When to test for prostate cancer: Finding a balance

A conversation with Fritz H. Schroder, M.D., the principal investigator of the European Randomized Study of Screening for Prostate Cancer

The word “cancer” inevitably draws a quick reaction from patients. Conventional wisdom tells us to rid the body of these rogue cells at any cost. Yet, in the case of prostate cancer, this logic is called into question. Many men who have prostate cancer and either never learn they have it or choose not to treat it often live long lives, eventually dying of something else. Recently, the U.S. Preventive Services Task Force began recommending that men ages 75 or older forgo prostate cancer screening, noting that the potential harm of treating screen-detected cancer may outweigh the benefits in this age group. That’s because many screen-detected cancers can take a decade or longer to cause symptoms. But the treatment complications, which often include erectile dysfunction and urinary incontinence, are immediate and can have a negative impact on a man’s quality of life.

The attempt to balance quality of life with the benefits of early detection has led to an ongoing debate about when to screen — in particular, whether or not all men should be screened beginning at age 50. On the one hand, screening has been shown to identify potentially lethal cancers at an early and curable stage. One study estimates that one in seven men with screen-detected prostate cancer might be at risk of dying of the disease. On the other hand, current screening and biopsy regimens do not adequately differentiate aggressive cancers from slow-growing ones. It’s estimated that more than 50% of prostate cancers diagnosed during population-based screening are indolent, meaning they would not affect a man during his natural lifetime. (See “Population-based screening defined.”)

Many countries, including Great Britain, provide prostate cancer screening to men who ask for it, but do not encourage routine population-based prostate cancer screening in asymptomatic men. Their health officials cite a lack of large-scale studies showing that mass screening and early treatment reduce death from prostate cancer. Critics also point to the fact that prostate-specific antigen (PSA) testing is imprecise. The test measures a protein made by prostate cells, but it is not a cancer-specific test. PSA levels often rise due to benign conditions like an enlarged prostate, infection, or aging. However, the test does offer men a chance to discover cancer before they develop symptoms, and while there is debate over its effectiveness, many are hesitant to halt it.

Instead, many groups are taking a more measured approach. For instance, the American Cancer Society does not recommend routine prostate cancer screening for average-risk men over the age of 50, but it does emphasize that these men should be “offered” the PSA test and encouraged to make an informed decision. Likewise, the National Cancer Institute recommends that patients be well informed about the benefits and risks of prostate cancer screening, early detection, and treatment.

Fortunately for the millions of men concerned about prostate cancer, two major randomized studies are beginning to shed light on the critical issues. (See “Randomized controlled trials.”) In the United States, the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial includes a study of more than 70,000 men ages 55 to 74 to determine the effectiveness of annual prostate cancer screening. (See “Following the PLCO.”) In Europe, the largest-ever randomized study on screening for prostate cancer is also under way. More than 260,000 men from eight countries (See Figure 1) are enrolled in the European Randomized Study of Screening for Prostate Cancer (ERSPC).

The principal investigator of the ERSPC trial, Dr. Fritz Schroder, from the Department of Urology at Erasmus Medical Center in the Netherlands, recently spoke with the editors of Perspectives about the effectiveness of prostate cancer screening and how it can be improved.

What is the overall objective of the PLCO and ERSPC trials?

In both trials, the most important endpoint is the rate of death from prostate cancer. If these two studies can show that population-based screening reduces the rate of death from prostate cancer by more than 20% at an acceptable cost in terms of quality of life and money, governments worldwide will likely introduce screening programs, which will then be included in paid health care plans. Our hope, as investigators, is that this in fact will happen and that early diagnosis can be offered to all men at risk, to decrease the burden of suffering and potential death from prostate cancer.

What are your general thoughts about the risks and benefits of screening?

Screening has the potential to find aggressive and potentially lethal cancers early, and there is evidence from a randomized trial that, compared with watchful waiting and delayed treatment, radical prostatectomy early in the disease process lowers a man’s chance of dying of prostate cancer. [See “Watchful waiting?”] However, after eight years, only about 25% of the men in the group that delayed treatment developed metastatic disease. So, men who choose to be screened take the chance that they may face a cancer diagnosis and have to make choices about treatment that may be unnecessary. However, men who are well informed about the potential risks and benefits of screening and subsequent treatment should not be denied the early diagnostic tests.

