PSMA PET/CT in the low- to intermediate-risk prostate cancer: when and why?

Prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA PET/CT) represents a significant advancement in the imaging of prostate cancer (PCa), yet its application in low- and intermediate-risk cases continues to be a topic of active discussion. This article delves into the nuanced role of PSMA PET/CT, critically analyzing its strengths and limitations in these specific risk categories. For patients with low-risk PCa, PSMA PET/CT demonstrates limited effectiveness in routine staging due to its minimal tracer uptake in low-grade tumors. However, its ability to differentiate between low- and high-grade tumors suggests a promising role in active surveillance, offering a potential noninvasive method for monitoring disease progression and aiding in treatment decision-making. In the intermediate-risk PCa setting, the high specificity of PSMA PET/CT in nodal staging makes it a valuable asset for precise surgical and radiation therapy planning. The article underscores the necessity for further research to fully realize the potential of PSMA PET/CT in PCa management, particularly in developing more personalized treatment approaches in these clinical scenarios.

PSMA PET/CT in the management of low- and intermediate-risk PCa is a topic of emerging interest in the uro-oncology community. Current research sheds light on its pros and cons in this setting, revealing limitations in the routine staging of low-risk cases, while simultaneously suggesting potential benefits in active surveillance and precise nodal staging in intermediate-risk scenarios. The article aims to analyze this evolving area, offering insights into the current and potential applications of PSMA PET/CT in the diagnostic landscape of PCa.

PSMA PET/CT IN THE LOW-RISK SETTING

Currently, only a limited amount of data are available regarding the potential role of PSMA PET/CT or PET/magnetic resonance (MR) in low-risk PCa. Overall, we identified six papers comprising 79 patients.1,2,3,4,5,6 The limited utilization of PSMA PET/CT in this context stems from the association between PSMA expression and aggressive disease features, including the Gleason score.7 Specifically, Gultekin et al.4 and Ergül et al.6 reported low PSMA uptake in primary tumors among low-risk PCa patients. These findings suggest a limited PSMA PET/CT sensitivity in staging PCa in this clinical scenario. Consequently, according to the most recent 2023 version of the European Association of Urology (EAU) guidelines,8 PSMA PET/CT is currently not recommended for the routine staging of low-risk PCa.

However, the low PSMA expression in low-risk primary tumors poses the basis for considering the use of PSMA PET/CT in active surveillance for this subset of patients.1 In a multicenter prospective study known as PRIMARY, Emmett et al.9 enrolled men with suspected PCa and assessed the effectiveness of combined imaging using multiparametric magnetic resonance imaging (mpMRI) and PSMA PET/CT in detecting clinically significant PCa (csPCa). In these patients, the tracer uptake intensity, measured by the maximum standardized uptake value (SUVmax), correlated with the International Society of Urological Pathology (ISUP) grade. Moreover, a decreased risk of false negatives was observed when combining PSMA PET/CT with mpMRI compared to MRI alone. Altogether, this suggests the potential for next-generation imaging in detecting csPCa and reducing unnecessary biopsies. In another study, Scheltema et al.10 confirmed that PSMA PET accurately differentiates areas containing csPCa from those containing insignificant or no PCa within the prostate.

Figure 1 displays an emblematic example of a low-risk PCa patient under active surveillance in whom PSMA PET-guided biopsy was performed. The patient is a 67-year-old male under active surveillance for an ISUP Grade Group 1 PCa. The patient was submitted to mpMRI and PSMA PET/CT at IRCCS Ospedale Policlinico San Martino, Genova, Italy. While mpMRI resulted negative for suspicious lesions (axial T2-weighted; Figure 1a), PSMA PET/CT showed the presence of two highly suspicious areas for PCa (axial images; Figure 1b–1d) with the higher SUVmax equal to 19.8. The biopsy targeted to the PSMA uptake located in the right lobe demonstrated the presence of an ISUP Grade Group 3 PCa. Informed consent for publication of this image was obtained from the patient and this study was approved by the Regional Ethical Committee of Liguria (Genova, Italy; Approval No. 343/2019).

Figure 1.

Emblematic case of PSMA-guided biopsy in a low-risk PCa patient under active surveillance. (a) mpMRI, (b) low-dose CT, (c) PSMA PET, and (d) hybrid PSMA PET/CT are displayed. PSMA: prostate-specific membrane antigen; PCa: prostate cancer; mpMRI: multiparametric magnetic resonance imaging; CT: computed tomography; PET: positron emission tomography.

Although these preliminary findings are promising, further studies are needed to reinforce the role of PSMA PET/CT in active surveillance.

