Partial ablation versus radical prostatectomy in intermediate-risk prostate cancer: the PART feasibility RCT

Active monitoring

Active monitoring protocols involve regular clinical examination, PSA measurements, mpMRI and repeat biopsies. If these parameters suggest the risk of progression, men are offered radical treatment. A number of Phase II studies have shown that signs of progression lead to intervention within 5 years of diagnosis in approximately one-third of patients undergoing AM. 3,4 For those with intermediate-risk disease, AM has been reported as conferring an 84% 5-year metastasis-free survival rate. 5 However, observational strategies can lead to significant anxiety. 6

Active monitoring has been tested in clinically localised PCa in the ProtecT (Prostate testing for cancer and Treatment) trial,7 which reported that, although RP and radiotherapy were associated with lower rates of disease progression, 44% of men assigned to AM did not receive radical treatment and avoided side effects. Men with newly diagnosed, localised PCa therefore need to consider the critical trade-off between the short- and long-term effects of radical treatments on urinary, bowel and sexual function and the higher risks of disease progression with AM, as well as the effects of each of these options on quality of life (QoL).

Radical prostatectomy

Radical prostatectomy involves total open, laparoscopic or robot-assisted surgery to remove the entire prostate gland and seminal vesicles. The proportion of PCa patients receiving surgery varies with age; 8% of PCa patients receive a major surgical resection as part of their cancer treatment, with fewer resections in the oldest age group (0% in those aged ≥ 85 years) than in the youngest group (29% in those aged 15–54 years). 8

Radical radiotherapy

Radical radiotherapy in the form of external beam radiotherapy (EBRT) is a common treatment in the UK for men diagnosed with localised PCa. It is usually preceded by 3–6 months of neoadjuvant androgen suppression, and is given in daily fractions over 4–8 weeks on an outpatient basis. In large reported series, EBRT conferred a 5-year disease-free survival of between 78% and 80%, or 88% and 94% in combination with hormone therapy. 9–12 IMRT, an optimised form of EBRT, is delivered in some centres. 13

Brachytherapy

Brachytherapy can be given either as permanent radioactive seed implantation or as high-dose brachytherapy using a temporary source. For localised PCa, the 5-year biochemical failure rates are similar for permanent seed implantation, high-dose (> 72 Gy) external radiation, combination seed/external beam irradiation and RP. 14

Radical, extensive treatments carry the potential for significant short-, medium- and long-term morbidity such as urinary leakage, erectile dysfunction and radiotherapy toxicity. At present, there is little difference between RP and radical radiotherapy in terms of cancer control in the short to medium term; much of the decision-making process that governs treatment allocation is based on the differences in the side-effect profiles associated with the various interventions. 13

The recently published clinical- and patient-reported outcomes from the ProtecT trial7 demonstrate that each treatment option has a particular pattern of adverse effects on QoL in the short term: urinary incontinence and sexual dysfunction are worst after surgery, followed by recovery by a number of men but persistent difficulties for some, and bowel problems are worst after radiation, with sexual dysfunction mostly related to neoadjuvant androgen deprivation therapy. Although adverse effects of interventions can be avoided initially with AM, there is a natural decline in urinary and sexual function symptoms over time, and the adverse impacts of radical treatments will be experienced when such treatments are received. 15,16 These side-effect profiles have been described consistently, even with more modern and contemporary radical treatment options, such as robot-assisted surgery and different forms of radiation, including brachytherapy. It is, therefore, true that contemporaneous men who are treated with current forms of radical therapy will continue to suffer from the now well-described and well-documented side-effect profile patterns related to these treatments.

High-intensity focused ultrasound

High-intensity focused ultrasound uses ultrasound energy focused by an acoustic lens to cause tissue damage as a result of thermal coagulative necrosis and acoustic cavitation. The procedure is performed using a transrectal approach and may be performed under general or spinal anaesthesia as a day-case procedure.

Four systematic reviews of HIFU in the treatment of prostate cancer have been published. 21–24 Warmuth et al. 21 identified 20 uncontrolled prospective case series, totalling 3021 patients (2794 primary therapy and 227 salvage therapies). They concluded that, for all HIFU procedures, the biochemical disease-free rate at 1, 5 and 7 years was 78–84%, 45–84% and 69%, respectively. The negative biopsy rate was 86% at 3 months and 80% at 15 months. Overall survival rates and PCa-specific survival rates were 90% and 100% at 5 years and 83% and 98% at 8 years, respectively. AEs included complications of the urinary tract (1–58%), erectile function (1–77%) and the rectum (0–15%), and pain (1–6%). Lukka et al. 22 found that there were no adequate RCTs or meta-analyses. They concluded that the current evidence on HIFU use in PCa patients is of low quality, rendering it difficult to draw conclusions about its efficacy. Veereman et al. 23 found very low-quality evidence in case series of patients who received HIFU treatment with no comparison with AM or radical treatment. These suggested an overall survival rate of ≤ 89% and a PCa survival rate of ≤ 99% after 5 years, but these numbers vary depending on the patient’s risk category. Longer-term effects on QoL are unknown. Kuru et al. 24 conclude that HIFU treatment, and especially focal ablation of tumour foci, seems to be a safe alternative to standard treatment, with fewer side effects. The oncological results seem satisfactory but need further follow-up to validate this practice of PCa control. 24

Cryotherapy

Cryotherapy is the localised destruction of tissue by extremely cold temperatures followed by thawing, and may be performed under general or regional anaesthesia. Cryoneedles or probes are inserted into the prostate via the perineum, using image guidance. Argon gas is circulated through needles or probes, generating very low temperatures and causing the formation of ice around the prostate with profound tissue destruction. Newer cryotherapy techniques allow these needles to be removed or repositioned so that the frozen zone conforms to the exact size and shape of the target tissue.

In 2008, a Cochrane systematic review25 of prostate cryotherapy as a primary treatment was published, and recommended that RCTs comparing cryotherapy with established treatments for early PCa be conducted. All eight studies identified were case series (two of which were retrospective), with a total of 1483 patients. At 5 years, overall survival was reported as 89–92% in two studies and disease-specific survival was 94% in one study. The major complications observed in all studies included impotence (47–100%), incontinence (1.3–19.0%) and urethral sloughing (3.9–85.0%), with less common complications of fistula (0–2%), bladder neck obstruction (2–55%), stricture (2.2–17.0%) and pain (0.4–3.1%). Most patients were discharged the following day (range 1–4 days). Since 2008, one Canadian RCT,26 comparing cryotherapy with EBRT as primary therapy for localised PCa in > 200 men, has been reported. With a median follow-up period of 100 months, no significant difference in disease progression was observed between the two arms. 26 However, because of recruitment difficulties, the study was closed before the target accrual was reached.

