A nerve-sparing technique to guide robot-assisted radical prostatectomy (RARP) for prostate cancer eased the surgery’s negative effects on erectile function, a phase 3 study showed, with more patients having no/mild erectile dysfunction a year after surgery, along with fewer severe cases
Erectile function scores at 12 months favoured the nerve-sparing NeuroSAFE technique, averaging 12.7 versus 9.7 in the standard RARP arm on the International Index of Erectile Function (IIEF-5) scale (P<0.0001), reported Greg Shaw, MBBS, MD, of University College London Hospitals NHS Foundation Trust.
Moreover, 20% of participants in the NeuroSAFE group compared with 14% in the standard group had an IIEF-5 score of 21 or greater on the 25-point scale, where higher scores represent better erectile function, reports Medpage Today.
Descriptive analyses showed that by 12 months’ post-surgery, fewer patients treated with NeuroSAFE had severe erectile dysfunction (38% vs 56% with standard RARP) while more patients had no or mild erectile dysfunction (39% vs 23%, respectively).
“To our knowledge, this is the first randomised controlled trial which demonstrates a benefit to an intervention for erectile function recovery performed in radical prostatectomy,” Shaw said during a presentation at last week’s European Association of Urology meeting in Madrid. The study was published concurrently in Lancet Oncology.
Surgery took longer with NeuroSAFE (174 vs 131 min), “but that investment in time translated into an increase in the amount of nerve sparing that we were able to perform”, Shaw observed, with bilateral nerve sparing reported in 82.1% of patients in the NeuroSAFE group compared with 56.4% in the standard RARP group.
Regarding the study’s secondary outcome of urinary incontinence, an improvement was seen with NeuroSAFE at three months, but the difference lost statistical significance by six months.
In terms of oncological outcomes, Shaw reported there was relatively little difference between the NeuroSAFE and standard arms in prostate-specific antigen persistence (3.8% vs 2.7%, respectively) or in biochemical recurrence (5.5% vs 3.7%). However, the use of adjuvant therapy was fourfold greater in the NeuroSAFE arm (4.4% vs 1.1%).
In explaining the rationale behind the trial – NeuroSAFE PROOF – Shaw said it was very difficult to know the exact extent of prostate cancer and how it relates to the nerves that are closely approximated to the prostate capsule.
“With prostatectomy, we tend to err on the side of oncological control, and many patients who have organ-confined disease with definitive pathology have non-nerve-sparing surgery,” he added. “We don’t spare nerves when we could have.”
NeuroSAFE, which was developed by the Martini-Klinik in Hamburg, Germany, is an intraoperative, frozen section technique in which surgeons get feedback in real time while performing nerve-sparing prostatectomy.
“They get to find out if that has resulted in a significant positive surgical margin, which may represent an issue with oncological control, and gives them an opportunity to regain that oncological control by performing a secondary resection,” Shaw said.
However, the evidence for NeuroSAFE has been limited to retrospective studies, thus the need for a randomised trial. The trial was conducted between January 2019 and December 2022 at five National Health Services hospitals in the UK.
Key eligibility criteria were a diagnosis of non-metastatic prostate cancer deemed suitable to undergo RARP, good erectile function (defined as an IIEF-5 score of ≥22) without medical erectile function assistance, and no previous prostate cancer treatment.
The trial included 407 patients, 381 of whom eventually went to surgery and were randomised to the NeuroSAFE and standard RARP groups.
About 30% of patients were black and 5% Asian; more than 90% of patients had cancer that was defined as clinically significant.
The incidence of adverse events (AEs) and serious AEs was similar between the groups.
There were 20 AEs and six serious AEs reported in the NeuroSAFE group, including hospital admissions for postoperative haematuria, gastric ulcer, pelvic haematoma, urinary tract infection, an unrelated hospital admission, and one reoperation for postoperative haemorrhage.
In the standard arm, there were 25 AEs and five serious AEs, including hospital admissions for urethrovesical anastomosis leak, postoperative haematuria, infected scrotal haematoma, and pelvic haematoma.
