reach significance (p > 0.10; Supplementary Figs. 1 and 2).
Forest plot of the proportion of 68Ga–prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET) positivity by patient cohort type. ES = effect size; CI = confidence interval. Reference numbers for the studies are as in Table 1.
In assessing disease recurrence, PSMA PET positivity increased with the PSA category (Fig. 4). For patients with PSA <0.2 ng/ml, the pooled estimate was 42%, which increased to 58%, 76%, and 95% for the 0.2–0.99, 1.00–1.99, and >2.00 ng/ml PSA subgroups, respectively. There was high heterogeneity within the <0.2 and 1.00–1.99 ng/ml subgroups and very high heterogeneity between subgroups (I2 = 97.4%); the test for small-study effects did not reach significance (Supplementary Fig. 3). In meta-regression analysis (Fig. 5), the predicted positivity was 48% (95% CI 38–57%) for PSA of 0.2 ng/ml, 56% (95% CI 49–64%) for 0.5 ng/ml, and 70% (95% CI 63–76%) for 1.0 ng/ml.
Forest plot of the proportion of 68Ga–prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET) positivity by PSA category. ES = effect size; CI = confidence interval. Reference numbers for the studies are as in Table 1.
Scatterplot of prostate specific antigen (PSA) level versus the proportion of 68Ga–prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET) positivity. The blue line is the meta-regression prediction and shading shows the 95% confidence interval. The size of the circles is related to the inverse of the variance.
A similar finding was observed for PSAdt: the pooled PSMA positivity was 64% for PSAdt ≥6 mo and 92% for PSAdt <6 mo (Fig. 6). There was high heterogeneity between the subgroups (I2 = 84.2%) and evidence of a small-study effect in the long PSAdt subgroup (Supplementary Fig. 4).
Forest plot of the proportion of 68Ga–prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET) positivity by prostate-specific antigen doubling time (PSA-dt) category. ES = effect size; CI = confidence interval.
As a sensitivity analysis, we excluded subpopulations with a sample size of less than ten and repeated the meta-analyses. This decreased the point estimate for 68Ga-PSMA PET positivity in the primary staging cohort to 27% (95% CI 15–42%). All other effects were negligible, with differences of ≤2% in the point estimates and CI boundaries for overall positivity and two PSA category proportions.
Of the studies included, 11 reported histopathologic correlation with 68Ga-PSMA PET; however, only five met the aforementioned inclusion criteria (summarised in Table 2). Of the five studies reporting the predictive ability of 68Ga-PSMA PET imaging with respect to histology-proven disease, per-patient and per-lesion analyses were possible for four studies each (Fig. 7). For per-lesion analysis, the summary sensitivity is 80% and specificity is 97%. For per-patient analysis, the summary sensitivity and specificity are both 86%, although the confidence intervals are especially wide because of the low patient numbers.
Studies with histopathologic correlation data for 68Ga PSMA PET–positive lesions included in pooled analysis
a Not included in the pooled analysis as data points did not meet the inclusion criteria.
HP = histopathology; LND = lymph node dissection; SS = sensitivity; SP = specificity.
68Ga-PSMA PET is a novel targeted imaging modality that may improve the identification of metastatic prostate cancer. Our meta-analysis results identified indication, PSA, and PSA-based kinetics as risk factors for positive imaging. Furthermore, pooled sensitivity and specificity for the available data appear promising compared to alternative imaging modalities for metastatic prostate cancer.
The current study highlights the growing body of evidence supporting the use of 68Ga-PSMA PET for primary staging. In this setting, groups have reported pooled positivity of 40%. Given that the risk of metastatic spread is unlikely in low-risk disease, a majority of the studies included patients with intermediate- and high-risk prostate cancer in accordance with the D’Amico classification [47]
To date, the majority of data outlining the utility of 68Ga-PSMA PET are in the setting of secondary staging for biochemical recurrence after definitive therapy. In clinical practice, early detection and highly accurate localisation of disease recurrence are critical, as these may facilitate initiation of subsequent therapies, such as radiotherapy [54]
Pooled data from the current study highlight the promising detection rates for 68Ga-PSMA PET in prostate cancer with low PSA or PSAdt. Despite advances in bone scintigraphy and CT imaging, detection of locoregional or distant recurrence with low PSA has been problematic. Therefore, most guidelines recommend imaging when patients are symptomatic or PSA levels are >10 ng/ml [4]
An increasing number of centres are reporting early outcomes for 68Ga-PSMA PET, particularly in Germany and Australia, with results for many series yet to be published [59]
There are several limitations to the current study. First, a majority of the series used for meta-analysis were derived from small, retrospective, single-institutional studies. In addition, the heterogeneous nature of the patient cohorts, treatment protocols, and study designs included represents a potential limitation of the data available for analysis. Second, of the studies used for pooled sensitivity and specificity data, the majority had a small sample size and assessed patients in the primary staging setting. Additional data in the future will undoubtedly be of benefit for such analyses.
The absence of accurate imaging for detection of small-volume metastases in advanced prostate cancer has prompted the introduction of 68Ga-PSMA PET. The results of the current study suggest that PSA and associated kinetics predict the risk of metastatic disease diagnosed by 68Ga-PSMA PET. This novel imaging modality appears to provide superior sensitivity and specificity compared to alternative techniques. These promising early results for 68Ga-PSMA PET indicate a significant need for further clinical data.
Author contributions: Nathan Lawrentschuk had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Lawrentschuk, Perera, Papa.
Acquisition of data: Perera, Papa, Christidis, Wetherell.
Analysis and interpretation of data: Papa, Perera, Hofman.
Drafting of the manuscript: Perera, Papa, Hofman, Murphy, Bolton.
Critical revision of the manuscript for important intellectual content: Murphy, Bolton, Hofman, Lawrentschuk.
Statistical analysis: Papa.
Obtaining funding: None.
Administrative, technical, or material support: None.
Supervision: Bolton, Lawrentschuk, Murphy, Hofman.
Other: None.
Financial disclosures: Nathan Lawrentschuk certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None.
Funding/Support and role of the sponsor: None.
Acknowledgments: Marlon Perera is supported by a Royal Australasian College of Surgeons scholarship.
Prostate cancer is among the most prevalent cancers worldwide and is the third most common cause of cancer-associated mortality among men [1]
Prostate-specific membrane antigen (PSMA) is a transmembrane protein with a 707-amino-acid extracellular portion. The PSMA gene (FOLH1) is located on the short arm of chromosome 11. PSMA is expressed in the apical region of prostatic cells, the epithelium surrounding prostatic ducts [6]
To date, the use of 68Ga-PSMA has been well reported, with the compound Glu-NH-CO-NH-Lys-(Ahx)-[68Ga]-HBED (68Ga-PSMA-11) developed by the Heidelberg group in Germany. Initial series revealed superior sensitivity and specificity profiles compared to conventional choline-based tracers [19]
A systematic review was performed in accordance with Cochrane Collaboration and Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) guidelines [20]
Studies evaluating the utility of 68Ga-PSMA PET in detection of metastatic disease in advanced prostate cancer were included for analysis. Study designs considered for inclusion were clinical trials, prospective studies, and retrospective cohorts or comparative series. Studies assessing the diagnostic utility of 68Ga-PSMA PET in prostate cancer staging (before definitive treatment) or staging for recurrent disease (following therapy) were included for assessment. Studies were excluded if 68Ga-PSMA PET was used in assessing primary (prostatic) disease only or a specific visceral metastatic deposit (eg, pulmonary or cerebral metastases). In the current analysis, only studies using the 68Ga-PSMA-11 PSMA surface antigen HBED-CC (PSMA-11) were included for analysis provided the tracer was bound to 68Ga. Studies were excluded if alternative PSMA-bound radiotracers were used (eg, 18F or 99mTc tracers). No language or sample-size restrictions were used. Where duplicate study populations or analyses of repeated data were identified from the literature review, the publication reporting a larger sample size was used for analysis.
The primary outcome was to identify predictors of 68Ga-PSMA PET positivity. Studies that included only 68Ga-PSMA PET–positive studies were excluded, as predictive data were not available for analysis. The secondary outcome measure was the sensitivity and specificity of 68Ga-PSMA PET–positive lesions in advanced prostate cancer. For sensitivity and specificity analysis, only studies that included routine 68Ga-PSMA PET before preplanned lymph node dissection were included. Inclusion of series for which nodal biopsy was performed at the clinician's discretion does not provide meaningful false-negative data and thus does not provide accurate specificity values. An inadequate number of studies robustly assessed prostatic bed recurrence or suspicious bony metastatic disease in the manner outlined above. Therefore, we only assessed sensitivity and specificity values for 68Ga-PSMA PET in lymph nodes.
Studies were assessed for quality using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool [22]
The following information was extracted from each study: sample size, age, indication for PET (primary staging or recurrent disease staging), PSA, previous therapies, initial cancer stage, 68Ga-PSMA PET characteristics, rates of positive PET, and histopathologic correlation data. Rates of 68Ga-PSMA PET positivity were collected and stratified by pre-PET PSA and PSA doubling time (PSAdt) when possible. When histopathologic correlation data were available, numbers of true positives, false positives, true negatives, and false negatives were collected, as appropriate. For studies that included 68Ga-PSMA PET for both primary staging and recurrent cancer staging, the extracted data are displayed separately when available.
Extracted data were collated in Excel 2007 (Microsoft Corporation, Redmond, CA, USA) and analysis was performed using Stata v.12.0SE (College Station, TX, USA). Meta-analysis of proportions was performed using the metaprop command in Stata [23]
In patients undergoing a scan for disease recurrence, we performed a PSA level analysis. Note that for the cohort used by Afshar-Oromieh et al [14]
Random-effects meta-regression with Freeman-Tukey transformation was performed for study-defined PSA categories where the reference point was <2 ng/ml. We could not assign a valid reference point for categories greater than this as the reporting of PSA means, medians, and ranges was heterogeneous. Values were back-transformed using the equation described by Miller [26]
Summary sensitivity, specificity, and hierarchical receiver operating characteristic curves were created using the midas command [27]
Using the systematic search strategy outlined in the Supplementary material, 1895 articles were identified, of which 189 were duplicate records and excluded. Of the remaining 1706 records, 1470 were not relevant to the research question. A further 202 were conference abstracts, reviews, letters, and editorials that could not be quality assessed, and thus were excluded. From the remaining 34 articles, 11 were excluded as they did not contain relevant results and five contained duplicate data. One additional study was excluded as patients were enrolled following negative choline-based PET, and thus provided a skewed patient population [28]
Of the 16 studies relevant to the meta-analysis, one was prospective and 15 were retrospective in nature. Two studies included outcomes for 68Ga-PSMA PET performed before definitive therapy (primary staging), eight reported outcomes for biochemical recurrence or disease progression staging (secondary staging), and six included mixed groups. Basic details for the studies included are listed in Table 1.
Characteristics of the studies included
a The tracer used in all cases was 68Ga-PSMA-11.
b PET was used for 95 patients and magnetic resonance imaging for all 130 patients.
c Mean.
ADT = androgen deprivation therapy; ARTx = adjuvant radiotherapy; BCR = biochemical recurrence; CE = contrast-enhanced; CT = computerised tomography; CTx = chemotherapy; HIFU = high-intensity focused ultrasound; HR = high resolution;, LND = lymph node dissection, LNM = lymph node metastases; NCE = non–contrast-enhanced; NR = not reported; PCa = Prostate cancer; PET = positron emission tomography; PSMA = prostate-specific membrane antigen; RP = radical prostatectomy; RTx = primary radiotherapy; SRP = salvage prostatectomy.
While patient selection was generally acceptable in the studies included, a few studies did not clearly report the inclusion criteria. Furthermore, several studies included mixed patient populations including primary and secondary staging groups, raising concerns regarding applicability. All the studies clearly reported methodology for the index test and were thus not considered a significant source of potential bias. Of the studies included, 11 involved a reference test: histopathologic correlation of 68Ga-PSMA PET–positive lesions. However, in terms of flow and timing, multiple studies were at risk of bias, as many included targeted biopsies of suspicious lesions only. Such articles were excluded from sensitivity and specificity analyses because the false-negative data are not accurate. In total, five studies performed 68Ga-PSMA PET before planned lymph node sampling. Summary findings for the QUADAS-2 appraisal are illustrated in Figure 2.
(A) Appraisal of the quality of the studies included according to the Quality Assessment for Diagnostic Studies-2 (QUADAS-2) tool [22]
In total, we analysed 16 studies involving 1309 patients who underwent a 68Ga-PSMA PET scan, of which 926 (70.7%) were positive. In an overall meta-analysis by cohort type, 40% (95% CI 19–64%) of scans were positive for patients undergoing primary staging and 76% (95% CI 66–85%) for those undergoing secondary staging (Fig. 3). There was high heterogeneity between groups and within all subgroups (I2 > 70%). Egger's test for small-study effects did not reach significance (p > 0.10; Supplementary Figs. 1 and 2).
Forest plot of the proportion of 68Ga–prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET) positivity by patient cohort type. ES = effect size; CI = confidence interval. Reference numbers for the studies are as in Table 1.
In assessing disease recurrence, PSMA PET positivity increased with the PSA category (Fig. 4). For patients with PSA <0.2 ng/ml, the pooled estimate was 42%, which increased to 58%, 76%, and 95% for the 0.2–0.99, 1.00–1.99, and >2.00 ng/ml PSA subgroups, respectively. There was high heterogeneity within the <0.2 and 1.00–1.99 ng/ml subgroups and very high heterogeneity between subgroups (I2 = 97.4%); the test for small-study effects did not reach significance (Supplementary Fig. 3). In meta-regression analysis (Fig. 5), the predicted positivity was 48% (95% CI 38–57%) for PSA of 0.2 ng/ml, 56% (95% CI 49–64%) for 0.5 ng/ml, and 70% (95% CI 63–76%) for 1.0 ng/ml.
Forest plot of the proportion of 68Ga–prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET) positivity by PSA category. ES = effect size; CI = confidence interval. Reference numbers for the studies are as in Table 1.
Scatterplot of prostate specific antigen (PSA) level versus the proportion of 68Ga–prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET) positivity. The blue line is the meta-regression prediction and shading shows the 95% confidence interval. The size of the circles is related to the inverse of the variance.
A similar finding was observed for PSAdt: the pooled PSMA positivity was 64% for PSAdt ≥6 mo and 92% for PSAdt <6 mo (Fig. 6). There was high heterogeneity between the subgroups (I2 = 84.2%) and evidence of a small-study effect in the long PSAdt subgroup (Supplementary Fig. 4).
Forest plot of the proportion of 68Ga–prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET) positivity by prostate-specific antigen doubling time (PSA-dt) category. ES = effect size; CI = confidence interval.
As a sensitivity analysis, we excluded subpopulations with a sample size of less than ten and repeated the meta-analyses. This decreased the point estimate for 68Ga-PSMA PET positivity in the primary staging cohort to 27% (95% CI 15–42%). All other effects were negligible, with differences of ≤2% in the point estimates and CI boundaries for overall positivity and two PSA category proportions.
Of the studies included, 11 reported histopathologic correlation with 68Ga-PSMA PET; however, only five met the aforementioned inclusion criteria (summarised in Table 2). Of the five studies reporting the predictive ability of 68Ga-PSMA PET imaging with respect to histology-proven disease, per-patient and per-lesion analyses were possible for four studies each (Fig. 7). For per-lesion analysis, the summary sensitivity is 80% and specificity is 97%. For per-patient analysis, the summary sensitivity and specificity are both 86%, although the confidence intervals are especially wide because of the low patient numbers.
Studies with histopathologic correlation data for 68Ga PSMA PET–positive lesions included in pooled analysis
a Not included in the pooled analysis as data points did not meet the inclusion criteria.
HP = histopathology; LND = lymph node dissection; SS = sensitivity; SP = specificity.
68Ga-PSMA PET is a novel targeted imaging modality that may improve the identification of metastatic prostate cancer. Our meta-analysis results identified indication, PSA, and PSA-based kinetics as risk factors for positive imaging. Furthermore, pooled sensitivity and specificity for the available data appear promising compared to alternative imaging modalities for metastatic prostate cancer.