Vascular-targeted photodynamic therapy

Vascular-targeted photodynamic therapy uses light to activate a photosensitising drug, administered intravenously, to produce instantaneous vessel occlusion and subsequent tissue necrosis. The light is delivered by optical fibres placed transperineally under transrectal ultrasound guidance. VTP is given under general anaesthesia and can be carried out on a day-case basis.

Small case series of VTP have been reported in groups receiving primary therapy and those receiving salvage therapy. The initial drug-dose escalation studies, followed by a light-dose escalation study, were performed in men who progressed following EBRT. 27–30 These studies showed that around 60% of men receiving whole-gland treatment at the maximal and light drug doses had a complete response to treatment. Side effects included two rectourethral fistulae, one of which required surgical intervention. Urinary side effects tended to last for ≤ 6 months. In a study of 40 men with no previous treatment for PCa, early results showed no significant side effects. 31 Recently, a manufacturer-sponsored Phase III RCT comparing VTP with AM in 413 men with very low-risk disease has been published with 2-year follow-up data. 20 It found VTP to be safe and effective, with a 66% reduced risk of treatment failure (adjusted hazard ratio 0.34, 95% confidence interval 0.24 to 0.46) compared with AM; however, the VTP group experienced more frequent and severe side effects, although these were mostly mild and of short duration. The most common side effect was difficulty passing urine, and in all cases this resolved within 2 months of treatment. Outcomes for 5- and 10-year progression and survival are not known. The major limitation of this study20 is that the cohort of men investigated had low-risk disease; active treatment is currently not recommended for low-risk PCa by most international guidelines, including the National Institute for Health and Care Excellence (NICE) recommendations, which advocate that such men are offered primarily AM because of the insignificant risk of disease progression.

Other ablative technologies

Other ablative technologies are currently under evaluation, but there is not sufficient evidence to be used within the context of a RCT. Examples include radiofrequency ablation, which acts by converting radiofrequency waves to heat, resulting in thermal damage. RITA has recently been proposed as a treatment for PCa. 32–35 Interstitial laser photocoagulation was reported by Amin et al. ,36 who described a percutaneous technique for local ablation. Irreversible electroporation is a new non-thermal ablation method that uses short pulses of direct current (DC) to create irreversible pores in the cell membrane, thus causing cell death. 37,38 This technology is in the early clinical phases of development, and a RCT is currently under way. 39

These newer techniques have been evaluated in a systematic review by Ramsay et al. ,40 who conclude that they have not been evaluated with sufficient reliability to inform their utilisation within the NHS. There is, however, some evidence that cancer-specific outcomes in the short term are either better than or equivalent to either EBRT or RP, with comparable adverse effect profiles; however, there is a possible increased risk of dysuria and urinary retention. Valerio et al. 41 undertook a more recent systematic review and concluded that there is evidence that focal therapy is safe and has low detrimental impact on continence and potency, but they note that the oncological outcome has yet to be evaluated against the standard of care. Combined with the increasing incidence of clinically localised PCa, demand for these less aggressive, organ-sparing treatments is expected to increase. 40 A further important consideration is the rapid evolution of the technologies over time, with constant new developments to improve energy delivery, targeting, safety and imaging. Focal therapy relies on accurately assessing the status of the disease in the prostate, using imaging and biopsies for which the technology is improving and becoming more widely disseminated. Transperineal prostate mapping (TPM) biopsies provide the optimal biopsy strategy for accurately mapping disease within the prostate with sensitivity of > 90% for 0.2-cc and 0.5-cc lesions. 42

Ongoing and recently completed studies clearly indicate that the evidence base for partial ablation (PA) therapies – in particular, focal ablative therapies – is increasing. However, the quality of the evidence base will not improve substantially given that the majority of these studies are case series. Research efforts in the use of ablative therapies in the management of PCa should focus on conducting more rigorous, high-quality studies. Ramsay et al. 40 identify HIFU and brachytherapy as the most promising newer interventions, but these lack high-quality evaluation. They recommended evaluation by multicentre RCTs, with long-term follow-up, to include predefined assessment of cancer-specific, dysfunction and health-related quality of life (HRQoL) measures, as well as economic evaluations to inform economic modelling.

Sampling and recruitment

Data collection

Data analysis

Inclusion criteria

Men were eligible if they had unilateral, clinically significant intermediate-risk PCa or dominant unilateral clinically significant intermediate-risk and small contralateral low-risk disease and met all of the following criteria:

• Gleason score of 7(3+4 or 4+3) or

• a high-volume Gleason score of 6 (a cancer core length of > 4 mm)

• a PSA level of ≤ 20 ng/ml

• a clinical stage ≤ T2b disease

• a life expectancy of ≥ 10 years

• be fit, eligible and normally destined for radical surgery

• have no concomitant cancer

• have no previous treatment of their PCa

• have sufficient proficiency in the English language to understand written and verbal information about the trial, its consent process and the study questionnaires.

Exclusion criteria

• Unfit for radical surgery.

• Significant bilateral disease.

• Low-risk disease (i.e. a Gleason score of ≤ 6, PSA level of 10 ng/ml).

• High-risk disease (i.e. a Gleason score of ≥ 8, PSA level of > 20 ng/ml).

• Clinical T3 disease (extracapsular locally advanced).

• Men who have received previous active therapy for PCa.

• Men with evidence of extraprostatic disease.

• Men with an inability to tolerate a TRUS.

• Men with a latex allergy.

• Men who had undergone a transurethral resection of the prostate (TURP) for symptomatic lower urinary tract symptoms in the previous 6 months.

• Metal implants/stents in the urethra.

• Prostatic calcification and cysts that interfere with effective delivery of HIFU.

• Men with renal impairment and a glomerular filtration rate (GFR) of < 35 ml/minute/1.73 m².

• Unable to give consent to participate in the trial, as judged by the attending clinicians.

Appropriate patients were identified by the dedicated research nurse or clinician. Potential patients were identified at the multidisciplinary team (MDT) meeting, during which histopathological data were discussed. Men with a histological diagnosis of intermediate-risk PCa following a biopsy (see Trial management processes) and mpMRI (see Safety), and evidence of unilateral, clinically localised disease, were assessed for the PART trial. Some patients required a targeted or template biopsy to confirm unilateral disease. Patients who were ineligible for the PART trial were informed by their doctor, who discussed their treatment options with them.

Once confirmed as eligible for the study, patients were approached at urology/oncology clinics in the centres and provided with a patient information leaflet (PIL) (see Report Supplementary Material 3), detailing the exact nature of the trial, what it would involve for the participant, the implications and constraints of the protocol and the known side effects and any risks involved in taking part. Patients who fulfilled all the entry criteria for the trial were invited to attend an information appointment. Patients were given ample time to discuss the trial with family, friends and their general practitioner (GP) (there were typically around 6 weeks between MDT discussion, counselling and then randomisation). If the patient agreed to take part, they were asked to sign an informed consent form (ICF) (see Report Supplementary Material 4).

