Where we stand about screening NOW!

As we have already, albeit briefly, reported, two “major” papers were published in the New England Journal of Medicine today, and they both were designed to address the appropriateness of mass screening for prostate cancer — among men over the age of 55 years in the USA and over 50 years in Europe respectively.

We wish to state two things immediately:

  • These papers have only (perhaps) resolved one of the many issues that have driven the screening controversy for the past 20 years.
  • What you have or will read in or hear from the mass media almost certainly will be (or already has been) a vast over-simplification of the complexities inherent in these two papers.

We want to begin by clearly stating that mass screening of all men over a certain age for risk of prostate cancer is not at all the same thing as individual testing for prostate cancer risk. Statistics do not apply to individuals, and decisions about health care are extremely personal, as they most certainly should be. Even if both of the studies published today had categorically proven that, on average, mass screening for prostate cancer was associated with absolutely no survival benefit whatsoever, this would still not have meant that testing of individuals was necessarily inappropriate.

Second, we wish to make it very clear that the issue of whether screening for prostate cancer is appropriate needs to be very carefully separated from the issue of whether the potential harms of prostate cancer treatment are worth the risk of screening. These are two different if closely related discussions — but they are all too often addressed as if they were one issue.

Third, we recommend to every reader of this article that (if at all possible) you watch all of the videotaped discussion between Dr. Philip Kantoff (a member of the Scientific Advisory Board of The “New” Prostate Cancer InfoLink) and Dr. Mary McNaughton-Collins, which appears on the web site of the New England Journal of Medicine. This is a thoughtful and helpful discussion of the two papers, and although the discussants take two different approaches in thinking about these studies, they come to very similar conclusions about the implications of the data — as does Dr. Michael Barry in his editorial on these two papers, where he states that:

… a shared decision-making approach to PSA screening [between the individual patient and his physician], as recommended by most guidelines, seems more appropriate than ever.

So, with all of this said, let’s see what we have actually been taught by these two studies.

The first article, by Andriole et al., is the initial report of prostate cancer data from the so-called PCLO trial. Between 1993 and 2001, this study enrolled 76,693 men at 10 study centers in the USA into its prostate cancer component. These men were randomly assigned to one or other of two groups: an annual screening group of 38,343 men and a “usual care” group of 38,350 control patients.

The men in the annual screening group were offered a PSA test every year for 6 years and a physical examination (a DRE) every year for 4 years. All PSA tests were performed at a single laboratory. The men in the screening group and their health care providers were given the results of these tests and decided together on any necessary follow-up evaluations. It is very important to understand that men in the “usual care” group also received PSA and DRE tests according to the recommendations of certain professional organizations. The distinction is that these men were not being screening rigorously according to the specific guidelines used for the screening group. All patients were followed  for 7 to 10 years and all cancers, deaths, and causes of death were identified and recorded.

The results of this US trial are as follows:

  • There was an 86 percent compliance rate for annual PSA testing in the screening group, and an 86 percent compliance with DRE testing.
  • Rates of PSA testing in the usual care group ranged from 40 percent in the first year to 52 percent in the sixth year and for DRE testing in these men they ranged from 41 percent in the first year to 46 percent in the fourth year; in other words, approximately half of the men in the control group were being regularly tested for risk of prostate cancer!
  • At 7 years of follow-up, the incidence of prostate cancer in the screening group was 116/10,000  person-years (2,820 cancers diagnosed) and the incidence of prostate cancer in the control group was 95/10,000 person-years (2,322 cancers diagnosed).
  • The incidence of prostate cancer-specific death was 2.0/10,000 person-years (50 deaths) in the screening group and 1.7/10,000 person-years (44 deaths) in the control group.

The authors of the study conclude only 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 second article, by Schröder et al., is the initial report of data from the European Randomized Study of Screening for Prostate Cancer (the ERPC study). Because this study involved patients from 7 different European countries, and there were differences in the study protocol from country to country, this is an extremely difficult study from which to interpret results with a high degree of confidence. However …

The investigators identified 182,000 men aged between 50 and 74 years of age from 7 different European countries starting in “the early 1990s”. (The precise dates that different countries started to enroll patients into this trial varied.) As in the PCLO trial, these men were randomly assigned to a screening group or to a control group. However, there the comparison ends. In the ERPC study, men in the screening group received a PSA test at an average of once every 4 years and the men in the control group supposedly did not receive PSA tests at all. The 162,243 men included in this particular analysis had a predefined core age of between 55 and 69 years. The primary outcome of the study was the rate of death from prostate cancer, and the mortality follow-up was the same for both groups of patients, ending on the last day of December 2006.

