Comparative Performance of 68Ga-PSMA-11 PET/CT and Conventional Imaging in the Primary Staging of High-Risk Prostate Cancer Patients Who Are Candidates for Radical Prostatectomy

This prospective study aimed to (1) compare the diagnostic performance of 68Ga-PSMA-11 PET/CT with respect to conventional imaging (computed tomography (CT) and bone scintigraphy (BS)) in the primary staging of high-risk prostate cancer (PCa) patients and (2) validate PSMA-PET/CT accuracy in pelvic nodal staging in comparison with postoperative histopathology and assess PSMA-PET/CT’s impact on patient management. Sixty castration-sensitive high-risk (ISUP 4–5 and/or PSA > 20 ng/mL and/or cT3) PCa patients eligible for radical prostatectomy were enrolled (median PSA 10.10 [IQR: 6.22–17.95] ng/mL). PSMA-PET/CT, compared with CT, identified nodal (N) and/or distant metastases (M1) in 56.7% (34/60) vs. 13.3% (8/60) (p < 0.001) of patients: N + 45% vs. 13.3% (p < 0.001), M1a 11.7% vs. 1.7% (p = 0.03), M1b 23.3% vs. 1.7% (p < 0.001). Compared with BS, PSMA-PET/CT localized unknown skeletal metastases in 15% (9/60) of cases, with no false negative findings. Overall, PSMA-PET/CT led to a TNM upstaging in 45.0% (27/60) of cases, with no evidence of downstaging, resulting in a change in management in up to 28.8% (17/59) of patients. Compared with histopathology data (n = 32 patients), the per-patient accuracy of PSMA-PET/TC for detecting pelvic nodal metastases was 90.6%. Overall, the above evidence supports the use of PSMA-PET/CT in the diagnostic workup of high-risk prostate cancer staging.


Introduction
The accurate staging of prostate cancer (PCa) is essential for treatment planning in high-risk patients.Radical prostatectomy with or without lymphadenectomy and definitive radiotherapy (RT) are the main curative treatments for PCa.However, a significant proportion of patients may experience disease recurrence following these interventions.A more accurate disease staging could prove beneficial in enhancing initial treatment, subsequently reducing the risk of relapse.Until recently, clinical guidelines have recommended the use of conventional imaging (CI) techniques such as computed tomography (CT) and bone scintigraphy (BS) for the primary staging of high-risk PCa; however, such techniques have suboptimal accuracy.In this context, the novel radiopharmaceuticals for molecular imaging which target the prostate-specific membrane antigen (PSMA) have gained traction.PSMA is a transmembrane glycoprotein constitutively expressed within the apical epithelium of prostatic secretory ducts and overexpressed in PCa cells, in which it migrates to the luminal surface as malignant transformation occurs.
In the past years, PSMA positron emission tomography/computed tomography (PSMA-PET/CT) has become an established imaging modality for restaging patients with early biochemical recurrence or persistence [1][2][3][4][5]; indeed, the European Association of Urology (EAU) guidelines recommend performing a PSMA-PET scan in patients with PSA failure after radical treatment, provided that the imaging data can potentially impact the patient's clinical management [6].More recently, literature studies have demonstrated the higher sensitivity of molecular imaging with PSMA PET/CT compared to conventional imaging in the setting of the primary staging of high-risk PCa [7,8].Accordingly, the revised EAU guidelines recommend performing PSMA-PET/CT imaging (if available) in the primary staging of intermediate and high-risk PCa patients [6].However, in the absence of clear data regarding the ideal management and prognosis of patients staged with PSMA-PET/CT, they advise caution when basing therapeutic decisions on molecular imaging findings, especially in cases of patients with metastases detectable only by PET/CT.Therefore, more studies evaluating the diagnostic performance of PSMA-PET/CT and its impact on patient management are needed.This prospective study, which reflects real-world practice, aimed to evaluate the 68 Ga-PSMA-11 PET/TC diagnostic performance in the primary staging of patients with high-risk PCa compared to conventional imaging modalities, as well as to assess its potential impact on patient management.Furthermore, the diagnostic accuracy of 68 Ga-PSMA-11 PET/CT in pelvic nodal staging was assessed using postoperative histopathology data as a reference standard.

