The Great Prostate Debate

The prostate-specific antigen (PSA) assay has been around for over 30 years, but ever since its approval by the FDA in 1986 for the surveillance of prostate cancer (PrCa), it has created confusion, disagreement and division amongst the healthcare community in terms of its potential to screen for the disease.

Recently, the Canadian Task Force on Preventative Health Care updated their guidelines to advise against PSA screening. This wasn’t without controversy – many still feel that although PSA test results must be interpreted with caution, it’s still the best option available to identify patients who require biopsy for a more definitive PrCa diagnosis. But what does the evidence say?

Recent data released by the European Randomised Study of Screening for Prostate Cancer (ERSPC) (1) – the largest ever PrCa screening study (13 years and more than 180,000 male participants from eight countries) – led its investigators to come down on the anti-screening side of the debate. Nevertheless, the study did demonstrate a 21 percent reduction in PrCa mortality in men who undergo screening compared with those who don’t. That figure rises to 27 percent when selection bias due to non-participation is accounted for. However, the investigators believe that the potential downsides of screening still outweigh the benefits, estimating that roughly 40 percent of men were over-diagnosed by screening.

On the other side of the debate, many remain in favor of PSA screening in certain situations, including the American and Canadian Urological Associations and the charity group Prostate Cancer Canada. The counterargument is that PSA testing is effective if used carefully, and that there is no alternative for early PrCa diagnosis.

So, the big question: is PSA screening an essential diagnostic tool or a dangerously misused assay?

Lifesaver or Healthcare Nightmare?

The man who discovered prostate-specific antigen speaks out on the test’s misuse and the potential harm caused.

How did you discover prostate-specific antigen (PSA) and have you been surprised by its impact?

In the late 1960s, I was looking for a cancer-specific marker for prostate cancer (PrCa), but what I found instead was PSA – an antigen specific to the prostate, not cancer. Did I anticipate the huge impact it would have on the medical community? In a word, no. I never thought it would be used for screening; the only use I could see, because of its specificity for the prostate, was to monitor men who had already been diagnosed and treated. The re-appearance of PSA could suggest positive surgical margins following prostatectomy, a recurrence of the disease following other treatment, and/or the presence of micrometastasis not identified at initial diagnosis. So at that time, I continued my search for an antigen specific to PrCa.

How was the PSA test developed?

Approximately ten years after my discovery, Beckman Coulter (formerly Hybritech) developed the first validated blood test for PSA levels. At first, it was only used as I had envisioned – for monitoring of patients after treatment for PrCa, and it was approved by the FDA for this purpose in 1986. But more and more people started using the test off label to screen for PrCa. It was like a tsunami. In 1994, the FDA approved the test in concert with a digital rectal examination (DRE) for screening, i.e., the diagnosis of PrCa in asymptomatic men. On the basis of the submitted data, I believe the FDA made a terrible mistake – one that has resulted in the over-diagnosis and over-treatment of millions of men with their attendant morbidities.

Why are you such a vocal opponent of PSA screening?

There are four main arguments (or cruxes) against the test:

• It’s not cancer-specific
PSA is specific to the prostate, not to PrCa. Changes in PSA level could be caused by benign prostate hyperplasia (BPH) or prostatitis, not just PrCa.

• There is no diagnostic level
The level of PSA defined as ‘elevated’ is arbitrary. One man could have a level of 11 ng/ml and be cancer free, while another could have a level of 0.5 ng/ml and have PrCa. Consequently, the false positive rate when using PSA can be as high as 80 percent; to use a test this inaccurate on asymptomatic men is tantamount to criminal.

• It cannot distinguish between indolent (non-aggressive) and aggressive PrCa
The two types of PrCa can be likened to a “turtle” and a “rabbit”: symbolizing indolent and aggressive PrCa, respectively. If, by analogy, you have them both in a box without a lid, the “turtle” would crawl around the box and go nowhere, whereas the “rabbit” may at any time jump out, meaning that the cancer will spread. Some cancers are turtles allowing a patient to live for years without treatment. The level of PSA cannot tell you which type of cancer you’re dealing with.

• Prostate cancer is an age-related disease
By the time men reach 70 years of age, as many as 80 percent will have PrCa. In many cases the cancer will be a “turtle”. Therefore, a PSA-prompted biopsy may or may not (related to the age of the individual) find cancer – but if it does, is it a “turtle or a “rabbit” –  and that's something the PSA test cannot tell you this, so millions of men are being over-diagnosed and over-treated.

