Risk stratification key to reducing prostate cancer mortality

There are have been few more contentious issues in modern medicine than testing for prostate cancer. On one side of the argument, those defending the many imperfect trials in the area that fail to answer the question, and on the other, clinicians (GPs, urologists and oncologists) see the devastating effects of the disease, too often passed-off as part of the ageing process. The truth lies somewhere in between. Finally, evidence is accumulating from well-performed trials, and the fog is starting to lift. Recent GP guidelines from the National Cancer Control Programme (NCCP) were published to support GPs,¹ but the area is moving fast and Ireland must keep up.

<h3 class=”subheadMIstyles”>Role of primary care</h3>

So why must prostate cancer detection involve primary care? A situation has developed whereby widespread and non-systematic PSA testing, alongside over-diagnosis and over-treatment for prostate cancer over the years, has left the public with a confused message on prostate cancer.  PSA testing has caused anxiety and confusion in primary care, which was essentially burdened with a blood test that nobody understood, and came without a ‘user’s guide’. Other common cancers (colorectal, cervical and breast) do not defer to GPs to decide on whether to refer to a specialist or not. Centralised testing protocols take the responsibility off GPs, who can get on with treating their patients’ other medical problems.

Early detection of prostate cancer and awareness is an essential part of proactive healthcare, if we are to make serious inroads into mortality rates. Prostate cancer represents the most common non-cutaneous male cancer today and the second-most common cancer killer in men (urological cancers in fact make up three of the top nine cancers in men).² Having a middle-aged man attend his GP for a PSA would engage many men in healthcare who may not ordinarily attend the GP. Certainly, an opportunity many GPs and preventative health specialists would relish, where a middle-aged man could not only have his PSA checked, but use the opportunity to perform a cardiac check, dietary and exercise advice and mental health check, among others. The current European Association of Urology (EAU) prostate cancer guidelines (2015) recommend every man to have a baseline PSA done in their mid-40s,³ and this could be the catalyst for a mid-life wellness review for Irish men.

<img src=”../attachments/835f18e5-4989-4a32-a8fa-506f2a89ddbc.JPG” alt=”” />

<h3 class=”subheadMIstyles”>Role of the patient and making advances</h3>

Direct patient involvement in the recent NCCP GP guidelines and in the Irish Prostate Cancer Outcomes Research (IPCOR) project allows the end-user a voice. It also confers a degree of responsibility on the patient that they too must play their role.

Prostate cancer campaigns, such as the Know Your Number campaign in the US, encouraged men to get their PSA checked and to engage in early cancer detection. This was recently highlighted by Ben Stiller’s revelation in the <em>New York Times</em>, whose urologist had advised him to have a PSA check, as he was in his mid-40s (in conflict with current US guidelines on PSA testing, but in keeping with European guidelines). Efforts by global charities such as Movember have led to the worldwide annual phenomenon of growing a moustache. Many men get involved, as a family member may have been affected by prostate cancer. Having a first-degree relative (brother, father) doubles the risk; if two first-degree relatives are affected, there is five-fold increased risk. The presence of mutations in BRCA2 gene increases the risk of prostate cancer and may be linked to hereditary prostate cancer, particularly in younger men. Many may not be aware, but Ireland is part of the global effort against prostate cancer, led by Movember and supported by the Irish Cancer Society. There are many Irish scientists and clinicians engaged in this effort who have been working with global leaders, sharing biological samples and data for many years, such as Clinical Trials Ireland and the clinical trials units, radiation oncology trials and the Prostate Cancer Research Consortium.

<h3 class=”subheadMIstyles”>Concept of risk stratification</h3>

Several recent publications have highlighted the prognostic value of a baseline PSA reading in younger men in their mid-40s.⁴ PSA values remain low in most men, until BPH develops in men in their 50s and 60s and in Ireland, age-related PSA referral values have been adopted to reflect this.¹ However, PSA values in men in their mid-40s are associated with their subsequent risk of development of prostate cancer (Figure 1) over the next 25 years.³ PSA data on Irish men is limited, but two studies found that the mean PSA aged 45 years is approximately 0.75ug/l (0.73-156).^5,6

Several recent studies now suggest that using a cut-off between 1 and 1.2 ug/l can stratify men into high risk and low risk for their lifetime risk of developing either bone metastases or dying from prostate cancer.³ This allows for men at an increased risk of prostate cancer to be more closely monitored, and for potentially life-saving interventions to be made at an early stage. The Rotterdam arm of the ERSPC study showed a 47 per cent reduction in prostate cancer mortality and 60 per cent reduction in bone metastases over 18 years’ follow-up in men having a PSA checked every two years.⁷  Those deemed low risk are followed periodically at much larger intervals. Additional modalities such as the Prostate Health Index (PHI), 4K score (Opko), followed by multi-parametric MRI, further stratifies men into higher risk and quantifies the need to biopsy.

As the current system of opportunistic PSA testing has been shown to be of no benefit, and potentially harmful, a new evidence-based approach, with both health and financial benefits, should be adopted.⁸ This early detection algorithm (Figure 2) has been proposed to the National Screening Service (NSS) by the Irish Society of Urology (ISU) and the NCCP. It has the potential to reduce prostate cancer mortality by up to 50 per cent.⁷ Research at the Conway Institute, UCD, by Prof William Watson, using data obtained from the NCCP rapid-access clinics, has produced the Irish prostate cancer calculator, which can be used to determine a patient’s individual risk of high-grade prostate cancer on biopsy.⁹ This can be used to advise the patient to avoid a biopsy.