It was clearly stated that the participant was free to withdraw from the trial at any time for any reason, without prejudice to future care and with no obligation to give the reason for withdrawal. In the event of withdrawal, the choice of treatment was decided on by the patient and his clinical team.

Patients randomised to radical prostatectomy

• Routine removal of catheter at 10–14 days.

• Follow-up in the clinic at approximately 6 weeks post surgery as per routine NHS care. Patients will have had a PSA test prior to their follow-up appointment, the result of which should be available.

• Follow-up in the clinic approximately every 3 months post surgery in the first year and then approximately every 6 months, as per routine NHS care, for 3 years (see Appendix 2). Patients will have had a PSA test prior to their follow-up appointment, the result of which should be available. If at any point disease progression is suspected (i.e. a PSA level rising to ≥ 0.2 µg/ml) the patient will be restaged.

Patients randomised to partial ablation

• Routine removal of catheter at 7 days.

• For centres new to performing HIFU, a study-specific mpMRI was performed on the first five patients at 2 weeks post HIFU.

• Followed up routinely at approximately 6 weeks post surgery as per routine NHS care. Patients will have had a PSA test prior to their follow-up appointment, the result of which should be available.

• Followed up in the clinic approximately every 3 months post surgery for the first year and then approximately every 6 months, as per routine NHS care, for 3 years. Patients will have had a PSA test prior to their follow-up appointment, the result of which should be available.

• Standard care included a mpMRI at 12 months.

• Standard care included transrectal biopsies at 12 months.

• Standard care included a mpMRI at 3 years.

• Standard care included transrectal biopsy at 3 years.

Radical prostatectomy

In patients receiving RP, primary treatment failure was defined as a rising serum PSA level reaching ≥ 0.2 ng/ml following initial reduction to < 0.1 ng/ml after surgery; or a failure of serum PSA to reach the level of < 0.1 ng/ml after surgery; or clinical progression to local recurrence/systemic disease.

Partial ablation

In patients receiving PA, primary treatment failure was determined by a combination of repeat prostate biopsies, serum PSA level and clinical appearance of symptoms/signs suggesting disease progression. Prostate biopsies following PA would determine one of five defined scenarios:

1. negative biopsies, in which case the patient would continue to be followed up as described

2. positive biopsy in the originally treated area, in which case the patient would be allowed one additional HIFU treatment before the treatment is classed as having failed

3. positive biopsy in the untreated area demonstrating a new focus of intermediate-risk disease, in which case the patient would be offered additional PA in this area

4. positive biopsies in any area of the prostate demonstrating low-risk, low-volume disease, in which case the patient will not require additional treatment and follow-up will continue as described

5. positive biopsy following two consecutive treatments in any area of the prostate, in which case the treatment will be deemed as having failed.

If follow-up biopsies demonstrate high-risk disease at any point, this will be considered as primary treatment failure and patients will be offered whole-gland treatment in accordance with standard of care.

In the presence of primary treatment failure as described above, the patient would be re staged using pelvic cross-sectional imaging and bone imaging. Patients would be fully informed of their disease status, grade, clinical stage and the treatment options, such as salvage EBRT. Regardless of decisions about additional interventions, patients would continue to be followed up and analysed within the trial in accordance with ITT, with full documentation of subsequent treatments.

Radiology

All the mpMRI was performed in accordance with European Society of Urogenital Radiology (ESUR) guidelines, using both 1.5- and 3-tesla magnetic field strengths and a pelvic phased-array coil. Standard T1, T2, diffusion-weighted and dynamic contrast-enhanced mpMRI sequences were performed.

The pre-treatment scans were reported using the standardised reporting Prostate Imaging and Data Reporting System (PI-RADS) scoring system approved by ESUR, with a local T stage also reported. Additionally, it was agreed that the degree of capsular abutment of identified tumour would be recorded to the nearest millimetre, and patients with abutment of > 15 mm were regarded as ineligible for the study.

The post-HIFU treatment scans were performed at three time points: within the first month post HIFU for centres new to performing HIFU, and at 12 and 36 months. The early scans focused on assessing technical treatment success and complications, whereas the later scans focused on identification of disease, particularly the position of the tumour on the initial scan.

We aimed to establish the ability of early post-HIFU mpMRI to determine whether or not treatment has been adequate and the likelihood of local relapse, by reviewing the non-enhancing volume on initial scans against appearances at 12 and 36 months.

The reports were provided on a standard template across all centres, with the prostate divided into anterior and posterior, right and left, and three sectors: base, mid and apex.

Pathology

Biopsies and RP specimens were reported at the local trial centres to the requirements set in Dataset for Histopathology Reports for Prostatic Carcinoma. 67 Gleason grading was undertaken using the 2005 International Society of Urological Pathology’s modified Gleason grading system. 68 Pathological tumour, node, metastasis (TNM) staging was undertaken using TNM Classification of Malignant Tumours. 69

Interviews

The QRI researcher approached 23 staff members to take part, and a total of 13 one-to-one interviews were conducted between July and November 2015. Interviews were conducted by the QRI researcher. Eight interviews were conducted face to face and five were conducted by telephone. The final sample of interviewees consisted of the trial manager, 11 recruiting clinicians (four of whom were members of the TMG) and one research nurse. At least one representative from each of the recruiting centres was interviewed. Interviews lasted an average of 43 minutes (range 31–53 minutes).

Recorded consultations

A total of 64 recruitment appointments, with 54 different patients, were obtained (in the case of five patients, two consultations were recorded). The first recording was received in September 2015. A total of 22 recordings were made before any QRI feedback had been provided and 45 were made after QRI feedback had been provided. Consultations lasted an average of 27 minutes (range 10–42 minutes). Twelve different recruiters (11 consultant urologists and one research nurse) led the consultations. Audio-recordings were obtained from four recruiting centres. One centre did not any provide recordings, another provided two recorded consultations (although both of these patients were ineligible), two centres provided 14 recordings and one centre provided 34 recordings.

Support for the study

Those involved in the study were asked about the existing evidence and the rationale for the study. HIFU was described as an ‘exciting’ and ‘promising’ alternative to radical procedures. Most of the recruiters described findings from observational studies, which suggested that HIFU had a lower side-effect profile in terms of erectile dysfunction or incontinence and acceptable outcomes in terms of cancer control. Recruiters described how much of the research had been conducted within UCH, and several commented that Oxford running the study was a strength as it was considered an ‘impartial’ centre:

I think this trial is needed because there has been a lot of hype or buzz about HIFU and focal therapy for some years now.

Interview, recruiter

I think having a study that is being led by a sort of equivocal centre is probably going to be very good for the study.

Interview, recruiter

Overall, there was strong commitment to a randomised study comparing RP with HIFU:

It’s an important study, I think everyone would like it to succeed.

