The PSA test – the picture becomes slightly clearer

The controversy over the PSA prostate cancer blood test has been rumbling on, on both sides of the Atlantic, for many years.

Does screening for prostate cancer with the PSA test actually save lives? Does it cause too many false alarms? Do the risks outweigh the benefits? These questions have lacked clear answers for a long time. And, as Kat wrote about, it can be confusing for men trying to decide whether to have a test or not.

To try to clarify things, several large clinical trials are in place around the world. This week, two of them reported early results in the New England Journal of Medicine.

On the surface of it, their results are contradictory. The first trial, carried out in the US, suggests that screening doesn’t save extra lives, and leads to unnecessary treatment. But the other, European, trial hints that screening does in fact save extra lives.

Who’s right? Lets take a close look at how the studies were done, and precisely what they found, to try to understand what this means for PSA testing.

The PLCO trial design

The Prostate, Lung, Colorectal and Ovarian (PLCO) trial was set up in the United States in 1992 to look at the feasibility of screening for these cancers. The prostate cancer part of this trial recruited about 76,000 men between the ages of 55 and 74, at 10 centres across the US.

About half of these men were offered a PSA test every year for 6 years. If the result was above a certain value, they were then offered a rather uncomfortable procedure politely known to doctors as a ‘digital rectal exam‘ (and to everyone else as ‘a finger up the bottom’). This checks for any physical problems such as an enlarged prostate.

If the combined results suggested there might be a problem, the men and their doctors were notified, so further investigation could be done.

The other half of the men on the trial were offered “usual care” – meaning ‘whatever their health insurers considered appropriate’. Crucially, this meant that the control group for the study contained men who could also potentially be screened for prostate cancer.

According to this analysis, over half of men in the ‘unscreened’ group actually received some form of prostate cancer screening (compared to over eight-out-of-ten men in the ‘screened’ group).

The PLCO results

Overall, 2,820 men in the screened group were diagnosed with prostate cancer, compared with 2,322 in the control group.

Additionally, 174 out of the 76,000 men on the trial died from prostate cancer, split roughly evenly between the screened and unscreened groups (50 vs 44). This is a relatively small number and limits how confident the authors could be in their results.

The authors state that

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 ERSPC trial design

The European Randomised Study of Screening for Prostate Cancer (ERSPC) trial also started 15 years ago, and involved a much larger group of 162,000 men, aged between 55 and 69. But rather than a single co-ordinated trial like PLCO, ERSPC was much more diverse – it was carried out across seven countries, all of whom have slightly different ways of treating prostate cancer.

The men were randomly put in to one of two groups – the first were invited for a PSA test every 4 years (as opposed to annually in the PLCO trial) and a digital rectal exam twice over the study period. Again, if their PSA level was above a certain value their doctor was notified. But crucially, this level was lower than in the PLCO trial.

The other group received no screening. And, this being Europe, where PSA testing is generally less widely used than in the States, there were far fewer men in the unscreened group who ended up being screened.

On average, men were followed for 9 years – a shorter period than in PLCO.

The ERSPC trial results

Twice as many men in the screening group were diagnosed with prostate cancer, compared to the unscreened group And 214 men in the screened arm actually died of prostate cancer, compared with 326 in the unscreened arm – a 20 per cent reduction in deaths.

But (according to an accompanying editorial)  when you compare the number of men who were screened, and the number who were then treated for suspected cancer, and the number who died, it turns out that:

The 73,000 men in the screening group underwent more than 17,000 biopsies, undoubtedly many more than did men in the control group.

1,410 men would need to be offered screening and an additional 48 would need to be treated to prevent one prostate-cancer death during a 10-year period

Clearly, the trials are telling us some interesting – and conflicting – things about prostate cancer screening. How should we interpret the results?

These are early results

Firstly, both of these trials have only followed men for about ten years so far. That may seem like a pretty long time, but it’s possible that the benefits of screening men in their 50s won’t be seen until they’re much older.

So we look forward to seeing longer term results for both these trials, and an analysis of the quality of life implications and cost-effectiveness of PSA testing, as well as lives saved.

Differences in treatment

We still don’t know the most effective treatment for men diagnosed with prostate cancer. Some cancers grow slowly, some quickly – it is clear that these types of cancers will require different treatments, but doctors don’t know how to tell the difference reliably.

In these trials, men were offered a wide range of different possible treatments, from ‘watch-and wait’ to invasive surgery.  This is especially true of the ERSPC trial, which was carried out in seven different countries. The vagueness and variety of what the trials report as ‘treatment’ makes it difficult to draw firm conclusions.