Study Design
As part of a prospective study, sixty (n = 60) consecutive PCa patients underwent whole-body 68 Ga-PSMA-11 PET/CT imaging at our institution (Department of Nuclear Medicine, University Hospital of Turin) between April 2021 and January 2024.The patients were enrolled according to the following inclusion criteria: (1) histologically proven diagnosis of PCa; (2) high-risk classification according to the d'Amico criteria (ISUP 4-5 and/or PSA > 20 ng/mL and/or cT3); (3) eligibility for radical prostatectomy (i.e., ≥10 years life expectancy and no major contraindication for radical prostatectomy); and (4) CT and BS performed within three months of 68 Ga-PSMA-11 PET/TC.The exclusion criteria were (1) an inability to undergo a PET/CT scan; and (2) previous treatments, including androgen deprivation therapy (ADT).

Procedures and Image Interpretation
The radiopharmaceutical ( 68 Ga-PSMA-11) was synthesized in the radiochemistry laboratory of the Division of Nuclear Medicine of the AOU Città della Salute e della Scienza, University of Turin, as previously documented [9], in accordance with procedural guidelines [10,11]. 68Ga-PSMA-11 was administered intravenously (1.8-2.2MBq/kg) to all patients, followed by hydration with 0.5 L of saline solution during uptake.Informed consent was obtained from all subjects before administration.The diagnostic imaging did not require specific patient preparation. 68Ga-PSMA-11 PET/CT imaging was performed according to standard recommendations, as previously described [9], using a digital PET/CT scanner (Vereos, Philips HealthCare, Eindhoven, The Netherlands).PET emission data were co-registered with a low-dose CT scan for attenuation correction and reconstructed with the ordered subset expectation maximization (OSEM) algorithm (3 iterations, 15 subsets).Two experienced nuclear medicine physicians independently reviewed the PET/CT images, and any resulting discrepancy was solved by consensus.In accordance with the E-PSMA procedure guidelines [10,11], a per-region analysis was performed.Pathological findings were defined as areas of increased focal radiopharmaceutical uptake compared to the background, not localized in sites of known physiologic uptake.
A contrast-enhanced diagnostic CT scan of the abdomen and pelvis was acquired using a 64-slice CT scanner (Optima, GE Healthcare, Milwaukee, WI, USA).In accordance with the current protocol recommendations of the Italian Society of Medical and Interventional Radiology (SIRM), CT scans were acquired with a voltage level up to 120 kV based on the patient's BMI and a dose-modulated tube current (automated mAs).A contrast volume (Iomeprolo 400 mg/mL) up to 0.63 gI/Kg was injected at 2.0 mL/sec, and imaging was performed approximately 70-90 s after contrast injection for the portal venous phase.CT images were reconstructed with the slice thickness down to 1 mm.The images were analyzed using a dedicated workstation (Advantage Windows, General Electric, Boston, MA, USA).
Bone scintigraphy was performed using a gamma camera (Discovery NM/CT 670 ES, GE Healthcare, Milwaukee, WI, USA), equipped with low-energy high-resolution (LEHR) collimators and an energy window centered at 140 keV ± 10%.According to the procedural recommendations of the Italian Association of Nuclear Medicine (AIMN), 2-4 h after the intravenous administration of 300-740 MBq of 99m Tc-HMDP, whole-body planar images in anterior and posterior projections were acquired with a scan speed of 12-15 cm/min and a matrix size of 256 × 1024 pixels.Additional static or tomographic imaging (single-photon emission computed tomography SPECT) of areas of interest was performed according to clinical evaluation, and SPECT data were co-registered with a low-dose CT scan for the attenuation correction and anatomical localization of scintigraphic findings.The images were analyzed using the Xeleris v4 software (GE Healthcare, USA).
In this prospective observational study, clinical decisions were based on conventional imaging (CT and bone scintigraphy) according to guidelines.However, a retrospective evaluation of the PET-driven change in management was performed by assessing the potential impact of PET imaging on the subsequent patient management, taking into account the additional findings from molecular imaging.The change in management criteria were defined as follows: (a) switch to systemic therapy due to previously unknown metastatic involvement; (b) change in the lymphadenectomy template in patients who are candidates for surgical treatment; (c) modification of the RT treatment planning and/or hormonal treatment; (d) potential stereotactic ablative RT (SABR) treatment in the case of the novel identification of oligometastatic disease spread; and (e) identification of collateral PSMA-avid oncologic findings (unrelated to PCa).Finally, the presence of false positive findings solely at conventional imaging (i.e., bone scintigraphy) was recorded, since in this case, staging with PSMA-PET/CT could obviate the need for further confirmatory tests, thus impacting patients' management.