Interview, recruiter

We don’t have any high-quality, randomised, comparative trial results, so it’s crying out really for a randomised trial and a good comparator would be radical prostatectomy.

Interview, recruiter

However, the QRI identified a number of issues that affected recruitment. These are outlined in the following section.

Organisational challenges

Several logistical obstacles disrupted the anticipated recruitment timelines, including the delivery of HIFU equipment in two centres (Sheffield and Bristol). In January 2015, it became evident that if the centre did not own a HIFU machine, the cost of hiring one was not covered in the original costing tariff. The TMG approached the manufacturers of the HIFU device to determine if the machine could be rented for free, which was not possible. The TMG then approached both Basingstoke and Southampton centres that were offering HIFU routinely, in May 2016. In Sheffield, an excess treatment cost (ETC) bid was submitted and successfully awarded so that part of the shortfall was covered by the Clinical Commissioning Group. However, ensuring the ETC took nearly 10 months and, as a result, recruitment in Sheffield (a high-yielding recruitment centre) was severely delayed:

HIFU is a new technology and costings in the NHS in terms of R&D [research and development] finance and the way they are costing it is quite difficult. What it meant was that the cost of hiring a HIFU machine if the site didn’t own it wouldn’t have been covered in the original tariff, so there would be a shortfall to the trust essentially. This had quite a severe knock-on effect in two of the original sites, Sheffield and Bristol, because they don’t own a HIFU machine and HIFU wasn’t routinely offered there. I think that might have been the biggest delay.

Interview, TMG

Obtaining research and development (R&D) approval in all centres, apart from Oxford, took significantly longer than hoped. In some institutions, it took as long as 6 months from submitting the site-specific information (SSI) form to centre R&D approval being issued. Many staff involved in recruitment to the study left their roles. This included the proposed PI for Bristol, and, in December 2015, the TMG made the decision not to pursue activating this centre. Research nurses from two active centres also left their roles (November 2015 in Basingstoke, April 2016 in Southampton and December 2016 again in Basingstoke), meaning that all new staff had to be recruited and subsequently trained:

We’re 6 months in and we’ve not even hit the start button for our R&D approval. That’s the biggest problem.

Interview, recruiter

Table 2 provides an overview of the organisational issues encountered. Although it was anticipated that all five centres would begin recruitment in January 2015, delays in activating the centres meant that, combined, a total of 30 recruiting months were lost.

Previous randomised controlled trial experience

Before the PART trial, many of those interviewed had not been involved in recruiting to randomised studies and had therefore not received any support or training for their role as recruiters. The exception to this was several recruiters from Oxford and Sheffield, who had received recruitment training for the ProtecT trial. Analysis of the data showed that, overall, these recruiters appeared more comfortable with the concept of uncertainty, with the need for pragmatic inclusion criteria and with explaining trial concepts to patients. This is further discussed throughout this chapter, but is exemplified by the following quotations:

I have seen patients that have been recruited to different trials through my training, but I haven’t, personally, been responsible for recruiting to trials [. . .] I have no idea whether HIFU’s going to work or not, so it makes it very difficult to know how much of that information to tell patients. The problem with HIFU is that I have no idea whether, in a year’s time or whatever it is, 20% of all the people that are having HIFU need a further treatment, or whether it’s 2% or whether it’s 50%. Therefore, it’s very difficult to then talk to patients about it. Whereas, if they opt for surgery, I can say to them, based on their disease parameters, that their chance of having a recurrence is something like 5% to 10% in 10 years.

Interview, recruiter

I think we need to be confident on our uncertainty, and you know, I’ve learned a lot by being involved in ProtecT [. . .] We have a national reputation for being good with prostate cancer, and we acknowledge that there are uncertainties in the decision-making, which is why we run clinical trials.

Interview, recruiter

Discomfort regarding the inclusion criteria

The method of determining suitability for the various treatment options was a complex process that took into consideration a large number of factors. All recruiters explained that the Gleason score was a key factor in determining whether or not the patient was regarded as being at ‘intermediate risk’ – a key eligibility criterion. The study specified a Gleason score of 7 as the inclusion criterion, but there was considerable concern about perceptions of differential levels of risk depending on whether the patient’s score was a ‘4 + 3’ or ‘3 + 4’ dominant pattern. As one recruiter remarked, ‘4 + 3 is just not the same as 3 + 4, they’re very different’. Some recruiters expressed concerns about whether or not men with a score of 4 + 3 were suitable for HIFU and instead felt that a prostatectomy was more appropriate. Equally, there was uncertainty about whether or not a patient with a 3 + 4 score would be ‘overtreated’ with prostatectomy. These patients were considered to be more suitable for HIFU or AM. The following quotations highlight the different responses to the two scores:

3 + 4’s, I think they are maybe the best ones to treat with HIFU, where they’ve got mainly pattern 3, but a bit of pattern 4. I think you can be pretty confident that you’re going to wipe out that pattern 4 when you do the treatment.

Interview, recruiter

I was just marginally uncomfortable because he had a 4 + 3 and he was 50 years old and it was quite a significant volume of tumour. I just found myself thinking, ‘Do you know what? I wonder if you’d be better off having a radical prostatectomy’.

Interview, recruiter

A further aspect of the inclusion criteria was the cancer core length. In the protocol, this was stated as > 4 mm. However, there was a feeling that patients who had larger core lengths – although technically eligible for the PART trial – would be more suited to RP:

If there’s a younger man with more volume of disease, longer cores and such. It’s a bigger lump on MRI. I might be tempted to, though I’d be reluctant to put him through HIFU, he needs surgery.

Interview, recruiter

Recruiters also described how the protocol stated that patients eligible for the PART trial must be expected to live for 5–10 years. Generally, most clinicians appeared to feel uncomfortable with treating men > 70 years old with a prostatectomy. There was also a feeling that patients who were younger would benefit more from the prostatectomy rather than HIFU.

Consultation:

What would be your advice? Which treatment, in this particular case?

I think, for someone who is fitter and younger like you, that surgery offers more benefits at this stage.

[Patient opts for radical prostatectomy.]

Alongside these clinical factors, patients’ personal circumstances were carefully taken into account. For example, recruiters emphasised the difference between curing and treating cancer. For instance, they described scenarios in which a patient might opt for a treatment that they did not necessarily feel was the ‘best’ but that suited their personal circumstances:

We know with prostate cancer it is not just which treatment is best of getting rid of cancer; it is a whole load of other stuff that they have to consider. We know that some people will choose a less good cancer operation or cancer treatment. Say, in my opinion, radiotherapy is not as good as surgery, but for some people choosing radiotherapy is the best for them because of all of the other concerns they have about surgery.

Interview, recruiter

Recruiter bias towards a particular arm

During the interviews, many of the recruiters expressed clear preferences for a particular treatment option and explained that this made it difficult to be in equipoise and to randomise to the PART trial:

What you may find is that for every single patient you could have a strong opinion that takes you away from equipoise. The trouble is the real life situation will have all of those details. Every single man will have some sort of thing . . . This all factors in to the consultation and what you recommend to someone. To have equipoise and randomise in this I think is very challenging.