‘Contamination’ of the unscreened group

In both trials, but especially the PLCO trial, some men who were in the unscreened group actually ended up having a PSA test – probably as part of their health insurance or because of suspected prostate cancer symptoms.

This may have significantly affected the results, by cutting deaths from prostate cancer in this group, and reducing any differences the trial was designed to show.

The trials used different PSA measures

In the US trial, men with PSA levels higher than four nanograms per millilitre of blood were offered a digital rectal exam.

But in the European trial, the threshold was three nanograms per millilitre. So the European trial will have spotted more cancers, but also given more false alarms – meaning more men would have had unnecessary treatment, despite the number of lives saved.

But – looking at it another way –  this also means that the US trial may have missed more early, treatable cancers – and this could help explain why it didn’t show a reduction in death rates (since more men in the screening group will have died from undetected prostate cancer).

No age-adjustment

Even more importantly, this isn’t how PSA screening is used ‘in real life’. Doctors in the UK frequently compare the PSA result to a man’s age when working out whether to investigate further. So another criticism of both trials would be that they didn’t reflect how a national screening programme would actually work.

Statistical significance

The reduction in death rates seen in the ERSPC trial was only just what the statisticians call ‘significant’ – meaning that they were only just sure that it was a ‘real’ result and not down to random variations in the data. (For the statistically minded amongst you – the ‘p-value‘ was 0.04).

‘Number needed to treat’

Even though the ERSPC trial showed a reduction in deaths, an awful lot of men had to be screened, and treated, to achieve this. As mentioned above, over ten years, nearly fifty men would be treated for every life saved.

A related figure for breast cancer screening is reported to be 10 women treated to save one life.

So according to ERSPC, PSA screening might lead to five times as many men being potentially unnecessarily investigated for prostate cancer, as women would for breast cancer.  This is important, because investigation for prostate cancer can sometimes cause impotence and incontinence.

“First – do no harm”

These trials have not settled the prostate screening debate (and some critics even argue that it will never be settled).

We believe that are still many things we need to find out before we can say for sure that widespread PSA screening does more good than harm. So we need to see the longer term results of the PLCO and ERSPC trials, and of the other large screening trials that have yet to report.

And – crucially – we need to work out how to tell the difference between aggressive and slow-growing cancers. It’s likely that any future screening test will use more than just PSA – so we need to find new markers for the disease, and work out how our genes are involved.

We also need to work out how best to treat men diagnosed with early prostate cancer. There are trials underway looking at exactly that, including the US PIVOT trial, and the ProtecT trial that we’re helping fund.

But what these latest trials do tell us is that, based on the available evidence, the UK’s Prostate Cancer Risk Management (PCRM) programme is still the best way to manage prostate cancer in this country.

Under the PCRM, men who are worried about the disease can talk to their GP, who will explain to them the risks and benefits of the PSA test, and help them make up their mind whether to go ahead with a test or not. Although this system is not ideal, it’s the best we can do, given what we know. As the editorial in the NEJM said,

The implications of the trade-offs reflected in these data, like beauty, will be in the eye of the beholder.

Some well-informed clinicians and patients will still see these trade-offs as favourable; others will see them as unfavourable. As a result, a shared decision-making approach to PSA screening, as recommended by most guidelines, seems more appropriate than ever.

Health service capacity

A final point. As more men become aware of the issue, more will likely ask their GP about PSA testing. We believe it is essential that, given the proper information, men should have access to a PSA test if they decide they want one.

And if their results suggest they might have cancer, they need to see a specialist in good time. So we must ensure that our health service is fully equipped and staffed to cope.

And the country needs to be prepared if the future data show that a screening programme is worthwhile. So we welcome the announcement that UK National Screening Committee will be reviewing the evidence.

Detecting cancer early is absolutely critical to save lives. Designing screening programmes is hard, takes a long time, and has to be done right. Prostate cancer screening is tantalisingly close… but it’s not here quite yet.

Henry

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References:

Gerald L. Andriole et al (2009). Mortality Results from a Randomized Prostate-Cancer Screening Trial New England Journal of Medicine DOI: 10.1056/NEJMoa0810696

Fritz H. Schröder et al. (2009). Screening and Prostate-Cancer Mortality in a Randomized European Study New England Journal of Medicine DOI: 10.1056/NEJMoa0810084

Michael J. Barry (2009). Screening for Prostate Cancer — The Controversy That Refuses to Die New England Journal of Medicine DOI: 10.1056/NEJMe0901166

Dubben, H. (2009). Trials of prostate-cancer screening are not worthwhile The Lancet Oncology, 10 (3), 294-298 DOI: 10.1016/S1470-2045(09)70066-X