The ERSPC is your brainchild. What inspired you?

I was always fascinated about the possibility of early detection of prostate cancer. In the 1980s, my partner, the famous medical radiation oncologist Dr. van der Werf-Messing, and I planned a study using digital rectal examination as a means of screening. It wasn’t funded. In 1990, we saw data about the use of PSA screening in the early detection of prostate cancer. This got us excited about the prospect of a randomized trial to determine whether population-based prostate cancer screening is effective. By 1991, professor Louis Denis and I had begun pilot studies in Belgium and the Netherlands, and by 1994 the study officially began. Subsequently, centers in Sweden, Finland, France, Spain, Italy, and Switzerland decided to participate.

How is the study designed? How does it compare to the PLCO study in the United States?

Our study is PSA-driven, with a biopsy indicated for men who have a PSA level of 3.0 ng/ml or higher. We screen participants every four years, with the exception of Sweden, which screens every two years. The PLCO study in the United States screens with a combination of PSA testing and digital rectal exams initially, then on an annual basis for three years, followed by two additional years of PSA-only screening. So, it will be interesting to compare the effectiveness of various screening intervals. Both trials randomly assign participants either to take part in routine screening or to be part of a control arm in which they are offered standard medical care. We have enrolled many more men over all, so the ERSPC has a statistical advantage. Our analysis will be based on prostate cancer mortality up to the end of 2008. The results of our first analysis should be published by 2010, while the final analysis of the PLCO study is due by 2015.

Coordinating a study that spans eight countries is a logistical feat. How was the ERSPC implemented and funded?

Grants from the European Union pay for the international collaboration, including funding for seven monitoring committees, semiannual meetings of representatives from each country, and the independent data center in London. Each country covers its local expenses and clinical health care costs of its own participants. To identify both control and screening populations, we use each nation’s cancer and population registries. Half of the countries require informed consent before a patient is randomly assigned to one group or another. As a result, participant compliance with screening is high in these countries. In countries that don’t have this rule, about 20% to 30% of the men initially assigned to the screening arm decide not to participate. We have been able to adjust for this in our power calculations.

Once the men are enrolled in the study, following those in the screening arm is straightforward because they are seen during regular checkups with local physicians. Gathering data from men in the control arm requires thorough analysis of cancer and cause-of-death registries, and committee review to verify cases of prostate cancer. Our data managers also keep track of other health-related conditions and information, including quality-of-life issues, for further analysis.

Once a man is diagnosed with prostate cancer, does the study assign him to a certain type of treatment? Or is that decision left up to him and his physician?

We don’t regulate who can have which treatment, but we try to ensure that there are no significant differences in the treatment options between the screening and the control arms of the study. We also work with the health care systems to ensure that appropriate clinical staging and cancer assessment is taking place for each participant.

Are there hurdles when it comes to ensuring accuracy of the data?

Yes. One ongoing threat for both the ERSPC and the PLCO studies is the issue of opportunistic screening, which occurs when men in either arm of the trial decide to be screened for prostate cancer outside the trial protocol. Fortunately — and curiously — most of the abnormal PSA tests haven’t led to a biopsy. We were able to adjust for this problem, which we refer to as contamination, early on by boosting enrollment and factoring in a 20% contamination rate over all, which we have verified with the registries. We have to continue to follow the rate of contamination and adjust the results accordingly.

Some studies have shown that men who are regularly screened for prostate cancer actually live longer than men who aren’t. How do you explain this, and have you encountered this in the ERSPC?

This phenomenon is called the self-selection, or healthy screening, bias. [See “Self-selection bias.”] It was documented in the Dutch section of the ERSPC. The men participating in the trial lived longer than those outside the trial. That’s probably due to the additional medical attention they were given. If a man enters a screening program, he is likely to be watched more carefully, not only for prostate cancer, but also for other health conditions, which can then be addressed sooner and more effectively. This is in line with observations made in the field of cardiovascular disease.