The current study highlights the growing body of evidence supporting the use of 68Ga-PSMA PET for primary staging. In this setting, groups have reported pooled positivity of 40%. Given that the risk of metastatic spread is unlikely in low-risk disease, a majority of the studies included patients with intermediate- and high-risk prostate cancer in accordance with the D’Amico classification [47]
To date, the majority of data outlining the utility of 68Ga-PSMA PET are in the setting of secondary staging for biochemical recurrence after definitive therapy. In clinical practice, early detection and highly accurate localisation of disease recurrence are critical, as these may facilitate initiation of subsequent therapies, such as radiotherapy [54]
Pooled data from the current study highlight the promising detection rates for 68Ga-PSMA PET in prostate cancer with low PSA or PSAdt. Despite advances in bone scintigraphy and CT imaging, detection of locoregional or distant recurrence with low PSA has been problematic. Therefore, most guidelines recommend imaging when patients are symptomatic or PSA levels are >10 ng/ml [4]
An increasing number of centres are reporting early outcomes for 68Ga-PSMA PET, particularly in Germany and Australia, with results for many series yet to be published [59]
There are several limitations to the current study. First, a majority of the series used for meta-analysis were derived from small, retrospective, single-institutional studies. In addition, the heterogeneous nature of the patient cohorts, treatment protocols, and study designs included represents a potential limitation of the data available for analysis. Second, of the studies used for pooled sensitivity and specificity data, the majority had a small sample size and assessed patients in the primary staging setting. Additional data in the future will undoubtedly be of benefit for such analyses.
The absence of accurate imaging for detection of small-volume metastases in advanced prostate cancer has prompted the introduction of 68Ga-PSMA PET. The results of the current study suggest that PSA and associated kinetics predict the risk of metastatic disease diagnosed by 68Ga-PSMA PET. This novel imaging modality appears to provide superior sensitivity and specificity compared to alternative techniques. These promising early results for 68Ga-PSMA PET indicate a significant need for further clinical data.
Author contributions: Nathan Lawrentschuk had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Lawrentschuk, Perera, Papa.
Acquisition of data: Perera, Papa, Christidis, Wetherell.
Analysis and interpretation of data: Papa, Perera, Hofman.
Drafting of the manuscript: Perera, Papa, Hofman, Murphy, Bolton.
Critical revision of the manuscript for important intellectual content: Murphy, Bolton, Hofman, Lawrentschuk.
Statistical analysis: Papa.
Obtaining funding: None.
Administrative, technical, or material support: None.
Supervision: Bolton, Lawrentschuk, Murphy, Hofman.
Other: None.
Financial disclosures: Nathan Lawrentschuk certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None.
Funding/Support and role of the sponsor: None.
Acknowledgments: Marlon Perera is supported by a Royal Australasian College of Surgeons scholarship.
Prostate cancer is among the most prevalent cancers worldwide and is the third most common cause of cancer-associated mortality among men [1]
Prostate-specific membrane antigen (PSMA) is a transmembrane protein with a 707-amino-acid extracellular portion. The PSMA gene (FOLH1) is located on the short arm of chromosome 11. PSMA is expressed in the apical region of prostatic cells, the epithelium surrounding prostatic ducts [6]
To date, the use of 68Ga-PSMA has been well reported, with the compound Glu-NH-CO-NH-Lys-(Ahx)-[68Ga]-HBED (68Ga-PSMA-11) developed by the Heidelberg group in Germany. Initial series revealed superior sensitivity and specificity profiles compared to conventional choline-based tracers [19]
A systematic review was performed in accordance with Cochrane Collaboration and Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) guidelines [20]
Studies evaluating the utility of 68Ga-PSMA PET in detection of metastatic disease in advanced prostate cancer were included for analysis. Study designs considered for inclusion were clinical trials, prospective studies, and retrospective cohorts or comparative series. Studies assessing the diagnostic utility of 68Ga-PSMA PET in prostate cancer staging (before definitive treatment) or staging for recurrent disease (following therapy) were included for assessment. Studies were excluded if 68Ga-PSMA PET was used in assessing primary (prostatic) disease only or a specific visceral metastatic deposit (eg, pulmonary or cerebral metastases). In the current analysis, only studies using the 68Ga-PSMA-11 PSMA surface antigen HBED-CC (PSMA-11) were included for analysis provided the tracer was bound to 68Ga. Studies were excluded if alternative PSMA-bound radiotracers were used (eg, 18F or 99mTc tracers). No language or sample-size restrictions were used. Where duplicate study populations or analyses of repeated data were identified from the literature review, the publication reporting a larger sample size was used for analysis.
The primary outcome was to identify predictors of 68Ga-PSMA PET positivity. Studies that included only 68Ga-PSMA PET–positive studies were excluded, as predictive data were not available for analysis. The secondary outcome measure was the sensitivity and specificity of 68Ga-PSMA PET–positive lesions in advanced prostate cancer. For sensitivity and specificity analysis, only studies that included routine 68Ga-PSMA PET before preplanned lymph node dissection were included. Inclusion of series for which nodal biopsy was performed at the clinician's discretion does not provide meaningful false-negative data and thus does not provide accurate specificity values. An inadequate number of studies robustly assessed prostatic bed recurrence or suspicious bony metastatic disease in the manner outlined above. Therefore, we only assessed sensitivity and specificity values for 68Ga-PSMA PET in lymph nodes.
Studies were assessed for quality using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool [22]
The following information was extracted from each study: sample size, age, indication for PET (primary staging or recurrent disease staging), PSA, previous therapies, initial cancer stage, 68Ga-PSMA PET characteristics, rates of positive PET, and histopathologic correlation data. Rates of 68Ga-PSMA PET positivity were collected and stratified by pre-PET PSA and PSA doubling time (PSAdt) when possible. When histopathologic correlation data were available, numbers of true positives, false positives, true negatives, and false negatives were collected, as appropriate. For studies that included 68Ga-PSMA PET for both primary staging and recurrent cancer staging, the extracted data are displayed separately when available.
Extracted data were collated in Excel 2007 (Microsoft Corporation, Redmond, CA, USA) and analysis was performed using Stata v.12.0SE (College Station, TX, USA). Meta-analysis of proportions was performed using the metaprop command in Stata [23]
In patients undergoing a scan for disease recurrence, we performed a PSA level analysis. Note that for the cohort used by Afshar-Oromieh et al [14]
Random-effects meta-regression with Freeman-Tukey transformation was performed for study-defined PSA categories where the reference point was <2 ng/ml. We could not assign a valid reference point for categories greater than this as the reporting of PSA means, medians, and ranges was heterogeneous. Values were back-transformed using the equation described by Miller [26]
Summary sensitivity, specificity, and hierarchical receiver operating characteristic curves were created using the midas command [27]
Using the systematic search strategy outlined in the Supplementary material, 1895 articles were identified, of which 189 were duplicate records and excluded. Of the remaining 1706 records, 1470 were not relevant to the research question. A further 202 were conference abstracts, reviews, letters, and editorials that could not be quality assessed, and thus were excluded. From the remaining 34 articles, 11 were excluded as they did not contain relevant results and five contained duplicate data. One additional study was excluded as patients were enrolled following negative choline-based PET, and thus provided a skewed patient population [28]
Of the 16 studies relevant to the meta-analysis, one was prospective and 15 were retrospective in nature. Two studies included outcomes for 68Ga-PSMA PET performed before definitive therapy (primary staging), eight reported outcomes for biochemical recurrence or disease progression staging (secondary staging), and six included mixed groups. Basic details for the studies included are listed in Table 1.
Characteristics of the studies included
a The tracer used in all cases was 68Ga-PSMA-11.
b PET was used for 95 patients and magnetic resonance imaging for all 130 patients.
c Mean.
ADT = androgen deprivation therapy; ARTx = adjuvant radiotherapy; BCR = biochemical recurrence; CE = contrast-enhanced; CT = computerised tomography; CTx = chemotherapy; HIFU = high-intensity focused ultrasound; HR = high resolution;, LND = lymph node dissection, LNM = lymph node metastases; NCE = non–contrast-enhanced; NR = not reported; PCa = Prostate cancer; PET = positron emission tomography; PSMA = prostate-specific membrane antigen; RP = radical prostatectomy; RTx = primary radiotherapy; SRP = salvage prostatectomy.
While patient selection was generally acceptable in the studies included, a few studies did not clearly report the inclusion criteria. Furthermore, several studies included mixed patient populations including primary and secondary staging groups, raising concerns regarding applicability. All the studies clearly reported methodology for the index test and were thus not considered a significant source of potential bias. Of the studies included, 11 involved a reference test: histopathologic correlation of 68Ga-PSMA PET–positive lesions. However, in terms of flow and timing, multiple studies were at risk of bias, as many included targeted biopsies of suspicious lesions only. Such articles were excluded from sensitivity and specificity analyses because the false-negative data are not accurate. In total, five studies performed 68Ga-PSMA PET before planned lymph node sampling. Summary findings for the QUADAS-2 appraisal are illustrated in Figure 2.
(A) Appraisal of the quality of the studies included according to the Quality Assessment for Diagnostic Studies-2 (QUADAS-2) tool [22]
In total, we analysed 16 studies involving 1309 patients who underwent a 68Ga-PSMA PET scan, of which 926 (70.7%) were positive. In an overall meta-analysis by cohort type, 40% (95% CI 19–64%) of scans were positive for patients undergoing primary staging and 76% (95% CI 66–85%) for those undergoing secondary staging (Fig. 3). There was high heterogeneity between groups and within all subgroups (I2 > 70%). Egger's test for small-study effects did not reach significance (p > 0.10; Supplementary Figs. 1 and 2).
Forest plot of the proportion of 68Ga–prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET) positivity by patient cohort type. ES = effect size; CI = confidence interval. Reference numbers for the studies are as in Table 1.
In assessing disease recurrence, PSMA PET positivity increased with the PSA category (Fig. 4). For patients with PSA <0.2 ng/ml, the pooled estimate was 42%, which increased to 58%, 76%, and 95% for the 0.2–0.99, 1.00–1.99, and >2.00 ng/ml PSA subgroups, respectively. There was high heterogeneity within the <0.2 and 1.00–1.99 ng/ml subgroups and very high heterogeneity between subgroups (I2 = 97.4%); the test for small-study effects did not reach significance (Supplementary Fig. 3). In meta-regression analysis (Fig. 5), the predicted positivity was 48% (95% CI 38–57%) for PSA of 0.2 ng/ml, 56% (95% CI 49–64%) for 0.5 ng/ml, and 70% (95% CI 63–76%) for 1.0 ng/ml.
Forest plot of the proportion of 68Ga–prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET) positivity by PSA category. ES = effect size; CI = confidence interval. Reference numbers for the studies are as in Table 1.
Scatterplot of prostate specific antigen (PSA) level versus the proportion of 68Ga–prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET) positivity. The blue line is the meta-regression prediction and shading shows the 95% confidence interval. The size of the circles is related to the inverse of the variance.
A similar finding was observed for PSAdt: the pooled PSMA positivity was 64% for PSAdt ≥6 mo and 92% for PSAdt <6 mo (Fig. 6). There was high heterogeneity between the subgroups (I2 = 84.2%) and evidence of a small-study effect in the long PSAdt subgroup (Supplementary Fig. 4).
Forest plot of the proportion of 68Ga–prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET) positivity by prostate-specific antigen doubling time (PSA-dt) category. ES = effect size; CI = confidence interval.
As a sensitivity analysis, we excluded subpopulations with a sample size of less than ten and repeated the meta-analyses. This decreased the point estimate for 68Ga-PSMA PET positivity in the primary staging cohort to 27% (95% CI 15–42%). All other effects were negligible, with differences of ≤2% in the point estimates and CI boundaries for overall positivity and two PSA category proportions.
Of the studies included, 11 reported histopathologic correlation with 68Ga-PSMA PET; however, only five met the aforementioned inclusion criteria (summarised in Table 2). Of the five studies reporting the predictive ability of 68Ga-PSMA PET imaging with respect to histology-proven disease, per-patient and per-lesion analyses were possible for four studies each (Fig. 7). For per-lesion analysis, the summary sensitivity is 80% and specificity is 97%. For per-patient analysis, the summary sensitivity and specificity are both 86%, although the confidence intervals are especially wide because of the low patient numbers.
Studies with histopathologic correlation data for 68Ga PSMA PET–positive lesions included in pooled analysis
a Not included in the pooled analysis as data points did not meet the inclusion criteria.
HP = histopathology; LND = lymph node dissection; SS = sensitivity; SP = specificity.
68Ga-PSMA PET is a novel targeted imaging modality that may improve the identification of metastatic prostate cancer. Our meta-analysis results identified indication, PSA, and PSA-based kinetics as risk factors for positive imaging. Furthermore, pooled sensitivity and specificity for the available data appear promising compared to alternative imaging modalities for metastatic prostate cancer.
The current study highlights the growing body of evidence supporting the use of 68Ga-PSMA PET for primary staging. In this setting, groups have reported pooled positivity of 40%. Given that the risk of metastatic spread is unlikely in low-risk disease, a majority of the studies included patients with intermediate- and high-risk prostate cancer in accordance with the D’Amico classification [47]
To date, the majority of data outlining the utility of 68Ga-PSMA PET are in the setting of secondary staging for biochemical recurrence after definitive therapy. In clinical practice, early detection and highly accurate localisation of disease recurrence are critical, as these may facilitate initiation of subsequent therapies, such as radiotherapy [54]
Pooled data from the current study highlight the promising detection rates for 68Ga-PSMA PET in prostate cancer with low PSA or PSAdt. Despite advances in bone scintigraphy and CT imaging, detection of locoregional or distant recurrence with low PSA has been problematic. Therefore, most guidelines recommend imaging when patients are symptomatic or PSA levels are >10 ng/ml [4]
An increasing number of centres are reporting early outcomes for 68Ga-PSMA PET, particularly in Germany and Australia, with results for many series yet to be published [59]
There are several limitations to the current study. First, a majority of the series used for meta-analysis were derived from small, retrospective, single-institutional studies. In addition, the heterogeneous nature of the patient cohorts, treatment protocols, and study designs included represents a potential limitation of the data available for analysis. Second, of the studies used for pooled sensitivity and specificity data, the majority had a small sample size and assessed patients in the primary staging setting. Additional data in the future will undoubtedly be of benefit for such analyses.
The absence of accurate imaging for detection of small-volume metastases in advanced prostate cancer has prompted the introduction of 68Ga-PSMA PET. The results of the current study suggest that PSA and associated kinetics predict the risk of metastatic disease diagnosed by 68Ga-PSMA PET. This novel imaging modality appears to provide superior sensitivity and specificity compared to alternative techniques. These promising early results for 68Ga-PSMA PET indicate a significant need for further clinical data.
Author contributions: Nathan Lawrentschuk had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Lawrentschuk, Perera, Papa.
Acquisition of data: Perera, Papa, Christidis, Wetherell.
Analysis and interpretation of data: Papa, Perera, Hofman.
Drafting of the manuscript: Perera, Papa, Hofman, Murphy, Bolton.
Critical revision of the manuscript for important intellectual content: Murphy, Bolton, Hofman, Lawrentschuk.
Statistical analysis: Papa.
Obtaining funding: None.
Administrative, technical, or material support: None.
Supervision: Bolton, Lawrentschuk, Murphy, Hofman.
Other: None.
Financial disclosures: Nathan Lawrentschuk certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None.
Funding/Support and role of the sponsor: None.
Acknowledgments: Marlon Perera is supported by a Royal Australasian College of Surgeons scholarship.
Prostate cancer is among the most prevalent cancers worldwide and is the third most common cause of cancer-associated mortality among men [1]
Prostate-specific membrane antigen (PSMA) is a transmembrane protein with a 707-amino-acid extracellular portion. The PSMA gene (FOLH1) is located on the short arm of chromosome 11. PSMA is expressed in the apical region of prostatic cells, the epithelium surrounding prostatic ducts [6]
To date, the use of 68Ga-PSMA has been well reported, with the compound Glu-NH-CO-NH-Lys-(Ahx)-[68Ga]-HBED (68Ga-PSMA-11) developed by the Heidelberg group in Germany. Initial series revealed superior sensitivity and specificity profiles compared to conventional choline-based tracers [19]
A systematic review was performed in accordance with Cochrane Collaboration and Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) guidelines [20]
Studies evaluating the utility of 68Ga-PSMA PET in detection of metastatic disease in advanced prostate cancer were included for analysis. Study designs considered for inclusion were clinical trials, prospective studies, and retrospective cohorts or comparative series. Studies assessing the diagnostic utility of 68Ga-PSMA PET in prostate cancer staging (before definitive treatment) or staging for recurrent disease (following therapy) were included for assessment. Studies were excluded if 68Ga-PSMA PET was used in assessing primary (prostatic) disease only or a specific visceral metastatic deposit (eg, pulmonary or cerebral metastases). In the current analysis, only studies using the 68Ga-PSMA-11 PSMA surface antigen HBED-CC (PSMA-11) were included for analysis provided the tracer was bound to 68Ga. Studies were excluded if alternative PSMA-bound radiotracers were used (eg, 18F or 99mTc tracers). No language or sample-size restrictions were used. Where duplicate study populations or analyses of repeated data were identified from the literature review, the publication reporting a larger sample size was used for analysis.