What are the consequences of over-treatment and over-diagnosis?

The results of the inappropriate treatment of an indolent PrCa can be devastating for patients. Incontinence and impotence are two common side-effects. And let’s not forget the potential psychological aspect. Loss of bladder control can be life altering and debilitating; erectile dysfunction can have a profound effect on wellbeing and may negatively affect relationships. Supporters of screening argue that despite these risks it is still better to be alive – but some men’s lifespans after treatment may be identical to those who weren’t screened. These men are receiving unnecessary treatment that is leaving them maimed for the rest of their lives.

What about large, long-term studies, such as the European Randomized Study of Screening for Prostate Cancer (ERSPC), that indicate a reduction in mortality through screening?

I believe that particular study is flawed – just how deeply flawed I can’t say, as the investigators won’t release all of their data. Firstly, the ERSPC claimed to show a 21 percent decrease in mortality from PrCa in men who were screened versus those who weren’t (1). However, many of the men who were not screened and who developed PrCa received hormonal monotherapy, which (according to some recent studies) may actually cause progression of localized disease (2). If non-screened men had then received a treatment that accelerated their cancer, it could have seriously compromised the results of the study. Another issue is that large amounts of the data were taken from the Göteborg, Sweden study (3), which showed very large reductions in PrCa mortality; including this patient data may have skewed the overall results in favor of screening. There is a strong possibility that the overall reduction in mortality is in fact a much lower number.

Why has screening been so widely adopted in some countries given its low accuracy?

In the US at least, I think there are two main reasons for this: the sway of celebrity and the almighty dollar.

By way of example in terms of the quest for the almighty dollar, in 1989, five years before the FDA approved the PSA test as a screening tool, Schering-Plough found a way to “supercharge” the market for their PSA test. They paid an advertising firm US$1.2 million to promote screening, so from the very beginning this test has been well marketed by people who stand to profit from it. In the US alone, we spend three billion dollars a year on screening asymptomatic men. In the last 20 years (since FDA approval in 1994) that’s 60 billion dollars. Having the test itself isn’t too costly for the patient, but it creates a domino effect, by prompting an ultrasound, a biopsy, and so on. When you tell a man he has cancer (perhaps the most feared word in any language), his first inclination is to do whatever it takes to get rid of it. Although there are many outstanding urologists who have the patient’s interests at heart, they can sometimes be overshadowed by opportunists who see this process merely as a means of making money.

The influence of our celebrity culture is another problem. For example, in recent years, the famous baseball player Reggie Jackson has been coming on the radio to tell the public that instead of buying shirts or ties for Father’s Day, they should offer something meaningful: a PSA test. A point I often make is that depending on your father’s age, giving him a PSA test is often synonymous with actually giving him PrCa – he may well have an indolent form (a “turtle”). In reaction, he follows up with a biopsy and suddenly an essentially healthy man believes he is at risk of dying from PrCa. I have another example: when Rudy Giuliani – New York City mayor on 9/11 – was diagnosed with PrCa (partly through PSA level assessment), he opted for radiation therapy. When the public see people they admire getting treatment and the type, it can influence their decisions. “If it’s good enough for Rudy, it’s good enough for me.”

What other options are there for detecting and managing PrCa?

Right now, if you are an asymptomatic man with a normal DRE and no elevated risk of PrCa, I would say the best thing you can do is nothing. Patients who are at a higher risk (the two well-known examples being men with a family history of PrCa and black men) may wish to consider monitoring PSA levels over time, to spot any substantial elevation. But all this can tell you is that something may be wrong with their prostate – for example, prostatitis or BPH – and not necessarily that they have cancer.

When PrCa has already been diagnosed, watchful waiting (better known as active surveillance) is an option for men who are unsure whether to proceed with treatment, potentially risking their quality of life to treat an indolent cancer that may not need to be treated. First initiated by British urologist, Chris Parker, this involves establishing the histological characteristics of the tumor (Gleason score), PSA level and results of a DRE. The patient can then be reassessed periodically to monitor any clinical changes that may warrant further action.