Along these same lines, men who consent to taking part in medical studies tend to be healthier than those who do not. Using our data from Sweden, we found that overall mortality is much higher in those who refuse screening than in those who consent to it. We have a statistical technique to control for this in our analysis of the results; we have to take these biases into account.

Early on in the study, you changed the screening parameters and the criteria for recommending a biopsy. What prompted this?

When we first began, we were using a PSA cutoff of 4 ng/ml or above and a digital rectal examination [DRE] as combined screening tools. [See “Screening with DRE.”] If the DRE was abnormal, regardless of the PSA level, we would do a biopsy. But we found that the DRE was too insensitive. In men with an abnormal DRE and a PSA in the range of 2 to 3 ng/ml, we were conducting biopsies on 100 men just to find 10 cancers. In men with an abnormal DRE and a PSA between 0 and 1 ng/ml, we were conducting 48 biopsies to find one cancer. Meanwhile, we determined that we were missing a large number of cancers in men with PSA levels in the 3 to 4 ng/ml range because they were not being detected by DRE. So, we changed the protocol and in 1997 began PSA-only screening with a cutoff of 3 ng/ml. We have since validated that approach with additional studies. [For an overview of screening methods, see “Prostate cancer screening tests.”]

What about the potential for cancer with a PSA level below 3 ng/ml?

We just did a study that asks the question: “Is it necessary to detect all prostate cancers in men with a serum PSA below 3 ng/ml?” We looked at biopsy data from the National Cancer Institute’s Prostate Cancer Prevention Trial, which showed that there are cancers that are diagnosable in men with a PSA below 3 ng/ml. We then compared 12-year outcomes from our Rotterdam-based study and found that it would have taken more than 15,000 biopsies to detect fewer than 100 cancers. Our conclusion is that we don’t need to diagnose all the cancers in men with PSA levels below 3 ng/ml when repeated screenings are planned. In men with PSAs at this level, cancer can often be detected in follow-up screenings while still at a curable stage. [See “PSA <3 ng/ml.”]

For those men who initially present with a PSA between 2 and 3 ng/ml, it would be nice to have a better screening test than PSA. A study in Finland has shown that including a measurement of free PSA, a portion of the total PSA, improves the specificity of the test and is very useful when total PSA levels are in the 2- to 3- ng/ml range. Testing free PSA appears to help better predict the likelihood of cancer when done in combination with standard PSA testing.

Are you going to continue studying new ways to screen?

Yes. We’ve actually reached an agreement with European Urology to publish five papers under the main heading “How to screen for prostate cancer after 2008.” We’ve already published one on PSA, PSA velocity, and PSA derivatives, which includes free PSA. The second paper will focus entirely on the molecular subforms of PSA, and the third one will review rectal examination. Then we will go into biopsy regimens and try to determine a better approach; the biopsy schemes currently used to maximize detection are not in line with a sensible way of looking for prostate cancer.

What about genetic profiling?

Genetic profiling will be important. We’re looking at the PCA3 gene, which can be detected in urine. PCA3 RNA is overexpressed in prostate cancer cells and may be a better indicator of cancer than PSA, which is not cancer-specific. We’re also looking at the TMPRSS2:ERG fusion gene in urine to see if it could improve prostate cancer predictions.* These types of tests may help us avoid unnecessary biopsies. Eventually, we envision having a series of markers that could be used alone or in combination with refined PSA testing.

The ERSPC trial has generated numerous scientific papers on a range of topics pertaining to prostate cancer. What is the count so far?

It’s up to 337 published papers, and we continue to learn more. We list all publications on the ERSPC Web site, www.erspc.org.

What has been the most important finding to date?

I would say, at this point, the data on the overdiagnosis of prostate cancer and what we term indolent disease. In 2007, we were able to validate what’s known as the Kattan nomogram, which is an algorithm used to determine which cancers are not likely to lead to the death of the patient. Michael Kattan’s data, published in 2003, showed that in two large clinical series, about 20% of prostate cancers that were diagnosed with biopsies and treated with radical prostatectomy were indolent. In our study, we validated his nomogram. We also found that 49% of men diagnosed with prostate cancer by screening appeared to have indolent disease. The Cleveland Clinic, in an independent validation, came to the same conclusion we did.