The primary outcome was to identify predictors of 68Ga-PSMA PET positivity. Studies that included only 68Ga-PSMA PET–positive studies were excluded, as predictive data were not available for analysis. The secondary outcome measure was the sensitivity and specificity of 68Ga-PSMA PET–positive lesions in advanced prostate cancer. For sensitivity and specificity analysis, only studies that included routine 68Ga-PSMA PET before preplanned lymph node dissection were included. Inclusion of series for which nodal biopsy was performed at the clinician's discretion does not provide meaningful false-negative data and thus does not provide accurate specificity values. An inadequate number of studies robustly assessed prostatic bed recurrence or suspicious bony metastatic disease in the manner outlined above. Therefore, we only assessed sensitivity and specificity values for 68Ga-PSMA PET in lymph nodes.
Studies were assessed for quality using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool [22]
The following information was extracted from each study: sample size, age, indication for PET (primary staging or recurrent disease staging), PSA, previous therapies, initial cancer stage, 68Ga-PSMA PET characteristics, rates of positive PET, and histopathologic correlation data. Rates of 68Ga-PSMA PET positivity were collected and stratified by pre-PET PSA and PSA doubling time (PSAdt) when possible. When histopathologic correlation data were available, numbers of true positives, false positives, true negatives, and false negatives were collected, as appropriate. For studies that included 68Ga-PSMA PET for both primary staging and recurrent cancer staging, the extracted data are displayed separately when available.
Extracted data were collated in Excel 2007 (Microsoft Corporation, Redmond, CA, USA) and analysis was performed using Stata v.12.0SE (College Station, TX, USA). Meta-analysis of proportions was performed using the metaprop command in Stata [23]
In patients undergoing a scan for disease recurrence, we performed a PSA level analysis. Note that for the cohort used by Afshar-Oromieh et al [14]
Random-effects meta-regression with Freeman-Tukey transformation was performed for study-defined PSA categories where the reference point was <2 ng/ml. We could not assign a valid reference point for categories greater than this as the reporting of PSA means, medians, and ranges was heterogeneous. Values were back-transformed using the equation described by Miller [26]
Summary sensitivity, specificity, and hierarchical receiver operating characteristic curves were created using the midas command [27]
Using the systematic search strategy outlined in the Supplementary material, 1895 articles were identified, of which 189 were duplicate records and excluded. Of the remaining 1706 records, 1470 were not relevant to the research question. A further 202 were conference abstracts, reviews, letters, and editorials that could not be quality assessed, and thus were excluded. From the remaining 34 articles, 11 were excluded as they did not contain relevant results and five contained duplicate data. One additional study was excluded as patients were enrolled following negative choline-based PET, and thus provided a skewed patient population [28]
Of the 16 studies relevant to the meta-analysis, one was prospective and 15 were retrospective in nature. Two studies included outcomes for 68Ga-PSMA PET performed before definitive therapy (primary staging), eight reported outcomes for biochemical recurrence or disease progression staging (secondary staging), and six included mixed groups. Basic details for the studies included are listed in Table 1.
Characteristics of the studies included
a The tracer used in all cases was 68Ga-PSMA-11.
b PET was used for 95 patients and magnetic resonance imaging for all 130 patients.
c Mean.
ADT = androgen deprivation therapy; ARTx = adjuvant radiotherapy; BCR = biochemical recurrence; CE = contrast-enhanced; CT = computerised tomography; CTx = chemotherapy; HIFU = high-intensity focused ultrasound; HR = high resolution;, LND = lymph node dissection, LNM = lymph node metastases; NCE = non–contrast-enhanced; NR = not reported; PCa = Prostate cancer; PET = positron emission tomography; PSMA = prostate-specific membrane antigen; RP = radical prostatectomy; RTx = primary radiotherapy; SRP = salvage prostatectomy.
While patient selection was generally acceptable in the studies included, a few studies did not clearly report the inclusion criteria. Furthermore, several studies included mixed patient populations including primary and secondary staging groups, raising concerns regarding applicability. All the studies clearly reported methodology for the index test and were thus not considered a significant source of potential bias. Of the studies included, 11 involved a reference test: histopathologic correlation of 68Ga-PSMA PET–positive lesions. However, in terms of flow and timing, multiple studies were at risk of bias, as many included targeted biopsies of suspicious lesions only. Such articles were excluded from sensitivity and specificity analyses because the false-negative data are not accurate. In total, five studies performed 68Ga-PSMA PET before planned lymph node sampling. Summary findings for the QUADAS-2 appraisal are illustrated in Figure 2.
(A) Appraisal of the quality of the studies included according to the Quality Assessment for Diagnostic Studies-2 (QUADAS-2) tool [22]
In total, we analysed 16 studies involving 1309 patients who underwent a 68Ga-PSMA PET scan, of which 926 (70.7%) were positive. In an overall meta-analysis by cohort type, 40% (95% CI 19–64%) of scans were positive for patients undergoing primary staging and 76% (95% CI 66–85%) for those undergoing secondary staging (Fig. 3). There was high heterogeneity between groups and within all subgroups (I2 > 70%). Egger's test for small-study effects did not reach significance (p > 0.10; Supplementary Figs. 1 and 2).
Forest plot of the proportion of 68Ga–prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET) positivity by patient cohort type. ES = effect size; CI = confidence interval. Reference numbers for the studies are as in Table 1.
In assessing disease recurrence, PSMA PET positivity increased with the PSA category (Fig. 4). For patients with PSA <0.2 ng/ml, the pooled estimate was 42%, which increased to 58%, 76%, and 95% for the 0.2–0.99, 1.00–1.99, and >2.00 ng/ml PSA subgroups, respectively. There was high heterogeneity within the <0.2 and 1.00–1.99 ng/ml subgroups and very high heterogeneity between subgroups (I2 = 97.4%); the test for small-study effects did not reach significance (Supplementary Fig. 3). In meta-regression analysis (Fig. 5), the predicted positivity was 48% (95% CI 38–57%) for PSA of 0.2 ng/ml, 56% (95% CI 49–64%) for 0.5 ng/ml, and 70% (95% CI 63–76%) for 1.0 ng/ml.
Forest plot of the proportion of 68Ga–prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET) positivity by PSA category. ES = effect size; CI = confidence interval. Reference numbers for the studies are as in Table 1.
Scatterplot of prostate specific antigen (PSA) level versus the proportion of 68Ga–prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET) positivity. The blue line is the meta-regression prediction and shading shows the 95% confidence interval. The size of the circles is related to the inverse of the variance.
A similar finding was observed for PSAdt: the pooled PSMA positivity was 64% for PSAdt ≥6 mo and 92% for PSAdt <6 mo (Fig. 6). There was high heterogeneity between the subgroups (I2 = 84.2%) and evidence of a small-study effect in the long PSAdt subgroup (Supplementary Fig. 4).
Forest plot of the proportion of 68Ga–prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET) positivity by prostate-specific antigen doubling time (PSA-dt) category. ES = effect size; CI = confidence interval.
As a sensitivity analysis, we excluded subpopulations with a sample size of less than ten and repeated the meta-analyses. This decreased the point estimate for 68Ga-PSMA PET positivity in the primary staging cohort to 27% (95% CI 15–42%). All other effects were negligible, with differences of ≤2% in the point estimates and CI boundaries for overall positivity and two PSA category proportions.
Of the studies included, 11 reported histopathologic correlation with 68Ga-PSMA PET; however, only five met the aforementioned inclusion criteria (summarised in Table 2). Of the five studies reporting the predictive ability of 68Ga-PSMA PET imaging with respect to histology-proven disease, per-patient and per-lesion analyses were possible for four studies each (Fig. 7). For per-lesion analysis, the summary sensitivity is 80% and specificity is 97%. For per-patient analysis, the summary sensitivity and specificity are both 86%, although the confidence intervals are especially wide because of the low patient numbers.
Studies with histopathologic correlation data for 68Ga PSMA PET–positive lesions included in pooled analysis
a Not included in the pooled analysis as data points did not meet the inclusion criteria.
HP = histopathology; LND = lymph node dissection; SS = sensitivity; SP = specificity.
68Ga-PSMA PET is a novel targeted imaging modality that may improve the identification of metastatic prostate cancer. Our meta-analysis results identified indication, PSA, and PSA-based kinetics as risk factors for positive imaging. Furthermore, pooled sensitivity and specificity for the available data appear promising compared to alternative imaging modalities for metastatic prostate cancer.
The current study highlights the growing body of evidence supporting the use of 68Ga-PSMA PET for primary staging. In this setting, groups have reported pooled positivity of 40%. Given that the risk of metastatic spread is unlikely in low-risk disease, a majority of the studies included patients with intermediate- and high-risk prostate cancer in accordance with the D’Amico classification [47]
To date, the majority of data outlining the utility of 68Ga-PSMA PET are in the setting of secondary staging for biochemical recurrence after definitive therapy. In clinical practice, early detection and highly accurate localisation of disease recurrence are critical, as these may facilitate initiation of subsequent therapies, such as radiotherapy [54]
Pooled data from the current study highlight the promising detection rates for 68Ga-PSMA PET in prostate cancer with low PSA or PSAdt. Despite advances in bone scintigraphy and CT imaging, detection of locoregional or distant recurrence with low PSA has been problematic. Therefore, most guidelines recommend imaging when patients are symptomatic or PSA levels are >10 ng/ml [4]
An increasing number of centres are reporting early outcomes for 68Ga-PSMA PET, particularly in Germany and Australia, with results for many series yet to be published [59]
There are several limitations to the current study. First, a majority of the series used for meta-analysis were derived from small, retrospective, single-institutional studies. In addition, the heterogeneous nature of the patient cohorts, treatment protocols, and study designs included represents a potential limitation of the data available for analysis. Second, of the studies used for pooled sensitivity and specificity data, the majority had a small sample size and assessed patients in the primary staging setting. Additional data in the future will undoubtedly be of benefit for such analyses.
The absence of accurate imaging for detection of small-volume metastases in advanced prostate cancer has prompted the introduction of 68Ga-PSMA PET. The results of the current study suggest that PSA and associated kinetics predict the risk of metastatic disease diagnosed by 68Ga-PSMA PET. This novel imaging modality appears to provide superior sensitivity and specificity compared to alternative techniques. These promising early results for 68Ga-PSMA PET indicate a significant need for further clinical data.
Author contributions: Nathan Lawrentschuk had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Lawrentschuk, Perera, Papa.
Acquisition of data: Perera, Papa, Christidis, Wetherell.
Analysis and interpretation of data: Papa, Perera, Hofman.
Drafting of the manuscript: Perera, Papa, Hofman, Murphy, Bolton.
Critical revision of the manuscript for important intellectual content: Murphy, Bolton, Hofman, Lawrentschuk.
Statistical analysis: Papa.
Obtaining funding: None.
Administrative, technical, or material support: None.
Supervision: Bolton, Lawrentschuk, Murphy, Hofman.
Other: None.
Financial disclosures: Nathan Lawrentschuk certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None.
Funding/Support and role of the sponsor: None.
Acknowledgments: Marlon Perera is supported by a Royal Australasian College of Surgeons scholarship.
Prostate cancer is among the most prevalent cancers worldwide and is the third most common cause of cancer-associated mortality among men [1]
Prostate-specific membrane antigen (PSMA) is a transmembrane protein with a 707-amino-acid extracellular portion. The PSMA gene (FOLH1) is located on the short arm of chromosome 11. PSMA is expressed in the apical region of prostatic cells, the epithelium surrounding prostatic ducts [6]
To date, the use of 68Ga-PSMA has been well reported, with the compound Glu-NH-CO-NH-Lys-(Ahx)-[68Ga]-HBED (68Ga-PSMA-11) developed by the Heidelberg group in Germany. Initial series revealed superior sensitivity and specificity profiles compared to conventional choline-based tracers [19]
A systematic review was performed in accordance with Cochrane Collaboration and Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) guidelines [20]
Studies evaluating the utility of 68Ga-PSMA PET in detection of metastatic disease in advanced prostate cancer were included for analysis. Study designs considered for inclusion were clinical trials, prospective studies, and retrospective cohorts or comparative series. Studies assessing the diagnostic utility of 68Ga-PSMA PET in prostate cancer staging (before definitive treatment) or staging for recurrent disease (following therapy) were included for assessment. Studies were excluded if 68Ga-PSMA PET was used in assessing primary (prostatic) disease only or a specific visceral metastatic deposit (eg, pulmonary or cerebral metastases). In the current analysis, only studies using the 68Ga-PSMA-11 PSMA surface antigen HBED-CC (PSMA-11) were included for analysis provided the tracer was bound to 68Ga. Studies were excluded if alternative PSMA-bound radiotracers were used (eg, 18F or 99mTc tracers). No language or sample-size restrictions were used. Where duplicate study populations or analyses of repeated data were identified from the literature review, the publication reporting a larger sample size was used for analysis.
The primary outcome was to identify predictors of 68Ga-PSMA PET positivity. Studies that included only 68Ga-PSMA PET–positive studies were excluded, as predictive data were not available for analysis. The secondary outcome measure was the sensitivity and specificity of 68Ga-PSMA PET–positive lesions in advanced prostate cancer. For sensitivity and specificity analysis, only studies that included routine 68Ga-PSMA PET before preplanned lymph node dissection were included. Inclusion of series for which nodal biopsy was performed at the clinician's discretion does not provide meaningful false-negative data and thus does not provide accurate specificity values. An inadequate number of studies robustly assessed prostatic bed recurrence or suspicious bony metastatic disease in the manner outlined above. Therefore, we only assessed sensitivity and specificity values for 68Ga-PSMA PET in lymph nodes.
Studies were assessed for quality using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool [22]
The following information was extracted from each study: sample size, age, indication for PET (primary staging or recurrent disease staging), PSA, previous therapies, initial cancer stage, 68Ga-PSMA PET characteristics, rates of positive PET, and histopathologic correlation data. Rates of 68Ga-PSMA PET positivity were collected and stratified by pre-PET PSA and PSA doubling time (PSAdt) when possible. When histopathologic correlation data were available, numbers of true positives, false positives, true negatives, and false negatives were collected, as appropriate. For studies that included 68Ga-PSMA PET for both primary staging and recurrent cancer staging, the extracted data are displayed separately when available.
Extracted data were collated in Excel 2007 (Microsoft Corporation, Redmond, CA, USA) and analysis was performed using Stata v.12.0SE (College Station, TX, USA). Meta-analysis of proportions was performed using the metaprop command in Stata [23]
In patients undergoing a scan for disease recurrence, we performed a PSA level analysis. Note that for the cohort used by Afshar-Oromieh et al [14]
Random-effects meta-regression with Freeman-Tukey transformation was performed for study-defined PSA categories where the reference point was <2 ng/ml. We could not assign a valid reference point for categories greater than this as the reporting of PSA means, medians, and ranges was heterogeneous. Values were back-transformed using the equation described by Miller [26]
Summary sensitivity, specificity, and hierarchical receiver operating characteristic curves were created using the midas command [27]
Using the systematic search strategy outlined in the Supplementary material, 1895 articles were identified, of which 189 were duplicate records and excluded. Of the remaining 1706 records, 1470 were not relevant to the research question. A further 202 were conference abstracts, reviews, letters, and editorials that could not be quality assessed, and thus were excluded. From the remaining 34 articles, 11 were excluded as they did not contain relevant results and five contained duplicate data. One additional study was excluded as patients were enrolled following negative choline-based PET, and thus provided a skewed patient population [28]
Of the 16 studies relevant to the meta-analysis, one was prospective and 15 were retrospective in nature. Two studies included outcomes for 68Ga-PSMA PET performed before definitive therapy (primary staging), eight reported outcomes for biochemical recurrence or disease progression staging (secondary staging), and six included mixed groups. Basic details for the studies included are listed in Table 1.
Characteristics of the studies included
a The tracer used in all cases was 68Ga-PSMA-11.
b PET was used for 95 patients and magnetic resonance imaging for all 130 patients.
c Mean.
ADT = androgen deprivation therapy; ARTx = adjuvant radiotherapy; BCR = biochemical recurrence; CE = contrast-enhanced; CT = computerised tomography; CTx = chemotherapy; HIFU = high-intensity focused ultrasound; HR = high resolution;, LND = lymph node dissection, LNM = lymph node metastases; NCE = non–contrast-enhanced; NR = not reported; PCa = Prostate cancer; PET = positron emission tomography; PSMA = prostate-specific membrane antigen; RP = radical prostatectomy; RTx = primary radiotherapy; SRP = salvage prostatectomy.
While patient selection was generally acceptable in the studies included, a few studies did not clearly report the inclusion criteria. Furthermore, several studies included mixed patient populations including primary and secondary staging groups, raising concerns regarding applicability. All the studies clearly reported methodology for the index test and were thus not considered a significant source of potential bias. Of the studies included, 11 involved a reference test: histopathologic correlation of 68Ga-PSMA PET–positive lesions. However, in terms of flow and timing, multiple studies were at risk of bias, as many included targeted biopsies of suspicious lesions only. Such articles were excluded from sensitivity and specificity analyses because the false-negative data are not accurate. In total, five studies performed 68Ga-PSMA PET before planned lymph node sampling. Summary findings for the QUADAS-2 appraisal are illustrated in Figure 2.
