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

ISRCTN	ISRCTN11447662
DOI	https://doi.org/10.1186/ISRCTN11447662
IRAS number	328263
ClinicalTrials.gov number	NCT06280781
Secondary identifying numbers	CPMS 59385, IRAS 328263

Submission date: 24/01/2024
Registration date: 07/02/2024
Last edited: 02/08/2024

Recruitment status: Recruiting
Overall study status: Ongoing
Condition category: Cancer

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Record updated in last year

Plain English summary of protocol

https://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-trial-looking-at-a-new-way-of-doing-active-surveillance-for-prostate-cancer-ip9-atlas

Background and study aims
The aim of this study for patients on active surveillance for prostate cancer is to demonstrate that the use of regular MRI scans is better able to detect cancer progression over 5 years compared to the current NICE-defined strategy.

Who can participate?
Patients aged 18 years or above with a diagnosis of localised prostate cancer in the 9 months before the screening visit and who have chosen active surveillance

What does the study involve?
Patients will be randomly allocated to either MRI scans or the current NICE-defined standard.
Current (NICE-defined active surveillance): PSA test 3 monthly in year 1 and then 6 monthly with rectal exam annually. MRI will be carried out at 12 months (if not had one at diagnosis). A biopsy will be required if indicated due to changes in rectal exam or PSA.
Planned (regular MRI-based active surveillance): Patients with a visible lesion or medium-risk cancer will have PSA 6 monthly and MRI annually. All other patients will undergo PSA 6 monthly and MRI in years 1, 3 and 5.
For all patients, a targeted biopsy will be carried out if the MRI PRECISE score is >/=4.

What are the possible benefits and risks of participating?
Participants will continue on their standard care pathway with monitoring, so will not be at risk of progression not being detected. Those patients in the intervention group will have additional MRI scans. These will be non-contrast so there is no risk from having repeated 1-2 yearly injections of gadolinium contrast. Patients with contraindications to MRI will not be taking part in the study so will not be exposed to an unnecessary MRI.

Where is the study run from?
Imperial College London (UK)

When is the study starting and how long is it expected to run for?
October 2023 to June 2032

Who is funding the study?
National Institute for Health and Care Research (NIHR) Health Technology Assessment (HTA) (UK)

Who is the main contact?
1. Increase Akinyemi, i.akinyemi@imperial.ac.uk
2. Hashim Ahmed, hashim.ahmed@imperial.ac.uk

Contact information

Miss Increase Akinyemi
Scientific

Imperial Prostate
ICTU, Stadium House
68 Wood Lane
London
W12 7RH
United Kingdom

Phone	+44 (0)207 594 7271
Email	i.akinyemi@imperial.ac.uk

Prof Hashim Ahmed
Scientific

Imperial College London
B Block, Division of Surgery
Hammersmith Hospital
Du Cane Road
London
W12 0HS
United Kingdom

ORCID ID	0000-0003-1674-6723
Phone	+44 (0)20 7594 1660
Email	hashim.ahmed@imperial.ac.uk

