The rationale for the early detection of prostate cancer is simple; prostate cancer that spreads beyond the prostate is currently incurable and detecting it while still localised to the prostate maximises the chance of cure. 

In 1967, pathologist Donald Gleason, described his pathological scoring system which has yet to be bettered. High-grade prostate cancer (Gleason score of 8, 9 and 10) are lethal tumours that are fatal in any group. Their detection at an early stage and appropriate treatment in a urological cancer centre will maximise the chances for cure while minimising the morbidity to the patient.

Waiting for symptoms to develop is too late. Any high-grade tumour that gives rise to symptoms is invariably at an incurable stage. The use of biomarkers such as prostate-specific antigen (PSA) allows the early detection of the disease, although particularly high-grade tumours may not produce PSA and digital rectal exam (DRE) is always a necessity. 

It is important to keep in mind the following:

• One in six men in Ireland will be diagnosed with prostate cancer
• One in six men diagnosed with prostate cancer will die from the disease every year
• Prostate cancer is the most common cancer in Irish men and the third most lethal cancer
• Ireland has the highest incidence of prostate cancer in Europe
• The incidence of prostate cancer will double in Ireland in the next 20 years.

Although a national strategy has been developed within the public healthcare sector, Rapid Access Prostate Clinics (RAP) services remain fragmented. Geographical variations occur in access to treatments, no oversight occurs in the private healthcare sector, and both support services and follow-up services for patients are lacking. 

RAP clinics have for the first time allowed the prioritisation of patients at risk of cancer to access a rapid assessment service and has allowed data to be collected, analysed and the quality of the service to be monitored. The establishment of a clinical leads network supported by the National Cancer Control Programme (NCCP) allows for high-level clinical communication between the HSE prostate cancer centres. This clinical leads network has recently decided to adopt new age-related PSA cut-off values that will trigger a referral (see Table 1).

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Early prostate cancer screening studies

Prostate cancer detection has evolved a lot in the past 25 years, when many of the original screening studies commenced. Although PSA is still used, the Prostate Health Index (PHI) and 4K tests are now used in larger centres and are more accurate in selecting patients for biopsy. 

In addition, nomograms to reduce unnecessary biopsies can be applied, MRI scans of the prostate can be used to detect significant disease and targeted biopsies and transperineal biopsies are utilised to detect disease much more accurately than before. In reviewing older studies, these techniques were not available.

In the Tyrol, Austria study (1993), 65,123 men were enrolled, one-third of whom were screened using PSA at least once during the five-year study. In 2008, a 25-year analysis demonstrated a 30% reduction in prostate cancer mortality in the men of Tyrol who were screened by PSA. The authors concluded that this was due to down-staging and aggressive treatment of prostate cancer.¹

A study in Quebec, Canada (1988) was heavily criticised for the methodologies used. Although 31,000 men were randomised to be screened, just 7,300 attended with only 10 patients dying of prostate cancer in the study period. Although the authors credited screening with a 62% reduction in prostate cancer mortality, an intent to treat analysis suggests no difference existed between the two groups.²

In the Swedish screening studies (1987), the first study randomly assigned every sixth man in Norrkoping to a PSA and DRE every three years. This small study was not sufficiently powered and no difference was seen in prostate cancer or overall mortality. 

The second study involved just 1,782 men who underwent DRE, PSA and transrectal ultrasound (TRUS) and were biopsied if the PSA was above 10ng/ml; no differences were seen between the screened and unscreened populations.³

In the US, PLCO screening study (1993), 76,693 men were randomised to either annual PSA and DRE or standard care. More than 40% of patients had already undergone prostate cancer testing, which weeded out many of the prostate cancers before the study even started. In addition, 53% of the control group had PSA testing beyond the scope of the trial so unfortunately the trial was insufficiently powered and fatally flawed.⁴

Contemporary prostate cancer screening studies

The European Randomised Study on Prostate Cancer screening ERSPC (1991) involved 162,000 men aged 50 to 69 years in seven European countries, of whom 72,693 were randomised to PSA testing every two to four years, with a PSA > 3ng/ml prompting a biopsy. At nine years of follow-up, there was a 20% reduction in prostate cancer mortality and a further analysis on metastatic disease demonstrated a 31% reduction at 12 years in the PSA screened group. 