As for direct replacements for PSA screening, there are several currently being developed (see What's the Alternative), but I think there is still some way to go before we have a reliable, validated test. It is noteworthy, however, that two of these prospective tests – the Prostate Health Index (PHI) and Progensa Prostate Cancer Antigen 3 (PCA3) – have been reviewed by the National Institute for Health and Care (NICE, the UK’s healthcare watchdog), which has indicated that neither of the tests improve diagnosis sufficiently to be recommended for clinical practice (4).

What do you think the future holds for PrCa diagnosis?

I first started searching for a PrCa marker over 45 years ago and to this day, I’m still looking. By training I’m an immunologist, specializing in immunopathology, and a lot of my work has focused on trying to understand why a tumor progresses to metastatic disease. I’m currently collaborating with a group at the University of Cardiff, Wales, to find a reliable PrCa marker, and while my colleagues and I don’t have anything definitive enough to discuss yet, we remain hopeful.

Ideally, the replacement for PSA screening would: i) be more reliable – we would have assurance that a normal test indicates absence of cancer, and ii) reduce mortality, without significant morbidity following treatment for an abnormal test.

As for the PSA test, I believe it will continue to lose favor as more organizations start to appreciate the drawbacks of screening and change their stance on it. That said, I suspect its use will continue for some time. There will always be people who believe something (however ineffective) is better than nothing – or who have a financial interest in PSA. Until we do have an alternative, it is of critical importance that doctors, patients and the public in general understand the severe limitations of this test – and the potentially harmful consequences.

Richard  J. Ablin is a professor of pathology at the University of Arizona College of Medicine, The Arizona Cancer Center and The BIO5 Institute, Tucson, AZ, and the author of “The Great Prostate Hoax: How Big Medicine Hijacked the PSA Test and Caused a Public Health Disaster”.

PSA Screening Saves Lives

Early detection, aided by screening, can help more men survive prostate cancer

Recent guidelines released by the Canadian Task Force on Preventive Health Care, which recommend against prostate-specific antigen (PSA) screening, do a disservice to both the general population and to health care providers. When developing their recommendations, the Task Force did not take into account the views of people living and working with the disease on a day-to-day basis, and I do not believe these recommendations reflect the reality of prostate cancer (PrCa) screening and diagnosis. Prostate Cancer Canada (PCC) is concerned that this new recommendation will negatively impact the doctor-patient relationship, and will result in men failing to be informed about a test that could directly impact their chances of surviving PrCa. Further, men simply don’t need another reason to put off taking the test, or seeing their doctor in general.

We know that early detection saves lives. The alternative to testing is a loss of the excellent survival rate early detection gives us. We also know that men diagnosed at a later stage are more likely to die of PrCa as late detection of this disease may potentially limit treatment options and diminish survival. While the PSA test isn’t perfect, elevated levels are currently our best indicator that something may be wrong with the prostate. This is especially necessary for a disease like PrCa, in which symptoms may only present themselves once the disease has progressed significantly.

PCC still recommends that men be screened using the PSA test because we believe the benefits of screening outweigh the negatives. The PSA test is a necessary entry point into an important diagnostic pathway. This simple blood test, combined with other risk factors, is an important resource for doctors to detect PrCa early and then monitor and treat as is appropriate for that individual.

The negatives of over-treatment (a problem often cited by critics of PSA screening) can be mitigated using active surveillance. Active Surveillance is an evidence-based approach that involves closely monitoring low-risk PrCa and aims to improve quality of life by reducing or delaying radical treatment until absolutely necessary. In Canada, active surveillance has become a standard option for the management of PrCa and is often the treatment of choice for men with low risk disease. Eliminating screening using the PSA test would make this method impossible.

Men should have an informed discussion with their health care provider to understand the pros and cons of screening, and they should know that a positive PSA test does not imply a need for immediate treatment. PCC believes in “smart screening”, a personalized approach where men are encouraged to be tested to establish a baseline PSA in their 40s, with follow up based on individuals’ risk profile.

Not everyone who is diagnosed with PrCa will require treatment, but anyone who does need treatment must first be diagnosed. PSA screening, when used appropriately, remains an essential tool to detect prostate cancer in its earliest stages when it is curable. Until a proven alternative becomes available, we will continue to advise doctors and patients of the continuing relevance of the PSA test as a screening tool.

