PSMA PET in Favourable Intermediate-Risk Prostate Cancer? Gold Mine or Money Pit

Abstract

Background/Objectives: Since the proPSMA trial, prostate-specific membrane antigen (PSMA) positron emission tomography (PET) scan has primarily replaced conventional imaging for staging newly diagnosed prostate cancer. The objective of this commentary is to summarise the existing literature on the role of PSMA PET in staging favourable intermediate-risk prostate cancer. Methods: A literature search was conducted on Embase and Ovid MEDLINE, and three retrospective cohort studies were identified. Results: Overall, these studies demonstrated a low prevalence of nodal and distant metastases, as well as modest diagnostic performance of PSMA positron emission tomography-computed tomography (PET-CT) in this patient group. Additionally, PSMA PET did not significantly outperform existing nomograms in predicting lymph node involvement. Conclusions: Given its limited sensitivity, low yield, and cost, the routine use of PSMA PET-CT in favourable intermediate-risk prostate cancer patients is not recommended. Further prospective studies and cost-effectiveness analyses are warranted to clarify its role in this population.

1. Introduction

The European Association of Urology (EAU) guidelines define intermediate-risk prostate cancer (PCa) as patients with either a prostate-specific antigen (PSA) level between 10 and 20 ng/mL, an International Society of Urological Pathology grade group (ISUP GG) of 2 or 3, or tumour stage T2b (cancer involves more than half of one lobe but not both lobes) (see

Table 1. Simplified European Association of Urology (EAU) and National Comprehensive Cancer Network (NCCN) risk stratification of prostate cancer.

EAU guideline	Low risk	Intermediate risk		High risk
	ISUP GG 1 And PSA < 10 ng/mL And ≤cT2a	ISUP GG 2/3 Or PSA 10–20 ng/mL Or cT2b		ISUP GG 4/5 Or PSA > 20 ng/mL Or ≥ cT2c
NCCN guideline	Low risk	Favourable intermediate risk	Unfavourable intermediate risk	High risk
	ISUP GG 1 And PSA < 10 ng/mL And ≤cT2a	ISUP GG 1 or 2 And <50% biopsy cores positive And 1 risk factor: PSA 10–20 ng/mL, or cT2b-T2c	ISUP GG 3 And/or ≥50% biopsy cores positive And/or ≥2 risk factors: PSA 10–20 ng/mL, or cT2b-T2c, or ISUP GG 2/3	ISUP GG 4/5 Or PSA > 20 ng/mL Or ≥cT3a

Abbreviations used: European Association of Urology (EAU), National Comprehensive Cancer Network (NCCN), prostate-specific antigen (PSA), International Society of Urological Pathology grade group (ISUP GG), clinical tumour stage (cT).

) [1]. The National Comprehensive Cancer Network (NCCN) guidelines further categorise this group of patients into favourable and unfavourable intermediate-risk diseases. Favourable intermediate-risk disease consists of ISUP GG 1 or 2 patients with less than 50% of biopsy cores positive, having only one intermediate-risk factor: PSA 10–20 ng/mL, or tumour stage T2b-T2c (involving both lobes). The unfavourable disease was defined as ISUP GG 3 PCa, and/or ≥50% of biopsy cores positive, and/or more than one intermediate-risk factor [2].

Management options for intermediate-risk PCa broadly consist of active treatment or active surveillance in selected cases. Since the proPSMA trial, prostate-specific membrane antigen (PSMA) PET-CT (positron emission tomography–computed tomography) has primarily replaced these conventional imaging methods with computed tomography (CT) and bone scintigraphy due to its superior sensitivity and specificity [3]. Despite this shift, limited literature exists on the detection rates of metastatic disease using PSMA PET-CT in intermediate-risk PCa, especially in patients with favourable intermediate-risk PCa [4]. This commentary aimed to summarise existing literature on the role of PSMA-positron emission tomography (PET) in favourable intermediate-risk PCa.