Statistical Analysis
For each patient, the collected data included information about age, multiparametric magnetic resonance imaging (mpMRI) findings, disease staging at conventional imaging (CT and BS), prostate biopsy and histopathological grading, PSA measurements, findings at PSMA-PET/CT imaging, and postoperative histopathology data.Anonymized data regarding the patients' clinical features and imaging findings (PSMA-PET, CT, BS) were stored and queried using a relational database [12].
Population characteristics were presented as absolute/relative frequencies for categorical variables and as a median (Inter Quartile Range (IQR)) for continuous ones.Inferential statistics were performed using the Mann-Whitney test for continuous covariates and Fisher's exact test for categorical ones, respectively.CT and PSMA PET/CT detection rates were compared using McNemar's exact test.PSMA PET/CT's accuracy in detecting pelvic nodal metastases was compared with histopathology in terms of sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy.
All reported p-values were two-sided, at the conventional 5% significance level.The data were analyzed as of April 2024 using IBM SPSS Statistics for Windows, version 26.0 (IBM Corp., Armonk, NY, USA).

Comparative Performance of Bone Scintigraphy and PSMA-PET/CT
Bone scintigraphy detected suspicious bone metastases in 16.7% (10/60) of patients, with oligometastatic involvement in 90% of cases.Suspicious findings at bone scintigraphy were later confirmed only in 4/10 patients.No conclusive pathologic findings were detected solely at bone scintigraphy.On the other hand, PSMA-PET/CT identified novel skeletal metastases (M1b) undetected at BS in 15% (9/60) of patients, with PSMA-RADS ≥4 findings in 66.7% (6/9) of them.
Figures 1 and 2 present two clinical cases of metastatic PCa at PSMA-PET/CT undetected at conventional imaging (i.e., CT and bone scintigraphy).

PSMA-PET/CT Accuracy in Pelvic Lymph Node Staging
The accuracy of 68 Ga-PSMA-11 PET/CT in pelvic lymph node staging was evaluated using the postoperative histopathology data of 32 patients as a reference standard.The analysis was conducted both on a per-patient and per-region (hemipelvis) basis.

Biochemical Response after Radical Prostatectomy
Follow-up data after the radical prostatectomy were available in 29 patients.In the subcohort (n = 23) with concordance between conventional and molecular imaging results at staging (i.e., no additional distant or loco-regional metastases outside the surgical template at PSMA-PET/CT), 73.9% (17/23) of patients achieved a complete biochemical response after radical prostatectomy and lymphadenectomy, while 26.1% (6/23) had biochemical persistence.Among those with persistence, five had positive surgical margins, and one showed neuroendocrine differentiation, which can limit PSMA-PET/CT sensitivity.
In the subcohort of patients (n = 6) with additional distant or loco-regional metastases identified at staging PSMA-PET/CT, 83.3% (5/6) had biochemical persistence and the follow-up PSMA-PET/CT scan confirmed the nodal/skeletal metastases previously identified at staging.Only one patient showed a complete biochemical response despite a suspicious skeletal metastasis at staging PSMA-PET/CT, which, however, was reported as equivocal (PSMA-RADS 3).

