Author:

Simon Crompton

Introduction

PSA is a protein produced by the prostate gland. In the early 1980s it was recognised that raised levels of PSA in the blood could indicate whether prostate cancer was progressing in men diagnosed with the disease. In the late 1980s and early 1990s, the potential of PSA blood testing as a diagnostic tool for men without symptoms was explored in the US and Europe.

Evidence about the effectiveness of PSA testing to diagnose prostate cancer at a stage early enough to treat has come mainly from Europe, notably from the European Randomised Study of Screening for Prostate Cancer (ERSPC). Begun in 1994, when European urologists and researchers recognised the need for robust evaluation of the potential benefits of PSA testing, the study has consistently demonstrated that structured PSA testing for men brings a significant reduction in prostate cancer mortality.

By 2009, those running ERSPC could claim it to be the largest ever randomised study on prostate cancer screening, involving 184,000 men in eight countries. Results published in 2012, based on an 11 year follow-up of 182,000 men, confirmed earlier findings: organised repeated PSA testing reduced their risk of dying from prostate cancer by 29% compared with no testing. These conclusive findings were not found in studies in the US, which were less rigorous and were to be discredited owing to contaminated results.

From the start of ERSPC, European urologists who led the initiative have emphasised that PSA screening for prostate cancer might bring risks as well as mortality benefits – particularly the possibility of overdiagnosis, where men with indolent prostate cancer might be unnecessarily treated and have reduced quality of life as a result. Reductions in continence and sexual function are commonly experienced after surgery and radiotherapy. Evidence from epidemiological, clinical, and autopsy studies have been used to examine prostate cancer overdiagnosis, with estimates ranging widely between 1.7% and 67%.

In the 21st century, ERSPC findings have played an important part in devising algorithms and risk stratification systems so that screening programmes can maximise mortality benefits and minimise overdiagnosis risks – most notably a screening formula being considered by the European Commission for adoption in the European Union. UK studies have indicated that the use of multiparametric MRI scanning after blood testing has revealed raised PSA levels can reduce the need for invasive biopsies and led to 18% more clinically significant cancers being identified.

PSA testing: origins

Up until the early 1990s, prostate cancer survival rates were poor due to late diagnosis. In Italy, for example, the Turin registry shows that five year survival of diagnosed 65–74 year olds was just 62.5% in 1990-1994. By 2004 it had increased to 94.9%.

Monique Roobol, epidemiologist and professor of decision making in urology at Erasmus University Medical Centre, Rotterdam – who with her colleagues played an important part in the development of ERSPC – says that urologists were struggling in the early 1990s. “Half the time the diagnosis was too late, so two out of three actually died of the disease. It is an incomparable situation with now.”

Prostate cancer symptoms usually only start to show once the disease is advanced. The main technique to identity prostate cancer before the 1990s was digital rectal examination (DRE). This could only detect palpable tumours – growths that were sufficiently advanced to be felt. It was of little use as a screening tool. Large numbers of biopsies were required after a positive DRE to diagnose a small number of tumours that were often too late to be effectively treated. What was urgently needed was a test that could detect prostate cancer in its early, treatable stages, before symptoms started to show.

A protein produced in the prostate gland had been identified by various scientists, and given various names, since the 1960s. The earliest report on the properties of antigens in the prostate was by American urologist Rubin Flocks in 1960, and in 1979 T. Ming Chu and his team at Roswell Park Memorial Institute in New York characterised PSA and demonstrated its presence in normal and malignant prostate tissue, showing that it was virtually prostate specific. It was first measured quantitatively in the blood in the 1980s when it was found that elevated serum levels of PSA suggested benign enlargement or cancer of the prostate. Thomas Stamey of Stanford University found that PSA was useful for monitoring patients already known to have prostate cancer and in 1986 the US Food and Drug approved the first PSA test for this purpose.

However, it wasn’t until 1991 that the first results were published indicating that the PSA test was a more accurate method of detecting prostate cancer than DRE. The lead author was American urologist Bill Catalona from the Washington School of Medicine. He was the first to suggest that PSA could be used as a first-line screening test for prostate cancer.

Investigating PSA as a screening tool

When Catalona completed his ground-breaking study, indicating that combining measurement of serum PSA concentration and rectal examination provided a better method of detecting prostate cancer than rectal examination alone, he was contacted by Fritz Schroeder, professor of urology and head of the urology department at Erasmus University, Rotterdam, who invited him to the Netherlands. The two had first met when Schroeder was a post-doctoral fellow in the US and became friends. “I met him through Patrick Walsh, who had been my chief when I trained in urology,” says Catalona. “He and Fritz Schroeder were post-doctoral fellows or residents at UCLA. So I visited Fritz in the Netherlands and gave a presentation on our study and brought all the study materials.”