PSMA PET/CT IN THE INTERMEDIATE-RISK SETTING

Currently, there are three phase III trials available on the use of PSMA PET/CT in the primary staging of PCa: proPSMA trial of Hofman et al.11 with 302 patients, study of Hope et al.12 with 764 patients, and LIGHTHOUSE trial of Surasi et al.13 with 372 patients. Two of these trials enrolled patients with intermediate-risk PCa (n = 289 in total).12,13 Additionally, 14 more studies are currently available on this subject, encompassing a total of 591 patients.4,5,14,15,16,17,18,19,20,21,22,23,24,25

Most of these studies have primarily focused on nodal staging. Compared to conventional imaging, PSMA PET/CT demonstrates higher sensitivity in detecting pathological nodes. In the study conducted by Malaspina et al.,18 the sensitivity was 0.87 (95% confidence interval [CI]: 0.71–0.95) for PSMA PET/CT, while it was 0.37 (95% CI: 0.22–0.55) for MRI and 0.26 (95% CI: 0.14–0.43) for CT. Furthermore, Szigeti et al.19 found a 10% higher sensitivity for PSMA PET/CT than MRI in the nodal assessment. The phase III trial by Hope et al.12 reported a sensitivity of 0.40 (95% CI: 0.34–0.46) and a specificity of 0.95 (95% CI: 0.92–0.97) considering histopathology as the standard of reference. In this study, some patients initially classified as falsely positive for nodal involvement exhibited persistent PSA levels. Subsequent restaging PSMA PET/CT scans indicated positivity in the same nodes, suggesting that these nodes may not have been accurately removed during surgery, potentially leading to an inaccurate histopathological reference.12 When considering this aspect in further analyses, the sensitivity increased to 0.44 (95% CI: 0.33–0.55), and the specificity rose to 0.97 (95% CI: 0.94–0.99). Similar data were obtained in the SALT trial,14 and in the LIGHTHOUSE phase III trial,13 which enrolled a higher percentage of intermediate-risk patients, compared to the study by Hope et al.12 Other trials have reported similar results.5,6,15,16,17

Taken together, these data highlight that albeit higher than conventional imaging methods, PSMA PET/CT offers limited sensitivity for nodal staging. This reduced sensitivity can be partially attributed to PET’s relatively low spatial resolution (roughly 5 mm), which restricts its ability to detect the smallest lymph nodes. However, since the negative predictive value (NPV) of a diagnostic tool depends on the prevalence of the outcome of interest (namely, nodal involvement in this case), considering that the probability of positive nodes at lymphadenectomy is relatively low in the intermediate-risk setting, undergoing PSMA PET/CT could potentially enable these patients to avoid the risks associated with this surgical procedure.21

On the one hand, the high specificity of PSMA PET/CT allows for accurate guidance of surgical and radiation procedures in these patients. If nodes are PSMA-positive, it indicates the presence of the disease, even when PSMA-avid nodes are found in atypical sites. This is relevant as in a relatively high percentage of cases in N+ staging (around 36% according to Koerber et al.20), nodal metastases are located outside the pelvis. The standard pelvic lymph node dissection (PLND) might be insufficient for these patients, as they already have disseminated disease beyond the surgical template. In these cases, PSMA PET/CT may guide the extension of the surgical resection or the irradiation field.

Regarding M staging, the proPSMA study demonstrated the superior accuracy of PSMA PET/CT compared to conventional imaging for detecting visceral and bone metastases.11 However, this study specifically focused on patients with high-risk PCa. Only a few studies have explored the role of PSMA PET/CT for M staging in intermediate-risk PCa, and they have generally found that the added value of this imaging technique is quite limited in this patient group.13,22,23,24 This limitation can be attributed to the very low risk of ab initio metastatic disease in patients who do not fall into the high-risk category. In a study by Yaxley et al.,24 metastases were identified only in 6.4% of men with ISUP Grade Group 2 or 3 PCa.

An emerging research topic is the prognostic role of PSMA PET/CT imaging findings at the time of staging.25,26 In a recent study, Roberts et al.27 analyzed the primary tumor, showing that a higher PSMA uptake, measured by means of SUVmax, is predictive of a shorter biochemical recurrence-free survival after radical prostatectomy. In addition, van Leeuwen et al.28 explored the prognostic role of lymph node positivity at staging in intermediate- and high-risk patients. They showed that nodal PSMA positivity highly increases the risk of biochemical persistence of PSA after radical prostatectomy, with a higher predictive value than presurgery PSA, Gleason score, and clinical T stage.28

CONCLUSIONS

In patients with low-risk PCa, PSMA PET/CT should not be routinely used to stage the disease, mainly due to the low or absent tracer uptake in low-grade tumors. However, the ability to distinguish between low- and high-grade tumors based on PSMA uptake makes this imaging tool potentially valuable for active surveillance.

Regarding intermediate-risk patients, PSMA PET/CT has a limited role in evaluating visceral and bone metastases, given their low prevalence in this subgroup of patients. However, it is a valuable imaging technique for nodal staging, thanks to its high specificity, which allows for accurate guidance of surgical and radiation procedures. Furthermore, given the relatively low probability of positive nodes at lymphadenectomy in the intermediate-risk setting, patients with a negative result for nodal involvement on PSMA PET/CT may avoid PLND and its associated surgical risks, especially considering the limited clinical benefits of the procedure.

AUTHOR CONTRIBUTIONS

LS performed the literature search. LS and MB equally contributed to the manuscript writing and reviewing. Both authors read and approved the final manuscript.

COMPETING INTERESTS

MB reports personal fees from AAA and General Electric Healthcare outside the submitted work. LS declares no competing interests.