(A) Appraisal of the quality of the studies included according to the Quality Assessment for Diagnostic Studies-2 (QUADAS-2) tool [22]
In total, we analysed 16 studies involving 1309 patients who underwent a 68Ga-PSMA PET scan, of which 926 (70.7%) were positive. In an overall meta-analysis by cohort type, 40% (95% CI 19–64%) of scans were positive for patients undergoing primary staging and 76% (95% CI 66–85%) for those undergoing secondary staging (Fig. 3). There was high heterogeneity between groups and within all subgroups (I2 > 70%). Egger's test for small-study effects did not reach significance (p > 0.10; Supplementary Figs. 1 and 2).
Forest plot of the proportion of 68Ga–prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET) positivity by patient cohort type. ES = effect size; CI = confidence interval. Reference numbers for the studies are as in Table 1.
In assessing disease recurrence, PSMA PET positivity increased with the PSA category (Fig. 4). For patients with PSA <0.2 ng/ml, the pooled estimate was 42%, which increased to 58%, 76%, and 95% for the 0.2–0.99, 1.00–1.99, and >2.00 ng/ml PSA subgroups, respectively. There was high heterogeneity within the <0.2 and 1.00–1.99 ng/ml subgroups and very high heterogeneity between subgroups (I2 = 97.4%); the test for small-study effects did not reach significance (Supplementary Fig. 3). In meta-regression analysis (Fig. 5), the predicted positivity was 48% (95% CI 38–57%) for PSA of 0.2 ng/ml, 56% (95% CI 49–64%) for 0.5 ng/ml, and 70% (95% CI 63–76%) for 1.0 ng/ml.
Forest plot of the proportion of 68Ga–prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET) positivity by PSA category. ES = effect size; CI = confidence interval. Reference numbers for the studies are as in Table 1.
Scatterplot of prostate specific antigen (PSA) level versus the proportion of 68Ga–prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET) positivity. The blue line is the meta-regression prediction and shading shows the 95% confidence interval. The size of the circles is related to the inverse of the variance.
A similar finding was observed for PSAdt: the pooled PSMA positivity was 64% for PSAdt ≥6 mo and 92% for PSAdt <6 mo (Fig. 6). There was high heterogeneity between the subgroups (I2 = 84.2%) and evidence of a small-study effect in the long PSAdt subgroup (Supplementary Fig. 4).
Forest plot of the proportion of 68Ga–prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET) positivity by prostate-specific antigen doubling time (PSA-dt) category. ES = effect size; CI = confidence interval.
As a sensitivity analysis, we excluded subpopulations with a sample size of less than ten and repeated the meta-analyses. This decreased the point estimate for 68Ga-PSMA PET positivity in the primary staging cohort to 27% (95% CI 15–42%). All other effects were negligible, with differences of ≤2% in the point estimates and CI boundaries for overall positivity and two PSA category proportions.
Of the studies included, 11 reported histopathologic correlation with 68Ga-PSMA PET; however, only five met the aforementioned inclusion criteria (summarised in Table 2). Of the five studies reporting the predictive ability of 68Ga-PSMA PET imaging with respect to histology-proven disease, per-patient and per-lesion analyses were possible for four studies each (Fig. 7). For per-lesion analysis, the summary sensitivity is 80% and specificity is 97%. For per-patient analysis, the summary sensitivity and specificity are both 86%, although the confidence intervals are especially wide because of the low patient numbers.
Studies with histopathologic correlation data for 68Ga PSMA PET–positive lesions included in pooled analysis
a Not included in the pooled analysis as data points did not meet the inclusion criteria.
HP = histopathology; LND = lymph node dissection; SS = sensitivity; SP = specificity.
68Ga-PSMA PET is a novel targeted imaging modality that may improve the identification of metastatic prostate cancer. Our meta-analysis results identified indication, PSA, and PSA-based kinetics as risk factors for positive imaging. Furthermore, pooled sensitivity and specificity for the available data appear promising compared to alternative imaging modalities for metastatic prostate cancer.
The current study highlights the growing body of evidence supporting the use of 68Ga-PSMA PET for primary staging. In this setting, groups have reported pooled positivity of 40%. Given that the risk of metastatic spread is unlikely in low-risk disease, a majority of the studies included patients with intermediate- and high-risk prostate cancer in accordance with the D’Amico classification [47]
To date, the majority of data outlining the utility of 68Ga-PSMA PET are in the setting of secondary staging for biochemical recurrence after definitive therapy. In clinical practice, early detection and highly accurate localisation of disease recurrence are critical, as these may facilitate initiation of subsequent therapies, such as radiotherapy [54]
Pooled data from the current study highlight the promising detection rates for 68Ga-PSMA PET in prostate cancer with low PSA or PSAdt. Despite advances in bone scintigraphy and CT imaging, detection of locoregional or distant recurrence with low PSA has been problematic. Therefore, most guidelines recommend imaging when patients are symptomatic or PSA levels are >10 ng/ml [4]
An increasing number of centres are reporting early outcomes for 68Ga-PSMA PET, particularly in Germany and Australia, with results for many series yet to be published [59]
There are several limitations to the current study. First, a majority of the series used for meta-analysis were derived from small, retrospective, single-institutional studies. In addition, the heterogeneous nature of the patient cohorts, treatment protocols, and study designs included represents a potential limitation of the data available for analysis. Second, of the studies used for pooled sensitivity and specificity data, the majority had a small sample size and assessed patients in the primary staging setting. Additional data in the future will undoubtedly be of benefit for such analyses.
The absence of accurate imaging for detection of small-volume metastases in advanced prostate cancer has prompted the introduction of 68Ga-PSMA PET. The results of the current study suggest that PSA and associated kinetics predict the risk of metastatic disease diagnosed by 68Ga-PSMA PET. This novel imaging modality appears to provide superior sensitivity and specificity compared to alternative techniques. These promising early results for 68Ga-PSMA PET indicate a significant need for further clinical data.
Author contributions: Nathan Lawrentschuk had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Lawrentschuk, Perera, Papa.
Acquisition of data: Perera, Papa, Christidis, Wetherell.
Analysis and interpretation of data: Papa, Perera, Hofman.
Drafting of the manuscript: Perera, Papa, Hofman, Murphy, Bolton.
Critical revision of the manuscript for important intellectual content: Murphy, Bolton, Hofman, Lawrentschuk.
Statistical analysis: Papa.
Obtaining funding: None.
Administrative, technical, or material support: None.
Supervision: Bolton, Lawrentschuk, Murphy, Hofman.
Other: None.
Financial disclosures: Nathan Lawrentschuk certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None.
Funding/Support and role of the sponsor: None.
Acknowledgments: Marlon Perera is supported by a Royal Australasian College of Surgeons scholarship.
Prostate cancer is among the most prevalent cancers worldwide and is the third most common cause of cancer-associated mortality among men [1]
Prostate-specific membrane antigen (PSMA) is a transmembrane protein with a 707-amino-acid extracellular portion. The PSMA gene (FOLH1) is located on the short arm of chromosome 11. PSMA is expressed in the apical region of prostatic cells, the epithelium surrounding prostatic ducts [6]
To date, the use of 68Ga-PSMA has been well reported, with the compound Glu-NH-CO-NH-Lys-(Ahx)-[68Ga]-HBED (68Ga-PSMA-11) developed by the Heidelberg group in Germany. Initial series revealed superior sensitivity and specificity profiles compared to conventional choline-based tracers [19]
A systematic review was performed in accordance with Cochrane Collaboration and Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) guidelines [20]
Studies evaluating the utility of 68Ga-PSMA PET in detection of metastatic disease in advanced prostate cancer were included for analysis. Study designs considered for inclusion were clinical trials, prospective studies, and retrospective cohorts or comparative series. Studies assessing the diagnostic utility of 68Ga-PSMA PET in prostate cancer staging (before definitive treatment) or staging for recurrent disease (following therapy) were included for assessment. Studies were excluded if 68Ga-PSMA PET was used in assessing primary (prostatic) disease only or a specific visceral metastatic deposit (eg, pulmonary or cerebral metastases). In the current analysis, only studies using the 68Ga-PSMA-11 PSMA surface antigen HBED-CC (PSMA-11) were included for analysis provided the tracer was bound to 68Ga. Studies were excluded if alternative PSMA-bound radiotracers were used (eg, 18F or 99mTc tracers). No language or sample-size restrictions were used. Where duplicate study populations or analyses of repeated data were identified from the literature review, the publication reporting a larger sample size was used for analysis.
The primary outcome was to identify predictors of 68Ga-PSMA PET positivity. Studies that included only 68Ga-PSMA PET–positive studies were excluded, as predictive data were not available for analysis. The secondary outcome measure was the sensitivity and specificity of 68Ga-PSMA PET–positive lesions in advanced prostate cancer. For sensitivity and specificity analysis, only studies that included routine 68Ga-PSMA PET before preplanned lymph node dissection were included. Inclusion of series for which nodal biopsy was performed at the clinician's discretion does not provide meaningful false-negative data and thus does not provide accurate specificity values. An inadequate number of studies robustly assessed prostatic bed recurrence or suspicious bony metastatic disease in the manner outlined above. Therefore, we only assessed sensitivity and specificity values for 68Ga-PSMA PET in lymph nodes.
Studies were assessed for quality using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool [22]
The following information was extracted from each study: sample size, age, indication for PET (primary staging or recurrent disease staging), PSA, previous therapies, initial cancer stage, 68Ga-PSMA PET characteristics, rates of positive PET, and histopathologic correlation data. Rates of 68Ga-PSMA PET positivity were collected and stratified by pre-PET PSA and PSA doubling time (PSAdt) when possible. When histopathologic correlation data were available, numbers of true positives, false positives, true negatives, and false negatives were collected, as appropriate. For studies that included 68Ga-PSMA PET for both primary staging and recurrent cancer staging, the extracted data are displayed separately when available.
Extracted data were collated in Excel 2007 (Microsoft Corporation, Redmond, CA, USA) and analysis was performed using Stata v.12.0SE (College Station, TX, USA). Meta-analysis of proportions was performed using the metaprop command in Stata [23]
In patients undergoing a scan for disease recurrence, we performed a PSA level analysis. Note that for the cohort used by Afshar-Oromieh et al [14]
Random-effects meta-regression with Freeman-Tukey transformation was performed for study-defined PSA categories where the reference point was <2 ng/ml. We could not assign a valid reference point for categories greater than this as the reporting of PSA means, medians, and ranges was heterogeneous. Values were back-transformed using the equation described by Miller [26]
Summary sensitivity, specificity, and hierarchical receiver operating characteristic curves were created using the midas command [27]
Using the systematic search strategy outlined in the Supplementary material, 1895 articles were identified, of which 189 were duplicate records and excluded. Of the remaining 1706 records, 1470 were not relevant to the research question. A further 202 were conference abstracts, reviews, letters, and editorials that could not be quality assessed, and thus were excluded. From the remaining 34 articles, 11 were excluded as they did not contain relevant results and five contained duplicate data. One additional study was excluded as patients were enrolled following negative choline-based PET, and thus provided a skewed patient population [28]
Of the 16 studies relevant to the meta-analysis, one was prospective and 15 were retrospective in nature. Two studies included outcomes for 68Ga-PSMA PET performed before definitive therapy (primary staging), eight reported outcomes for biochemical recurrence or disease progression staging (secondary staging), and six included mixed groups. Basic details for the studies included are listed in Table 1.
Characteristics of the studies included
a The tracer used in all cases was 68Ga-PSMA-11.
b PET was used for 95 patients and magnetic resonance imaging for all 130 patients.
c Mean.
ADT = androgen deprivation therapy; ARTx = adjuvant radiotherapy; BCR = biochemical recurrence; CE = contrast-enhanced; CT = computerised tomography; CTx = chemotherapy; HIFU = high-intensity focused ultrasound; HR = high resolution;, LND = lymph node dissection, LNM = lymph node metastases; NCE = non–contrast-enhanced; NR = not reported; PCa = Prostate cancer; PET = positron emission tomography; PSMA = prostate-specific membrane antigen; RP = radical prostatectomy; RTx = primary radiotherapy; SRP = salvage prostatectomy.
While patient selection was generally acceptable in the studies included, a few studies did not clearly report the inclusion criteria. Furthermore, several studies included mixed patient populations including primary and secondary staging groups, raising concerns regarding applicability. All the studies clearly reported methodology for the index test and were thus not considered a significant source of potential bias. Of the studies included, 11 involved a reference test: histopathologic correlation of 68Ga-PSMA PET–positive lesions. However, in terms of flow and timing, multiple studies were at risk of bias, as many included targeted biopsies of suspicious lesions only. Such articles were excluded from sensitivity and specificity analyses because the false-negative data are not accurate. In total, five studies performed 68Ga-PSMA PET before planned lymph node sampling. Summary findings for the QUADAS-2 appraisal are illustrated in Figure 2.
(A) Appraisal of the quality of the studies included according to the Quality Assessment for Diagnostic Studies-2 (QUADAS-2) tool [22]
In total, we analysed 16 studies involving 1309 patients who underwent a 68Ga-PSMA PET scan, of which 926 (70.7%) were positive. In an overall meta-analysis by cohort type, 40% (95% CI 19–64%) of scans were positive for patients undergoing primary staging and 76% (95% CI 66–85%) for those undergoing secondary staging (Fig. 3). There was high heterogeneity between groups and within all subgroups (I2 > 70%). Egger's test for small-study effects did not reach significance (p > 0.10; Supplementary Figs. 1 and 2).
Forest plot of the proportion of 68Ga–prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET) positivity by patient cohort type. ES = effect size; CI = confidence interval. Reference numbers for the studies are as in Table 1.
In assessing disease recurrence, PSMA PET positivity increased with the PSA category (Fig. 4). For patients with PSA <0.2 ng/ml, the pooled estimate was 42%, which increased to 58%, 76%, and 95% for the 0.2–0.99, 1.00–1.99, and >2.00 ng/ml PSA subgroups, respectively. There was high heterogeneity within the <0.2 and 1.00–1.99 ng/ml subgroups and very high heterogeneity between subgroups (I2 = 97.4%); the test for small-study effects did not reach significance (Supplementary Fig. 3). In meta-regression analysis (Fig. 5), the predicted positivity was 48% (95% CI 38–57%) for PSA of 0.2 ng/ml, 56% (95% CI 49–64%) for 0.5 ng/ml, and 70% (95% CI 63–76%) for 1.0 ng/ml.
Forest plot of the proportion of 68Ga–prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET) positivity by PSA category. ES = effect size; CI = confidence interval. Reference numbers for the studies are as in Table 1.
Scatterplot of prostate specific antigen (PSA) level versus the proportion of 68Ga–prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET) positivity. The blue line is the meta-regression prediction and shading shows the 95% confidence interval. The size of the circles is related to the inverse of the variance.
A similar finding was observed for PSAdt: the pooled PSMA positivity was 64% for PSAdt ≥6 mo and 92% for PSAdt <6 mo (Fig. 6). There was high heterogeneity between the subgroups (I2 = 84.2%) and evidence of a small-study effect in the long PSAdt subgroup (Supplementary Fig. 4).
Forest plot of the proportion of 68Ga–prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET) positivity by prostate-specific antigen doubling time (PSA-dt) category. ES = effect size; CI = confidence interval.
As a sensitivity analysis, we excluded subpopulations with a sample size of less than ten and repeated the meta-analyses. This decreased the point estimate for 68Ga-PSMA PET positivity in the primary staging cohort to 27% (95% CI 15–42%). All other effects were negligible, with differences of ≤2% in the point estimates and CI boundaries for overall positivity and two PSA category proportions.
Of the studies included, 11 reported histopathologic correlation with 68Ga-PSMA PET; however, only five met the aforementioned inclusion criteria (summarised in Table 2). Of the five studies reporting the predictive ability of 68Ga-PSMA PET imaging with respect to histology-proven disease, per-patient and per-lesion analyses were possible for four studies each (Fig. 7). For per-lesion analysis, the summary sensitivity is 80% and specificity is 97%. For per-patient analysis, the summary sensitivity and specificity are both 86%, although the confidence intervals are especially wide because of the low patient numbers.
Studies with histopathologic correlation data for 68Ga PSMA PET–positive lesions included in pooled analysis
a Not included in the pooled analysis as data points did not meet the inclusion criteria.
HP = histopathology; LND = lymph node dissection; SS = sensitivity; SP = specificity.