Discussion
The primary staging of high-risk PCa patients has traditionally relied on the use of abdominal-pelvic CT and bone scintigraphy for the detection of lymph nodal and distant metastases.However, these imaging techniques have intrinsic limitations in terms of sensitivity and specificity.Molecular imaging with PSMA-PET/CT has emerged as an accurate imaging modality for the detection of PCa localizations in different clinical settings, including the primary staging of high-risk PCa patients.However, the diagnostic advantage of PSMA-PET/CT in relation to patients' clinical characteristics, its accuracy compared to histopathology, and its impact on patient management are still a matter of debate.Therefore, this prospective study, which reflects real-world practice, aimed to evaluate the 68 Ga-PSMA-11 PET/TC diagnostic performance in the primary staging of patients with high-risk PCa compared to conventional imaging modalities, as well as to assess its potential impact on patient management.Furthermore, the diagnostic accuracy of 68 Ga-PSMA-11 PET/CT in pelvic nodal staging was assessed using postoperative histopathology data as a reference standard.
In our study, PSMA-PET/CT identified a significantly higher proportion of metastatic patients compared to conventional imaging (CI) (56.7% vs. 16.7%),both in terms of locoregional nodal metastases (N1M0, 25% vs. 8.3%) and distant metastases (M1, 31.7% vs. 8.3%); overall, molecular imaging led to a TNM upstaging in 45.0% (27/60) of patients.The present results about PET/CT detection rates are in line with the study of Zacho et al. [14], reporting a 46% rate of metastatic localizations (N1 and/or M1) and a 27% prevalence of scans positive for locoregional nodal invasion in high-risk PCa patients.As for distant metastatic localizations, the multicenter prospective study by Roach et al. [15] on 108 intermediate and high-risk PCa patients reported a lower detection rate (6%); however, the variability in the detection rate compared to the present study could be due to the different cohort characteristics.Indeed, our real-life study population is characterized by a higher a priori probability of metastatic localizations with respect to the intermediate-risk PCa subgroup included by Roach and colleagues.More recently, a study by Luining et al. [16] on 1879 EAU high-risk PCa patients (mainly scanned with 18 F-DCFPyL and 68 Ga-PSMA-11) reported an overall scan positivity rate of 45%, with a 10% prevalence of locoregional disease and a 35% rate of distant metastatic involvement.Interestingly, they also showed that the prevalence of metastatic disease can range widely between 20% and 60% among high and very-high PCa risk-groups, thus highlighting the potential benefit of further stratifying the prognostic groups (as in the NCCN-National Comprehensive Cancer Network or CPG-Cambridge Prognostic Group classifications).At present, this hypothesis could not be tested in our prospective cohort due to the limited sample size, which prevented further stratification.
In the present analysis, BS detected suspicious bone metastases in 16.7% (10/60) of patients, with a performance comparable to the 12-14% BS detection rate reported by Shanmugasundaram et al. [19] and Luining et al. [16] in EAU high-risk PCa patients.In accordance with the known limited specificity of BS, skeletal involvement was confirmed only in 4/10 patients.Indeed, BS has been reported to show more equivocal lesions than PSMA-PET/CT (15.9% vs. 1.4%) in previous literature studies [20], leading to higher FP rates (16.0-34.8% vs. 0-11.8%)[17].PSMA-PET/CT could thus potentially lower the risk of over-staging and/or treatment delay due to further testing.However, it is well known that PSMA-PET/CT performance in skeletal staging can be affected by the specific radiotracer.In fact, higher FP rates are known to occur with 18 F-PSMA-1007.In our study with 68 Ga-labelled PMSA, PET/CT was able to identify novel skeletal metastases undetected at BS in 15% (9/60) of patients with no cases of understaging, thus confirming its previously reported higher detection rates [21].
Globally, in our study, 68 Ga-PSMA-11 PET/CT had the potential to change management in 28.8% (17/59) of patients staged with CI.This is in agreement with previous studies where the reported rate of change in management ranged between 21% and 28% [7,15,25], as well as with the results of a later metanalysis [26] on 1099 patients, which reported a 28% (95% CI: 23.0-34.0%)rate.
In our study, the great majority of pathologic findings at PSMA-PET/CT had a PSMA-RADS score ≥4, showing a good reader confidence in the scans evaluation.This is in line with the data reported by the proPSMA trial [7], in which PET/CT was associated with a lower rate of equivocal findings compared to CI (7% vs. 23%) and with a higher inter-reader agreement (κ = 0•87 for nodal and κ = 0•88 for distant metastases).Similarly, a following metanalysis reported a higher inter-reader agreement for PSMA-PET (0.78-0.92) than for CI (0.40-0.55) across four studies [3,18,27,28].
When comparing molecular imaging to CI, further aspects should also be taken into account, such as diagnostic radiation exposure and cost-effectiveness.Indeed, aside from its higher diagnostic performance, PSMA-PET/CT could also allow for significantly reducing the radiation exposure compared to CI, as reported by Hofman et al. (8.4 vs. 19.2mSv) [7,37].Considering the improved diagnostic accuracy and the reduced diagnostic radiation exposure, PSMA-PET/CT has the potential for increased cost-effectiveness compared to CI: indeed, from a patient and healthcare perspective, the increased costs of molecular imaging could be balanced by the benefits and cost savings resulting from a more accurate disease staging, a more effective image-guided approach, an improved quality of life, and the avoidance of unnecessary treatments [38,39].A previous cost-effectiveness analysis in the Australian setting has demonstrated an advantage for PSMA-PET/CT over conventional imaging [40], but more robust confirmatory data are still needed.Recently, a preliminary cost-effectiveness analysis in the USA and European settings (Belgium, Germany, Italy, and the Netherlands) has also been published [41].
Finally, in parallel with the future larger adoption of PSMA-PET/CT in the primary staging of prostate cancer, further research should also be aimed towards exploring the impact of different PSMA radiotracers on patients' outcomes.Indeed, in a recent study by Bauckneht et al. [42], different imaging modalities were shown to significantly influence the outcomes of a cohort of 402 oligorecurrent PCa patients undergoing MDT: specifically, 68 Ga-PSMA-11 PET/CT-guided MDT demonstrated longer PFS (HR: 0.51, 95% CI: 0.26-1.00)and PFS2 (HR: 0.24, 95% CI: 0.09-0.60)compared to 18 F-PSMA-1007 PET/CT-guided MDT, as well as longer PFS, PFS2, and OS compared to choline-PET/CT-guided MDT.