The results of the ERPC study are as follows:

  • 82 percent of men assigned to the screening group accepted at least one offer of screening.
  • The cumulative incidence of prostate cancer in the screening group was 8.2 percent at a median follow-up of 9 years.
  • The cumulative incidence of prostate cancer in the control group was 4.8 percent over the same median time frame.
  • The rate of death in the screening group as compared to the control group was 0.80 (i.e., 20 percent lower).
  • The absolute difference in risk of death in the screening group as compared to the control group was 0.71.
  • These data imply that, to prevent a single death from prostate cancer, 1,410 men would need to be screened and 48 additional cases of prostate cancer would need to be treated relative to the men in the unscreened population.
  • Looking only at those men who were tested during the first round of screening, the rate of death in the screening group as compared to the control group was 0.73.

In this study the authors concluded as follows: “PSA-based screening reduced the rate of death from prostate cancer by 20 percent but was associated with a high degree of overdiagnosis.”

So what can we say that we have learned?

Well in the first place, it is very clear that the vast majority of men diagnosed with prostate cancer do not die of their disease within 10 years — whether they are screened or not. Every qualified commentator on these papers whose opinions we have either heard or read so far makes this point. Whether we like it or not, this information does support the recent statement of the USPHS Task Force that mass screening of men over 75 years of age is not appropriate. However, it does not negate the Iowa Consensus guidance that every man of 75 or over should have a discussion with this doctor about whether continued PSA and DRE testing is appropriate and necessary! If there is one thing that can be absolutely concluded from these two studies, we believe it is the wisdom of the Iowa Prostate Cancer Consensus guidelines.

The second conclusion that can clearly be drawn from these studies is that a 10-year follow-up is insufficient to determine whether prostate cancer screening has an overall mortality benefit. The 20 percent benefit demonstrated by the ERPC study at 9 years is only border-line significant (P = 0.04). It is our understanding that follow-up of subjects in the PCLO study will be continued, but follow-up of men in the ERPC study has (perhaps unfortunately) been terminated.

The only third conclusion that we are able to draw from these studies is that the debate has not been resolved. From this point on — until better data is available — The “New” Prostate InfoLink’s general statement about prostate cancer screening will read as follows:

The only two large, randomized studies of prostate cancer screening, involving men between 50 and 74 years of age, have not been able to offer a definitive recommendation regarding the value of prostate cancer screening that can be generally applied to most men.

At this time we believe every man should have an individual discussion with his doctor about the benefits and risks of PSA testing and physical examination as a guide toward the possible need for prostate biopsy. The timing of that discussion and the subsequent actions of the patient and his doctor can only be determined on the basis of individual risk and personal perspective.

We recognize that some of our readers will not, perhaps, agree with this viewpoint.

The “New” Prostate Cancer InfoLink has long been of the opinion that this debate will never be resolved unless and until some other test is available that can better differentiate between the probable presence of  high, intermediate, and low risk forms of prostate cancer without the need for prostate biopsy. The studies published today have further confirmed this opinion, and should offer a strong stimulus to the urologic oncology research community to focus greater attention on this issue and less on the esoterica of PSA-based screening.

11 Responses

  1. I haven’t had chance to have an in depth look at either paper but from what I have seen The “New” Prostate InfoLink’s view is a pretty fair assessment.

  2. “…this debate will never be resolved unless and until some other test is available that can better differentiate between the probable presence of high, intermediate, and low risk forms of prostate cancer without the need for prostate biopsy.”

    That would fill the bill. So would a non-invasive, accurate, reliable method of imaging early prostate cancer, that could be treated with available focal therapies: cryo or HIFU.

  3. Actually Steve, I do not agree with you about this. Unless an imaging test can also resolve the issue of high, intermediate, or low risk disease you have not resolved the need for a biopsy, which is the first step down the slippery slope of invasive action and risk for overtreatment. A man who really doesn’t need treatment doesn’t need focal therapy any more than he needs whole gland therapy.

  4. Steve:

    The screening issue may never be resolved using DRE and the PSA test but improvements in the way the results are interpreted and acted upon have changed for the better, over the years.

    It might take 5 or 10 years before a 100% accurate PC test comes along and especially one that provides ease of use and is cost effective for screening purposes.

    I think a quote from Time.com sums up the current position regarding the PSA test: “It’s not precise, but it is science — and for now that’s the best we’ve got.”

  5. These studies that end up with very similar results really point up the issue of limitations in our diagnostic methods. PSA included!

    The individual should know what his situation is to the best of our present diagnostic technology. Then, let him research as well as he can what his options are.