<img src=”../attachments/d5f6b067-a041-4d24-8ba8-29ac15e058d2.JPG” alt=”” />

<strong>Figure 2: The proposed early prostate cancer detection algorithm submitted to HIQA. An organised risk stratification approach may produce significant reduction in mortality and healthcare costs</strong>

<strong><br /></strong>

<h3 class=”subheadMIstyles”>The current diagnostic pathway — NCCP guidelines</h3>

The development of rapid-access prostate clinics in eight hospitals across the State has centralised prostate cancer diagnostics and allows for Irish patients to benefit from modern diagnostic techniques. Long waiting lists are now building for MRI scans and MRI-targeted prostate biopsies in these hospitals, demonstrating their success. The mean waiting time from referral to targeted biopsy in one Dublin rapid-access centre is currently 228 days, while a recent email from an NHS colleague had a flyer attached from their healthcare system advocating a 17-day turn-around from referral to MRI and subsequent MR-targeted trans-perineal biopsy.

At the recent EAU meeting in Copenhagen, the PRECISION trial¹⁰ has clearly demonstrated that the MRI first, followed by a targeted biopsy, should be the standard of care and must be supported by all healthcare stakeholders. Multi-parametric imaging of the prostate performed to the highest standard with PIRADS v2 reporting is an essential component in efforts to reduce unnecessary biopsy and prostate cancer over-diagnosis. In men with an elevated PSA, the PHI and 4K score tests are highly-specific tests that can further inform a biopsy. These tests are not currently centrally-funded and therefore are not available in Ireland. Their use reduces the need for prostate biopsy up to by 40 per cent.¹¹  Following a biopsy, the Prolaris and Oncotype DX tests can be performed on the biopsy material and determine which patients will benefit from active surveillance or radical therapy. Again, this is not centrally-funded, and thus is not available in Ireland.

<h3 class=”subheadMIstyles”>Conclusion</h3>

Baseline PSA testing in men in their 40s risk-stratifies men in to high- or low-risk groups for the subsequent development of clinically-significant prostate cancer. Regular testing and early interventions in this high-risk group has the potential to make a significant impact in reducing mortality from prostate cancer in Irish men.

<img src=”../attachments/504bc8c6-a9b7-4166-999d-7fcaf6b7deed.JPG” alt=”” />

<p class=”subheadMIstyles”><strong>References</strong>

<p class=”listnumberedallotherlinesMIstyles”>https://www.hse.ie/eng/services/list/5/cancer/profinfo/resources/gpreferrals/gp-prostate-referral-form-and-guideline.html.

<p class=”listnumberedallotherlinesMIstyles”>Annual report of the National Cancer Registry Ireland 2017 (www.ncri.ie).

<p class=”listnumberedallotherlinesMIstyles”>EAU guidelines on Prostate cancer 2015 (www.uroweb.org).

<p class=”listnumberedallotherlinesMIstyles”>Hans Lilja, David Ulmert, Thomas Björk et al.  Long-term prediction of prostate cancer up to 25 years before diagnosis of prostate cancer using prostate kallikreins measured at age 44-to-50 years. <em>Journal of Clinical Oncology</em>, 2007 25:4, 431-436

<p class=”listnumberedallotherlinesMIstyles”>K Heverin, A Griffin, P O’Shea, H Moore, P McGing, V Crowley, Galvin D, M Fitzgibbon. PSA testing: How do our methods really compare? (Unpublished data.)

<p class=”listnumberedallotherlinesMIstyles”>Casey RG, Hegarty PK, Conroy R, Rea D, Butler MR, Grainger R, McDermott T, Thornhill JA. The distribution of PSA age-specific profiles in healthy Irish men between 20 and 70. <em>ISRN Oncol</em>, 2012;2012:832109

<p class=”listnumberedallotherlinesMIstyles”>Vickers AJ, Ulmert D, Sjoberg DD, et al. Strategy for detection of prostate cancer based on relation between prostate-specific antigen at age 40-55 and long -term risk of metastasis: Case-control study. <em>BMJ</em>, 2013;346:f2023.

<p class=”listnumberedallotherlinesMIstyles”>Arnsrud Godtman R, Holmberg E, Lilja H, Stranne J, Hugosson J. Opportunistic testing versus organised prostate-specific antigen screening: Outcome after 18 years in the Göteborg randomised population-based prostate cancer screening trial. <em>Eur Urol</em>, 2015 Sep;68(3):354-60

<p class=”listnumberedallotherlinesMIstyles”>Foley RW, Lundon DJ, Murphy K et al. Predicting prostate cancer: Analysing the clinical efficacy of prostate cancer risk calculators in a referral population. <em>Ir J Med Sci</em>, 2015 Sep;184(3):701-6.

<p class=”listnumberedallotherlinesMIstyles”>MRI-targeted or standard biopsy for prostate cancer diagnosis. Veeru Kasivisvanathan, MRCS, Antti S Rannikko, PhD, Marcelo Borghi, MD, Valeria Panebianco, MD. PRECISION Study Group Collaborator. March 19, 2018.

Badrinath Konety, Stephen Zappala, Dipen Parekh, Danielle Osterhout et al. The 4K score reduces prostate biopsy rates in community and academic Urology practice. <em>Reviews in Urology,</em> 232:17(4), 2015.

<img src=”../attachments/f717a6c3-ba2e-463b-bda3-919282d6acc3.JPG” alt=”” />

<strong>This clinical feature has been supported by a medical educational sponsorship</strong>