At the planned 13 year analysis, prostate cancer mortality has been reduced by 27%, with this figure expected to rise over time. In order to achieve this, 781 men needed to be called to screening and 27 men had to undergo treatment to save one life; remember, this was a time when active surveillance and brachytherapy and other less invasive treatments were not readily available for low and intermediate-grade disease. 

This study concluded that well informed men should undergo testing if they wish to do so but that widespread national testing could not be recommended at that time, owing to the large number of men who would undergo radical treatment.⁵

The Goteborg trial (1994) is a Swedish cohort within the ERSPC who underwent PSA testing every two years. All men were randomised on the same day in Sweden and followed for 14 years. At this time, the screened arm demonstrates a 56% reduction in prostate cancer mortality. This led to an insignificant improvement in the numbers needed to screen, 293, and the numbers needed to treat, 12, in order to prevent one cancer death.⁶

In total, two meta-analyses (including a Cochrane systematic review) reviewed many of these trials, some with flawed methodologies, and concluded that screening was of little benefit. To include the earlier trials is of course erroneous and the well constructed and methodologically sound ERSPC and Goteborg studies need to be repeated on a European-wide basis.

PSA as a predictor of lethal prostate cancer

Unlike any other cancer, we now have a serum biomarker that is predictive of prostate cancer over a 25-year period. In Malmö, Sweden, investigators analysed serum samples stored in the 1960s and 1970s on men aged 35 to 50 years undergoing cardiac drug trials.⁷

The samples were thawed, the PSA values were calculated and using their national cancer registry, the development of prostate cancer in the intervening period was documented. Serum PSA (>1ng/ml) at the age of 45 strongly predicted for a prostate cancer over the next 25 years, defining a high-risk cohort of men (see Table 2). 

Using this test, most men are at low risk and therefore can be tested infrequently, whereas the high-risk group can be screened more regularly. As a result of this trial, the European Urological Association (EAU) recommends all men to have a baseline PSA performed at the age of 45.

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Advances in diagnostics

Almost all screening studies have concluded that better biomarkers for prostate cancer are required, and finally new technologies are starting to appear. In addition, with new imaging technologies with multi-parametric MRI scanning and PSMA-PET CT scans, a new dawn is emerging in the management of prostate cancer and its accurate diagnosis and staging.

Biomarkers

Prostate Health Index: The PHI is a calculation based on the ratio of pro-PSA and free PSA in the serum. It out-performs total PSA testing (AUC 0.73). This is best used to guide biopsy where PSA is from 2-10ng/ml.

PCA3: This is a calculated ratio between urinary PCA3 RNA and PSA RNA in a voided urine sample following prostate massage. A reading of 35 or more increases the risk of cancer (AUC 0.75). Best used to decide on re-biopsy.

4K score: This analyses four separate serum kalikreins and biological data to generate a prognostic score as to the development of metastases. A score of >7.5% predicts a group at high-risk of metastases over the subsequent 20 years and this can assist when deciding on the need for treatment.

Genetic analysis (on prostate biopsy material)

Oncotype DX assesses 12 cancer-related genes involved in important cellular pathways and five reference genes to derive a genomic prostate score. The GPS categorises patients in to ‘very low’, ‘low’ or ‘intermediate’ risk and is useful in determining which patients are suitable for active surveillance or not.

Prolaris similarly examines 31 cancer-related genes and 15 housekeeping genes to measure tumour cell growth characteristics. Low expression of these genes is associated with a low risk of progression.

Imaging

Multiparametic (MP)-MRI prostate is defined as including three of the following four sequences: Standard T1 and T2 cross-sectional imaging, dynamic contrasted enhanced (DCE), diffusion weighted imaging (DWI) and proton spectroscopic MRI (usually omitted). Some centres offer prostate MRI but do not perform MP-MRI and this is not recommended.