Stuart Edmonds is the Vice President of Research, Health Promotion and Survivorship at Prostate Cancer Canada, a national foundation dedicated to the elimination of the disease through research, education, support and awareness.

Risks Eclipse Benefits

The Canadian Task Force on Preventative Health Care recommends against screening. But changing the opinions of clinicians and patients is no easy task.

When it comes to prostate-specific antigen (PSA) testing, Canada has a lot in common with other countries – it is a widely used screening method for prostate cancer (PrCa), and most men in the right age range are likely to have had their PSA levels measured at least once. Most urologist associations and regional guidelines encourage screening, and many doctors and patients believe it is the best way to detect PrCa early. As part of the Canadian Task Force on Preventative Health Care (CTFPHC), my colleagues and I reviewed the effectiveness of PSA screening, and we have now recommended against it. However, opinions of the test vary greatly and it still plays a large role in PrCa detection, despite the lack of supporting evidence.

Based on what I believe was an extremely rigorous review of the current literature (including the European Randomized Study of Screening for Prostate Cancer (1) and the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial) using GRADE methodology (a systematic review system which is becoming an international standard (5)) we concluded that there is no strong proof that screening will significantly reduce mortality – we found only a 0.1 percent absolute risk reduction in PrCa mortality). It appears that the potential problems (for example, overtreatment) eclipse the small potential benefit (see infographic) (6).

We therefore recommend against screening men in all age groups, with a strong recommendation against screening for men under 55 and over 70, and a weak recommendation for those 55–69 years old, which essentially means that men in this age range may wish to consider their own preferences with regards to screening. The recommendations against screening also apply to men at higher risk (for example, those with a family history of PrCa). However, we do suggest that clinicians may wish to discuss the pros and cons of testing with high-risk patients.

Despite finding little evidence to support the use of PSA testing, the task force recommendations don’t reflect current practices in Canada, and as an independent organization funded by the government, they are not necessarily approved or followed. Many urologists we have spoken to – as well as the patient advocacy group Prostate Cancer Canada – do not agree with our findings, and have concerns about our study. Screening is a subject which still causes a lot of division within the healthcare community, both in Canada and around the world.

The controversy surrounding PSA means that we are not likely to see widespread changes in the near future; but despite the resistance we are encountering, time will tell. Three years ago, the US preventative task force published a similar guideline, which generated a considerable amount of dispute in the literature – but since then, there has been a decrease in PSA screening.

I believe there is likely to be a similar reaction to our recommendations. Attitudes will begin to change – slowly. Many people still associate screening programs with a reduction in PrCa mortality, but our results show this reduction is very small. Moreover, countries without such screening programs, such as the UK, have also seen PrCa mortality drop, which indicates that other factors, such as improved therapies, are influencing survival.

Screening can often do more harm than good, and patients and clinicians alike must weigh the benefits of screening against the potential health risks; this is a medical debate I expect to continue for some time to come.

Neil Bell is a member of the Canadian Task Force on Preventative Health Care, a family physician and a Professor of the Department of Family Medicine, University of Alberta.

Intelligent and Individualized

PSA is still a valuable tool – it is our approach that needs to change.

As a urologist and former chairman of the Prostate Cancer Guideline Working Group of the European Association of Urology (EAU), I’ve been involved in creating and updating the European guidelines for the use of PSA for the testing and screening of prostate cancer (PrCa). I believe the key to success with PSA is to use it in the right way – PSA monitoring and subsequent treatment must be individualized, risk-based and, above all, intelligent.

In Germany, we don’t perform mass PSA screening due to the lack of convincing data and, simply because the tests are not reimbursed by insurance companies. Having said that, many urologists in private practice here believe that early detection of PrCa can be achieved with annual PSA assessments – a practice that’s not based on scientific evidence. The most recent German guidelines for the diagnosis and treatment of PrCa are to inform men at the age of 45 years (40 years if there is a family history) with a life expectancy of at least 10 years that PSA is an option, although it does have potential consequences. If the patient chooses to undergo PSA testing, the timing of follow-up examinations will depend on the serum PSA concentration and may vary between one year (PSA > 2.5 ng/ml) and four years (PSA < 1.0 ng/ml).