    Hopefully, he will use an MD truly knowlegeable in prostate cancer who can and will review all his options. Some men can live with the knowledge that they do have cancer in the gland and not take action while others will insist on “dealing with it” ASAP. It is an individual decision and will continue to be an individual decision regardless of what these studies conclude.

  6. Dave,

    I agree with your post there.

    I think this article gives an informed view on the two recent papers: Leader in Prostate Health Urges Prostate Cancer Screening in Face Of Contradicting Data.

  7. I found this comment at the NEJM website fascinating:

    “Have we EVER been asking the right question? For 20 years the prostate cancer screening issue has been driven by the interests of groups of physicians and commercial organizations. Patients whose cancer has been diagnosed and effectively treated have inevitably been dragged into this debate along the way as advocates for screening. … ”

    I, as the wife of a patient, would like to know which interest groups are driving PC screening. And are you saying that patients are being recruited as salespeople for various PC treatments (e.g., robotic surgery).? Also, Ted and I are wondering about the meaning of “effectively treated”. Does this mean that surgery is a “cure” for PC or puts the pt in remission? Or did the patient just make it out of surgery OK?

    I can’t help wondering why this whole subject was left out of your InfoLink summary. I rely on your blog to tell me what’s going on, and I usually find the discussions fair and balanced.

  8. Dear Leah: The reason that I placed that comment on the NEJM site is because it was intended to stimulate conversation beyond the constraints of The “New” Prostate Cancer InfoLink.

    I have never hidden the fact that I have had years of experience as a marketer of drugs for the treatment of prostate cancer. Look at my page on the Social Network. A drug company was the original and sole sponsor of Prostate Cancer Awareness Week. Urologists benefited massively from the implementation of Prostate Cancer Awareness Week in its original form. So did the drug company in question. I was “party” to that initiative. Urologists have long been the single most ardent group of physicians promoting the importance of mass screening for prostate cancer. They got to do more surgeries and prescribe more hormone therapy. Commercial companies that make PSA tests are also (for a fairly obvious reason) in favor of mass screening, as are all the laboratories that process those blood samples. The earlier that patients get diagnosed and treated, the sooner they will have a biochemical recurrence (if they are likely to have one) and so the more likely they are to need second or third line therapy of some type (radiation, drugs, you name it).

    Every patient who is tested, diagnosed with prostate cancer and successfully treated with no adverse effects (or at least, with minimal adverse effects that do not significantly impact his satisfaction with the outcome of treatment) almost inevitably becomes an “advocate” for prostate cancer screening. I am not saying that patients are being “recruited.” I am saying that there is a self-fulfilling prophecy at work. “Effectively treated” is defined in the mind of the individual patient … So long as one hasn’t had a recurrence and one’s side effects are acceptable, I would assume the patient thinks he has been effectively treated — whether he needed that treatment or not.

    Some 15 years ago, on the original Prostate Cancer InfoLink and on PPML, I and a small number of others who would raise the potential benefits of watchful waiting, would be ridiculed and abused by patients who had been screened, diagnosed, and treated to their satisfaction because it was (wrongly) assumed that if you didn’t get treated your prostate cancer would kill you.

    The material on the InfoLink was (I hope) fair and balanced. I try very hard to make it so, but I am far from perfect. This is me expressing my entirely personal opinion. I hope you think I am entitled to one.

    The two questions that I believe the prostate cancer community has failed to address in a really serious manner for 20 years are, “Who really needs a diagnosis for prostate cancer?” and “Who really needs aggressive treatment that comes with serious risks for debilitating side effects?” I am not saying that we have made no attempt to address these questions. I am simply saying that by comparison with the huge sums of money that have been poured into the new forms of therapy, the amounts of money that have gone into highly structured attempts to analyze risk and come up with better tests have been minimal.

    I hold two completely contradictory positions. I believe that every man has the right to know his risk for prostate cancer and make the best personal decision he can about what to do about it. At the same time, I hold the contradictory opinion that a large (if indeterminate) percentage of the men who actually go and get aggressive therapy might have been better off if they never had. I would like to think we could resolve this contradiction.

    Lastly, let me say that I have never “hidden” this opinion. I must have discussed it with hundreds of different people over the years — from a recent president at the AUA who is a good friend of mine and who I have known for nearly 20 years down to men I met briefly at social events.

  9. Thanks, Mike.

  10. I can’t help but wonder what the 20,000+ men in this country who die from prostate cancer each year would recommend to others about mass screening.

  11. Dear Ken:

    I cannot speak for the dead, but what I can tell you is that a joint statement is going to be released by many of America’s prostate cancer advocacy, education, and support organizations early on Monday. We will be posting this statement on the web site at 9 a.m. that morning.

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