68Ga-PSMA PET is a novel targeted imaging modality that may improve the identification of metastatic prostate cancer. Our meta-analysis results identified indication, PSA, and PSA-based kinetics as risk factors for positive imaging. Furthermore, pooled sensitivity and specificity for the available data appear promising compared to alternative imaging modalities for metastatic prostate cancer.
The current study highlights the growing body of evidence supporting the use of 68Ga-PSMA PET for primary staging. In this setting, groups have reported pooled positivity of 40%. Given that the risk of metastatic spread is unlikely in low-risk disease, a majority of the studies included patients with intermediate- and high-risk prostate cancer in accordance with the D’Amico classification [47]
To date, the majority of data outlining the utility of 68Ga-PSMA PET are in the setting of secondary staging for biochemical recurrence after definitive therapy. In clinical practice, early detection and highly accurate localisation of disease recurrence are critical, as these may facilitate initiation of subsequent therapies, such as radiotherapy [54]
Pooled data from the current study highlight the promising detection rates for 68Ga-PSMA PET in prostate cancer with low PSA or PSAdt. Despite advances in bone scintigraphy and CT imaging, detection of locoregional or distant recurrence with low PSA has been problematic. Therefore, most guidelines recommend imaging when patients are symptomatic or PSA levels are >10 ng/ml [4]
An increasing number of centres are reporting early outcomes for 68Ga-PSMA PET, particularly in Germany and Australia, with results for many series yet to be published [59]
There are several limitations to the current study. First, a majority of the series used for meta-analysis were derived from small, retrospective, single-institutional studies. In addition, the heterogeneous nature of the patient cohorts, treatment protocols, and study designs included represents a potential limitation of the data available for analysis. Second, of the studies used for pooled sensitivity and specificity data, the majority had a small sample size and assessed patients in the primary staging setting. Additional data in the future will undoubtedly be of benefit for such analyses.
The absence of accurate imaging for detection of small-volume metastases in advanced prostate cancer has prompted the introduction of 68Ga-PSMA PET. The results of the current study suggest that PSA and associated kinetics predict the risk of metastatic disease diagnosed by 68Ga-PSMA PET. This novel imaging modality appears to provide superior sensitivity and specificity compared to alternative techniques. These promising early results for 68Ga-PSMA PET indicate a significant need for further clinical data.
Author contributions: Nathan Lawrentschuk had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Lawrentschuk, Perera, Papa.
Acquisition of data: Perera, Papa, Christidis, Wetherell.
Analysis and interpretation of data: Papa, Perera, Hofman.
Drafting of the manuscript: Perera, Papa, Hofman, Murphy, Bolton.
Critical revision of the manuscript for important intellectual content: Murphy, Bolton, Hofman, Lawrentschuk.
Statistical analysis: Papa.
Obtaining funding: None.
Administrative, technical, or material support: None.
Supervision: Bolton, Lawrentschuk, Murphy, Hofman.
Other: None.
Financial disclosures: Nathan Lawrentschuk certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None.
Funding/Support and role of the sponsor: None.
Acknowledgments: Marlon Perera is supported by a Royal Australasian College of Surgeons scholarship.
Prostate cancer is among the most prevalent cancers worldwide and is the third most common cause of cancer-associated mortality among men [1]
Prostate-specific membrane antigen (PSMA) is a transmembrane protein with a 707-amino-acid extracellular portion. The PSMA gene (FOLH1) is located on the short arm of chromosome 11. PSMA is expressed in the apical region of prostatic cells, the epithelium surrounding prostatic ducts [6]
To date, the use of 68Ga-PSMA has been well reported, with the compound Glu-NH-CO-NH-Lys-(Ahx)-[68Ga]-HBED (68Ga-PSMA-11) developed by the Heidelberg group in Germany. Initial series revealed superior sensitivity and specificity profiles compared to conventional choline-based tracers [19]
A systematic review was performed in accordance with Cochrane Collaboration and Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) guidelines [20]
Studies evaluating the utility of 68Ga-PSMA PET in detection of metastatic disease in advanced prostate cancer were included for analysis. Study designs considered for inclusion were clinical trials, prospective studies, and retrospective cohorts or comparative series. Studies assessing the diagnostic utility of 68Ga-PSMA PET in prostate cancer staging (before definitive treatment) or staging for recurrent disease (following therapy) were included for assessment. Studies were excluded if 68Ga-PSMA PET was used in assessing primary (prostatic) disease only or a specific visceral metastatic deposit (eg, pulmonary or cerebral metastases). In the current analysis, only studies using the 68Ga-PSMA-11 PSMA surface antigen HBED-CC (PSMA-11) were included for analysis provided the tracer was bound to 68Ga. Studies were excluded if alternative PSMA-bound radiotracers were used (eg, 18F or 99mTc tracers). No language or sample-size restrictions were used. Where duplicate study populations or analyses of repeated data were identified from the literature review, the publication reporting a larger sample size was used for analysis.
The primary outcome was to identify predictors of 68Ga-PSMA PET positivity. Studies that included only 68Ga-PSMA PET–positive studies were excluded, as predictive data were not available for analysis. The secondary outcome measure was the sensitivity and specificity of 68Ga-PSMA PET–positive lesions in advanced prostate cancer. For sensitivity and specificity analysis, only studies that included routine 68Ga-PSMA PET before preplanned lymph node dissection were included. Inclusion of series for which nodal biopsy was performed at the clinician's discretion does not provide meaningful false-negative data and thus does not provide accurate specificity values. An inadequate number of studies robustly assessed prostatic bed recurrence or suspicious bony metastatic disease in the manner outlined above. Therefore, we only assessed sensitivity and specificity values for 68Ga-PSMA PET in lymph nodes.
Studies were assessed for quality using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool [22]
The following information was extracted from each study: sample size, age, indication for PET (primary staging or recurrent disease staging), PSA, previous therapies, initial cancer stage, 68Ga-PSMA PET characteristics, rates of positive PET, and histopathologic correlation data. Rates of 68Ga-PSMA PET positivity were collected and stratified by pre-PET PSA and PSA doubling time (PSAdt) when possible. When histopathologic correlation data were available, numbers of true positives, false positives, true negatives, and false negatives were collected, as appropriate. For studies that included 68Ga-PSMA PET for both primary staging and recurrent cancer staging, the extracted data are displayed separately when available.
Extracted data were collated in Excel 2007 (Microsoft Corporation, Redmond, CA, USA) and analysis was performed using Stata v.12.0SE (College Station, TX, USA). Meta-analysis of proportions was performed using the metaprop command in Stata [23]
In patients undergoing a scan for disease recurrence, we performed a PSA level analysis. Note that for the cohort used by Afshar-Oromieh et al [14]
Random-effects meta-regression with Freeman-Tukey transformation was performed for study-defined PSA categories where the reference point was <2 ng/ml. We could not assign a valid reference point for categories greater than this as the reporting of PSA means, medians, and ranges was heterogeneous. Values were back-transformed using the equation described by Miller [26]
Summary sensitivity, specificity, and hierarchical receiver operating characteristic curves were created using the midas command [27]
Using the systematic search strategy outlined in the Supplementary material, 1895 articles were identified, of which 189 were duplicate records and excluded. Of the remaining 1706 records, 1470 were not relevant to the research question. A further 202 were conference abstracts, reviews, letters, and editorials that could not be quality assessed, and thus were excluded. From the remaining 34 articles, 11 were excluded as they did not contain relevant results and five contained duplicate data. One additional study was excluded as patients were enrolled following negative choline-based PET, and thus provided a skewed patient population [28]
Of the 16 studies relevant to the meta-analysis, one was prospective and 15 were retrospective in nature. Two studies included outcomes for 68Ga-PSMA PET performed before definitive therapy (primary staging), eight reported outcomes for biochemical recurrence or disease progression staging (secondary staging), and six included mixed groups. Basic details for the studies included are listed in Table 1.
Characteristics of the studies included
a The tracer used in all cases was 68Ga-PSMA-11.
b PET was used for 95 patients and magnetic resonance imaging for all 130 patients.
c Mean.
ADT = androgen deprivation therapy; ARTx = adjuvant radiotherapy; BCR = biochemical recurrence; CE = contrast-enhanced; CT = computerised tomography; CTx = chemotherapy; HIFU = high-intensity focused ultrasound; HR = high resolution;, LND = lymph node dissection, LNM = lymph node metastases; NCE = non–contrast-enhanced; NR = not reported; PCa = Prostate cancer; PET = positron emission tomography; PSMA = prostate-specific membrane antigen; RP = radical prostatectomy; RTx = primary radiotherapy; SRP = salvage prostatectomy.
While patient selection was generally acceptable in the studies included, a few studies did not clearly report the inclusion criteria. Furthermore, several studies included mixed patient populations including primary and secondary staging groups, raising concerns regarding applicability. All the studies clearly reported methodology for the index test and were thus not considered a significant source of potential bias. Of the studies included, 11 involved a reference test: histopathologic correlation of 68Ga-PSMA PET–positive lesions. However, in terms of flow and timing, multiple studies were at risk of bias, as many included targeted biopsies of suspicious lesions only. Such articles were excluded from sensitivity and specificity analyses because the false-negative data are not accurate. In total, five studies performed 68Ga-PSMA PET before planned lymph node sampling. Summary findings for the QUADAS-2 appraisal are illustrated in Figure 2.
(A) Appraisal of the quality of the studies included according to the Quality Assessment for Diagnostic Studies-2 (QUADAS-2) tool [22]
In total, we analysed 16 studies involving 1309 patients who underwent a 68Ga-PSMA PET scan, of which 926 (70.7%) were positive. In an overall meta-analysis by cohort type, 40% (95% CI 19–64%) of scans were positive for patients undergoing primary staging and 76% (95% CI 66–85%) for those undergoing secondary staging (Fig. 3). There was high heterogeneity between groups and within all subgroups (I2 > 70%). Egger's test for small-study effects did not reach significance (p > 0.10; Supplementary Figs. 1 and 2).
Forest plot of the proportion of 68Ga–prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET) positivity by patient cohort type. ES = effect size; CI = confidence interval. Reference numbers for the studies are as in Table 1.
In assessing disease recurrence, PSMA PET positivity increased with the PSA category (Fig. 4). For patients with PSA <0.2 ng/ml, the pooled estimate was 42%, which increased to 58%, 76%, and 95% for the 0.2–0.99, 1.00–1.99, and >2.00 ng/ml PSA subgroups, respectively. There was high heterogeneity within the <0.2 and 1.00–1.99 ng/ml subgroups and very high heterogeneity between subgroups (I2 = 97.4%); the test for small-study effects did not reach significance (Supplementary Fig. 3). In meta-regression analysis (Fig. 5), the predicted positivity was 48% (95% CI 38–57%) for PSA of 0.2 ng/ml, 56% (95% CI 49–64%) for 0.5 ng/ml, and 70% (95% CI 63–76%) for 1.0 ng/ml.
Forest plot of the proportion of 68Ga–prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET) positivity by PSA category. ES = effect size; CI = confidence interval. Reference numbers for the studies are as in Table 1.
Scatterplot of prostate specific antigen (PSA) level versus the proportion of 68Ga–prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET) positivity. The blue line is the meta-regression prediction and shading shows the 95% confidence interval. The size of the circles is related to the inverse of the variance.
A similar finding was observed for PSAdt: the pooled PSMA positivity was 64% for PSAdt ≥6 mo and 92% for PSAdt <6 mo (Fig. 6). There was high heterogeneity between the subgroups (I2 = 84.2%) and evidence of a small-study effect in the long PSAdt subgroup (Supplementary Fig. 4).
Forest plot of the proportion of 68Ga–prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET) positivity by prostate-specific antigen doubling time (PSA-dt) category. ES = effect size; CI = confidence interval.
As a sensitivity analysis, we excluded subpopulations with a sample size of less than ten and repeated the meta-analyses. This decreased the point estimate for 68Ga-PSMA PET positivity in the primary staging cohort to 27% (95% CI 15–42%). All other effects were negligible, with differences of ≤2% in the point estimates and CI boundaries for overall positivity and two PSA category proportions.
Of the studies included, 11 reported histopathologic correlation with 68Ga-PSMA PET; however, only five met the aforementioned inclusion criteria (summarised in Table 2). Of the five studies reporting the predictive ability of 68Ga-PSMA PET imaging with respect to histology-proven disease, per-patient and per-lesion analyses were possible for four studies each (Fig. 7). For per-lesion analysis, the summary sensitivity is 80% and specificity is 97%. For per-patient analysis, the summary sensitivity and specificity are both 86%, although the confidence intervals are especially wide because of the low patient numbers.
Studies with histopathologic correlation data for 68Ga PSMA PET–positive lesions included in pooled analysis
a Not included in the pooled analysis as data points did not meet the inclusion criteria.
HP = histopathology; LND = lymph node dissection; SS = sensitivity; SP = specificity.
68Ga-PSMA PET is a novel targeted imaging modality that may improve the identification of metastatic prostate cancer. Our meta-analysis results identified indication, PSA, and PSA-based kinetics as risk factors for positive imaging. Furthermore, pooled sensitivity and specificity for the available data appear promising compared to alternative imaging modalities for metastatic prostate cancer.
The current study highlights the growing body of evidence supporting the use of 68Ga-PSMA PET for primary staging. In this setting, groups have reported pooled positivity of 40%. Given that the risk of metastatic spread is unlikely in low-risk disease, a majority of the studies included patients with intermediate- and high-risk prostate cancer in accordance with the D’Amico classification [47]
To date, the majority of data outlining the utility of 68Ga-PSMA PET are in the setting of secondary staging for biochemical recurrence after definitive therapy. In clinical practice, early detection and highly accurate localisation of disease recurrence are critical, as these may facilitate initiation of subsequent therapies, such as radiotherapy [54]
Pooled data from the current study highlight the promising detection rates for 68Ga-PSMA PET in prostate cancer with low PSA or PSAdt. Despite advances in bone scintigraphy and CT imaging, detection of locoregional or distant recurrence with low PSA has been problematic. Therefore, most guidelines recommend imaging when patients are symptomatic or PSA levels are >10 ng/ml [4]
An increasing number of centres are reporting early outcomes for 68Ga-PSMA PET, particularly in Germany and Australia, with results for many series yet to be published [59]
There are several limitations to the current study. First, a majority of the series used for meta-analysis were derived from small, retrospective, single-institutional studies. In addition, the heterogeneous nature of the patient cohorts, treatment protocols, and study designs included represents a potential limitation of the data available for analysis. Second, of the studies used for pooled sensitivity and specificity data, the majority had a small sample size and assessed patients in the primary staging setting. Additional data in the future will undoubtedly be of benefit for such analyses.
The absence of accurate imaging for detection of small-volume metastases in advanced prostate cancer has prompted the introduction of 68Ga-PSMA PET. The results of the current study suggest that PSA and associated kinetics predict the risk of metastatic disease diagnosed by 68Ga-PSMA PET. This novel imaging modality appears to provide superior sensitivity and specificity compared to alternative techniques. These promising early results for 68Ga-PSMA PET indicate a significant need for further clinical data.
Author contributions: Nathan Lawrentschuk had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Lawrentschuk, Perera, Papa.
Acquisition of data: Perera, Papa, Christidis, Wetherell.
Analysis and interpretation of data: Papa, Perera, Hofman.
Drafting of the manuscript: Perera, Papa, Hofman, Murphy, Bolton.
Critical revision of the manuscript for important intellectual content: Murphy, Bolton, Hofman, Lawrentschuk.
Statistical analysis: Papa.
Obtaining funding: None.
Administrative, technical, or material support: None.
Supervision: Bolton, Lawrentschuk, Murphy, Hofman.
Other: None.
Financial disclosures: Nathan Lawrentschuk certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None.
Funding/Support and role of the sponsor: None.
Acknowledgments: Marlon Perera is supported by a Royal Australasian College of Surgeons scholarship.
Prostate cancer is among the most prevalent cancers worldwide and is the third most common cause of cancer-associated mortality among men [1]
Prostate-specific membrane antigen (PSMA) is a transmembrane protein with a 707-amino-acid extracellular portion. The PSMA gene (FOLH1) is located on the short arm of chromosome 11. PSMA is expressed in the apical region of prostatic cells, the epithelium surrounding prostatic ducts [6]
To date, the use of 68Ga-PSMA has been well reported, with the compound Glu-NH-CO-NH-Lys-(Ahx)-[68Ga]-HBED (68Ga-PSMA-11) developed by the Heidelberg group in Germany. Initial series revealed superior sensitivity and specificity profiles compared to conventional choline-based tracers [19]
A systematic review was performed in accordance with Cochrane Collaboration and Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) guidelines [20]
Studies evaluating the utility of 68Ga-PSMA PET in detection of metastatic disease in advanced prostate cancer were included for analysis. Study designs considered for inclusion were clinical trials, prospective studies, and retrospective cohorts or comparative series. Studies assessing the diagnostic utility of 68Ga-PSMA PET in prostate cancer staging (before definitive treatment) or staging for recurrent disease (following therapy) were included for assessment. Studies were excluded if 68Ga-PSMA PET was used in assessing primary (prostatic) disease only or a specific visceral metastatic deposit (eg, pulmonary or cerebral metastases). In the current analysis, only studies using the 68Ga-PSMA-11 PSMA surface antigen HBED-CC (PSMA-11) were included for analysis provided the tracer was bound to 68Ga. Studies were excluded if alternative PSMA-bound radiotracers were used (eg, 18F or 99mTc tracers). No language or sample-size restrictions were used. Where duplicate study populations or analyses of repeated data were identified from the literature review, the publication reporting a larger sample size was used for analysis.