Interview, recruiter

Those who favoured prostatectomy expressed concerns that HIFU would not remove all of the cancer. Conversely, advocates of HIFU expressed concerns that a prostatectomy would be overtreating cancer and compromising QoL. These recruiters questioned whether or not prostatectomy was a ‘cure’ for cancer at the cost of the patient’s sexual function and continence, whereas HIFU offered an opportunity to ‘control’ the disease while maintaining these functions:

So I have complete confidence that HIFU has fewer side effects [. . .] But they definitely, they are compromising their cancer treatment by taking the risks that we’re only treating one part of the prostate. And so there might be another part of the prostate which has some prostate cancer in. So that they [patients] understand after I’ve told them.

Interview, recruiter

I’m wondering if we are overtreating those men [with intermediate-risk disease] though, by doing radical prostatectomy.

Interview, recruiter

The consultations demonstrated that these beliefs were conveyed to the patients. Loaded terminology was frequently adopted, such as describing ‘conventional surgery’ and an ‘experimental’, ‘alternative’ and ‘novel’ HIFU. There were many consultations in which the concept of uncertainty was not introduced to the patient. Instead, recruiters often provided treatment recommendations:

I think that surgery or radiotherapy, for someone who is young and fit like you, with slightly more bulky disease, would be more appropriate. So, I don’t think the trial is right for you.

Consultation, recruiter

[Patient opts for radical prostatectomy.]

Consultation:

If you have surgery, with the kind of disease you have, you’d almost certainly not die of prostate cancer.

I think I’d prefer to be alive.

[Patient opts for radical prostatectomy.]

Discomfort with exploring patient preferences

In the consultations recorded, treatment options described usually included prostatectomy, EBRT and AM. In addition, cryotherapy, permanent seed brachytherapy, temporary brachytherapy and CyberKnife^® (Accuray, Sunnyvale, CA, USA) were occasionally discussed. Analysis of the consultations suggested that several recruiters struggled with outlining all the options that were available to patients in a concise manner, and seemed unclear when and how to mention the PART trial without bombarding the patient with too much information:

There are a lot of things to discuss in that 20-minute consultation. At that point, they don’t know whether their cancer needs treating or doesn’t need treating. They don’t know whether they can be watched safely or whether they need a form of radical treatment. They don’t know the side effects of surgery, the side effects of radiotherapy, what kind of surgery they would get, or whether they would have conventional radiotherapy or whacky therapy. There are so many options.

Interview, recruiter

There are already choices, and then you throw at them, ‘Oh, by the way, there’s a randomised trial. That’s another thing we can offer to you’.

Interview, recruiter

There was some evidence to suggest that patients appeared overwhelmed by their options:

The options are the problem. There’s just so much to choose from.

Consultation, patient

I asked my GP about this, because I said that, ‘One of the problems I’m having is that there are so many options open to me and I’m not being given clear advice on one rather than any of the others’.

Consultation, patient

After receiving their diagnosis, most patients sought information from a variety of sources, including other health-care professionals, the internet and friends or relatives; therefore, all recruiters explained that most patients often came to consultations with preconceptions about the treatment options. These preferences were constructed as ‘fixed’, and most recruiters expressed discomfort with discussing these:

Sometimes patients just come in and say, ‘I don’t want radiotherapy. I have googled it and it is not for me. I don’t want brachytherapy. I have googled it and it is not for me. I want surgery.’ Patients are now empowered with knowledge so I think most of the time once they have been given the diagnosis they are googling. I think they know. It’s their decision, and I think it is the right decision.

Interview, recruiter

When patients did express preferences, most recruiters did not discuss these further. Consequently, the study was often not discussed. This meant that, in such cases, there was insufficient evidence to demonstrate that patients fully understood the key information about each treatment and were basing their decision on correct information.

Consultation:

I think I would prefer to have it zapped [HIFU].

Sure. That’s absolutely fine, no, totally understand.

[PART trial not discussed in consultation.]

In contrast, those who had been involved in the ProtecT trial emphasised the importance of exploring patient views and understanding:

Usually, a patient decision is often based on misinformation rather than a personal decision . . . There is a fine line, we must not cross the line, but I think if they have misunderstandings about the disease or the trial, it’s our duty to clarify that, and then the decision is theirs. It’s always about bouncing the decision to them and making sure they understand.

Interview, recruiter

Difficulty explaining randomisation

Many recruiters felt that the concept of randomisation was a key reason why patients did not want to join the study. However, analysis of consultations showed that very few explained the rationale for randomisation. Instead, recruiters tended to focus on the process of randomisation and use metaphors such as ‘lucky dip’ and ‘toss of a coin’. In addition, there was a tendency to explain randomisation in a negative manner (i.e. focusing on the lack of control/choice):

The downside is you’re going into it not knowing which one you’re going to go for.

Consultation, recruiter

Consultation:

It is asking men to agree to have the choice taken away from them.

You don’t have a choice in that?

You don’t have a choice.

[Reason for randomisation not discussed, patient declined participation in the PART trial.]

The consultations suggested that these explanations were off-putting for patients, and there was little evidence to show that patients understood why randomisation was necessary:

Well I don’t want to be like a contestant on a quiz show.

Consultation, patient

Hmmm . . . But I don’t get a choice with the study, do I?

Consultation, patient

Recruitment session at collaborators’ meeting

In December 2015, a collaborators’ meeting was hosted in Oxford with 30 key centre staff in attendance from all active centres. The day included a two-part session on recruiting to the PART trial, led by the QRI researcher. This featured a presentation of the findings of phase I, which were supplemented with anonymised quotations to illustrate the key issues. Overall, the session aimed to improve recruiter engagement with the study. Because the interviews highlighted the lack of individual equipoise between the recruiters, the session primarily focused on the lack of randomised evidence comparing prostatectomy with HIFU, the extent to which there was community equipoise (i.e. by demonstrating the conflicting biases for the treatment arms), and examples of how recruiter beliefs could influence patient preferences. Furthermore, because many recruiters had not been involved in randomised studies before the PART trial, the session emphasised the ways in which recruiting to RCTs differed from standard practice, with the aim of encouraging recruiters to feel more comfortable with the concept of uncertainty and refrain from providing treatment recommendations. Alongside this, the researcher discussed the importance of approaching all eligible patients so that all men had the opportunity to consider the study. Recruiters were encouraged to explore patient preferences in future discussions to ensure that men were making a fully informed decision. The session was interactive, with honest and open discussions being encouraged.

