Evaluating the Effects of Frozen Section Technology on Oncological and Functional Outcomes at Radical Prostatectomy.

Study Overview
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Brief Summary
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In summary this trial will test whether this new surgical technique can be used to make surgery safer and more effective whilst allowing improved quality of life for patients having surgery for prostate cancer. If the technique is proven effective the investigators will use the experience gained to promote its use throughout the NHS through training courses and publication and dissemination of the resultant data. Staff from centres participating in this trial will be fully trained in the NeuroSAFE technique. A patient and public involvement afternoon was held for participants of the NeuroSAFE PROOF feasibility study, family members, men with prostate cancer, and staff members at UCLH. The event was supported by the charity Orchid Cancer appeal. The high levels of attendance was demonstrative of the support within our patient group for the work of this trial. The trial team listened to the comments made by participants and members of the public and have made some changes to the design of our trial as a result of this feedback.

Detailed Description
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Prostate cancer is very common and results in the death of many men in the developed world. Prostate cancer that has not spread outside the prostate can usually be cured by surgical removal of the prostate gland (radical prostatectomy). Radical Prostatectomy can be associated with urinary incontinence due to damage to the involuntary sphincter and erectile dysfunction due to damage of the nerves that run within the outer coverings of the prostate. Surgical sparing of these nerves to preserve quality of life may risk leaving cancer cells behind often meaning that the patients need extra treatment with radiotherapy. This trial is designed to evaluate a new method designed to decrease the risk of compromising cancer control associated with sparing of the nerves as well as evaluate effects on the need for radiotherapy after surgery if cancer is left behind. The Investigators will also evaluate effects on the quality of life in patients who have undergone RARP. The trial is needed now because the nature of prostate cancers treated surgically is changing rapidly. The techniques developed in low risk cancer to spare the nerves which run alongside the prostate, may not necessarily be safe when used on the more aggressive cancers operated on nowadays and if they are adopted without adequate investigation, the risk is that patients will be exposed to increased risk of cancer recurrence and needing extra treatment with radiotherapy with consequent side effects and extra cost to the NHS. On the outside of the prostate, within its outermost coverings, run the nerves thought to be responsible for producing erections. Preservation of these nerves has also been linked to more rapid reestablishment of urinary continence following surgical removal of the prostate. Robotic technology has been developed which allows the prostate to be removed through very small incisions. The surgeons view is magnified in 3D, which facilitates the peeling off of the outer layers, containing the nerves (so called nerve sparing). With nerve sparing the nerves controlling erections are left intact whilst the prostate itself, along with the cancer within it, is removed. This increases the patient's chances of getting erections of sufficient quality for penetrative sex. Data from several case series, including our own, suggest that the higher the degree of nerve sparing performed, the more likely a patient is to be potent and continent of urine. In our series, bilateral nerve sparing results in 85% of men being able to get usable erections*, whereas only 45% of men will have useable erections* when only one side is spared. Nerve sparing has largely been developed and the effects have been evaluated in the USA where prostate cancer is detected at an earlier stage because PSA screening is performed commonly. In the UK, where PSA screening is not commonly carried out, tumours resected at surgery are larger and more aggressive, often having spread through the capsule of the prostate. In addition, the move away from surgery for small low-grade tumours in the UK means that the prostate cancers treated by surgery are larger and more aggressive overall. This means that the tumours are closer to the outer limit of the prostate because the more aggressive tumours tend to work their way out through the outer capsule of the prostate. A nerve sparing approach is associated with an increased risk that tumour will be left on the surface of the resected specimen. This is referred to as a positive surgical margin (PSM). One of the principles of (radical) cancer surgery is that cancerous tissue should be removed with a covering of non-cancerous tissue to give the best chance of cure (a so called negative or clear surgical margin). Positive surgical margins are associated with an increased chance of recurrence following surgery and require further treatment, usually with radiotherapy, which is expensive and engenders its own side effects. The investigators plan to evaluate the use of a modified version of a frozen section technique called NeuroSAFE in promoting nerve sparing without diminishing the oncological effects of surgery by generating PSMs. During this frozen section technique, once the prostate is removed, the areas of prostate adjacent to the spared nerves are sliced from the surgical specimen and rapidly frozen and stained so that they can be examined carefully by a pathologist. If the pathologist identifies a positive surgical margin, the spared nervous tissue on that side will be surgically resected before the patient is woken up at the end of the operation. When this is done the cancer behaves as if it had been resected with a negative surgical margin at the outset. Frozen section analysis does not add much time to the surgical procedure, as once the prostate is removed, the rest of the operation (joining the bladder to the urethra and removing pelvic lymph nodes) can proceed whilst the frozen section analysis is performed. Patients enrolled to the trial will be randomised between A) standard UK nerve sparing practice, wherein the degree to which the nerves can be spared is determined by the operating surgeon based on clinical examination, biopsy results and multi-parametric MRI and B) bilateral nerve sparing with frozen section analysis. The Trial team recently surveyed UK robotic prostatectomists and confirm that currently UK surgeons predominately rely on MRI, biopsy and Digital Rectal Exam (DRE) findings to determine whether they can spare nerves, but that there is little consistency in the means by which a surgeon decides whether or not they can spare nerves in a particular case. Our survey tells us that UK surgeons do not use frozen section to direct nerve sparing with only 5% of UK prostatectomists ever having used it at all. What are the potential outcomes of this research? This trial will provide a thorough evaluation of a new technique designed to minimise the occurrence of PSM and exposure to extra treatment or cancer recurrence. It will generate vital data regarding the cost/benefit of using this procedure. The relationship between the degree and frequency of nerve sparing on quality of life will be evaluated in terms of sexual potency and urinary continence in UK patients undergoing RALP. The assessment of these functions will include patient reported outcomes. * At 2 years following surgery using Viagra or an equivalent PDE5i.

