Prostate-specific membrane antigen (PSMA) radio-guided surgery in prostate cancer: expanding the spectrum of tracers and technologies for patient-tailored molecular-guided surgery

The exploration of prostate-specific membrane antigen (PSMA)-targeted therapies and diagnostic tools has been a focal point in prostate cancer (PCa) research due to high PSMA expression in the majority of PCa patterns, offering a specific target for both imaging and therapeutic interventions (1). The recent development and application of PSMA-targeted radio-guided surgery (RGS) presents a novel and promising strategy in the surgical management of PCa, with a specific focus on the optimization of the identification of lymph nodal metastases (LNM), which is a well-defined negative prognostic risk factor in PCa and whose removal might maximize local disease control. Therefore, given the current lack of specific guidance for optimal lymph node dissection (LND) templates, the optimization of intraoperative guidance might help in defining the ideal LND strategy with the potential effect of reducing the risk of recurrence and the need for additional therapies (2-4). Based on this premise, Schilham and colleagues designed a prospective study to evaluate the safety and feasibility of ¹¹¹In-PSMA RGS in primary PCa patients, who presented with one or more lymph nodes (LNs) suggestive of metastasis on preoperative ¹⁸F-PSMA positron emission tomography/computed tomography (PET/CT) imaging (5). This approach aims to guide surgeons in real-time to PSMA-expressing LNs during pelvic LND, with the goal of enhancing precision and allowing a guided detection and removal of PSMA-avid LNM. The inclusion of 20 newly diagnosed PCa patients allows to assess the application of this innovative technique in the specific clinical setting of primary PCa.

The authors should be complimented for their remarkable work which adds further important evidence in the context of novel intraoperative guidance techniques for PCa surgery. The protocol has been designed as a feasibility phase I/II study and, as such, it was primarily intended to address the question on the safety of ¹¹¹In-PSMA RGS. Based on this, one of the study’s cornerstone findings is the absence of tracer-related adverse events, underscoring the safety of ¹¹¹In-PSMA RGS. This is in line with what was reported by other series using different tracers. For example, a prospective phase II trial failed to show adverse events associated with the administration of ^99mTc-PSMA-I&S and the use of an intraoperative drop-in gamma probe (6). Similarly, the studies by Gondoputro et al. and Yılmaz et al. did not show higher rates of adverse events associated with radio guidance, and no severe complications exceeding Clavien-Dindo Grade I were observed (7,8). The study by Schilham et al. was also able to support the effectiveness of the procedure through the successful perioperative detection and removal of a high percentage of the ¹⁸F-PSMA PET/CT-suspicious lesions, where 88% of ¹⁸F-PSMA PET-suggestive RGS-target lesions were successfully removed.

The study outcomes suggest several key clinical implications. Firstly, the high rate of successful lesion removal and intraoperative detection of LNMs indicates that ¹¹¹In-PSMA RGS can significantly enhance the surgical management of PCa and the ability to maximize local disease control. By enabling the targeted removal of metastatic LNs, this approach may contribute to more personalized and less invasive treatment strategies. This result signifies a notable advancement in optimizing LND, potentially minimizing the need for extensive lymph nodal dissections and thereby reducing associated morbidity. Furthermore, the close correlation between ¹¹¹In-PSMA RGS findings and histopathology results strengthens the argument for incorporating this technique into standard surgical protocols, potentially improving postoperative outcomes, and reducing the risk of biochemical recurrence.

There are also important considerations that should be made on the secondary outcomes of the study. In particular, the high concordance with preoperative PET scan demonstrated the high accuracy of intraoperative PSMA PET imaging, which is in fact able to precisely identify all suspicious lesions. This aspect is particularly important for confirming the optimal LND template, but it may also play a crucial role in the near future given the potential upcoming introduction of novel radio-guided treatment options. Indeed, the recent LuTectomy trial has shown the potential for a clinical and pathological response after initial [¹⁷⁷Lu]Lu-PSMA-617 treatment (9). Therefore, the correct identification of correspondence of nodal lesions shown in the current study may support the use of these novel treatment strategies in selected cases. In addition to the comments above, filling this knowledge gap in terms of PSMA expression heterogeneity could also have relevant implications for future application of radio-ligand therapy, even in the context of localized disease; therefore, optimizing the definition of PSMA expression on a molecular pattern may also allow to identify those patients who could potentially be candidate for neoadjuvant radio-guided therapy. However, whether such a treatment strategy may allow a complete omission of LND is still unknown and difficult to foresee. Last but not least, Schilham and colleagues also provide an insight on the oncological effect of using ¹¹¹In-PSMA RGS. Data on such outcomes are very limited in the literature with no comparative studies available to date. Only in the context of recurrent PCa, Knipper et al. have demonstrated that RGS surgery might be associated with a lower rate of biochemical progression compared to standard template salvage LND (10); however, similar data in the primary setting are missing and will indeed represent a topic of research in the upcoming years.