The EAU guidelines differ from the German ones; they are formed by an interdisciplinary group consisting of urologists, medical oncologists, radiation oncologists, pathologists and an advisory panel of radiologists and physicians from nuclear medicine. They are frequently updated and take into consideration all new published trials on diagnosis and treatment. The EAU does not recommend PSA mass screening, but does recommend baseline PSA serum concentration assessment in men under 50 years. Depending on this initial measurement, follow-up should be every 1–2 years (PSA >1.0 ng/ml) or 4–6 years (< 1.0 ng/ml) (7).

Despite the EAU’s guidelines being based on the most up-to-date evidence available, a recent survey which analyzed PSA and diagnostic work-up practices in a cohort of ~600 men, revealed compliance levels of only 35–45 percent. Such statistics show that we have a lot of work to do when it comes to raising awareness and educating healthcare providers – be it through symposia, meetings or publications such as this. When used correctly, I believe that PSA and free total PSA ratio are currently the best routine options for daily practice.

Although PSA is useful, there is always room for improvement. Risk calculators have been validated but are rarely used. For example, the Prostate Cancer Prevention Trial (PCPT) and the European Randomised Study of Screening for Prostate Cancer (ERSPC) calculators combine PSA level with other parameters, such as age, family history, and digital rectal examination results, to give a modified risk score. Such resources are currently underutilized, and I think they could significantly decrease the number of unnecessary prostate biopsies currently performed based on PSA assessment alone.

In the future, we may see entirely different approaches, such as new serum or urinary biomarkers, which may further improve diagnosis. One example is TMPRSS2-ERG, a fusion gene present in 40–80 percent of PrCa. However, it is still unclear how findings like this could be incorporated into early detection methods. Until new approaches are validated and proven, I expect PSA to remain the standard.

Axel Heidenreich is the director and chairman of the Department of Urology at the University of Aachen and the Certified EURO Prostate Cancer Centre, Germany. He has also served as chairman of the Prostate Cancer Guideline Working Group of the European Association of Urology until 2013.

Cutting Prostate Cancer Deaths

Regular PSA tests could reduce prostate cancer mortality by as much as 51 percent – but methods must improve before mass screening can be used safely.

A study of the Rotterdam arm of the European Randomised Study of Screening for Prostate Cancer (ERSPC) found that screening can significantly reduce deaths from prostate cancer (PrCa) – if the screening protocol is strictly followed.

“In the Netherlands, there is no official screening program – if a man wants a PSA test, he needs to consult his doctor. However, Data from the Dutch central agency for statistics shows that in 2011, 24 percent of men over 40 had taken a test in the last five years for screening purposes, demonstrating the test’s popularity” explains Leonard Bokhorst, amedical researcher at the Erasmus Medical Center, the Netherlands.

Leonard and his colleagues conducted an analysis of the Dutch section of the ERSPC, with some surprising results. They studied a total of 34,833 men in the Dutch arm, who received either regular PSA screening, or no screening at all. “We found that the effects of screening can be diluted by nonattendance (seen in around 5 percent of participants) and contamination – that is to say, men also seeking tests from their own doctors, which approximately 20 percent of participants did,” he explains, “correcting for these factors meant that the risk of death from prostate cancer for those who took part in screening was reduced by up to 51 percent, as compared to no screening at all(8).”

This finding resulted from using the following screening protocol:

• screening started in the age range of 55–69 years
• a four year testing interval was used until the age of 75
• a biopsy was taken if PSA level is abnormal (in this case, a level of higher than 3.0 ng/ml)

“Without following a strict screening protocol, the reduction in mortality may be lower, and the potential for undesirable side effects, such as over-diagnosis, may be greater,” says Bokhorst.

So based on these results, did Bokhorst and his colleagues conclude that PSA screening is effective? “PSA is currently the only proven tool for reducing PrCa death through early detection, but the risk of negative side effects means that screening for PrCa with PSA alone is currently not recommended. The key to better PrCa screening is to improve the balance of harm versus benefit. Supplementary tools and information, such as including risk calculators, are extremely important; doctors should start making use of these complementary methods to better predict PrCa risk. The use of MRI also looks like a promising technique to detect men at increased risk of especially aggressive PrCa. Such approaches can reduce the amount of unnecessary biopsies and reduce over-diagnosis of low risk PrCa.”

If screening methods are improved, suggests Bokhorst, they may become a viable option for the detection of PrCa – but only in well-informed patients who are aware of the negative side effects. Until then, mass screening programs are simply not a sensible option.