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Prostate specific antigen (PSA) has long been debated regarding its merits as a serum biomarker for the detection of prostate cancer.
A case report in the Journal of the American Medical Association (JAMA) in 2004 recounts the author’s experience as a family medicine resident, when he was sued for letting a patient decide whether to be screened for prostate cancer after engaging him in shared decision-making, as current guidelines recommend. The patient declined screening, was later found to have prostate cancer and successfully sued the practice, in essence, for encouraging shared decision-making. The doctor was exonerated, but his residency programme was found liable for teaching him to engage patients in shared decision-making to decide whether to screen for prostate cancer.
While many doctors believe that case represents a gross miscarriage of medical ethics, it highlights the lack of clear guidance on the issue of PSA testing. In general, the situation has improved. Since the advent and establishment of PSA testing, there are less people dying from prostate cancer and there are randomised, controlled trial results now available to contribute toward Level 1 evidence (evidence-based medicine).
Unfortunately, there are still people who are being over-diagnosed and over-treated, and the challenge remains not whether patients should be screened for prostate cancer, but what can be done to make screening more effective.
Despite the issues of over-treatment and anxiety, PSA screening (especially in symptomatic men) has led to lives being saved. A 2014 American Cancer Society report demonstrated an age-adjusted decrease in prostate cancer-specific mortality of nearly 50 per cent, and a reduction in patients presenting with metastatic disease of approximately 70 per cent.
Unfortunately, the main crux of this is that for those who are still metastatic at diagnosis, the overall life expectancy has not significantly changed over the last 20 years. This, in addition to screening, is the new focus of prostate cancer research, with significant funds dedicated to trying to determine which treatment modalities will benefit whom, and how to risk stratify these patients with the minimum effect on quality of life.
There have been three major studies over the last number of years (US, European and Swedish) trying to identify the utility of prostate cancer screening, followed by a controversial US Preventive Services Task Force (USPSTF) recommendation on PSA screening issued in 2012.
The US Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial looked at 76,000 men randomised to two groups: screening vs non-screening. After a median follow-up of 13 years, they concluded that there was an increase in diagnoses (Figure 1), but no overall difference in prostate cancer mortality.
Unfortunately, the authors failed to properly account for the fact that 45 per cent of all patients had a PSA measurement prior to enrolment, and 52 per cent of the control group (no screening) also had a PSA test. This then led to a study that simply measured partial vs intensive screening.
The European Randomised Study of Screening for Prostate Cancer (ERSPC) followed 182,000 men screened every four years, with a median follow-up of 13 years. This study demonstrated a relative decreased risk of death from prostate cancer of 21 per cent. The number needed to screen in this study to prevent one cancer death (NNS) was 781, with the number needed to diagnose (NND) to prevent one cancer death at 27. Furthermore, the ERSPC group demonstrated a decreased risk of metastases of 30 per cent in those in whom there was intent to treat, and a 42 per cent decreased risk of metastases in those who were actually screened.
Within the Rotterdam section of the ERSPC, the authors attributed an overall 32 per cent decreased risk in prostate cancer-specific mortality following screening. If non-attendances were accounted for, this increased to 51 per cent.
The Swedish prostate cancer screening trial based out of Goteborg followed 20,000 men for a median of 14 years, with strict screening and non-screening arms, using the lowest PSA threshold values of the three trials at 2.5-3.0ng/ml.
This study, with the longest follow-up, demonstrated a 44 per cent relative risk reduction in overall prostate cancer mortality with the use of screening (0.5 per cent vs 0.9 per cent). A total of 44 per cent of men diagnosed with prostate cancer in this study chose to undergo surveillance, and the NNS and NND dropped further, to 293 and 12, respectively.
Other screening tools
How does PSA compare against other screening tools currently used in practice? If one simply focuses on the NNS, then PSA does not perform as poorly as initially thought, compared with other well-established screening programmes (Table 1).
One of the major obstacles to PSA screening which has led to a media and public backlash is the USPSTF publication in 2012. The summary of this stated: “The USPSTF recommends against the service. There is moderate or high uncertainty that the service has no benefit, or that the harms outweigh the benefit.” This was characterised as Grade D evidence, which, put simply, means that any estimate of an effect is very uncertain, or no expert opinion, or no direct research evidence, or one or more studies with very severe limitations.