Recruiter tips and guidance

The challenges associated with structuring consultations and explaining trial-specific processes (i.e. randomisation) were addressed through circulation of a ‘tips sheet’ in February 2016 (see Report Supplementary Material 8). This two-page document contained advice for structuring the consultation and presenting the treatment options in a balanced manner. The document also featured guidance on introducing the study and explaining randomisation. This was placed on the study website and laminated copies were posted to 22 recruiters from all five centres. The key points were summarised in monthly recruitment newsletters that were circulated to all recruiters. Those involved in the trial were also sent several recruitment e-mails. These provided guidance for specific issues, such as exploring patient preferences and optimising recruitment in centres offering HIFU outside the PART trial, in addition to outlining how the rationale for the PART trial was strengthened by the publication of the ProtecT trial findings.

Site recruitment reviews

Between December 2015 and January 2017, group feedback sessions at each recruiting centre were conducted. In addition to the QRI researcher, the principal investigator (PI) and lead research nurse, all centre staff involved in the trial were encouraged to join the meeting so that the team could discuss recruitment to date, areas of difficulty and plans for improving recruitment. Sessions often began with an overview of the screening log data and discussion of patient pathways. These sessions were another opportunity to reinforce the generic key points from the sessions at the collaborators’ meeting, and there was also a focus on specific issues that had emerged from the analysis of the appointment recordings in each clinical centre. For instance, the sessions covered a variety of issues, such as discussing competing research studies, clarifying particular roles within the team and introducing the treatments that were available at each centre. A total of seven recruitment reviews were conducted.

Individual feedback

Recruiters who had provided at least three recorded consultations were provided with individual feedback by the QRI researcher. This was presented and discussed in a supportive and confidential manner, which was supplemented with a written summary. The feedback highlighted instances of good practice in terms of shared decision-making and informed consent, and made suggestions as to what might be improved. In total, individual feedback was provided to three recruiting surgeons.

Pre- and post-feedback recruitment rates

Between January and November 2015, 15 patients were recruited. In this time, the average number of patients agreeing to be randomised was 1.4 per month. In addition, the conversion rate (the numbers of eligible men invited to join the PART trial who then went on to be randomised) was 20% (15/75). Phase II of the QRI began in December 2015, and continued for the duration of the study until recruitment ended in March 2017. During this time, 67 patients were recruited. On average, this equated to 4.5 patients per month. In addition, the conversion rate increased to 37%. Furthermore, after the initial intervention in December 2015, several centres (rather than predominantly Oxford) began recruiting more consistently. Although it is not possible to determine the precise impact that the QRI had on recruitment, this suggests that it had a positive impact.

Changes in information provision

Post feedback: why did some patients continue to decline?

Although there were clear improvements in the way that recruiters described the study and engaged in patient discussions, the conversion rate was still lower than the target of 50%. There were a number of reasons for this. For instance, there were several consultations in which, even though the recruiter balanced the treatment options and explained the study well, patients did not want their treatment to be allocated. The following consultation provides an example of this.

Consultation:

How do you feel about being allocated a decision?

Not my style really. I’m the boss, I make the decisions.

Can you understand the philosophy of that though?

Yes I absolutely understand the philosophy, yes, it’s research, I do that as well, so I have to understand it because it’s got to be ran– [. . .] I’m torn actually because I sense that going for the trial is a good thing generally because this is something we should try and do.

Since we don’t know, since this is a difficult choice, entering a trial allows you to be allocated one of two very good treatments. One thing we know is that people who are managed in trials generally do better than people who aren’t in trials.

Yes, I know, my medical help at the hospital have been telling me exactly that, but I’m a risk taker.

Although recruiters began to engage in discussions about preferences, patient preferences were still the main reason why patients declined to participate in the trial. For instance, several patients declined to participate in the study because they wanted other forms of radical treatments (such as radiotherapy) or PA (such as cryotherapy) that were not available in the trial. These treatments would, however, be included in a main study comparing radical treatments with ablative therapies, and so removing this barrier to recruitment would probably lead to more recruits.

I’m going towards the radiotherapy, purely because I thought it was, well, painless. I thought it wasn’t going to hurt me. As much as I’m a man, you don’t want to put yourself through anything you don’t really have to unless you have to.

Consultation, patient

Some patients declined to participate in the study because they did not want the entire prostate removed. These men expressed concerns about the impact that radical treatments would have on their erectile functioning and wanted to pursue a treatment that would give them a greater chance of maintaining an active sex life.

Consultation:

I am not really in favour of having the whole lot out.

Basically he doesn’t want to lose his sex life yet. That is the one of the main . . .

Too many side effects and I have got an active sex life.

You can give me the options, but I understand why you can’t advise me. But as I said to my friend here, that I see this as a house. And we’ve got a bit of dry rot in one of the bedrooms. And I don’t see that as a reason to knock the house down. We treat the dry rot . . . Because I’m very sexually active. And I want to be for the next few years.

Conversely, other patients stated that they wanted a RP because it gave them the greatest chance of removing all the cancer. These patients stated that they were prepared to accept the higher risk of side effects of radical treatment:

If you’ve got a problem, get rid of the damn thing. You’ve got gangrene in your finger, cut your finger off, don’t try and cure it.

Patient, consultation

I just want surgery. I just want it out of my body [. . .] To be quite honest with you, a physical relationship, it wouldn’t be the be-all and end-all of it all.

Patient, consultation

Variation between centres

It is important to acknowledge that there was also considerable variation between the centres regarding conversion rates, that is, the proportion of eligible patients consenting to randomisation (Table 4).

Although NICE guidelines72 state that HIFU is not recommended other than in the context of controlled clinical trials comparing HIFU with established interventions (such as surgery), HIFU was openly available on the NHS at three of the five participating centres (Basingstoke, Southampton and UCH). Two of these centres had the lowest conversion rates (21%) and one did not recruit any participants (UCH). UCH was anticipated to be a strong recruiter owing to the high number of procedures that are performed at the centre each year. However, as it became clear that this centre was recognised nationally as a specialist centre for HIFU, this meant that patients were referred to it from surrounding and distant hospitals specifically for HIFU treatment. These patients expressed strong preferences for HIFU, and none agreed to be participants in the PART trial.

Both Southampton and Basingstoke found recruitment challenging because HIFU was available locally, outside the PART trial. For instance, Basingstoke was active for 4 months before it randomised a participant. Before QRI feedback, seven patients were approached. Although one participant was randomised, four patients opted for HIFU and two had surgery. In Southampton, in the 2 months before QRI feedback, seven patients also were approached. Only one was randomised, whereas three declined the study because they did not want surgery and instead wanted HIFU. The remaining three participants chose radiotherapy (which would be included in a main study). Therefore, before QRI support, both centres had a conversion rate of 14% each.

Following on from QRI feedback, the consultations provided from Southampton and Basingstoke showed considerable improvements in how the recruiters discussed the PART trial. However, there were still a number of patients who declined to participate in the study and opted for HIFU. In the following consultation, the recruiter introduced the concept of uncertainty early in the consultation, conveyed enthusiasm for the study and balanced the treatment options well. Nonetheless, the patient states that he would prefer to have HIFU.

