# Nerve-Sparing in High-Risk Prostate Cancer: Advantages and Pitfalls of Current Strategies and Technologies

## TL;DR

This review discusses strategies to improve prostate cancer surgery outcomes by balancing cancer removal with nerve preservation in high-risk patients.

## Contribution

The paper evaluates emerging intraoperative technologies for margin assessment in high-risk prostate cancer surgery.

## Key findings

- Intraoperative frozen section analysis reduces positive surgical margins but is resource-intensive.
- Fluorescence confocal microscopy and PSMA-based imaging show promise for rapid margin assessment in high-risk prostate cancer.
- PSMA-targeted fluorescence-guided surgery enables real-time tumor detection and selective re-resection.

## Abstract

High-risk prostate cancer carries a relevant risk of positive surgical margins after radical prostatectomy, which may lead to disease recurrence and the need for additional treatments. At the same time, preserving the neurovascular bundles is crucial to maintain postoperative sexual function, even in selected high-risk patients. This review summarizes current and emerging strategies to assess surgical margins and guide nerve-sparing decisions in high-risk prostate cancer. Preoperative imaging and risk calculators support surgical planning but remain limited in detecting microscopic tumor extension. Intraoperative techniques, such as frozen section analysis, can reduce positive margins and enable selective nerve sparing (defined as a side-specific, risk-adapted preservation strategy), although they are resource-intensive. Novel technologies, including fluorescence confocal microscopy and PSMA-based imaging approaches, offer rapid, biologically driven margin assessment and appear particularly promising in high-risk disease. Integrating preoperative risk stratification with intraoperative margin assessment may improve oncologic outcomes while preserving function, but high-quality prospective studies are still required.

Background and Objective: Positive surgical margins (PSMs) remain a major challenge during radical prostatectomy, particularly in patients with high-risk prostate cancer (HR-PCa), where extracapsular extension, multifocal disease, and aggressive tumor biology substantially increase the likelihood of incomplete resection. In this setting, PSMs are strongly associated with early biochemical recurrence and frequently prompt adjuvant or salvage treatments, potentially exposing patients to overtreatment and added morbidity. Materials and Methods: To review and critically appraise established and emerging intraoperative technologies for surgical margin assessment during radical prostatectomy, with a specific focus on their potential role and relevance in patients with HR-PCa. Evidence Acquisition: A non-systematic literature review was performed using Pubmed, MEDLINE, Web of Science, and Google Scholar, focusing on preoperative, intraoperative ex vivo, and intraoperative in vivo technologies for margin assessment. Emphasis was placed on techniques with potential applicability to HR-PCa, where real-time intraoperative decision-making is particularly consequential. Evidence Synthesis: Preoperative tools, including multiparametric MRI, PSMA-PET imaging, and predictive nomograms, aid surgical planning but show limited sensitivity for microscopic extracapsular extension, especially in high-risk disease. Intraoperative frozen section analysis reduces positive surgical margin rates while enabling selective nerve-sparing (defined as a side-specific, risk-adapted preservation strategy); however, its widespread adoption is constrained by substantial logistical and resource requirements, and robust oncological outcome data in high-risk populations remain limited. Novel ex vivo approaches, such as fluorescence confocal microscopy and specimen-based PSMA PET/CT imaging, offer rapid whole-gland or targeted margin assessment with reduced dependency on dedicated pathology workflows. In parallel, emerging in vivo technologies, particularly PSMA-targeted near-infrared-fluorescence-guided surgery, enable real-time detection of residual tumor and facilitate selective re-resection, representing a biology-driven approach that may be especially suited to HR-PCa. Conclusions: In high-risk prostate cancer, intraoperative margin assessment technologies may extend beyond functional preservation and play a central role in optimizing oncological radicality and multimodal treatment sequencing. While NeuroSAFE remains the reference standard, PSMA-based ex vivo and in vivo technologies are particularly promising in HR-PCa due to their ability to integrate tumor biology into surgical decision-making. Prospective studies focusing on high-risk-specific oncological and patient-reported outcomes are needed before widespread clinical implementation.