The primary outcome was to identify predictors of 68Ga-PSMA PET positivity. Studies that included only 68Ga-PSMA PET–positive studies were excluded, as predictive data were not available for analysis. The secondary outcome measure was the sensitivity and specificity of 68Ga-PSMA PET–positive lesions in advanced prostate cancer. For sensitivity and specificity analysis, only studies that included routine 68Ga-PSMA PET before preplanned lymph node dissection were included. Inclusion of series for which nodal biopsy was performed at the clinician's discretion does not provide meaningful false-negative data and thus does not provide accurate specificity values. An inadequate number of studies robustly assessed prostatic bed recurrence or suspicious bony metastatic disease in the manner outlined above. Therefore, we only assessed sensitivity and specificity values for 68Ga-PSMA PET in lymph nodes.
Studies were assessed for quality using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool [22]
The following information was extracted from each study: sample size, age, indication for PET (primary staging or recurrent disease staging), PSA, previous therapies, initial cancer stage, 68Ga-PSMA PET characteristics, rates of positive PET, and histopathologic correlation data. Rates of 68Ga-PSMA PET positivity were collected and stratified by pre-PET PSA and PSA doubling time (PSAdt) when possible. When histopathologic correlation data were available, numbers of true positives, false positives, true negatives, and false negatives were collected, as appropriate. For studies that included 68Ga-PSMA PET for both primary staging and recurrent cancer staging, the extracted data are displayed separately when available.
Extracted data were collated in Excel 2007 (Microsoft Corporation, Redmond, CA, USA) and analysis was performed using Stata v.12.0SE (College Station, TX, USA). Meta-analysis of proportions was performed using the metaprop command in Stata [23]
In patients undergoing a scan for disease recurrence, we performed a PSA level analysis. Note that for the cohort used by Afshar-Oromieh et al [14]
Random-effects meta-regression with Freeman-Tukey transformation was performed for study-defined PSA categories where the reference point was <2 ng/ml. We could not assign a valid reference point for categories greater than this as the reporting of PSA means, medians, and ranges was heterogeneous. Values were back-transformed using the equation described by Miller [26]
Summary sensitivity, specificity, and hierarchical receiver operating characteristic curves were created using the midas command [27]
Using the systematic search strategy outlined in the Supplementary material, 1895 articles were identified, of which 189 were duplicate records and excluded. Of the remaining 1706 records, 1470 were not relevant to the research question. A further 202 were conference abstracts, reviews, letters, and editorials that could not be quality assessed, and thus were excluded. From the remaining 34 articles, 11 were excluded as they did not contain relevant results and five contained duplicate data. One additional study was excluded as patients were enrolled following negative choline-based PET, and thus provided a skewed patient population [28]
Of the 16 studies relevant to the meta-analysis, one was prospective and 15 were retrospective in nature. Two studies included outcomes for 68Ga-PSMA PET performed before definitive therapy (primary staging), eight reported outcomes for biochemical recurrence or disease progression staging (secondary staging), and six included mixed groups. Basic details for the studies included are listed in Table 1.
Characteristics of the studies included
a The tracer used in all cases was 68Ga-PSMA-11.
b PET was used for 95 patients and magnetic resonance imaging for all 130 patients.
c Mean.
ADT = androgen deprivation therapy; ARTx = adjuvant radiotherapy; BCR = biochemical recurrence; CE = contrast-enhanced; CT = computerised tomography; CTx = chemotherapy; HIFU = high-intensity focused ultrasound; HR = high resolution;, LND = lymph node dissection, LNM = lymph node metastases; NCE = non–contrast-enhanced; NR = not reported; PCa = Prostate cancer; PET = positron emission tomography; PSMA = prostate-specific membrane antigen; RP = radical prostatectomy; RTx = primary radiotherapy; SRP = salvage prostatectomy.
While patient selection was generally acceptable in the studies included, a few studies did not clearly report the inclusion criteria. Furthermore, several studies included mixed patient populations including primary and secondary staging groups, raising concerns regarding applicability. All the studies clearly reported methodology for the index test and were thus not considered a significant source of potential bias. Of the studies included, 11 involved a reference test: histopathologic correlation of 68Ga-PSMA PET–positive lesions. However, in terms of flow and timing, multiple studies were at risk of bias, as many included targeted biopsies of suspicious lesions only. Such articles were excluded from sensitivity and specificity analyses because the false-negative data are not accurate. In total, five studies performed 68Ga-PSMA PET before planned lymph node sampling. Summary findings for the QUADAS-2 appraisal are illustrated in Figure 2.
(A) Appraisal of the quality of the studies included according to the Quality Assessment for Diagnostic Studies-2 (QUADAS-2) tool [22]
In total, we analysed 16 studies involving 1309 patients who underwent a 68Ga-PSMA PET scan, of which 926 (70.7%) were positive. In an overall meta-analysis by cohort type, 40% (95% CI 19–64%) of scans were positive for patients undergoing primary staging and 76% (95% CI 66–85%) for those undergoing secondary staging (Fig. 3). There was high heterogeneity between groups and within all subgroups (I2 > 70%). Egger's test for small-study effects did not reach significance (p > 0.10; Supplementary Figs. 1 and 2).
Forest plot of the proportion of 68Ga–prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET) positivity by patient cohort type. ES = effect size; CI = confidence interval. Reference numbers for the studies are as in Table 1.
In assessing disease recurrence, PSMA PET positivity increased with the PSA category (Fig. 4). For patients with PSA <0.2 ng/ml, the pooled estimate was 42%, which increased to 58%, 76%, and 95% for the 0.2–0.99, 1.00–1.99, and >2.00 ng/ml PSA subgroups, respectively. There was high heterogeneity within the <0.2 and 1.00–1.99 ng/ml subgroups and very high heterogeneity between subgroups (I2 = 97.4%); the test for small-study effects did not reach significance (Supplementary Fig. 3). In meta-regression analysis (Fig. 5), the predicted positivity was 48% (95% CI 38–57%) for PSA of 0.2 ng/ml, 56% (95% CI 49–64%) for 0.5 ng/ml, and 70% (95% CI 63–76%) for 1.0 ng/ml.
Forest plot of the proportion of 68Ga–prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET) positivity by PSA category. ES = effect size; CI = confidence interval. Reference numbers for the studies are as in Table 1.
Scatterplot of prostate specific antigen (PSA) level versus the proportion of 68Ga–prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET) positivity. The blue line is the meta-regression prediction and shading shows the 95% confidence interval. The size of the circles is related to the inverse of the variance.
A similar finding was observed for PSAdt: the pooled PSMA positivity was 64% for PSAdt ≥6 mo and 92% for PSAdt <6 mo (Fig. 6). There was high heterogeneity between the subgroups (I2 = 84.2%) and evidence of a small-study effect in the long PSAdt subgroup (Supplementary Fig. 4).
Forest plot of the proportion of 68Ga–prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET) positivity by prostate-specific antigen doubling time (PSA-dt) category. ES = effect size; CI = confidence interval.
As a sensitivity analysis, we excluded subpopulations with a sample size of less than ten and repeated the meta-analyses. This decreased the point estimate for 68Ga-PSMA PET positivity in the primary staging cohort to 27% (95% CI 15–42%). All other effects were negligible, with differences of ≤2% in the point estimates and CI boundaries for overall positivity and two PSA category proportions.
Of the studies included, 11 reported histopathologic correlation with 68Ga-PSMA PET; however, only five met the aforementioned inclusion criteria (summarised in Table 2). Of the five studies reporting the predictive ability of 68Ga-PSMA PET imaging with respect to histology-proven disease, per-patient and per-lesion analyses were possible for four studies each (Fig. 7). For per-lesion analysis, the summary sensitivity is 80% and specificity is 97%. For per-patient analysis, the summary sensitivity and specificity are both 86%, although the confidence intervals are especially wide because of the low patient numbers.
Studies with histopathologic correlation data for 68Ga PSMA PET–positive lesions included in pooled analysis
a Not included in the pooled analysis as data points did not meet the inclusion criteria.
HP = histopathology; LND = lymph node dissection; SS = sensitivity; SP = specificity.
68Ga-PSMA PET is a novel targeted imaging modality that may improve the identification of metastatic prostate cancer. Our meta-analysis results identified indication, PSA, and PSA-based kinetics as risk factors for positive imaging. Furthermore, pooled sensitivity and specificity for the available data appear promising compared to alternative imaging modalities for metastatic prostate cancer.
The current study highlights the growing body of evidence supporting the use of 68Ga-PSMA PET for primary staging. In this setting, groups have reported pooled positivity of 40%. Given that the risk of metastatic spread is unlikely in low-risk disease, a majority of the studies included patients with intermediate- and high-risk prostate cancer in accordance with the D’Amico classification [47]
To date, the majority of data outlining the utility of 68Ga-PSMA PET are in the setting of secondary staging for biochemical recurrence after definitive therapy. In clinical practice, early detection and highly accurate localisation of disease recurrence are critical, as these may facilitate initiation of subsequent therapies, such as radiotherapy [54]
Pooled data from the current study highlight the promising detection rates for 68Ga-PSMA PET in prostate cancer with low PSA or PSAdt. Despite advances in bone scintigraphy and CT imaging, detection of locoregional or distant recurrence with low PSA has been problematic. Therefore, most guidelines recommend imaging when patients are symptomatic or PSA levels are >10 ng/ml [4]
An increasing number of centres are reporting early outcomes for 68Ga-PSMA PET, particularly in Germany and Australia, with results for many series yet to be published [59]
There are several limitations to the current study. First, a majority of the series used for meta-analysis were derived from small, retrospective, single-institutional studies. In addition, the heterogeneous nature of the patient cohorts, treatment protocols, and study designs included represents a potential limitation of the data available for analysis. Second, of the studies used for pooled sensitivity and specificity data, the majority had a small sample size and assessed patients in the primary staging setting. Additional data in the future will undoubtedly be of benefit for such analyses.
The absence of accurate imaging for detection of small-volume metastases in advanced prostate cancer has prompted the introduction of 68Ga-PSMA PET. The results of the current study suggest that PSA and associated kinetics predict the risk of metastatic disease diagnosed by 68Ga-PSMA PET. This novel imaging modality appears to provide superior sensitivity and specificity compared to alternative techniques. These promising early results for 68Ga-PSMA PET indicate a significant need for further clinical data.
Author contributions: Nathan Lawrentschuk had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Lawrentschuk, Perera, Papa.
Acquisition of data: Perera, Papa, Christidis, Wetherell.
Analysis and interpretation of data: Papa, Perera, Hofman.
Drafting of the manuscript: Perera, Papa, Hofman, Murphy, Bolton.
Critical revision of the manuscript for important intellectual content: Murphy, Bolton, Hofman, Lawrentschuk.
Statistical analysis: Papa.
Obtaining funding: None.
Administrative, technical, or material support: None.
Supervision: Bolton, Lawrentschuk, Murphy, Hofman.
Other: None.
Financial disclosures: Nathan Lawrentschuk certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None.
Funding/Support and role of the sponsor: None.
Acknowledgments: Marlon Perera is supported by a Royal Australasian College of Surgeons scholarship.
Prostate cancer is among the most prevalent cancers worldwide and is the third most common cause of cancer-associated mortality among men [1]
Prostate-specific membrane antigen (PSMA) is a transmembrane protein with a 707-amino-acid extracellular portion. The PSMA gene (FOLH1) is located on the short arm of chromosome 11. PSMA is expressed in the apical region of prostatic cells, the epithelium surrounding prostatic ducts [6]
To date, the use of 68Ga-PSMA has been well reported, with the compound Glu-NH-CO-NH-Lys-(Ahx)-[68Ga]-HBED (68Ga-PSMA-11) developed by the Heidelberg group in Germany. Initial series revealed superior sensitivity and specificity profiles compared to conventional choline-based tracers [19]
A systematic review was performed in accordance with Cochrane Collaboration and Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) guidelines [20]
Studies evaluating the utility of 68Ga-PSMA PET in detection of metastatic disease in advanced prostate cancer were included for analysis. Study designs considered for inclusion were clinical trials, prospective studies, and retrospective cohorts or comparative series. Studies assessing the diagnostic utility of 68Ga-PSMA PET in prostate cancer staging (before definitive treatment) or staging for recurrent disease (following therapy) were included for assessment. Studies were excluded if 68Ga-PSMA PET was used in assessing primary (prostatic) disease only or a specific visceral metastatic deposit (eg, pulmonary or cerebral metastases). In the current analysis, only studies using the 68Ga-PSMA-11 PSMA surface antigen HBED-CC (PSMA-11) were included for analysis provided the tracer was bound to 68Ga. Studies were excluded if alternative PSMA-bound radiotracers were used (eg, 18F or 99mTc tracers). No language or sample-size restrictions were used. Where duplicate study populations or analyses of repeated data were identified from the literature review, the publication reporting a larger sample size was used for analysis.
The primary outcome was to identify predictors of 68Ga-PSMA PET positivity. Studies that included only 68Ga-PSMA PET–positive studies were excluded, as predictive data were not available for analysis. The secondary outcome measure was the sensitivity and specificity of 68Ga-PSMA PET–positive lesions in advanced prostate cancer. For sensitivity and specificity analysis, only studies that included routine 68Ga-PSMA PET before preplanned lymph node dissection were included. Inclusion of series for which nodal biopsy was performed at the clinician's discretion does not provide meaningful false-negative data and thus does not provide accurate specificity values. An inadequate number of studies robustly assessed prostatic bed recurrence or suspicious bony metastatic disease in the manner outlined above. Therefore, we only assessed sensitivity and specificity values for 68Ga-PSMA PET in lymph nodes.
Studies were assessed for quality using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool [22]
The following information was extracted from each study: sample size, age, indication for PET (primary staging or recurrent disease staging), PSA, previous therapies, initial cancer stage, 68Ga-PSMA PET characteristics, rates of positive PET, and histopathologic correlation data. Rates of 68Ga-PSMA PET positivity were collected and stratified by pre-PET PSA and PSA doubling time (PSAdt) when possible. When histopathologic correlation data were available, numbers of true positives, false positives, true negatives, and false negatives were collected, as appropriate. For studies that included 68Ga-PSMA PET for both primary staging and recurrent cancer staging, the extracted data are displayed separately when available.
Extracted data were collated in Excel 2007 (Microsoft Corporation, Redmond, CA, USA) and analysis was performed using Stata v.12.0SE (College Station, TX, USA). Meta-analysis of proportions was performed using the metaprop command in Stata [23]
In patients undergoing a scan for disease recurrence, we performed a PSA level analysis. Note that for the cohort used by Afshar-Oromieh et al [14]
Random-effects meta-regression with Freeman-Tukey transformation was performed for study-defined PSA categories where the reference point was <2 ng/ml. We could not assign a valid reference point for categories greater than this as the reporting of PSA means, medians, and ranges was heterogeneous. Values were back-transformed using the equation described by Miller [26]
Summary sensitivity, specificity, and hierarchical receiver operating characteristic curves were created using the midas command [27]
Using the systematic search strategy outlined in the Supplementary material, 1895 articles were identified, of which 189 were duplicate records and excluded. Of the remaining 1706 records, 1470 were not relevant to the research question. A further 202 were conference abstracts, reviews, letters, and editorials that could not be quality assessed, and thus were excluded. From the remaining 34 articles, 11 were excluded as they did not contain relevant results and five contained duplicate data. One additional study was excluded as patients were enrolled following negative choline-based PET, and thus provided a skewed patient population [28]
Of the 16 studies relevant to the meta-analysis, one was prospective and 15 were retrospective in nature. Two studies included outcomes for 68Ga-PSMA PET performed before definitive therapy (primary staging), eight reported outcomes for biochemical recurrence or disease progression staging (secondary staging), and six included mixed groups. Basic details for the studies included are listed in Table 1.
Characteristics of the studies included
a The tracer used in all cases was 68Ga-PSMA-11.
b PET was used for 95 patients and magnetic resonance imaging for all 130 patients.
c Mean.
