English File Pre-intermediate Third Edition

[Shelly Takacs]

Inselecting centres for the main trial, there will be several factors to take into account. First, the centre should have experience in recruiting to surgical RCTs, for example the ProtecT trial centres. Second, although having an established focal therapy programme should be an advantage, the access to the treatment should be as per NICE guidelines and within a clinical trial, such that surgeon equipoise is maintained. It would be preferable to have a centre new to focal therapy and establish a new programme within the trial, rather than the situation in which patients and surgeons are presented with the option to receive the study treatment outside the study. Third, it is important that each centre has an established funding stream to fund any treatment within the trial (robotic surgery or focal therapy). Finally, there should be adequate research nurse support to facilitate recruitment in each centre. UCH, a tertiary referral centre where patients have already had a number of clinical consultations and have been referred for a specific treatment before hearing about the study, was unable to recruit any patients, and we would therefore consider carefully whether or not tertiary centres should be included in a main RCT.

High-intensity focused ultrasound was openly available on the NHS at Basingstoke and Southampton, and these centres had lower conversion rates (21% and 20%, respectively). Because these centres were recognised nationally as specialist centres for HIFU, patients were referred to them from surrounding and distant hospitals specifically for this procedure. Although there are clear advantages in using centres that have an established expertise in the new technologies, investment in centres without an existing regional referral network for HIFU would ensure that patients are more likely to participate in the PART trial. The QRI will work with potential new centres for the main RCT to understand their patient pathways and investigate referral patterns and numbers of eligible patients.

One of the barriers to recruitment was that the only radical treatment option was surgery, and the only PA option was HIFU. Participation in the trial was declined by 63% of patients because they wanted other forms of radical treatment (such as radiotherapy) or PA (such as cryotherapy). These treatments were not available in the feasibility trial; therefore, we will be expanding the radical options to include radiotherapy (which we have demonstrated has equivalence to surgery in terms of oncological outcomes in the ProtecT trial) and brachytherapy. In the PA arm, in addition to HIFU, we will add cryotherapy, VTP and focal brachytherapy. All of these technologies have been demonstrated to ablate tissue successfully, and will be offered depending on availability and expertise in individual centres. Excess NHS costs will need to be calculated and agreed in advance.

A projection of recruitment was undertaken, based on the performance of the four recruiting centres in the later part of the feasibility study, and is summarised in Table 23 and Figure 33.

If we base our calculation on a conservative average of recruiting one or two participants per month in each centre, we will be able to recruit up to 840 men in 14 recruiting centres over a period of 5 years.

For a main RCT, the third edition of the Dataset for Histopathology Reports for Prostatic Carcinoma81 will be used for reporting. For similar reasons, despite publication of an International Society of Urological Pathology (ISUP) consensus conference on Gleason grading in 2014,85 the histopathology SOP was not amended, but a main RCT would utilise the recommendations in the ISUP Gleason 2014 publication. It is mandatory from 1 January 2018 to use the eigth edition86 of TNM Classification of Malignant Tumours (TNM), rather than the seventh edition,69 which was in use for the duration of the feasibility study. The American Joint Committee on Cancer version of the eigth edition of TNM,87 rather than the Union for International Cancer Control version, will be used.86 This contains the recommendation that pT2 disease is no longer substaged but that all are categorised as pT2 without subcategorising into pT2a/2b/2c; thus, the CRFs for the main study will be amended to clarify this.87

Double reporting of RP specimens in real time would not be utilised in a main RCT as this is logistically very difficult and would slow entry into the trial and compromise recruitment. For a main RCT, ideally a comprehensive library of images would be created to enable central review of original diagnostic biopsies by two expert urological pathologists before final publication of results.

There were no problems with local reporting and filling in of CRFs in the feasibility study. However, it would be optimal for a main RCT to amend the PIL and ICF to explicitly allow scanning of all histology slides and long-term storage of the images. This will include original diagnostic biopsies at trial entry, post-HIFU biopsies and RP slides, with the following objectives:

General principles that will be adopted for a main RCT include strengthening of the PART trial pathology working group and establishing central review of cases. Before a main RCT commences, the current members of the PART trial pathology study working group will develop the histopathology SOP and guidance on requirements and training needed for pathologists participating in the trial. Digital pathology will form a larger component of the main RCT to overcome difficulties with sharing slides across a multicentre RCT and create a long-term record of the slides to avoid slides fading and so forth. This record is not just photographed images of the slides, but scans of the entire slide to enable them to be viewed digitally in a similar way to looking through a microscope. This will be flexible depending on local slide-scanning facilities. An ideal scenario would be scanning at the local centre and uploading to a secure cloud-based trial slide repository. As a minimum, slides can be sent to Oxford, where slide scanning facilities exist. A secure slide-hosting site would be created for the main RCT.

Pathology and radiology diagnostic pathway protocols would be standardised in a main RCT; this would be the remit of the pathology and radiology working groups, which have been established in the context of the feasibility study.

Completeness of the EQ-5D-5L was good in the feasibility study but could be improved. For a main RCT, we propose collecting the EQ-5D-5L alongside the patient resource use diary, rather than with other disease-specific QoL instruments. It is also vital to ensure that, at each follow-up visit, the EQ-5D-5L questionnaire is completed before the patient sees the consultant, when possible, to reduce bias. If the patient needs to take home the EQ-5D-5L questionnaire to complete, this needs to be coded, and structured timings of prompts from research nurses to complete and return questionnaires would be required.

Although not undertaken at this stage, a full costing and cost-effectiveness analysis would be performed in a main RCT and unit costs would be updated accordingly. A main RCT would include a full cost-effectiveness analysis with the adapted resource use and EQ-5D-5L data collected in this feasibility stage being collected alongside a full trial with longer participant follow-up. Long-term patient costs attributable to AEs, complications, treatment side effects and recurrences, and the related impact on QoL beyond the length of the trial, would be explored by developing a cost-effectiveness model to provide an estimate of cost-effectiveness extrapolated beyond the full within-trial analysis. A budget impact model with the cost of all trial procedures estimated using a micro-costing approach would be undertaken. The unit costs of a number of different delivery mechanisms for focal therapy would be estimated and used in a scenario analysis to explore the cost-effectiveness of different potential focal therapy delivery mechanisms: for example, comparing provision of the therapy by a local centre using owned equipment, a local centre hiring equipment, focal therapy delivered at specialised hubs and equipment purchased by one centre and taken to each centre.

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