Study details
Effect of NeuroSAFE-guided RARP versus standard RARP on erectile function and urinary continence in patients with localised prostate cancer (NeuroSAFE PROOF): a multicentre, patient-blinded, randomised, controlled phase 3 trial
Eoin Dinneen, Ricardo Almeida-Magana, Tarek Al-Hammouri, et al.
Published in Lancet Oncology on 24 March 2025
Summary
Background
Sparing the periprostatic neurovascular bundles during robot-assisted radical prostatectomy (RARP) improves postoperative erectile function and early urinary continence recovery. The NeuroSAFE technique, a standardised frozen section analysis, enables accurate real-time detection of positive surgical margins during nerve-sparing, increasing the likelihood of successful nerve preservation. However, the impact of the technique on patient outcomes remains uncertain. We aimed to assess the effect of NeuroSAFE-guided RARP versus standard RARP on erectile function and urinary continence.
Methods
NeuroSAFE PROOF was a multicentre, patient-blinded, randomised, controlled phase 3 trial done at five National Health Service hospitals in the UK. Key eligibility criteria were a diagnosis of non-metastatic prostate cancer deemed suitable to undergo RARP, good erectile function (defined as a score of ≥22 on the first 5 items of the International Index of Erectile Function [IIEF]) without medical erectile function assistance, and no previous prostate cancer treatment. No age limits were applied. Participants were randomly assigned (1:1) to standard RARP or NeuroSAFE-guided RARP using block randomisation, stratified by site. Masking of participants to allocation was maintained throughout, but patients were informed of their nerve-sparing status after the operation. Due to the nature of the intervention, operating teams were aware of treatment group. Nerve-sparing was guided by a preoperative plan in the standard RARP group and by intraoperative NeuroSAFE assessment in the NeuroSAFE group. The primary outcome was erectile function at 12 months, assessed using the IIEF-5 score, in the modified intention-to-treat population, which included all randomly assigned participants who had surgery. Secondary endpoints were urinary continence scores at 3 and 6 months, evaluated using the International Consultation on Incontinence Questionnaire (ICIQ), and the erectile function domain of the IIEF (IIEF-6) scores at 12 months.
Findings
Between Jan 6, 2019, and Dec 6, 2022, 407 patients were recruited, of whom 381 had surgery (190 participants in the NeuroSAFE group and 191 participants in the standard RARP group), and were included in the modified intention-to-treat population. Data for the primary outcome (IIEF-5 score at 12 months) were available for 344 participants (173 in the NeuroSAFE group and 171 participants in the standard RARP group). Median follow-up was 12·3 months (IQR 11·8–12·7). At 12 months, the mean IIEF-5 score was 12·7 (SD 8·0) in the NeuroSAFE group versus 9·7 (7·5) in the standard RARP group (adjusted mean difference 3·18 [95% CI 1·62 to 4·75]; p<0·0001). At 3 months, the ICIQ score was significantly lower in the NeuroSAFE group than the standard RARP group adjusted mean difference –1·41 [95% CI –2·42 to –0·41]; p=0·006). At 6 months, no significant difference in ICIQ score was observed between groups (adjusted mean difference –0·37 [95% CI –1·35 to 0·62]; p=0·46). At 12 months, the mean IIEF-6 score was higher in the NeuroSAFE group than in the standard RARP group (15·3 [SD 9·7] vs 11·5 [SD 9·0]; adjusted mean difference 3·92 [95% CI 2·01 to 5·83]; p<0·0001). Serious adverse events occurred in six (3%) of 190 patients in the NeuroSAFE group, and and in five (3%) of 191 patients in the standard RARP group. All adverse events were postoperative complications; no serious adverse events or deaths were attributed to the study intervention.
Interpretation
The use of NeuroSAFE to guide nerve-sparing during RARP improves patient-reported IIEF-5 scores at 12 months and short-term urinary continence. The erectile function benefit is enhanced in patients who would not otherwise have undergone bilateral nerve-sparing by standard practice.
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