ADT = androgen deprivation therapy; ARTx = adjuvant radiotherapy; BCR = biochemical recurrence; CE = contrast-enhanced; CT = computerised tomography; CTx = chemotherapy; HIFU = high-intensity focused ultrasound; HR = high resolution;, LND = lymph node dissection, LNM = lymph node metastases; NCE = non–contrast-enhanced; NR = not reported; PCa = Prostate cancer; PET = positron emission tomography; PSMA = prostate-specific membrane antigen; RP = radical prostatectomy; RTx = primary radiotherapy; SRP = salvage prostatectomy.
While patient selection was generally acceptable in the studies included, a few studies did not clearly report the inclusion criteria. Furthermore, several studies included mixed patient populations including primary and secondary staging groups, raising concerns regarding applicability. All the studies clearly reported methodology for the index test and were thus not considered a significant source of potential bias. Of the studies included, 11 involved a reference test: histopathologic correlation of 68Ga-PSMA PET–positive lesions. However, in terms of flow and timing, multiple studies were at risk of bias, as many included targeted biopsies of suspicious lesions only. Such articles were excluded from sensitivity and specificity analyses because the false-negative data are not accurate. In total, five studies performed 68Ga-PSMA PET before planned lymph node sampling. Summary findings for the QUADAS-2 appraisal are illustrated in Figure 2.
(A) Appraisal of the quality of the studies included according to the Quality Assessment for Diagnostic Studies-2 (QUADAS-2) tool [22]
In total, we analysed 16 studies involving 1309 patients who underwent a 68Ga-PSMA PET scan, of which 926 (70.7%) were positive. In an overall meta-analysis by cohort type, 40% (95% CI 19–64%) of scans were positive for patients undergoing primary staging and 76% (95% CI 66–85%) for those undergoing secondary staging (Fig. 3). There was high heterogeneity between groups and within all subgroups (I2 > 70%). Egger's test for small-study effects did not reach significance (p > 0.10; Supplementary Figs. 1 and 2).
Forest plot of the proportion of 68Ga–prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET) positivity by patient cohort type. ES = effect size; CI = confidence interval. Reference numbers for the studies are as in Table 1.
In assessing disease recurrence, PSMA PET positivity increased with the PSA category (Fig. 4). For patients with PSA <0.2 ng/ml, the pooled estimate was 42%, which increased to 58%, 76%, and 95% for the 0.2–0.99, 1.00–1.99, and >2.00 ng/ml PSA subgroups, respectively. There was high heterogeneity within the <0.2 and 1.00–1.99 ng/ml subgroups and very high heterogeneity between subgroups (I2 = 97.4%); the test for small-study effects did not reach significance (Supplementary Fig. 3). In meta-regression analysis (Fig. 5), the predicted positivity was 48% (95% CI 38–57%) for PSA of 0.2 ng/ml, 56% (95% CI 49–64%) for 0.5 ng/ml, and 70% (95% CI 63–76%) for 1.0 ng/ml.
Forest plot of the proportion of 68Ga–prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET) positivity by PSA category. ES = effect size; CI = confidence interval. Reference numbers for the studies are as in Table 1.
Scatterplot of prostate specific antigen (PSA) level versus the proportion of 68Ga–prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET) positivity. The blue line is the meta-regression prediction and shading shows the 95% confidence interval. The size of the circles is related to the inverse of the variance.
A similar finding was observed for PSAdt: the pooled PSMA positivity was 64% for PSAdt ≥6 mo and 92% for PSAdt <6 mo (Fig. 6). There was high heterogeneity between the subgroups (I2 = 84.2%) and evidence of a small-study effect in the long PSAdt subgroup (Supplementary Fig. 4).
Forest plot of the proportion of 68Ga–prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET) positivity by prostate-specific antigen doubling time (PSA-dt) category. ES = effect size; CI = confidence interval.
As a sensitivity analysis, we excluded subpopulations with a sample size of less than ten and repeated the meta-analyses. This decreased the point estimate for 68Ga-PSMA PET positivity in the primary staging cohort to 27% (95% CI 15–42%). All other effects were negligible, with differences of ≤2% in the point estimates and CI boundaries for overall positivity and two PSA category proportions.
Of the studies included, 11 reported histopathologic correlation with 68Ga-PSMA PET; however, only five met the aforementioned inclusion criteria (summarised in Table 2). Of the five studies reporting the predictive ability of 68Ga-PSMA PET imaging with respect to histology-proven disease, per-patient and per-lesion analyses were possible for four studies each (Fig. 7). For per-lesion analysis, the summary sensitivity is 80% and specificity is 97%. For per-patient analysis, the summary sensitivity and specificity are both 86%, although the confidence intervals are especially wide because of the low patient numbers.
Studies with histopathologic correlation data for 68Ga PSMA PET–positive lesions included in pooled analysis
a Not included in the pooled analysis as data points did not meet the inclusion criteria.
HP = histopathology; LND = lymph node dissection; SS = sensitivity; SP = specificity.
68Ga-PSMA PET is a novel targeted imaging modality that may improve the identification of metastatic prostate cancer. Our meta-analysis results identified indication, PSA, and PSA-based kinetics as risk factors for positive imaging. Furthermore, pooled sensitivity and specificity for the available data appear promising compared to alternative imaging modalities for metastatic prostate cancer.
The current study highlights the growing body of evidence supporting the use of 68Ga-PSMA PET for primary staging. In this setting, groups have reported pooled positivity of 40%. Given that the risk of metastatic spread is unlikely in low-risk disease, a majority of the studies included patients with intermediate- and high-risk prostate cancer in accordance with the D’Amico classification [47]
To date, the majority of data outlining the utility of 68Ga-PSMA PET are in the setting of secondary staging for biochemical recurrence after definitive therapy. In clinical practice, early detection and highly accurate localisation of disease recurrence are critical, as these may facilitate initiation of subsequent therapies, such as radiotherapy [54]
Pooled data from the current study highlight the promising detection rates for 68Ga-PSMA PET in prostate cancer with low PSA or PSAdt. Despite advances in bone scintigraphy and CT imaging, detection of locoregional or distant recurrence with low PSA has been problematic. Therefore, most guidelines recommend imaging when patients are symptomatic or PSA levels are >10 ng/ml [4]
An increasing number of centres are reporting early outcomes for 68Ga-PSMA PET, particularly in Germany and Australia, with results for many series yet to be published [59]
There are several limitations to the current study. First, a majority of the series used for meta-analysis were derived from small, retrospective, single-institutional studies. In addition, the heterogeneous nature of the patient cohorts, treatment protocols, and study designs included represents a potential limitation of the data available for analysis. Second, of the studies used for pooled sensitivity and specificity data, the majority had a small sample size and assessed patients in the primary staging setting. Additional data in the future will undoubtedly be of benefit for such analyses.
The absence of accurate imaging for detection of small-volume metastases in advanced prostate cancer has prompted the introduction of 68Ga-PSMA PET. The results of the current study suggest that PSA and associated kinetics predict the risk of metastatic disease diagnosed by 68Ga-PSMA PET. This novel imaging modality appears to provide superior sensitivity and specificity compared to alternative techniques. These promising early results for 68Ga-PSMA PET indicate a significant need for further clinical data.
Author contributions: Nathan Lawrentschuk had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Lawrentschuk, Perera, Papa.
Acquisition of data: Perera, Papa, Christidis, Wetherell.
Analysis and interpretation of data: Papa, Perera, Hofman.
Drafting of the manuscript: Perera, Papa, Hofman, Murphy, Bolton.
Critical revision of the manuscript for important intellectual content: Murphy, Bolton, Hofman, Lawrentschuk.
Statistical analysis: Papa.
Obtaining funding: None.
Administrative, technical, or material support: None.
Supervision: Bolton, Lawrentschuk, Murphy, Hofman.
Other: None.
Financial disclosures: Nathan Lawrentschuk certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None.
Funding/Support and role of the sponsor: None.
Acknowledgments: Marlon Perera is supported by a Royal Australasian College of Surgeons scholarship.
Prostate cancer is among the most prevalent cancers worldwide and is the third most common cause of cancer-associated mortality among men [1]
Prostate-specific membrane antigen (PSMA) is a transmembrane protein with a 707-amino-acid extracellular portion. The PSMA gene (FOLH1) is located on the short arm of chromosome 11. PSMA is expressed in the apical region of prostatic cells, the epithelium surrounding prostatic ducts [6]
To date, the use of 68Ga-PSMA has been well reported, with the compound Glu-NH-CO-NH-Lys-(Ahx)-[68Ga]-HBED (68Ga-PSMA-11) developed by the Heidelberg group in Germany. Initial series revealed superior sensitivity and specificity profiles compared to conventional choline-based tracers [19]
A systematic review was performed in accordance with Cochrane Collaboration and Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) guidelines [20]
Studies evaluating the utility of 68Ga-PSMA PET in detection of metastatic disease in advanced prostate cancer were included for analysis. Study designs considered for inclusion were clinical trials, prospective studies, and retrospective cohorts or comparative series. Studies assessing the diagnostic utility of 68Ga-PSMA PET in prostate cancer staging (before definitive treatment) or staging for recurrent disease (following therapy) were included for assessment. Studies were excluded if 68Ga-PSMA PET was used in assessing primary (prostatic) disease only or a specific visceral metastatic deposit (eg, pulmonary or cerebral metastases). In the current analysis, only studies using the 68Ga-PSMA-11 PSMA surface antigen HBED-CC (PSMA-11) were included for analysis provided the tracer was bound to 68Ga. Studies were excluded if alternative PSMA-bound radiotracers were used (eg, 18F or 99mTc tracers). No language or sample-size restrictions were used. Where duplicate study populations or analyses of repeated data were identified from the literature review, the publication reporting a larger sample size was used for analysis.
The primary outcome was to identify predictors of 68Ga-PSMA PET positivity. Studies that included only 68Ga-PSMA PET–positive studies were excluded, as predictive data were not available for analysis. The secondary outcome measure was the sensitivity and specificity of 68Ga-PSMA PET–positive lesions in advanced prostate cancer. For sensitivity and specificity analysis, only studies that included routine 68Ga-PSMA PET before preplanned lymph node dissection were included. Inclusion of series for which nodal biopsy was performed at the clinician's discretion does not provide meaningful false-negative data and thus does not provide accurate specificity values. An inadequate number of studies robustly assessed prostatic bed recurrence or suspicious bony metastatic disease in the manner outlined above. Therefore, we only assessed sensitivity and specificity values for 68Ga-PSMA PET in lymph nodes.
Studies were assessed for quality using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool [22]
The following information was extracted from each study: sample size, age, indication for PET (primary staging or recurrent disease staging), PSA, previous therapies, initial cancer stage, 68Ga-PSMA PET characteristics, rates of positive PET, and histopathologic correlation data. Rates of 68Ga-PSMA PET positivity were collected and stratified by pre-PET PSA and PSA doubling time (PSAdt) when possible. When histopathologic correlation data were available, numbers of true positives, false positives, true negatives, and false negatives were collected, as appropriate. For studies that included 68Ga-PSMA PET for both primary staging and recurrent cancer staging, the extracted data are displayed separately when available.
Extracted data were collated in Excel 2007 (Microsoft Corporation, Redmond, CA, USA) and analysis was performed using Stata v.12.0SE (College Station, TX, USA). Meta-analysis of proportions was performed using the metaprop command in Stata [23]
In patients undergoing a scan for disease recurrence, we performed a PSA level analysis. Note that for the cohort used by Afshar-Oromieh et al [14]
Random-effects meta-regression with Freeman-Tukey transformation was performed for study-defined PSA categories where the reference point was <2 ng/ml. We could not assign a valid reference point for categories greater than this as the reporting of PSA means, medians, and ranges was heterogeneous. Values were back-transformed using the equation described by Miller [26]
Summary sensitivity, specificity, and hierarchical receiver operating characteristic curves were created using the midas command [27]
Using the systematic search strategy outlined in the Supplementary material, 1895 articles were identified, of which 189 were duplicate records and excluded. Of the remaining 1706 records, 1470 were not relevant to the research question. A further 202 were conference abstracts, reviews, letters, and editorials that could not be quality assessed, and thus were excluded. From the remaining 34 articles, 11 were excluded as they did not contain relevant results and five contained duplicate data. One additional study was excluded as patients were enrolled following negative choline-based PET, and thus provided a skewed patient population [28]
Of the 16 studies relevant to the meta-analysis, one was prospective and 15 were retrospective in nature. Two studies included outcomes for 68Ga-PSMA PET performed before definitive therapy (primary staging), eight reported outcomes for biochemical recurrence or disease progression staging (secondary staging), and six included mixed groups. Basic details for the studies included are listed in Table 1.
Characteristics of the studies included
a The tracer used in all cases was 68Ga-PSMA-11.
b PET was used for 95 patients and magnetic resonance imaging for all 130 patients.
c Mean.
ADT = androgen deprivation therapy; ARTx = adjuvant radiotherapy; BCR = biochemical recurrence; CE = contrast-enhanced; CT = computerised tomography; CTx = chemotherapy; HIFU = high-intensity focused ultrasound; HR = high resolution;, LND = lymph node dissection, LNM = lymph node metastases; NCE = non–contrast-enhanced; NR = not reported; PCa = Prostate cancer; PET = positron emission tomography; PSMA = prostate-specific membrane antigen; RP = radical prostatectomy; RTx = primary radiotherapy; SRP = salvage prostatectomy.
While patient selection was generally acceptable in the studies included, a few studies did not clearly report the inclusion criteria. Furthermore, several studies included mixed patient populations including primary and secondary staging groups, raising concerns regarding applicability. All the studies clearly reported methodology for the index test and were thus not considered a significant source of potential bias. Of the studies included, 11 involved a reference test: histopathologic correlation of 68Ga-PSMA PET–positive lesions. However, in terms of flow and timing, multiple studies were at risk of bias, as many included targeted biopsies of suspicious lesions only. Such articles were excluded from sensitivity and specificity analyses because the false-negative data are not accurate. In total, five studies performed 68Ga-PSMA PET before planned lymph node sampling. Summary findings for the QUADAS-2 appraisal are illustrated in Figure 2.
(A) Appraisal of the quality of the studies included according to the Quality Assessment for Diagnostic Studies-2 (QUADAS-2) tool [22]
In total, we analysed 16 studies involving 1309 patients who underwent a 68Ga-PSMA PET scan, of which 926 (70.7%) were positive. In an overall meta-analysis by cohort type, 40% (95% CI 19–64%) of scans were positive for patients undergoing primary staging and 76% (95% CI 66–85%) for those undergoing secondary staging (Fig. 3). There was high heterogeneity between groups and within all subgroups (I2 > 70%). Egger's test for small-study effects did not reach significance (p > 0.10; Supplementary Figs. 1 and 2).
Forest plot of the proportion of 68Ga–prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET) positivity by patient cohort type. ES = effect size; CI = confidence interval. Reference numbers for the studies are as in Table 1.
In assessing disease recurrence, PSMA PET positivity increased with the PSA category (Fig. 4). For patients with PSA <0.2 ng/ml, the pooled estimate was 42%, which increased to 58%, 76%, and 95% for the 0.2–0.99, 1.00–1.99, and >2.00 ng/ml PSA subgroups, respectively. There was high heterogeneity within the <0.2 and 1.00–1.99 ng/ml subgroups and very high heterogeneity between subgroups (I2 = 97.4%); the test for small-study effects did not reach significance (Supplementary Fig. 3). In meta-regression analysis (Fig. 5), the predicted positivity was 48% (95% CI 38–57%) for PSA of 0.2 ng/ml, 56% (95% CI 49–64%) for 0.5 ng/ml, and 70% (95% CI 63–76%) for 1.0 ng/ml.
Forest plot of the proportion of 68Ga–prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET) positivity by PSA category. ES = effect size; CI = confidence interval. Reference numbers for the studies are as in Table 1.
Scatterplot of prostate specific antigen (PSA) level versus the proportion of 68Ga–prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET) positivity. The blue line is the meta-regression prediction and shading shows the 95% confidence interval. The size of the circles is related to the inverse of the variance.
A similar finding was observed for PSAdt: the pooled PSMA positivity was 64% for PSAdt ≥6 mo and 92% for PSAdt <6 mo (Fig. 6). There was high heterogeneity between the subgroups (I2 = 84.2%) and evidence of a small-study effect in the long PSAdt subgroup (Supplementary Fig. 4).
Forest plot of the proportion of 68Ga–prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET) positivity by prostate-specific antigen doubling time (PSA-dt) category. ES = effect size; CI = confidence interval.
As a sensitivity analysis, we excluded subpopulations with a sample size of less than ten and repeated the meta-analyses. This decreased the point estimate for 68Ga-PSMA PET positivity in the primary staging cohort to 27% (95% CI 15–42%). All other effects were negligible, with differences of ≤2% in the point estimates and CI boundaries for overall positivity and two PSA category proportions.