Schroeder too had studied the value of PSA and other markers for diagnosing prostate cancer. As he recalls in this article by Catalona: “I saw the data that he (Catalona) would soon publish in the New England Journal of Medicine, which showed that PSA testing led to the earlier diagnosis of curable disease. This inspired me to initiate pilot studies.”

It was Schroeder, says Catalona, who wanted to examine the potential of PSA in a larger, more systematic way. “My study was not a randomised controlled trial,” he says. “It just showed that PSA testing was better than anything else out there at that time for diagnosing prostate cancer. Fritz had the foresight to say that we had to launch clinical trials to compare screened populations with non-screened populations.”

Catalona and Schroeder continued to collaborate. Roobol was hired by Schroeder in 1991 to administer the pilot study. “Professor Schroeder thought this was something we needed to tackle correctly,” she says “We needed to work out a proper large trial to see if PSA testing brought genuine value to the early diagnosis of prostate cancer.”

At the time, Schroeder was chair of the prostate committee at the European Organisation for Research and Treatment of Cancer (EORTC), where the Belgian urologist Louis Denis was president. Both had helped found the organisation’s genito-urinary group in the early 1980s.

“They decided: right, let’s set up a pilot study and see whether it is feasible to get a trial up and running,” says Roobol. “They were very curious whether population-based screening would work – whether men would attend, how many biopsies it would generate and so on.”

As Schroeder, Denis and Roobol recalled in an article in 2004 in BJU International: “…it became clear that case-finding studies conducted around the world would be unable to produce evidence that screening for prostate cancer is effective in decreasing prostate cancer mortality at an acceptable cost in terms of quality of life and money. An answer to this question seems to be possible only by conducting a prospective randomised controlled trial (RCT) of screening.”

Funding was obtained from the EU’s Europe against Cancer programme and Monique Roobol was appointed data manager. “At the start, what Fritz offered me was an empty office, with no telephone and no desk,” says Roobol. “He said he didn’t have anything more, but he wanted me to set up a pilot study for screening. I said, ‘OK, that’s interesting.’”

“We contacted a GP practice in the vicinity of Rotterdam and asked them whether they would allow us access to male patients aged 55 to 74 so that we could do a small pilot to see what would happen if we invited those men to be screened. So we designed a simple randomised trial, one-to-one randomisation, and we offered PSA screening to these men.”

“The first question was: ‘Will they come?’ Because in 1991 the majority of men didn’t even know what you were talking about when you mentioned the prostate. It was a completely different scene. I did the blood drawing myself, and I had men asking me: ‘Is everything okay with my prostate now?’ They really didn’t have a clue what was going on.”

“So, that is how it started. I started making up the database, setting up the logistics to invite 1000 men, randomising them to a screening or control arm and then seeing what would happen.”

Another pilot study ran concurrently in Antwerp, Belgium, where Denis was based, and the results of both pilots were published in 1995. The conclusion: an RCT of screening for prostate cancer in Europe seemed to be feasible. But it was clear that the trial would need to be international to meet the ambitious sample size envisaged. There would also need to be centralised data collection.

The infrastructure for such a large trial was established: committees on epidemiology, pathology, PSA, quality control, causes of death, data monitoring, and the supervisory body of the study as a whole, the scientific committee. On 1 July 1994, the ERSPC officially began, with Belgium and the Netherlands the initial participants and Finland joining a year later.

By 2006 ERSPC involved 184,000 men in eight countries: Netherlands, Sweden, Finland, Belgium, France, Spain, Italy and Switzerland.

How ERSPC developed

On its launch the ERSPC was not without its critics. In the early 1990s, it was already known from autopsy studies that many men had indolent prostate cancer and died of other causes. “There was a big fear that we would diagnose all those indolent cancers, and experts were from the beginning worried that overdiagnosis could be a major problem with a screening programme,” says Roobol.

“We knew this right from the start – that most likely the majority of prostate cancer we detected, we did not need to detect. We also knew that PSA was prostate specific, but it certainly wasn’t prostate cancer specific, and elevated levels could be due to benign causes such as prostate enlargement. On the other hand, at that time we had this constant frustration of having to tell men we were too late to cure them. We could treat bone metastases but little more. Urologists felt powerless. So we knew something was needed, but we did not go into this blind. We knew that overdiagnosis was an issue.”

Schroeder and Denis acknowledged the need to address overdiagnosis. In a BMJ editorial in 1993, a year before the start of the ERSPC, Schroeder argued that, on evidence then, the sensitivity, specificity and predictive value of PSA testing were too low to justify its routine use in diagnosis. Furthermore, he said: “Early detection regimens should not be applied unless benefit is shown in terms of reduced mortality from cancer in randomised prospective trials.”

The point, and lasting importance, of the ERSPC trial, was that it would answer the benefit question that Schroeder posed.