Consultation:

At the moment we’re involved in, what we think, is an exciting trial, looking at and comparing the two surgical treatment options. I spend a lot of my time telling them they’ve got prostate cancer and they say to me, ‘What’s the right treatment? What should I go for?’. Sometimes I can give them a steer. But the more I have these discussions and the more I reflect on it all, it does make me think, ‘You know what [name], a lot of what you say is based on very little evidence’. We don’t really know whether treatment A is better than treatment B. In the long term, because there are no proper randomised trials comparing the options. I just want to tell you a little bit about the trial that we’re involved with. It’s called PART. It stands for partial ablation versus radical therapy, radical prostate removal. It’s the two surgical options being compared with each other. The good thing about the trial is, we know that if any man goes into a trial, the results of the treatments within the trial tend to be good. The outcomes are good. So that we do know. The only way, in the future, that we’re going to be able to properly compare whether the right treatment is complete removal or partial treatment using ultrasound – well, not whether it’s right or wrong and which is better, but when to use one or the other and how they compare – is by doing a randomised proper trial. That is the only way we’re ever going to get useful information that we can help other men in the future with their decision-making.

Well HIFU sounds better to me.

[Discussion about side effects and oncological outcomes, recruiter balances treatment options.]

From my perspective, with yours being a 4 plus 3, whatever way we were going to treat it, my preference would be that you were within the trial.

I want, really, what is going to be best for my situation, including the after effects . . . What’s the best solution for me?

I think the short answer is, if I’m being honest, I don’t know which the best option is. That’s why we’re doing the trial.

Looking at factors I think, what we’ve just talked about and discussed. I’d rather keep a part of it, if it was possible, part of the prostate and also a rapid solution. I would prefer a rapid solution. It seems that the HIFU is probably the best option, like I say, because if it doesn’t work or anything like that, then you just cut it out anyway and have surgery and you do the other thing anyway. You might just as well do the HIFU for that reason.

You understand that . . .

I know nothing is guaranteed.

This meant that recruitment was straightforward in the only two remaining centres (Oxford and Sheffield):

A lot of patients are a mixture of private and potentially NHS patients who have been diagnosed with prostate cancer intermediate risk. They have done their research and they have decided they don’t want any of the standard treatments, so radical prostatectomy or radical radiotherapy. They will have potentially taken a long time trying to get to UCL [University College London] so they can have HIFU.

Interview, TMG

Site selection

Four centres were originally proposed: Oxford, Bristol, Sheffield and UCH. However, there were individual problems at some of the centres (Bristol’s PI left the UK, and the NHS trust declined to support the trial, and UCH encountered insurmountable challenges to recruitment). We therefore added two new centres during the course of the study (Basingstoke and Southampton), which caused delays in optimising our recruitment strategy and necessitated an extension to the projected recruitment period. In addition, reimbursement of the HIFU ETCs was extremely difficult to secure in the centres; it required considerable efforts to secure these costs from other sources.

Quality-of-life assessments

The study was designed to assess the feasibility of assessing the various dimensions of HRQoL that may be affected by PA therapies or RP in a main RCT. The results of the study were encouraging, particularly with postprocedure follow-up, with favourable response rates overall and instruments being completed with few missing items. The exception was the somewhat less complete data provided for FACT-P, a much longer questionnaire than others in the required battery. There may be some element of redundancy in the battery of questionnaires that could be addressed to reduce respondent burden and rate of missing data.

The pattern of differences in QoL between treatments observed, particularly for urinary and sexual function, is consistent with other recent studies of focal therapies and provides positive evidence for the construct validity of instruments selected for the PART study. 79,80 Only a main RCT can provide clear evidence of short- and long-term effects on QoL of alternative treatments, which can be judged in conjunction with reliable evidence of disease and survival results in order to inform patients’ and clinicians’ judgements about trade-offs and treatment choices. 15

Health economics

Completeness levels across the health economic instruments were good, and trends in incomplete data were examined. In order to strengthen a main RCT, the following concerns have been identified from the data audit alongside the health economic analysis:

• Missing data in relation to the EQ-5D-5L instrument may be a result of patients requesting to take the PROMs survey pack home with them. There were no missing data at the domain level for patients who completed the EQ-5D-5L instrument. Discussion with the study nurses highlighted the fact that the patients did not have the time or physical space necessary to sit down and complete the survey pack. For the substantive phase of the trial, it would be more efficient if the EQ-5D-5L instrument (on its own and not as part of a PROMs survey pack) was presented to the patient on arrival at all follow-up visits and a request for immediate completion was made by the trial nurse. Further training and supportive material will also be supplied to trial nurses highlighting the importance of the EQ-5D-5L instrument in the overall assessment of whether or not the proposed intervention is cost-effective.

• The completeness level of the patient resource use diary was good, with 31 out of 41 (76%) participants fully completing the diary; however, completeness by section varied considerably. The rationale for the full completion of the patient diaries between each follow-up may need to be further explained through supplementary material and further discussion with the trial nurse. Issues with the interpretation of what items to include were also highlighted. For example, patients included initial procedure details given at the treatment visit in the diary; therefore, it will be necessary, for the substantive phase of the trial, to explain that the diaries are for resources used between, but not including, initial or subsequent follow-up visits. We will also explore redesigning data capture methods for days unable to undertake usual activities.

• The structure of the patient diary will be optimised for the main RCT to reduce incomplete sections. Certain items have been identified that were incomplete for most participants and solutions have been identified through consultation with the trial nurses to enhance the diary. The addition of ‘not-applicable’ tick boxes for each subsection is necessary for distinguishing between categories of missingness. Add-on checklists can also be included as reference material for patients. For example, the diary categorises medication and device usage into four subsections: (1) drugs or devices for erection problems, (2) medicines or devices for managing urinary problems, (3) other medicines or therapy for treatment-related problems (e.g. for anxiety or depression, pain, etc.) and (4) other aids or devices for treatment-related problems. A small sample of participants appeared to not have full knowledge of which medication was for which health problem, and so medications in particular were reported in incorrect sections. A comprehensive list of potential medications for sexual dysfunction and urinary problems may reduce the potential for mismatch in completing this section of the survey. A third defined category for digestive/bowel issues may be relevant to the disease area and further enhance the patient diary.

• In the patient diary, men were asked to report days during which health status affected their ability to carry out usual activities. Of those who completed this section, the mean number of days reported in suboptimal health was 32.9 (range 3–154 days). Currently, the patient diary does not request information on informal care; given the variation in days reported unable to carry out usual activities across trial arms, the addition of a further section on informal care may highlight a further economic benefit from the intervention.