Of the studies included, 11 reported histopathologic correlation with 68Ga-PSMA PET; however, only five met the aforementioned inclusion criteria (summarised in Table 2). Of the five studies reporting the predictive ability of 68Ga-PSMA PET imaging with respect to histology-proven disease, per-patient and per-lesion analyses were possible for four studies each (Fig. 7). For per-lesion analysis, the summary sensitivity is 80% and specificity is 97%. For per-patient analysis, the summary sensitivity and specificity are both 86%, although the confidence intervals are especially wide because of the low patient numbers.
Studies with histopathologic correlation data for 68Ga PSMA PET–positive lesions included in pooled analysis
a Not included in the pooled analysis as data points did not meet the inclusion criteria.
HP = histopathology; LND = lymph node dissection; SS = sensitivity; SP = specificity.
68Ga-PSMA PET is a novel targeted imaging modality that may improve the identification of metastatic prostate cancer. Our meta-analysis results identified indication, PSA, and PSA-based kinetics as risk factors for positive imaging. Furthermore, pooled sensitivity and specificity for the available data appear promising compared to alternative imaging modalities for metastatic prostate cancer.
The current study highlights the growing body of evidence supporting the use of 68Ga-PSMA PET for primary staging. In this setting, groups have reported pooled positivity of 40%. Given that the risk of metastatic spread is unlikely in low-risk disease, a majority of the studies included patients with intermediate- and high-risk prostate cancer in accordance with the D’Amico classification [47]
To date, the majority of data outlining the utility of 68Ga-PSMA PET are in the setting of secondary staging for biochemical recurrence after definitive therapy. In clinical practice, early detection and highly accurate localisation of disease recurrence are critical, as these may facilitate initiation of subsequent therapies, such as radiotherapy [54]
Pooled data from the current study highlight the promising detection rates for 68Ga-PSMA PET in prostate cancer with low PSA or PSAdt. Despite advances in bone scintigraphy and CT imaging, detection of locoregional or distant recurrence with low PSA has been problematic. Therefore, most guidelines recommend imaging when patients are symptomatic or PSA levels are >10 ng/ml [4]
An increasing number of centres are reporting early outcomes for 68Ga-PSMA PET, particularly in Germany and Australia, with results for many series yet to be published [59]
There are several limitations to the current study. First, a majority of the series used for meta-analysis were derived from small, retrospective, single-institutional studies. In addition, the heterogeneous nature of the patient cohorts, treatment protocols, and study designs included represents a potential limitation of the data available for analysis. Second, of the studies used for pooled sensitivity and specificity data, the majority had a small sample size and assessed patients in the primary staging setting. Additional data in the future will undoubtedly be of benefit for such analyses.
The absence of accurate imaging for detection of small-volume metastases in advanced prostate cancer has prompted the introduction of 68Ga-PSMA PET. The results of the current study suggest that PSA and associated kinetics predict the risk of metastatic disease diagnosed by 68Ga-PSMA PET. This novel imaging modality appears to provide superior sensitivity and specificity compared to alternative techniques. These promising early results for 68Ga-PSMA PET indicate a significant need for further clinical data.
Author contributions: Nathan Lawrentschuk had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Lawrentschuk, Perera, Papa.
Acquisition of data: Perera, Papa, Christidis, Wetherell.
Analysis and interpretation of data: Papa, Perera, Hofman.
Drafting of the manuscript: Perera, Papa, Hofman, Murphy, Bolton.
Critical revision of the manuscript for important intellectual content: Murphy, Bolton, Hofman, Lawrentschuk.
Statistical analysis: Papa.
Obtaining funding: None.
Administrative, technical, or material support: None.
Supervision: Bolton, Lawrentschuk, Murphy, Hofman.
Other: None.
Financial disclosures: Nathan Lawrentschuk certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None.
Funding/Support and role of the sponsor: None.
Acknowledgments: Marlon Perera is supported by a Royal Australasian College of Surgeons scholarship.
Prostate cancer is among the most prevalent cancers worldwide and is the third most common cause of cancer-associated mortality among men [1]
Prostate-specific membrane antigen (PSMA) is a transmembrane protein with a 707-amino-acid extracellular portion. The PSMA gene (FOLH1) is located on the short arm of chromosome 11. PSMA is expressed in the apical region of prostatic cells, the epithelium surrounding prostatic ducts [6]
To date, the use of 68Ga-PSMA has been well reported, with the compound Glu-NH-CO-NH-Lys-(Ahx)-[68Ga]-HBED (68Ga-PSMA-11) developed by the Heidelberg group in Germany. Initial series revealed superior sensitivity and specificity profiles compared to conventional choline-based tracers [19]
A systematic review was performed in accordance with Cochrane Collaboration and Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) guidelines [20]
Studies evaluating the utility of 68Ga-PSMA PET in detection of metastatic disease in advanced prostate cancer were included for analysis. Study designs considered for inclusion were clinical trials, prospective studies, and retrospective cohorts or comparative series. Studies assessing the diagnostic utility of 68Ga-PSMA PET in prostate cancer staging (before definitive treatment) or staging for recurrent disease (following therapy) were included for assessment. Studies were excluded if 68Ga-PSMA PET was used in assessing primary (prostatic) disease only or a specific visceral metastatic deposit (eg, pulmonary or cerebral metastases). In the current analysis, only studies using the 68Ga-PSMA-11 PSMA surface antigen HBED-CC (PSMA-11) were included for analysis provided the tracer was bound to 68Ga. Studies were excluded if alternative PSMA-bound radiotracers were used (eg, 18F or 99mTc tracers). No language or sample-size restrictions were used. Where duplicate study populations or analyses of repeated data were identified from the literature review, the publication reporting a larger sample size was used for analysis.
The primary outcome was to identify predictors of 68Ga-PSMA PET positivity. Studies that included only 68Ga-PSMA PET–positive studies were excluded, as predictive data were not available for analysis. The secondary outcome measure was the sensitivity and specificity of 68Ga-PSMA PET–positive lesions in advanced prostate cancer. For sensitivity and specificity analysis, only studies that included routine 68Ga-PSMA PET before preplanned lymph node dissection were included. Inclusion of series for which nodal biopsy was performed at the clinician's discretion does not provide meaningful false-negative data and thus does not provide accurate specificity values. An inadequate number of studies robustly assessed prostatic bed recurrence or suspicious bony metastatic disease in the manner outlined above. Therefore, we only assessed sensitivity and specificity values for 68Ga-PSMA PET in lymph nodes.
Studies were assessed for quality using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool [22]
The following information was extracted from each study: sample size, age, indication for PET (primary staging or recurrent disease staging), PSA, previous therapies, initial cancer stage, 68Ga-PSMA PET characteristics, rates of positive PET, and histopathologic correlation data. Rates of 68Ga-PSMA PET positivity were collected and stratified by pre-PET PSA and PSA doubling time (PSAdt) when possible. When histopathologic correlation data were available, numbers of true positives, false positives, true negatives, and false negatives were collected, as appropriate. For studies that included 68Ga-PSMA PET for both primary staging and recurrent cancer staging, the extracted data are displayed separately when available.
Extracted data were collated in Excel 2007 (Microsoft Corporation, Redmond, CA, USA) and analysis was performed using Stata v.12.0SE (College Station, TX, USA). Meta-analysis of proportions was performed using the metaprop command in Stata [23]
In patients undergoing a scan for disease recurrence, we performed a PSA level analysis. Note that for the cohort used by Afshar-Oromieh et al [14]
Random-effects meta-regression with Freeman-Tukey transformation was performed for study-defined PSA categories where the reference point was <2 ng/ml. We could not assign a valid reference point for categories greater than this as the reporting of PSA means, medians, and ranges was heterogeneous. Values were back-transformed using the equation described by Miller [26]
Summary sensitivity, specificity, and hierarchical receiver operating characteristic curves were created using the midas command [27]
Using the systematic search strategy outlined in the Supplementary material, 1895 articles were identified, of which 189 were duplicate records and excluded. Of the remaining 1706 records, 1470 were not relevant to the research question. A further 202 were conference abstracts, reviews, letters, and editorials that could not be quality assessed, and thus were excluded. From the remaining 34 articles, 11 were excluded as they did not contain relevant results and five contained duplicate data. One additional study was excluded as patients were enrolled following negative choline-based PET, and thus provided a skewed patient population [28]
Of the 16 studies relevant to the meta-analysis, one was prospective and 15 were retrospective in nature. Two studies included outcomes for 68Ga-PSMA PET performed before definitive therapy (primary staging), eight reported outcomes for biochemical recurrence or disease progression staging (secondary staging), and six included mixed groups. Basic details for the studies included are listed in Table 1.
Characteristics of the studies included
a The tracer used in all cases was 68Ga-PSMA-11.
b PET was used for 95 patients and magnetic resonance imaging for all 130 patients.
c Mean.
ADT = androgen deprivation therapy; ARTx = adjuvant radiotherapy; BCR = biochemical recurrence; CE = contrast-enhanced; CT = computerised tomography; CTx = chemotherapy; HIFU = high-intensity focused ultrasound; HR = high resolution;, LND = lymph node dissection, LNM = lymph node metastases; NCE = non–contrast-enhanced; NR = not reported; PCa = Prostate cancer; PET = positron emission tomography; PSMA = prostate-specific membrane antigen; RP = radical prostatectomy; RTx = primary radiotherapy; SRP = salvage prostatectomy.
While patient selection was generally acceptable in the studies included, a few studies did not clearly report the inclusion criteria. Furthermore, several studies included mixed patient populations including primary and secondary staging groups, raising concerns regarding applicability. All the studies clearly reported methodology for the index test and were thus not considered a significant source of potential bias. Of the studies included, 11 involved a reference test: histopathologic correlation of 68Ga-PSMA PET–positive lesions. However, in terms of flow and timing, multiple studies were at risk of bias, as many included targeted biopsies of suspicious lesions only. Such articles were excluded from sensitivity and specificity analyses because the false-negative data are not accurate. In total, five studies performed 68Ga-PSMA PET before planned lymph node sampling. Summary findings for the QUADAS-2 appraisal are illustrated in Figure 2.
(A) Appraisal of the quality of the studies included according to the Quality Assessment for Diagnostic Studies-2 (QUADAS-2) tool [22]
In total, we analysed 16 studies involving 1309 patients who underwent a 68Ga-PSMA PET scan, of which 926 (70.7%) were positive. In an overall meta-analysis by cohort type, 40% (95% CI 19–64%) of scans were positive for patients undergoing primary staging and 76% (95% CI 66–85%) for those undergoing secondary staging (Fig. 3). There was high heterogeneity between groups and within all subgroups (I2 > 70%). Egger's test for small-study effects did not reach significance (p > 0.10; Supplementary Figs. 1 and 2).
Forest plot of the proportion of 68Ga–prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET) positivity by patient cohort type. ES = effect size; CI = confidence interval. Reference numbers for the studies are as in Table 1.
In assessing disease recurrence, PSMA PET positivity increased with the PSA category (Fig. 4). For patients with PSA <0.2 ng/ml, the pooled estimate was 42%, which increased to 58%, 76%, and 95% for the 0.2–0.99, 1.00–1.99, and >2.00 ng/ml PSA subgroups, respectively. There was high heterogeneity within the <0.2 and 1.00–1.99 ng/ml subgroups and very high heterogeneity between subgroups (I2 = 97.4%); the test for small-study effects did not reach significance (Supplementary Fig. 3). In meta-regression analysis (Fig. 5), the predicted positivity was 48% (95% CI 38–57%) for PSA of 0.2 ng/ml, 56% (95% CI 49–64%) for 0.5 ng/ml, and 70% (95% CI 63–76%) for 1.0 ng/ml.
Forest plot of the proportion of 68Ga–prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET) positivity by PSA category. ES = effect size; CI = confidence interval. Reference numbers for the studies are as in Table 1.
Scatterplot of prostate specific antigen (PSA) level versus the proportion of 68Ga–prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET) positivity. The blue line is the meta-regression prediction and shading shows the 95% confidence interval. The size of the circles is related to the inverse of the variance.
A similar finding was observed for PSAdt: the pooled PSMA positivity was 64% for PSAdt ≥6 mo and 92% for PSAdt <6 mo (Fig. 6). There was high heterogeneity between the subgroups (I2 = 84.2%) and evidence of a small-study effect in the long PSAdt subgroup (Supplementary Fig. 4).
Forest plot of the proportion of 68Ga–prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET) positivity by prostate-specific antigen doubling time (PSA-dt) category. ES = effect size; CI = confidence interval.
As a sensitivity analysis, we excluded subpopulations with a sample size of less than ten and repeated the meta-analyses. This decreased the point estimate for 68Ga-PSMA PET positivity in the primary staging cohort to 27% (95% CI 15–42%). All other effects were negligible, with differences of ≤2% in the point estimates and CI boundaries for overall positivity and two PSA category proportions.
Of the studies included, 11 reported histopathologic correlation with 68Ga-PSMA PET; however, only five met the aforementioned inclusion criteria (summarised in Table 2). Of the five studies reporting the predictive ability of 68Ga-PSMA PET imaging with respect to histology-proven disease, per-patient and per-lesion analyses were possible for four studies each (Fig. 7). For per-lesion analysis, the summary sensitivity is 80% and specificity is 97%. For per-patient analysis, the summary sensitivity and specificity are both 86%, although the confidence intervals are especially wide because of the low patient numbers.
Studies with histopathologic correlation data for 68Ga PSMA PET–positive lesions included in pooled analysis
a Not included in the pooled analysis as data points did not meet the inclusion criteria.
HP = histopathology; LND = lymph node dissection; SS = sensitivity; SP = specificity.
68Ga-PSMA PET is a novel targeted imaging modality that may improve the identification of metastatic prostate cancer. Our meta-analysis results identified indication, PSA, and PSA-based kinetics as risk factors for positive imaging. Furthermore, pooled sensitivity and specificity for the available data appear promising compared to alternative imaging modalities for metastatic prostate cancer.
The current study highlights the growing body of evidence supporting the use of 68Ga-PSMA PET for primary staging. In this setting, groups have reported pooled positivity of 40%. Given that the risk of metastatic spread is unlikely in low-risk disease, a majority of the studies included patients with intermediate- and high-risk prostate cancer in accordance with the D’Amico classification [47]
To date, the majority of data outlining the utility of 68Ga-PSMA PET are in the setting of secondary staging for biochemical recurrence after definitive therapy. In clinical practice, early detection and highly accurate localisation of disease recurrence are critical, as these may facilitate initiation of subsequent therapies, such as radiotherapy [54]
Pooled data from the current study highlight the promising detection rates for 68Ga-PSMA PET in prostate cancer with low PSA or PSAdt. Despite advances in bone scintigraphy and CT imaging, detection of locoregional or distant recurrence with low PSA has been problematic. Therefore, most guidelines recommend imaging when patients are symptomatic or PSA levels are >10 ng/ml [4]
An increasing number of centres are reporting early outcomes for 68Ga-PSMA PET, particularly in Germany and Australia, with results for many series yet to be published [59]
There are several limitations to the current study. First, a majority of the series used for meta-analysis were derived from small, retrospective, single-institutional studies. In addition, the heterogeneous nature of the patient cohorts, treatment protocols, and study designs included represents a potential limitation of the data available for analysis. Second, of the studies used for pooled sensitivity and specificity data, the majority had a small sample size and assessed patients in the primary staging setting. Additional data in the future will undoubtedly be of benefit for such analyses.
The absence of accurate imaging for detection of small-volume metastases in advanced prostate cancer has prompted the introduction of 68Ga-PSMA PET. The results of the current study suggest that PSA and associated kinetics predict the risk of metastatic disease diagnosed by 68Ga-PSMA PET. This novel imaging modality appears to provide superior sensitivity and specificity compared to alternative techniques. These promising early results for 68Ga-PSMA PET indicate a significant need for further clinical data.
Author contributions: Nathan Lawrentschuk had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Lawrentschuk, Perera, Papa.
Acquisition of data: Perera, Papa, Christidis, Wetherell.
Analysis and interpretation of data: Papa, Perera, Hofman.
Drafting of the manuscript: Perera, Papa, Hofman, Murphy, Bolton.
Critical revision of the manuscript for important intellectual content: Murphy, Bolton, Hofman, Lawrentschuk.
Statistical analysis: Papa.
Obtaining funding: None.
Administrative, technical, or material support: None.
Supervision: Bolton, Lawrentschuk, Murphy, Hofman.
Other: None.
Financial disclosures: Nathan Lawrentschuk certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None.
Funding/Support and role of the sponsor: None.
Acknowledgments: Marlon Perera is supported by a Royal Australasian College of Surgeons scholarship.
Pooled data appear promising, especially in biochemical recurrence setting, suggesting favorable sensitivity and specificity profiles of 68 Ga-PSMA PET compared to choline-based PET imaging. 68 Ga-PSMA PET may help in localizing prostate cancer recurrence at lower PSA values.