The problem was that, despite the lack of evidence that it saved lives, PSA testing was already widely used. A contemporary survey showed that most American urologists tested for PSA in men older than 50 and there was pressure to widely apply PSA testing in European countries. In the UK, for example, doctor and influential newspaper columnist Thomas Stuttaford campaigned for PSA testing from 1995 onwards after his own prostate cancer had been diagnosed early after a PSA test and biopsy.

Denis communicated his unease about the situation even after the study had been running for a few years, on the ERSPC website: “There is no question in the minds of screening public health experts that this study is needed to provide a clear answer to an important health policy question – do men over 50 years of age need screening for prostate cancer? The answer is not as yet known, as stated in the 2003 publication of the European Code against Cancer.

“However, we live in an era of fast track communication where little patience is shown to a study that takes the 15 year natural history of prostate cancer into account and where innovations in diagnosis and treatment of prostate cancer are often seen as giving the answer to the question of screening and where questions on public health are sometimes met with suspicion on its stand towards the individual.

“There is now a situation of compromise in the medical community that the individual man requesting the well-known PSA-test should be fully informed on its consequences.”

The prevalence of PSA testing in some countries meant that the ERSPC trial faced the danger of ‘contamination’ – the inclusion of men in the control arm who had been, or would be, opportunistically screened for prostate cancer. The ERSPC researchers took great care to ensure that both arms of the study were as good as possible. They also recognised the problem of overdiagnosis, at least in part, by including lower and upper age limits for participants (which varied between centres) and stipulating a certain interval between PSA tests (in all centres apart from Sweden).

“There was also much discussion on the interval when we should re-screen, because that is also linked to unnecessary testing and overdiagnosis,” says Roobol. “In the majority of centres, we decided on a four year interval.”

As the study continued, and the follow-up period grew, adaptations continued to be made. “As soon as data came through, we studied it and made changes to the study. We obviously could not change the protocol, but other changes were required. For example, at the start we had a cut-off point that if a man’s PSA was 4 or higher, he had a biopsy. This was based on Catalona’s original study. But as soon as data became available we saw that we were diagnosing a lot of cancers at a PSA just below 4.

“We also found that including DRE and transrectal ultrasound in the procedure was pointless, because it detected hardly any cancer. So we decided to lower the cut-off PSA levels to 3, but to omit all the additional testing which was useless. So there was constant watching the data and seeing if things could be adjusted.”

Breakthrough results

In 2008 came the breakthrough: the moment, 15 years after the start of the study, when those at its core knew that it could have a meaningful impact on early diagnosis of prostate cancer. It happened at one of the twice-yearly meetings of the European consortium administering ERSPC, where principal investigators from each of the eight participating countries came together to discuss issues and progress. This time the meeting was held in Finland, on the tiny island of Seili.

“Obviously, throughout the trial we could not look at the data about the definitive end point, mortality,” says Roobol. “Only the data monitoring committee (DMC) could do this, so the principal investigators didn’t have a clue. At every meeting, there was a report from the DMC, which would basically report, ‘No issues: please continue’, and so on.

“So in 2008 we were on this very small island, where we met, dined, went on boat trips around the island – it was great fun. Now, suddenly, during our routine meeting on this island, the DMC made their report. But rather than just saying everything was fine, the chair of the committee, said: ‘Okay, we can report that we have reached a statistical difference between the two arms in respect to prostate cancer mortality. We have now shown it is significant that prostate cancer screening reduces mortality by 20%.’

“I will never forget this moment. It was amazing: after 15 years we had reached something. The whole room, all of these principal investigators sitting there, were flabbergasted. We had expected that there would be a benefit, but we had not expected it would become significant so early. And immediately it was: ‘Oh my god, we need to keep this a secret, we must not leave the island!’ – people were so excited. We all had to sign documents that we would not disclose the results and then obviously the big challenge of writing the manuscript started.”

The paper appeared in the New England Journal of Medicine in 2009. PSA screening was associated with a significant absolute reduction of 0.71 prostate-cancer death per 1,000 men after an average follow-up of 8.8 years, reported Schroeder, Denis, Roobol and the other trial investigators. “Despite some variation in screening procedures, the results from each centre were compatible with the main result: a lowering of the death rate from prostate cancer associated with screening.” At the same time, they said, the risk of overdiagnosis was about 50%.

Controversy about the evidence

The impact should have been immediate: a catalyst for policymakers around the world to investigate further the possibility of screening programmes, and ways to minimise overdiagnosis, now the principle of reducing deaths was proved.