Official Title
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A Single Blinded, IDEAL Stage 3, Multi-Centre, Randomised Controlled Trial to Assess NeuroSAFE Robotic Assisted Radical Prostatectomy (RARP) vs Standard Robotic Assisted Radical Prostatectomy (RARP) in Men With Prostate Cancer

Conditions
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Prostate Cancer

Intervention / Treatment
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* Procedure: NeuroSAFE procedure
* Procedure: Standard RARP


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men opting to undergo RARP for organ confined prostate cancer. Potent men (IIEF 22-25 not using PDE5i or other medications or vacuum pump) Men who are continent of urine (no self-reported urinary incontinence) Has given written informed consent Ability to read English sufficiently to answer questionnaires and understand PIS Exclusion Criteria: Unable to undergo robotic prostatectomy Known overactive bladder Previous treatment for prostate cancer Previous/current hormone treatment for prostate cancer Nerve sparing deemed futile due to locally advanced disease by surgeon and radiologist

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: A single blinded, multi-centre, randomised controlled trial. Parallel group, two-arm, with 1:1 allocation ratio between nerve sparing guided by NeuroSAFE and current UK practice (guided by MRI, biopsy and clinical examination).
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NeuroSAFE procedure<br>These patients will undergo robotic radical prostatectomy with bilateral nerve spare.The pathologist will remove the pre-painted surface of the gland (which had been in contact with the neurovascular bundles) using a sharp blade.The tissue sample will be snap frozen and embedded in OCT.Using a cryostat, 10 micron thick slices will be placed on slides.The entire length of the area of interest will be sampled in this way generating ≈10 frozen sections per side.The slides will be stained with H&E and will be examined by a consultant pathologist.As soon as examination is complete the pathologist will telephone the operating surgeon to give the result.Presence of cancer cells at the margin of resection constitutes a positive margin and the neurovascular bundle on that side will be resected | Procedure: NeuroSAFE procedure<br>* When the prostate is removed from within the patient as it is disconnected from its attachments. The specimen will then be painted (right=blue, left =black) by the operating surgeon and delivered expediently to the pathologist who will perform frozen section analysis of the painted areas. The pathologist will remove the pre-painted surface of the gland (which had been in contact with the neurovascular bundles) using a sharp blade. The tissue sample will be snap frozen and embedded in OCT. If a positive margin is reported by the pathologist, the entire neurovascular bundle on the affected side will be removed and sent for formal pathological examination.<br>* Other names: NeuroSAFE RARP;|
| Active Comparator: Control<br>These patients will undergo robotic radical prostatectomy with a nerve sparing procedure based on surgical planning performed by a consultant radiologist. The mp-MRI will be reviewed by a consultant radiologist along with the details of the prostate biopsy and DRE a decision to perform unilateral, bilateral or non-nerve sparing will be established and recorded in the clinical record form (CRF) for each patient. | Procedure: Standard RARP<br>* Patients will undergo the standard intervention - RARP without NeuroSAFE Frozen section