The phenomenal spatial resolution of T2-weighted MRI combined with DWI is highly predictive (>90%) for the detection of significant (≥ Gleason grade 7) prostate cancer (see Figure 1). Ideally, it would be used in all patients with an elevated PSA or perhaps as a screening tool in itself, prior to requiring biopsy. 

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After biopsy, MRI cannot be performed for at least six weeks due to haemorrhage and this can be a difficult time for patients who want treatment quickly. It is currently used in :

• Local staging of recently diagnosed prostate cancer
• Prostate evaluation prior to biopsy so that biopsies can be targeted
• Prostate evaluation after a negative biopsy where suspicion remains (eg. persistently elevated PSA)
• Examining for local recurrence after primary treatment.
• This investigation could potentially replace PSA as a screening tool in the future for prostate cancer (trials ongoing).

PSMA PET CT: Access to choline PET CT has been available for some time but a new FDG avid tracer linked to the prostate cancer specific marker PSMA, is yielding extraordinary images, often showing metastatic deposits in patients traditionally deemed candidates for curative treatment (see Figure 2); clearly these patients would fail their primary therapy. 

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Now that the detection of small volume metastases is possible, new trials are opening to determine if treating these metastatic sites as well as the primary site can confer either a cure or long-term gain for the patient. In addition, this scan is extremely useful in detecting disease recurrence following primary treatment, offering new opportunities to achieve cure in recurrent disease, not previously considered possible.

Summary

In the absence of an improved diagnostic biomarker, serum PSA remains the most practical and widely available test to aid in the early detection of lethal prostate cancer. Recent controversy has caused confusion, and in order to give guidance, a panel of world experts published the Melbourne Consensus statement (see Table 3). 

The latest results from the Goteborg trial were recently published in August of this year, and definitively demonstrate that opportunistic PSA testing that we currently practise is of little benefit, and that only a population based screening will significantly impact on prostate cancer mortality.⁸ The key findings are:

A 42% reduction in prostate cancer mortality

Using organised PSA screening, 139 men need to be screened and 13 diagnosed with prostate cancer to save one life (this is better than breast cancer screening)

Using ‘opportunistic’ PSA testing, 493 need to be screened and 23 diagnosed to save one life

PSA screening within an organised framework is more effective than current unorganised or opportunistic testing.

To summarise, there is now strong randomised evidence that PSA, when used in an organised screening-based approach can significantly impact on prostate cancer mortality. Over diagnosis is less of a problem but wider use of active surveillance and more accurate diagnostic methods as described earlier will further reduce its impact.

References

1. Bartsch G, Horninger W, Klocker H et al. Prostate cancer mortality after introduction of prostate-specific antigen mass screening in the Federal State of Tyrol, Austria. Urology 2001; 58:417-24 
2. Labrie F, Candas B, Cusan L et al. Screening decreases prostate cancer mortality: 11-year follow-up of the 1988 Quebec prospective randomized controlled trial. Prostate 2004; 59:311-8
3. Kjellman A, Akre O, Norming U et al. 15-year follow-up of a population based prostate cancer screening study. J Urol 2009; 181:1615-21 
4. Grubb RL 3rd, Pinsky PF, Greenlee RT et al. Prostate cancer screening in the Prostate, Lung, Colorectal and Ovarian cancer screening trial: update on findings from the initial four rounds of screening in a randomized trial. BJU Int 2008; 102:1524-30
5. Loeb S, Vonesh EF, Metter EJ et al. What is the true number needed to screen and treat to save a life with prostate-specific antigen testing? J Clin Oncol 2011; 29:464-7
6. Hugosson J, Carlsson S, Aus G et al. Mortality results from the Göteborg randomised population-based prostate cancer screening trial. Lancet Oncol 2010; 11:725-32
7. Lilja H, Ulmert D, Bjork T 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. J Clin Oncol 2007; 25:431-6
8. Godtman RA, Holmberg E, Lilja H et al. Opportunistic testing versus organized PSA screening: Outcome after 18 years in the randomized Goteborg population based prostate cancer screening trial. European Urology [Epub ahead of print]. doi: 10.1016/j.eururo.2014.12.006