However, it didn’t happen. In the same issue of NEJM, early results of an American trial investigating the impact of PSA screening were also published. The National Institutes of Health (NIH) trial, the Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial, began two years after the ERSPC pilots. The findings were very different than those of ERSPC. “After 7 to 10 years of follow-up, the rate of death from prostate cancer was very low and did not differ significantly between the two study groups,” the triallists concluded. The accompanying NEJM editorial was headlined: ‘Screening for prostate cancer – the controversy that refuses to die’.

What happened next was not movement but stasis: further debate about which trial was right, and whether screening did or didn’t work. As it turned out, the debate was completely unnecessary: subsequent investigations and modelling have revealed that the PLCO trial was severely contaminated, with 90% of men in the control arm undergoing some degree of PSA testing. “The PLCO can no longer be accurately called a trial of screening versus no screening,” wrote Matthew Cooperberg in Nature Reviews Urology in 2016.

Says Roobol: “The whole message of our research completely faded away in the discussion that started. It lasted eight years after publication, during which time professor Schroeder and I travelled the world presenting our results and explaining what they meant. Unfortunately, it usually ended up with us explaining why we saw something, and PLCO didn’t. Finally, in the last few years, the debate has stopped, and it has been generally accepted that organised screening programmes work. But it cost us at least eight years.”

Catalona calls the years between the publication of the PLCO trial results and 2018, “The dark ages of PSA testing… What had happened was that, when Fritz was going to publish his first ERSPCresults in the NEJM, there were many sceptics about PSA testing in the US. So it had been decided to publish the PLCO trial results, even though the data was not ready. People in the US were afraid that if Fritz reported a 20% mortality benefit in the NEJM, PSA screening would be unleashed all over the world.

“The publication of the two studies created a tremendous stir. In the US the feeling was: ‘The US research is bound to be better than the European so we are going to believe the NIH trial and figure out what is wrong with the ERSPC.’ That launched a series of articles attacking the ERSPC trial. In the aftermath, the US Preventive Services Task Force rushed ahead with updating national guidelines for PSA screening, and in 2011 it recommended against PSA screening for all men, period.

“That completely created a generation of students and family practitioners that were dead set against PSA screening and it had a profound effect in shutting down PSA screening in the US – and other parts of the world. During that time, the amount of high-risk disease started increasing and the prostate cancer mortality rate that had declined by 53% started creeping back up.”

However, the climate began to change as successive ERSPC updates, published in 2012, 2014 and 2019, confirmed the authority of the study’s findings. A turning point came in 2016, when a new analysis of the PLCO data was published in the American Journal of Medicine: it brought the PLCO findings very much in line with ERSPC. The evidence in favour of PSA screening to reduce prostate cancer mortality was becoming overwhelming, and in 2017, the US Preventive Services Task Force withdrew its influential recommendations, and recommended that PSA testing should be offered to all men aged 55 to 69.

“If it hadn’t been for ERSPC, the use of PSA as a screening tool would have been set back goodness knows how long,” says Bill Catalona. “Fritz did a wonderful job with that trial, and it’s had a tremendous impact.”

Modern relevance

Throughout the turbulent years, ERSPC collaborators continued their work on how to move forward with the proof of principle they had provided: balancing the risks and benefits of organised screening in terms of quality-adjusted-life years (QALYs), assessing the costs of introducing organised screening, and finding ways of reducing the risk of overdiagnosis through risk-stratification.

Alongside the increasing evidence of mortality benefits from screening for PSA, the early 21st century saw growing interest in the potential of active surveillance to substantially reduce the chances of overtreatment once men were diagnosed prostate cancer as result of PSA testing. Analysis of ERSPCdata indicated that as many as half of the cases diagnosed with prostate cancer in the screening group might never cause problems within a patient’s lifetime. Separate ERSPC findings also confirm that about 30% of detected cancers have non-aggressive features and are indolent or slow growing.

An ERSPC offshoot, PRIAS (Prostate cancer Research International: Active Surveillance), has produced a protocol for doctors to follow with patients diagnosed with prostate cancer, to advise who might undergo active treatment, and who might be carefully monitored over time (active surveillance).

The ERSPC findings have formed a central part of evidence submitted to the European Commission by organisations including the European Association of Urology and the European prostate cancer advocacy alliance, Europa Uomo, in an attempt to introduce PSA screening programmes in Europe. This campaigning, and associated papers, have argued that:

• Opportunistic screening using PSA testing does not work: structured screening, targeted at specific groups and stratifying risk, is required to ensure that benefits outweigh risks
• Specific criteria should determine who receives PSA screening
• If a PSA reading is greater than 3, risk calculators and multiparametric MRI scans should be used before any biopsy is taken
• All men who receive PSA tests should be well-informed about the risks and benefits.

In 2022, the European Commission was advised by the Science Advice for Policy by European Academies (SAPEA), and the EU’s chief scientific advisors that science supports the widespread introduction of organised prostate cancer screening using PSA blood tests.