Title: Improving outcomes for men undergoing surgery for prostate cancer. A study to evaluate the feasibility of a multicentre randomised controlled trial of frozen section technology to improve oncological and functional outcomes at robotic radical prostatectomy.
Funder: Department of Health and Social Care

Abstract: Localised prostate cancer is usually curable with surgery. Surgery often entails side effects of permanent impotence and temporary urinary incontinence. These side effects can be minimised by protecting the nerves that run in the outer layer of the prostate (nerve sparing), however this increases the risk of exposure of the underlying tumour (a positive surgical margin-PSM) and a need for extra treatment in the form of radiotherapy. PSMs are more likely to occur if the tumour is starting to grow out of the prostate (stage pT3a) and in areas where pT3a disease is suspected nerve sparing cannot safely be performed. At UCLH the chance of a man being potent after radical prostatectomy is dependent on the amount of nervous tissue left behind. 80% of men in whom the nervous tissue is spared on both sides of the prostate would be expected to be able to get erections adequate for penetrative sexual intercourse using phophodiesterase inhibitors (PDE5i's, viagra or similar). UK surgeons base a decision of whether to nerve spare or not on the degree of suspicion that pT3a disease is present, estimated from the patients prostate biopsies and MRI scan as well as a thorough clinical examination. Unfortunately, our ability to detect pT3a disease is limited. even with multiparametric MRI, which is regarded as the best way to distinguish pT2 from pT3a disease resulting in uncertainty as to when nerve sparing is oncologically safe. In order to decrease this uncertainty a group from Germany have developed the NeuroSAFE technique, where after nerve sparing, a frozen section analysis of the area adjacent to the nerve spare, is performed, whilst the surgeon completes the rest of the operation, and if a PSM is detected the nerve tissue is then excised. NeuroSAFE has been shown in cohort studies to decrease PSM rate whilst promoting nerve sparing and potency. No level one data exist regarding the effectiveness of this technique. The German centre where the technique was developed now performs the technique on all cases meaning the opportunity to evaluate the technique in the setting of an RCT has been missed. The technique is only performed routinely in one NHS centre, Lister Hospital. The current situation provides a unique opportunity to fully evaluate the benefits of this technique for NHS patients. The proposed study, NeuroSAFE PROOF, is a multicentre RCT designed to compare short term oncological and functional outcomes after robotic radical prostatectomy with nerve sparing performed according to current UK practice (based on a perceived risk of pT3a disease from prostate biopsy, MRI and examination findings) with patients who have undergone the NeuroSAFE procedure. For the feasibility phase 50 patients will be randomised 1:1. A NeuroSAFE training academy will be established. Outcome measures: Primary: The proportion of men undergoing radical prostatectomy who can be recruited and randomised within the study accross three NHS centres. Secondary: i- Health economic analysis including consideration of cost of adjuvant radiotherapy, management of impotence, and incontinence. ii- Proportion of men who are potent, with apparent cancer cure (negative surgical margins with undetectable PSA) at 12 months post-surgery. These two secondary outcome measures will be used to decide the best primary endpoint (functional or health economic) and generate formal power calculations for a multicentre RCT comparing NeuroSAFE with current practice. Important information will be obtained regarding the role of new MRI sequences in identifying pT3a disease through collaboration with the UCL BRC. The proposed study is to evaluate the potential benefit of a novel surgical technique for NHS patients before the procedure is taken up as it has been elsewhere and the opportunity to randomise/evaluate is lost.

Lay abstract: Prostate cancer is common and can often be cured with surgery. Sadly, this sometimes leads to a loss of erections, because the nerves that bring about the erections run in the outer part of the prostate. A process known as nerve sparing, increases the chance of men being potent after surgery. However, this type of surgery also increases the risk of cancer being left behind which will need more treatment, leaving men without the ability to achieve erection, even if they had nerve-sparing surgery. The prostate is enclosed by a capsule. Many men having their prostates removed have cancer that extends through the capsule of the prostate. Unfortunately, there isn t a good way of knowing this before surgery. Nerve sparing surgery in these patients result in cancer being left behind. A new technique called NeuroSAFE includes a step where a doctor looks at the prostate near where the nerves were, to check for exposed cancer. If cancer is found at the edge of the prostate, the nerve tissue is removed. Our long-term aim is to perform a large-scale trial where NeuroSAFE will be compared with the current UK practice for prostate cancer (nerve sparing based on an MRI scan, biopsy results and the way the prostate feels). This project will check whether men would be prepared to take part in a large scale trial where men are chosen for either NeuroSAFE or standard treatment at random, and that the NeuroSAFE technique can be taught to other UK centres (so that the large study can include men at other hospitals). Data from this study will allow us to plan the larger study in the future and work out how many men will be needed for the larger study in the future.

Research activity codes: 6.4 SURGERY
Health categories: CANCER AND NEOPLASMS