2. Materials and Methods

A literature search was conducted on Embase and Ovid MEDLINE to find current evidence on the role of PSMA PET in staging favourable intermediate disease (see Appendix A), and three manuscripts were identified (see

Table 2. Studies of the role of PSMA PET-CT in favourable intermediate-risk prostate cancer.

Authors	Year	Country	Risk Stratification	Size (n=)	Study Design	Radio-tracers	Outcomes (on PSMA PET Scans)	Conclusion
Dekalo et al. [4]	2022	Israel	NCCN	88	Retrospective cohort study	68Ga-PSMA-11	LNI = 4 (4/88, 4.5%) SVI = 8 (8/88, 9.1%) Extra-capsular extension = 0 (0/88, 0%)	Utilisation of 68Ga-PSMA PET/CT in favourable intermediate-risk prostate cancer patients pre-operatively demonstrated a low yield in identification of LNI at prostatectomy and therefore, the findings of this study do not support the routine use of this imaging in this subgroup of patients.
Luining et al. [5]	2024	The Netherlands	NCCN CPG	NCCN = 86 CPG = 160	Retrospective cohort study	Mixed tracers	NCCN group Locoregional disease = 3 (3/86, 3.5%) Distant metastases = 2 (2/86, 2.3%) CPG group Locoregional disease = 6 (6/160, 3.8%) Distant metastases = 5 (5/160, 3.1%)	Given that the prevalence of metastatic disease in patients with favourable intermediate-risk prostate cancer is relatively low, PSMA PET/CT should be omitted and reserved for patients with unfavourable intermediate or higher-risk disease.
Miller et al. [6]	2024	US	NCCN	195 (=number of patients with no nodal/metastatic involvement on conventional imaging)	Retrospective cohort study	Not specified	Nodal disease = 1.5% Oligometastatic disease (1–5 PSMA-positive distant metastases, with or without nodal disease) = 0% Widespread metastases (>10 PSMA metastases) = 0%	Overall, the rates of nodal or metastatic disease in favourable intermediate-risk patients were low and optimal resource allocation of routine PSMA PET staging in this patient group should be reconsidered.

Abbreviations used: Prostate-specific membrane antigen positron emission tomography (PSMA PET), National Comprehensive Cancer Network (NCCN), lymph node invasion (LNI), seminal vesicle invasion (SVI), Cambridge Prognostic Group (CPG), prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA PET/CT), prostate-specific membrane antigen (PSMA)

). All studies were retrospective cohort studies. Two were published in 2024 in Israel [5] and the United States [6], respectively, and one in 2022 in the Netherlands [4]. Miller et al. [6] and Dekalo et al. [4] utilised the NCCN risk classification system, while Luining et al. included two groups of favourable intermediate-risk patients based on the NCCN and Cambridge Prognostic Group (CPG) classification systems [5]. The CPG system defines favourable intermediate-risk prostate disease as having features including a Gleason score of 3+4 or PSA of 10-20 ng/mL and tumour stage T1 to T2 [5].

3. Results

Dekalo et al. included 88 patients with favourable intermediate-risk PCa in the retrospective cohort study, all of whom had 68Ga-PSMA PET scans before robotic-assisted radical prostatectomy (RARP) and bilateral pelvic lymph node dissection (PLND) [4]. Pre-operatively, 4.5% (n = 4) of the patients had lymph node invasion (LNI) on the PSMA PET scan, and 9.1% had seminal vesicle invasion (SVI, n = 8). The results were then compared with the pathological findings at RARP and PLND and showed sensitivity, specificity, positive predictive value, and negative predictive value of the ⁶⁸Ga-PSMA PET scan for identifying LNI and SVI were 53% and 50%, 98% and 87%, 70% and 25%, and 92% and 99%, respectively. Interestingly, Dekalo et al. also demonstrated no statistically significant difference (p = 0.87) in predicting the risk of LNI between the ⁶⁸Ga-PSMA PET scan and the nomogram developed by Gandaglia et al. [4,7].

