Approaches to long-term active surveillance of patients with prostate cancer (IP9 – ATLAS)

Progression in each group, defined as higher risk cancer on biopsy (Grade Group >/=3) or higher stage (>/=T3 or >/=N or >/=M1) over 5 years. Prostate cancer progression rates and time to progression in each randomised arm defined as:
1. Biopsy: grade progression to Grade Group 3 or greater or detection on biopsy of intraductal cancer or lymphovascular invasion. Many clinicians would include patients on active surveillance with a cribriform pattern on Grade Group so this is not a factor for progression.
2. Staging: cancer has spread to surrounding tissues (extracapsular), lymph node involvement or distant body parts as demonstrated on cross-sectional imaging including MRI, CT, bone scan or PET scans as deemed appropriate by the local multidisciplinary cancer team.

1. Cost-effectiveness of revising the prostate cancer active surveillance protocol to incorporate regular surveillance MRI at 5 years. The economic evaluation will estimate the long-term health outcomes and NHS costs of MRI-based active surveillance compared to the NICE-defined strategy and ascertain if the MRI-based strategy represents good value for money to the NHS. Cost and health outcomes associated with the interventions will be collected over the trial period. These costs and outcomes will be extrapolated and modelled over a longer time horizon than captured by the trial (e.g., the lifetime of the patient). This will involve developing a decision-analytic model to predict long-term quality-adjusted life expectancy and NHS costs given the observed differences in the trial’s primary endpoint of cancer progression at biopsy and relevant secondary endpoints. A model is required because a trial that could capture differences in risk of metastases, health-related quality of life, and life expectancy would be unfeasibly long and large. The researchers will take the NHS and Personal Social Services perspective, consistent with that used by the National Institute for Health and Care Excellence and follow relevant methods guidance for cost-effectiveness analysis.
2. Proportion of patients requiring biopsy measured at 5 years. Biopsy will be recommended when there is a change on the MRI or if there is a consistent rise in PSA over three readings that is concerning for progression even if the MRI shows no change and other factors such as infection or prostatitis have been ruled out.
3. MRI and biopsy-related adverse events: patients will be asked to self-report pain and discomfort (referred to as pain hereafter) immediately after and 7 days after biopsy on a 4-point Likert-type scale as none, mild, moderate, or severe. Specific related complications such as fever, flu-like shivers, pain, haematuria, haematochezia, and haemoejaculate will be self-reported at 35 to 90 days after the prostate biopsy as absent or present following biopsy on a purpose-designed questionnaire. For each symptom, patients will be asked to score the degree of “problem” as none, minor, moderate, or major. This will be used to derive a binary outcome for each symptom (present/moderate/severe problem vs. absent /minor problem).
4. Type of treatment for patients who progress and those who do not progress (prostatectomy, radiotherapy, brachytherapy, focal therapy) collected from health records at 5 years
5. Type of treatment for lower urinary symptoms for patients who progress and those who do not progress, collected from health records at 5 years
6. Use of systemic therapy and type in those who progress and those who do not progress, collected from health records at 5 years
7. Compliance measured as the proportion having each test (PSA, rectal exam, MRI) at each allocated timepoint and the proportion agreeing to a biopsy when clinically recommended at 5 years
8. Patient-reported outcome measures (PROMs) measured using validated questionnaires:
8.1. Urinary, erectile and bowel function measured using Expanded Prostate Cancer Index Composite (EPIC) annually from baseline to 5 years
8.2. Cancer-related anxiety measured using the Hospital Anxiety and Depression Scale (HADS) annually from baseline to 5 years
8.3. Overall health-related quality of life measured using EQ-5D-5L annually from baseline to 5 years
8.4. Patients undergoing biopsy will be asked to self-report pain and discomfort (referred to as pain hereafter) immediately after and 7 days after biopsy on a four-point Likert-type scale as none, mild, moderate, or severe. Specific related complications such as fever, flu-like shivers, pain, haematuria, haematochezia, and haemoejaculate will be self-reported at 35 to 90 days after prostate biopsy as absent or present following biopsy on a purpose-designed questionnaire. For each symptom, patients will be asked to score the degree of “problem” as none, minor, moderate, or major. This will be used to derive a binary outcome for each symptom (present/moderate/severe problem vs. absent /minor problem).
8.5. Patients undergoing an MRI complete a questionnaire on MRI-related side effects after the MRI but before the biopsy (if they have a biopsy)
9. Inter-observer variability in reporting surveillance MRI scans in the MRI group measured at 5 years

Longer-term follow-up:
All patients will be consented for linkage to national databases. Clinical outcomes can be collected after the study end on the use of subsequent tests and treatments as well as adverse events and survival at 5 years

Method/data source
MRI conduct: A study-specific MRI QA/QC Standard Operating procedure (SOP) will be drafted building on our experience in the PROMIS, PICTURE and PROSTAGRAM studies. Scanners will be either 1.5T or 3.0T in order to reflect current UK practice at each recruiting centre and would need to meet the required standards set out for the UK as stipulated in the recent NICE guidance (2019) and reflecting recent expert radiology consensus. Our lead radiology co-applicants alongside the NCITA imaging QA/QC process, will conduct a quality review of MRI scans of all centres prior to recruitment and optimise where necessary. However, since NICE recommended the use of MRI pre-biopsy, most centres have already gone through such a process within their local Cancer Alliance networks through a programme of work instigated by NHS England and the devolved nations that many in our group led on alongside membership of PCUK’s Prostate MRI national expert group for standardisation of mpMRI conduct. Patient preparation for the MRI scans will follow up-to-date guidance at the time of study set-up; the current guidance is set out in the following documents: PI-RADS v2.1 manual https://www.acr.org/-/media/ACR/Files/RADS/Pi-RADS/PIRADS-V2-1.pdf?la=en and Brizmohun et al.

Targeting and systematic biopsy protocol: We will follow standard care for centres in terms of type of analgesia/anaesthesia. Centres can use local anaesthetic, sedation or general anaesthetic; transperineal or transrectal route and visual-registration or image-fusion targeting. The exact anaesthesia type (local only, sedation, general anaesthetic) and biopsy type (transperineal vs transrectal, image fusion vs visual registration) will be recorded. The number of systematic cores will be set out in a SOP and centres will declare which systematic biopsy protocol they are using. 4-6 cores per target and unlimited targets in total per patient. Targeted biopsies will be carried out first, in order to minimise the impact of swelling on obtaining accurate sampling of targets. The EAU recommends regular biopsy in standard care every 2-3 years. In the new pathway, we will recommend biopsy when there is a change on the MRI or if there is a consistent rise in PSA over 3 readings that is concerning for progression even if the MRI shows no change and other factors such as infection or prostatitis have been ruled out.

The histological report will evaluate the following aspects for each target and each location of systematic biopsies carried out according to the Royal College of Pathology (UK) guidance number of biopsies, number positive for cancer, core length in mm, cancer presence, maximum cancer core length in mm (where continuous and discontinuous numbers are given, for the purpose of analysis, the continuous number will be used), primary, secondary and highest Gleason grade, percent pattern 4 and presence of cribriform pattern when Gleason 3+4, perineural invasion/lymphovascular invasion/intraductal components/neuroendocrine differentiation; and vii) other features (high grade prostatic intraepithelial neoplasia/atypical acini/inflammation/atrophy).