Limitations
This study is not exempt from limitations.First, the study cohort comprised 60 patients, and postoperative histopathology data were available only in a subgroup of 32 patients.However, the prospective design of the study and the histopathological validation of PSMA-PET/CT nodal findings represent strengths.Another limitation is the inability to obtain a histopathological validation of all PET/CT findings due to ethical and practical reasons; this aspect, together with the unavailability of composite follow-up data, limits the evaluation of the diagnostic accuracy.Nevertheless, it should be considered that all images were independently interpreted and reported by two nuclear medicine physicians following established guidelines [11], with good agreement and good confidence, as reflected by the PSMA-RADS values.Finally, although PSMA-PET has shown superior diagnostic capabilities over CI, larger prospective multicenter trials are still needed to further investigate whether the PSMA-PET/CT's impact on patients' management translates to improved longitudinal oncological outcomes.

Conclusions
68 Ga-PSMA-11 PET/TC showed a high diagnostic performance in the primary staging of high-risk prostate cancer, with a higher detection rate compared with conventional imaging, leading to a significant TNM upstaging and potential management change.At pelvic nodal staging, the PSMA-PET/CT findings showed a good correlation with the histopathology data.

Figure 3 .
Figure 3.Comparison of the diagnostic performance of conventional (CT + BS) and molecular imaging (PSMA-PET/CT): patients with pathologic findings detected by PSMA-PET/CT and conventional imaging, stratified by anatomical region.

Figure 4 .
Figure 4. Comparison of the diagnostic performance of conventional (CT + BS) and molecular imaging (PSMA-PET/CT): TNM staging and tumor burden evaluation.

Figure 3 .
Figure 3.Comparison of the diagnostic performance of conventional (CT + BS) and molecular imaging (PSMA-PET/CT): patients with pathologic findings detected by PSMA-PET/CT and conventional imaging, stratified by anatomical region.

Figure 3 .
Figure 3.Comparison of the diagnostic performance of conventional (CT + BS) and molecular imaging (PSMA-PET/CT): patients with pathologic findings detected by PSMA-PET/CT and conventional imaging, stratified by anatomical region.

Figure 4 .
Figure 4. Comparison of the diagnostic performance of conventional (CT + BS) and molecular imaging (PSMA-PET/CT): TNM staging and tumor burden evaluation.

Figure 4 .
Figure 4. Comparison of the diagnostic performance of conventional (CT + BS) and molecular imaging (PSMA-PET/CT): TNM staging and tumor burden evaluation.

Table 2 .
Potential change in management driven by PSMA-PET/CT.