Despite the promising results, several limitations must be acknowledged. First and foremost, even using a relatively low definition for intraoperative positivity (i.e., tumor-to-background ratio ≥2) the author reported a rate of missed LNM of 29%, which is in the high-end range compared to previous studies in primary PCa using different radionuclides (6). This finding is not surprising and should be considered in the context of the study design, which substantially differs from previous investigations. Indeed, the authors focused on men with at least 1 positive spot on preoperative PSMA PET. Of note, the rate of micrometastatic disease (<5 mm) in other nodes besides the one identified by preoperative imaging, which can be missed by PET (and, likely, by intraoperative PSMA RGS), can be as high as 40% (4,11). One might hypothesize that the spatial resolution of the gamma probe used for RGS can still miss the micrometastatic LNs typically present in this scenario. On the other hand, focusing on a population of patients with miN0 tumors could result in improved sensitivity of the technique, as previously reported (6). The inclusion of miN1 patients can also explain the low rate of false positive findings reported by the authors.

The authors do not provide in their analyses a detailed report of the histological characteristics of the missed lesions, but it is plausible to believe that false-negative findings may be related to the intrinsic limitation in the identification of micro-metastatic disease, shared with all PSMA-based diagnostic techniques available to date (12,13). Nonetheless, the relatively small sample size and the single-center nature of the study may limit the generalizability of the findings. The path forward should include larger, multicentre trials to validate the efficacy and safety of ¹¹¹In-PSMA RGS across a broader patient population and clinical settings. In fact, the technical aspects of PSMA RGS, including the need for specialized equipment and training, may pose challenges to its widespread adoption. Moreover, the study focuses on newly diagnosed patients with suggestive LNMs at preoperative imaging, and its applicability to patients with more advanced disease or in a recurrent setting remains to be explored.

Besides these intrinsic criticisms, the current analysis did not address some of the crucial open questions in the context of RGS for PCa that will need to be answered in the next few years. First, there is an impending need for investigating the impact of this technique on long-term outcomes, such as overall survival and quality of life. Biochemical recurrence and progression-free survival rates have been investigated in preliminary analyses from single-arm prospective studies, but they were characterized by short follow-up or non-comparative design, thus limiting the strength of the reported evidences (13). Second, advancements in PSMA-targeting radiotracers and imaging technologies could further refine the accuracy and utility of RGS, paving the way for its integration into multimodal treatment strategies for PCa. For instance, the introduction of image-guided approaches using near-infrared tracers such as indocyanine green-free or hybrid tracers can overcome the issues related to background noise signal of gamma-probes used and, in consequence, may result in increased accuracy in the identification of positive nodes (14). Finally, there is an impending need to deepen the insight on molecular and histological patterns of PCa to determine the exact features of the missed nodal metastases at RGS. While it remains unclear whether intraoperative guidance may overcome the space resolution limitation of preoperative PSMA-based imaging modalities (15), low or heterogeneous PSMA expression within tumoral metastases may be another important limiting factors for RGS (16). Therefore, further molecular analyses focusing on PSMA expression levels in lymph node metastases can allow to define the optimal correlation between PSMA expression and intraoperative signal to guarantee the best diagnostic accuracy for precise metastases identification during PSMA-RGS. This said, by adopting a tailored positivity threshold for intraoperative signal or by integrating novel hybrid tracers, it could be possible to detect more nodal metastases which might express low volume of PSMA or might be smaller than 3 mm, resulting in fewer positive nodes lost. Nonetheless, in the current changing clinical scenario where LND can be often omitted due to frequent false negatives and lack of evidence on its oncological efficacy, RGS can still play a fundamental role in providing directions to determine the exact locations of nodal metastases and ideally to define proper LND templates in patients with borderline indication or in those with evidence of nodal involvement outside standard templates without increasing the risk for complications.

To conclude, despite the weaknesses that are shared with previous analyses in similar clinical settings, the current study poses another landmark evidence supporting the role of RGS in the context of PCa. The study’s findings highlight the potential of ¹¹¹In-PSMA RGS to optimize the surgical management of PCa by enhancing the perioperative identification and removal of metastatic LNs. This approach aligns with the broader goals of precision surgery, offering a pathway to more targeted, effective, and less invasive treatments.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-24-32/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-32/coif). G.G. received grants from Italian Ministry of Health and was the PI and grant receiver on a prospective research project on PSMA radioguided surgery (NCT04832958). The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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