analysis<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Erectile Function | Comparison of the proportion of men who recover erectile function at 12-months according to allocated treatment arm (i.e. NeuroSAFE RARP [intervention] vs. standard RARP [control]). Erectile function is measured using the IIEF-5 questionnaire, where recovered function is defined as a score of 21 or more. o Pre-defined sub-group analysis: comparison of the proportion of men who recover erectile function at 12-months according to treatment arm, restricted to men who did not receive a pre-operative radiologist recommendation for bilateral nerve sparing | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Functional outcome - Urinary Continence | Comparison of the proportion of men who are continent at 3 months, measured using the ICIQ questionnaire, where continence is defined as a score of 5 or less between intervention and control arms. o Additional subgroup analysis: restricted to men who did not receive a pre-operative radiologist recommendation for bilateral nerve sparing | 3 and 6 months after surgery | 
| Oncological Outcomes - Biochemical recurrence (BCR) | Comparison of the proportion of men with BCR between NeuroSAFE and control arms within 12 months of surgery. BCR is defined as PSA>0.2 ng/ml post-surgery at any time during the 12 months. | 12 months after surgery | 
| Oncological Outcomes - Additional oncological treatments | 'Adjuvant treatment' refers to men who undergo additional cancer treatment without having BCR. A descriptive analysis of the proportion of men undergoing adjuvant oncological treatments (ADT and/or radiotherapy and/or chemotherapy) at or before 12 months of surgery will be conducted. 'Salvage treatment' refers to men who undergo additional cancer treatment following BCR. A descriptive analysis of the proportion of men undergoing adjuvant oncological treatments (ADT and/or radiotherapy and/or chemotherapy) at or before 12 months of surgery will be conducted. | 12 months after surgery | 
| Quality of life - EQ-5D-5L | A comparison of the proportion of men achieving the best quality of life according to the EQ-5D-5L between intervention and control arms. | 12 months and 24 months | 
| Quality of life - EQ-5D-5L Score | Analysis of EQ-5D-5L scores to produce QALYs at 12 months by arm | 12 months and 24 months | 
| Quality of life - RAND36 | Analysis of RAND36 scores to produce QALYs at 12 months by arm | 12 months and 24 months | 
| Oncological Outcomes - Positive surgical margins | Descriptive tabulation of PSM rates between NeuroSAFE RARP and standard RARP arms. PSMs will be grouped as: 0. Negative margin Intraprostatic margins Non-intraprostatic margins ≤ 1mm (included) Large non-intra prostatic margins and >1mm Very large non-intraprostatic margins and >3mm and/or multifocal Additional subgroup analysis: restricted to men who did not receive a pre-operative radiologist recommendation for bilateral nerve sparing. | At the time of intervention | 
| Health Economic Analysis | Use of the Health Economics Questionnaires to inform a health cost analysis of NeuroSAFE RARP vs. standard RARP. Economic analysis to assess healthcare resources use by arm and cost analysis to assess: Cost of intervention and control Cost of NHS resource use (medications, physiotherapy, Cost of private health care resources (medication, physiotherapy) Other private/societal costs (productivity losses, caregivers costs, out of pocket cost for transport, equipment) | 12 months and 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Prostate Cancer, Nerve sparing, NeuroSAFE, Frozen section