Study information

Study design	Randomized; Interventional; Design type: Process of Care, Imaging, Active Monitoring
Primary study design	Interventional
Secondary study design	Randomised controlled trial
Study setting(s)	Other
Study type	Treatment
Participant information sheet	Not available in web format, please use the contact details to request a patient information sheet
Scientific title	A randomised controlled trial of regular MRI scans compared to standard care in patients with prostate cancer managed using active surveillance
Study acronym	IP9 – ATLAS
Study objectives	To demonstrate that the use of regular MRI scans is better able to detect prostate cancer progression in men over 5 years compared to the current NICE-defined strategy.
Ethics approval(s)	Approved 14/12/2023, Wales Research Ethics Committee 3 (Health and Care Research Wales, Castlebridge 4, 15-19 Cowbridge Road East, Cardiff, CF11 9AB, UK; +44 (0)2922 941107, +44 (0)2922 940954, +44 (0)2922 940963; Wales.REC3@wales.nhs.uk), ref: 23/WA/0323
Health condition(s) or problem(s) studied	Prostate cancer
Intervention	Patients with prostate cancer who have chosen active surveillance to manage the disease will be informed of the study using the patient information sheet as well as speaking to their clinical and research team. If they wish to participate, written informed consent will be taken. Soon after consent, patients will be informed of their allocation. This will either be standard care active surveillance or the new regular MRI-based active surveillance. Standard care: These reflect standard care and there will be no additional follow-up visits required for the study. PSA blood tests will be carried out (at hospital or GP) every 3-6 months. Clinical examination will be carried out every year. In patients where these indicate a clinical suspicion of progression, further tests to detect or rule out progression of cancer will be carried out such as an MRI and biopsy. Follow-up in the study will proceed for 5 years after randomisation. Patients will be asked to fill in questionnaires about their health at the beginning and every year for 5 years. Intervention: PSA blood tests will be carried out (at hospital or GP) every 3-6 months. An MRI scan will be done once a year for 5 years for all men with Grade Group 2 cancer or a visible tumour on MRI. An MRI scan will be done at 1 year, 3 years and 5 years for all men with Grade Group 1 cancer or non-visible tumour on MRI. In patients where PSA changes or MRI changes indicate clinical suspicion of progression, a biopsy will be carried out to detect or rule out progression. Follow-up in the study will proceed for 5 years after randomisation. Patients will be asked to fill in questionnaires about their health at the beginning and every year for 5 years. The researchers will give all men in the study a booklet detailing what their active surveillance programme is and a table for them to write down their test results as well as take notes. The PPI representatives have also asked that we give some advice on dietary and lifestyle changes that might be of benefit to patients on active surveillance. Analysis of secondary outcomes will use multivariable logistic or linear regression, depending on the type of outcome data. MRI & biopsy-related adverse events and the proportion of patients agreeing to a biopsy when clinically recommended will be reported using summary statistics. PROMS data will be analysed using mixed linear models to account for the repeated measurements in time. Compliance with the allocated surveillance strategy will be monitored and reported by study arm. Compliance with each component of the intervention (PSA, rectal examination, MRI, biopsy) will be reported by study arm. During the trial, compliance with each component will be reported to the DMEC to ensure compliance with the protocol and, if necessary, evaluation of the need for remedial actions. Rates of MRI in both arms will be regularly monitored throughout the trial and these will be reported to the DMEC during the periodical DMEC meetings. A statistical analysis plan, outlining all the data analysis and hypothesis tests, will be written and agreed upon with the TSC and DMEC before any look at the data.
Intervention type	Other
Primary outcome measure	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.
Secondary outcome measures	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).
Overall study start date	01/10/2023
Completion date	30/06/2032

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	18 Years
Sex	Male
Target number of participants	Planned Sample Size: 1263; UK Sample Size: 1263
Key inclusion criteria	1. Age 18 years or above (no upper limit) 2. Patients with a prostate (either cis-male gender or trans-female gender with no prior androgen deprivation hormone use at all) 3. Diagnostic bi-parametric or multiparametric MRI 4. Diagnostic systematic biopsy +/- targeted biopsy 5. A histological diagnosis of localised prostate cancer of low or intermediate risk
Key exclusion criteria	1. On active surveillance for greater than 9 months prior to the screening date 2. Contraindication to MRI or gadolinium contrast 3. Previous hip replacement to both hips 4. Contraindication to performing a biopsy guided by a transrectal ultrasound probe
Date of first enrolment	01/07/2024
Date of final enrolment	30/06/2027