This is a big step forward because we’ve known since the 2003 publication of a study in the Journal of the National Cancer Institute that current screening regimens are overdiagnosing prostate cancer by about 54%. Overdiagnosis occurs when a screening test detects a cancer that, untreated, would not have affected a man during his natural lifetime. Having a nomogram that identifies a large portion of these indolent prostate cancers is important because it is unethical to overtreat so many cases of screen-detected prostate cancer. [See “Overdiagnosis and indolent disease.”]

I single this out as being very important because we anticipate that we will find a difference in prostate cancer mortality. But the European health care system officials are very critical. If we show them that we can reduce prostate cancer mortality by up to 30% but that we may, in turn, end up overdiagnosing and treating 50% of all men screened to accomplish it, they will ask us to go back to the drawing board. So it is essential to develop and test predictive tools like nomograms that can help us differentiate between cancers we should treat and those we should not. [See “Prostate cancer risk calculators.”]

We have used data from 6,288 ERSPC participants in Rotterdam to design a prostate cancer risk indicator that is more comprehensive than the one used by the National Cancer Institute. Together, a patient and his doctor enter PSA scores and other information. Using that data and biopsy results, it predicts whether a cancer is indolent or more aggressive. In the future, we expect that genetic risk factors will be added to existing parameters. As with any calculator, results can be skewed, so it’s best for a man to consult his doctor about the data.

Can the average patient access your nomogram and algorithm to assess his chance of having indolent cancer?

Yes, the ERSPC risk indicator is publicly accessible at www.uroweb.org. It makes predictions on several levels. The first level can be used by any man without consulting a doctor. It estimates the chances of having a positive biopsy based on age, family history, and urination complaints. Levels 2 to 6 are to be used with a physician.

Many men who appear to have an indolent or seemingly nonthreatening prostate cancer hold off on treatment, pursuing what’s called active surveillance, or watchful waiting. Do you know how many men diagnosed with prostate cancer in the ERSPC are practicing active surveillance?

With screening, we’re diagnosing many more cancers that can be characterized as indolent, so we are seeing more cases of active surveillance. We are also seeing many more men who get potentially curative treatment. It varies a little bit by country, but the proportion of men choosing active surveillance is now up to 30% or more in some centers.

To track this, we have established a cooperative active surveillance study called the PRIAS Project, which is short for Prostate Cancer Research International: Active Surveillance. An interactive Web site, www.prias-project.org, allows doctors from around the world to log on and add their patients on active surveillance to the study. I would encourage men to ask their doctors about it. In the end, we are very optimistic that we will answer the key questions: “Who are the best candidates for active surveillance?” and “What are the right trigger points for introducing treatment?” The criteria for pursuing active surveillance and reasons to initiate treatment are part of our risk indicator.

When are the results likely to be available?

The PRIAS Project is a prospective study, so it’s ongoing. We should gradually learn from it. We also have started a retrospective study, through which we have been collecting all cases of active surveillance for prostate cancer in the Scandinavian countries and in the Netherlands. It shows no prostate cancer deaths in five years for more than 600 men on active surveillance. We continue to look at treatment variables, so we hope to shed more light on the best screening approach and when to intervene with treatment.

When do you expect to have the final results of the entire ERSPC trial?

We will have a final analysis in 2010 on the basis of the 2008 data. We have, however, agreed that we would prolong the study for one year if we see a trend. So the final analysis of this study will be published at the latest in 2011. Obviously, if a significant difference in prostate cancer mortality emerges, the group will publish earlier.

What do you think the take-home message will be?

I hope the message will be that routine screening is effective. To make this acceptable, we have to continue improving upon current screening and diagnostic practices. Pinpointing which cancers are aggressive and which are indolent is critically important because we want to balance harm, in terms of negative effects, with the potentially lifesaving benefits of treatment. And we have to find a balance that will be accepted by health care providers around the world. That is going to be our task in the coming years.