The analysis of EQ-5D-5L utility scores highlights potential health gains for patients receiving HIFU compared with RP, with evidence suggesting that HIFU is unlikely to cause a loss in health benefit relative to RP. This exploration of the EQ-5D-5L data adds to the clear need to undertake a larger-scale trial assessing HIFU against other therapies for localised PCa.

Reported resource use in terms of contacts with health-care professionals and inpatient events was higher in the RP arm than in the HIFU arm. Whether or not this would persist in a larger-scale study is unknown; however, at baseline, both cohorts of participants exhibited similar clinical profiles and, for this reason, variation in resource use evidenced across follow-up is at least partially attributable to the trial procedures.

The usefulness of a patient diary versus retrieving data from electronic patient records/notes was assessed in this feasibility stage of the trial. Return rates were good for the patient diary, at 70%, and a wider range of health-care contact at primary and secondary care settings, as well as medication and device usage, can be captured in one data collection tool, aiding more robust analysis of resource use data.

Cost per treatment arm was not analysed. The overall objective of the feasibility study was to assess the feasibility and completeness of data collection regarding HRQoL and patient-reported resource use. Median time spent in hospital after treatment was 1 bed-day (IQR 1–4 bed-days) in the RP arm and 0 bed-days (IQR 0–2 bed-days) in the HIFU arm (see Table 7); one participant in the RP arm also spent a night in an ICU following treatment. The cost implications of the variation in resource use across trial arms suggest that there are potential savings from both a NHS perspective and a societal perspective. This needs to be examined alongside a full RCT. Furthermore, the cost of the HIFU treatment compared with RP is substantially lower. The 2014/15 unit costs66 for HIFU and robotic RP were £2848 and £7317, respectively; therefore, based on NHS reference costs alone, the cost to the NHS of RP is 2.6 times higher than the cost of HIFU, suggesting a potential for cost saving. However, NHS reference costs reflect a national average and, as each trust negotiates the cost and availability of the devices (long-term lease, purchase, or ad hoc hire) based on capacity/usage as well as other factors, these unit costs will vary considerably from centre to centre. To address this, in the full RCT, a full micro-costing would need be undertaken to provide a more robust unit cost estimate of HIFU and RP to improve precision in the comparison.

The use of patient diaries improves the level of resource use detail reported and reduces the potential for missing data, which are usually an issue with electronic patient records. In the PART trial, there was a good response rate to the patient resource use diary; however, certain sections need refinement, and further supplementary guidance for trial nurses and patients is needed in the main RCT.

Imaging

In the feasibility protocol, patients needed to have received a mpMRI before confirmation of eligibility for randomisation. Although in some of the centres, pre-biopsy imaging was routine practice, in others mpMRI was performed post diagnosis; therefore, a delay of approximately 3 months was incurred to obtain images void of postbiopsy artefacts. The need for this important component of the evaluation for eligibility was explained to participants, in order to avoid using PA in the presence of significant disease on the contralateral side of the prostate. This delay of 3 months represented an acceptable formal period of AM for the participant, following which mpMRI and further biopsies, as necessary, would determine eligibility. During the course of the study, urological practice has changed considerably in most centres, particularly after the publication of the NIHR HTA PROMIS, and the majority of UK urological departments now include mpMRI before biopsies, which will resolve the challenge encountered in the feasibility phase.

Pathology

During the feasibility study, a new national initiative, the National Cancer Research Institute – Cellular Molecular Pathology (NCRI CM-Path), was formed. One of its aims is to improve the quality of pathology input to clinical trials. The PART trial lead pathologist is a member of the NCRI CM-Path Workstream 2 (clinical trials) and is chairperson for the Tissue Access and Quality Assurance in Trials subgroup. Information gained from this initiative would be utilised to maximise a main RCT.

The period of the feasibility study was a time of great change for urological pathology, with new reporting guidelines introduced. Although pathology specimens were processed and reported to standards set in the Royal College of Pathologists’ Dataset for Histopathology Reports for Prostatic Carcinoma, second edition,67 a third edition has now been published. 81 It was not feasible to change to the newer version of this data set part-way through this feasibility study, as this would have led to inconsistency.

It was intended that central review of RP specimens would happen from other recruiting centres, but logistically this proved to be difficult. Any cases with bilateral or high-risk disease in the main RCT will be scanned and shared between the PART trial pathology working group. The purpose of this would be to verify the overall categorisation either as dominant unilateral intermediate-risk and small contralateral low-risk disease or bilateral/high-risk disease. The borderline between Gleason patterns 3 and 4 is not always entirely clear, and the distinction between these two categories may vary depending on interpathologist interpretation of Gleason pattern 3 versus Gleason pattern 4. Central review ensures standardisation.

Data collection tools

The PART feasibility study allowed a mixture of remote and central data entry at the outset. Centres were initially requested to enter data remotely; however, it became apparent that centres were struggling to manage data entry, owing to the large number of CRFs, PROMs questionnaire packs and resource use diaries being tested. To support centres, the PART trial office took over all data entry, apart from at the Royal Hallamshire Hospital, Sheffield, where a dedicated data entry clerk had already been identified to enter data.

Interventions

A main RCT would be opened up to additional PA modalities to reflect the available range of treatments that are currently being evaluated, as well as offering brachytherapy and IMRT in the radical ablation arm. We believe that this would enhance recruitment as patients may be more willing to participate when there is a wider range of treatment options available to them.

Impact of patient and public involvement

Patient representatives attended all TSC meetings and were supportive of the study’s progress and the importance of a larger RCT. The proposed main RCT would open the treatment arms up, and compare partial versus radical treatments. The patient representatives did not feel that there would be concerns from a patient perspective about which PA therapy they received, as long as they received assurances about the efficacy of the technique. Online completion of PROMs questionnaires was considered but as ≈10% of the OPCSG members did not have internet access, a paper option would remain necessary. Patients were sent the validated questionnaire pack and resource utilisation diary for review. The diary was deemed fairly clear and helpful feedback was received on the questionnaire pack, including:

• whether or not patients routinely weighed themselves, as a question in the pack relates to weight gain/loss

• the size of the questionnaire pack

• the layout of some of the questionnaires

• the repetition of some questions within the pack.

These comments will help to inform the design of the questionnaire pack for the main RCT.

We will involve the OPCSG in the dissemination of the feasibility results, and draw heavily on their views and support for the funding application for a main RCT.

Primary outcomes

• Primary treatment failure as demonstrated by the need for whole-gland ablation and/or secondary radiotherapy.

• Quality of life using conventional questionnaires to assess sexual outcomes, urinary continence and other functional outcomes.

Secondary outcomes

• Short-, medium- and long-term AEs related to treatments.

• Disease progression, including development of metastases.

• Resource utilisation and health economic evaluation in terms of cost per QALY.

• The role of imaging by mpMRI and biopsy protocols in determining suitability of patients for PA therapy.

• Disease-specific and all-cause mortality.