Locations

Countries of recruitment

England
United Kingdom
Wales

Study participating centres

Charing Cross Hospital

Fulham Palace Road
London
W6 8RF
United Kingdom

Morriston Hospital

Heol Maes Eglwys
Cwmrhydyceirw
Swansea
SA6 6NL
United Kingdom

Frimley Park Hospital

Portsmouth Road
Frimley
Camberley
GU16 7UJ
United Kingdom

Royal Devon and Exeter Hospital

Royal Devon & Exeter Hospital
Barrack Road
Exeter
EX2 5DW
United Kingdom

Ysbyty Glan Clwyd

Glan Clwyd Hospital
Rhuddlan Road
Bodelwyddan
Rhyl
LL18 5UJ
United Kingdom

Southampton

Southampton General Hospital
Tremona Road
Southampton
SO16 6YD
United Kingdom

Southmead Hospital

Southmead Road
Westbury-on-trym
Bristol
BS10 5NB
United Kingdom

Norfolk and Norwich University Hospital

Colney Lane
Colney
Norwich
NR4 7UY
United Kingdom

Basingstoke and North Hampshire Hospital

Aldermaston Road
Basingstoke
RG24 9NA
United Kingdom

Chelsea & Westminster Hospital

369 Fulham Road
London
SW10 9NH
United Kingdom

Royal Surrey County Hospital

Egerton Road
Guildford
GU2 7XX
United Kingdom

Queens Hospital

Queens Road
Croydon
CR9 2PQ
United Kingdom

Northampton

Northampton General Hospital
Cliftonville
Northampton
NN1 5BD
United Kingdom

Darent Valley Hospital

Darenth Wood Road
Dartford
DA2 8DA
United Kingdom

Bradford Royal Infirmary

Duckworth Lane
Bradford
BD9 6RJ
United Kingdom

Kings College Hospital

Mapother House
De Crespigny Park
Denmark Hill
London
SE5 8AB
United Kingdom

Maidstone

Maidstone Hospital
Hermitage Lane
Maidstone
ME16 9QQ
United Kingdom

Milton Keynes General Hospital

Milton Keynes Hospital
Standing Way
Eaglestone
Milton Keynes
MK6 5LD
United Kingdom

Freeman Hospital

Freeman Hospital
Freeman Road
High Heaton
Newcastle upon Tyne
NE7 7DN
United Kingdom

Kingston Hospital

Galsworthy Road
Kingston upon Thames
KT2 7QB
United Kingdom

Lister Hospital

Lister Hospital
Coreys Mill Lane
Stevenage
SG1 4AB
United Kingdom

Watford General Hospital

60 Vicarage Road
Watford
WD18 0HB
United Kingdom

St Peters Hospital

Spital Road
Maldon
CM9 6EG
United Kingdom

The Hillingdon Hospital

Pield Heath Road
Uxbridge
UB8 3NN
United Kingdom

St Thomas' Hospital

Westminster Bridge Road
London
SE1 7EH
United Kingdom

Sponsor information

Imperial College London
University/education

Faculty Building
Imperial Research Governance and Integrity Team (RGIT)
Imperial College London, Room 217, Medical School Building
Norfolk Place
London
W2 1PG
England
United Kingdom

Phone	+44 (0)2075949832
Email	cheuk-fung.wong@imperial.ac.uk
Website	http://www.imperial.ac.uk/
"ROR"	https://ror.org/041kmwe10

Funders

Funder type

Government

NIHR Evaluation, Trials and Studies Co-ordinating Centre (NETSCC); Grant Codes: NIHR152027

No information available

Results and Publications

Intention to publish date	30/06/2033
Individual participant data (IPD) Intention to share	Yes
IPD sharing plan summary	Available on request
Publication and dissemination plan	Planned publication in a high-impact peer-reviewed journal
IPD sharing plan	The datasets generated during and/or analysed during the current study will be available upon request. The publication will be in line with ICMJE requirements and therefore explicitly state the researchers' conditions on: data types; additional available documentation; window of availability (dates indicating opening and closure of access); eligibility of requests; types of analysis permitted; method of access. The researchers will post the data-sharing opportunity on their university websites. They will also take queries from interested third parties to assist and guide them to the opportunity. All subsequent publications of primary and secondary outcomes will be compliant with the NIHR Open Access Policy (https://www.nihr.ac.uk/documents/nihr-open-access-policy/12251). During the period of funding, the datasets will be collected and completed in the manner described above. The researchers anticipate opening up access beyond the existing research group within 24 months after funding is complete. There will be a lock-out period to enable the key outcomes of the studies to report first after which data access will be through application to the study group. Ahmed will act as the data custodian on behalf of Imperial College London and hold overall responsibility for data management. The persons responsible for data security and quality assurance will be Ahmed and Fiorentino.

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Protocol file	version 2.0	07/12/2023	03/07/2024	No	No

Additional files

ISRCTN11447662_Protocol_v2.0_07Dec2023.pdf

Editorial Notes

02/08/2024: A link to a plain English summary on CRUK was added.
03/07/2024: Protocol uploaded.
08/04/2024: ClinicalTrials.gov number added.
24/01/2024: Study's existence confirmed by the NIHR.