Luining et al. conducted a retrospective cohort study and included 2630 patients [5]. Among these, 86 and 160 patients were included in the favourable intermediate-risk groups based on the NCCN and CPG risk classification systems. In the NCCN group, 3.5% (n = 3) of patients had locoregional disease, and 2.3% (n = 2) had distant metastases. Similarly, 3.8% of patients had locoregional disease, and 3.1% had distant metastases in the CPG group. Similarly, Miller et al. reported that nodal and metastatic disease rates in favourable intermediate-risk patients with no nodal and metastatic disease on conventional imaging were 1.5% (n = 3) and 0%, respectively [6].

4. Discussion

In the primary staging of newly diagnosed high-risk prostate PCa, PSMA PET-CT has demonstrated higher accuracy than conventional imaging, as shown in the proPSMA trial [3]. The Society of Nuclear Medicine and Molecular Imaging recommends that PSMA PET-CT be performed in patients with unfavourable immediate-risk PCa and high-risk patients, similar to the guidelines from the NCCN [8]. However, due to insufficient evidence, the Society of Nuclear Medicine and Molecular Imaging advised that PSMA PET-CT is not indicated for patients with favourable intermediate-risk disease [8]. However, in some countries such as Australia, PSMA PET-CT is still funded to stage favourable intermediate-risk PCa [9].

Overall, the routine use of PSMA PET-CT for patients with favourable intermediate-risk PCa is not justified given its low sensitivity and the low prevalence of metastatic disease among this group. Luining et al. reported a low prevalence of metastatic disease in NCCN favourable intermediate-risk PCa compared to unfavourable-risk, high-risk, and very high-risk PCa patients, with the presence of metastatic disease at 5.8%, 12.5%, 22.4%, and 39.8%, respectively [5]. Therefore, the yield of performing PSMA PET scans for staging favourable intermediate-risk PCa for distant metastases appears low. Moreover, no additional metastases were detected on PSMA PET scans among favourable intermediate-risk patients who had no nodal or metastatic disease on conventional imaging in the study conducted by Miller et al. [6]. In terms of LNI, Dekalo et al. showed that only 5% of favourable intermediate-risk PCa patients had LNI on PSMA PET imaging. The sensitivity and positive predictive value of this imaging modality for the detection of LNI in the favourable intermediate-risk group were 50% and 25%, respectively, in this study [4], which were much lower than 83% and 97%, as reported in the proPSMA trial (which included primarily unfavourable intermediate- and high-risk patients) [3]. This may be because this group of patients is much less likely to have nodal involvement. Additionally, performing a PSMA PET scan was not beneficial, as the LNI prediction nomogram developed by Gandaglia et al. appears to give similar results [4].

Additionally, from an economic standpoint, it may not be cost-effective to use PSMA PET-CT as the primary staging imaging modality for patients in the favourable intermediate-risk group. The cost of PSMA PET-CT is estimated to be 1400 Australian dollars (860 euros) in Australia [9]. A cost-effectiveness analysis was undertaken by Song et al. in 2022 and concluded that PSMA PET-CT is likely to be cost-effective for patients with newly diagnosed intermediate- or high-risk prostate disease in Australia compared to conventional imaging. However, the test accuracy parameters used in this analysis did not subdivide the patients into favourable and unfavourable intermediate-risk and high-risk groups [10].

This commentary has limitations, as it only included three studies relevant to the topic of interest, all of which were retrospective. However, it highlighted a few gaps in the current literature that should be addressed in future research. First, more prospective studies are needed to evaluate the role of PSMA PET-CT in the primary staging of favourable intermediate-risk prostate disease. Second, further cost-effectiveness analysis of PSMA PET is also required to justify the routine use of this costly imaging modality in favourable intermediate-risk patients with PCa.

In conclusion, the routine use of PSMA PET-CT among men with favourable intermediate-risk PCa is not recommended, as suggested by the current literature and more prospective studies and cost-effective analyses are needed to evaluate the diagnostic performance and cost benefits of PSMA PET-CT in this population.