There were 16 members on this group including healthcare executives, paediatricians and obstetricians. However, there were no urologists, radiation oncologists or medical oncologists. It is not clear what the uptake of these recommendations will yet reveal. An earlier USPSTF statement from 2008 recommending against screening in >75-year-old men was analysed in the National Health Interview Survey (NHIS). This demonstrated no change in workplace practice as a result of the earlier recommendation.
Optimal PSA usage
The issue is no longer whether prostate cancer screening saves lives, but whom to treat, and how. There is a focus now on minimising over-detection and over-treatment. The classic 1994 autopsy paper by Sakr et al led to the common conception that men often died with prostate cancer, not because of it.
Now that PSA measurement has become prevalent, the idea of the cessation of screening is clearly not a viable option, given its proven benefits. The more intelligent use of PSA, however, is clearly desirable.
PSA usage recommendations include:
- The use of informed consent prior to any PSA test as per British, European and American guidelines
- Consider only if the estimated life expectancy is greater than eight-to-10 years. Not all men are the same, and therefore chronological age is controversial
- Do not give empiric antibiotics
- Repeat a newly-elevated PSA. With a single test sensitivity of 52 per cent, there are a number of things which may cause a transient rise, including UTIs, prostatitis, prostatic manipulation, benign prostatic hyperplasia, etc
- Do not biopsy purely based on PSA velocity
- Always perform a digital rectal exam. There are a number of prostate cancers which have a ‘normal’ serum PSA but abnormalities on prostate exam
- Novel screening strategies
There is also some data as to when is an appropriate time to consider stopping PSA testing (allowing for patient fitness and comorbidities). The US Baltimore Longitudinal Study of Ageing and the Malmo Prevention Project turned their attention to this.
The former group found that no person above the age of 75 years with a PSA of 3.5ng/ml or less died from prostate cancer. The latter showed that men with a PSA <1ng/ml at the age of 60 years had a 0.2 per cent risk of dying from prostate cancer at 85 years. The consensus recommendation was to stop (or relax) screening if:
- PSA <1ng/ml at 60 years; <2ng/ml at 70 years; <3ng/ml at 75 years.
The rationale behind repeating a newly-elevated PSA test arises from the Eastham et al study published in JAMA in 2003. Of 972 men randomly screened during a colon polyp prevention trial (median age 62 years), 40-to-55 per cent of PSA readings were within a normal range at a subsequent visit. A further study evaluated the role of PSA and PSA velocity in the control arm of the Prostate Cancer Prevention Trial (PCPT) and demonstrated that PSA velocity did not add a further predictive value to PSA alone, clinical examination and family history. The role of PSA kinetics has since been re-explored and has now been incorporated in a number of putative risk calculators for prostate cancer.
Novel screening strategies for prostate cancer have now diverged from PSA alone and have begun to include blood and serum markers (PCA3, T2-ERG, ‘free’ PSA), as well as serum biomarker panels such as prostate health index (PHI) and 4K (kallikrein panel). Other modalities include the increasing use of MRI and even germline mutation analyses (single nuclear polymorphisms, SNPs). The latter can provide information regarding risk but are not able to definitely tell whether prostate cancer is present.
The PHI and 4K panels are especially interesting as they have been shown to increase the sensitivity and specificity of prostate cancer screening vs PSA for not only all prostate cancers, but clinically significant prostate cancer.
PHI is a mathematical model developed by Beckman Coulter for a combined score: phi = ([-2]proPSA /free PSA) x √ PSA. If the p2PSA to free PSA ratio is high, the score goes up and the patient is more likely to be diagnosed with overall and clinically significant prostate cancer.
In conclusion, there is little doubt now that appropriate and carefully-selected PSA screening in men saves lives from prostate cancer mortality. Despite this, however, there has been a surge in not only the over-diagnosis and over-treatment of clinically insignificant disease, but also disease in men in which there will be no survival impact.
The development of newer strategies, risk calculators, nomograms and techniques to minimise over-detection (eg, PHI, 4K) and to improve on PSA are necessary, and are being developed and trialled. However, PSA is currently here to stay and is an extremely useful adjunct when used appropriately.
References available on request
A 56-year-old male has presented with some mild voiding lower urinary tract symptoms (IPSS 5/35), is overweight, smokes approximately 10 cigarettes per day and knows of two neighbours and a cousin who were each diagnosed with prostate caner. He is unaware of any further details but now wants to be screened for prostate cancer.
How would you approach this issue?