The 400,000+ CAP screening trial reports initial results

A while ago now we had first mentioned the “Cluster randomized trial of PSA testing for prostate cancer” or CAP trial — the single largest randomized trial of PSA screening for risk of prostate cancer to be implemented. The initial results of this study, as reported by Martin et al., have just been published in the Journal of the American Medical Association or JAMA.

Let’s start with a little summary.

  • The CAP trial enrolled a total of 419,582 eligible men aged between 50 and 69 years through 573 primary care practices in the UK between 2001 and 2009.
  • Patients were randomized to either
    • An invitation to attend a PSA testing clinic and receive a single screening PSA test or
    • Standard (unscreened) care
  • Of those eligible patients,
    • 415,357 were actually randomized into the trial.
    • Data from 408,825 of those men (98 percent) were suitable for inclusion in the final analysis.
    • Their average (mean) age was 59.0 ± 5.6 years.
    • 189,386 were randomized to the intervention group (i.e., they were invited to have a PSA test).
    • 219,439 were randomized to the control group (i.e., they didn’t get invited for a PSA test).

So this was a truly massive, actual screening trial among a large cohort of men in the primary age range for early detection of prostate cancer.

The trial was designed to provide initial data at 10 years of follow-up, and the trial’s primary endpoint at that 10-year time period was the impact on prostate cancer-specific mortality.

So … here are the initial results of this trial:

  • Among the intervention group of 189,386 men,
    • 75,707 (40 percent) actually attended the PSA testing clinic.
    • 67,313 (36 percent) underwent PSA testing.
    • 64,436 were found to have a valid PSA test result.
    • 6,857 of the men with a valid PSA result (11 percent) had a PSA level between 3.0 and 19.9 ng/ml.
    • 5,850/6,857 (85 percent) had a prostate biopsy.
  • After a median follow-up of 10 years,
    • 549 (0.30/1,000 person-years) in the intervention group died of prostate cancer.
    • 647 (0.31/1,000 person-years) in the control group died of prostate cancer.
    • 8,054 men in the intervention group (4.3 percent) were diagnosed with prostate cancer.
    • 7,853 men in the control group (3.6 percent) were diagnosed with prostate cancer.
    • 3,263 men in the intervention group (1.7 percent) were diagnosed with a Gleason score of 6 or lower.
    • 2,440 men in the control group (1.1 percent) were diagnosed with a Gleason score of 6 or lower.
    • 25,459 men in the intervention group had died of all causes.
    • 28,306 men in the control group had died of all causes.

The basic conclusions drawn by Martin et al. are as follows:

  • There was no significant difference in prostate cancer-specific mortality after a median follow-up of 10 years.
  • The detection of low-risk prostate cancer cases was increased by the use of a single PSA screening test
  • The findings to date do not support single PSA testing for population-based screening (although longer follow-up is planned).

An editorial commentary by Dr. Michael Barry is published in the same issue of JAMA. And yes, Dr. Barry is a member of the US Preventive Services Task Force — but he is also a well-respected authority on the diagnosis and management of prostate cancer.

Your sitemaster is not going to comment on this paper at this time (or on Dr. Barry’s editorial either). He thinks we all need a little time to let the results of this trial “sink in”. What your sitemaster is going to do, however, is thank and congratulate the research team and every single one of the > 400,000 men who participated in this trial for their efforts and their help. This is, as far as your sitemaster is aware, the single largest, best planned, and best executed trial of PSA screening for risk of prostate cancer conducted to date. And it will probably be the last one — if only for financial reasons!

18 Responses

  1. Hello, I am a cancer survivor and had a less invasive, nerve-sparing, robot-assisted, complete radical prostatectomy. Pathology results indicated that all the cancer was contained in the prostate capsule. It was about 6 months from my biopsy when I had the surgery. My PSA was 4.8 and my age was 69 years old and I was referred to a urologist. My Gleason Score was 3 + 4 = 7. This was in December of 2016 and the results of the biopsy gave me an “intermediate risk”.

    I am currently attending a “Man To Man” living with prostate cancer group and one of our new members was diagnosed with prostate cancer recently. His Gleason Score was 3 + 4 = 7, his PSA was 4.2 and his age is 65 years. I do not remember what his “risk factor” was, thinking maybe it was “intermediate”. He has been placed in a group on “active surveillance”.

    I asked my urologist before I had my surgery, could I be considered for “active surveillance”? He said at this time, with my Gleason of 7 (3 + 4) and my PSA of 4.8 with an “intermediate risk”, anything above a Gleason score of, as an example, 3 + 3 = 6 was not considered for “active surveillance”. My question is at this time now in 2018, has the Gleason score of 3 + 4 = 7 “intermediate risk” been reclassified as “low risk”?

  2. Dear William:

    The question of whether some men with intermediate-risk prostate cancer can be well managed on active surveillance (at least for a period of time) has been a controversial one.

    What has happened — and I think it happened in 2015 but I can’t be sure any more — is that the National Comprehensive Cancer Network accepted recommendations that “intermediate risk” be divided into two subcategories, as follows:

    — “Favorable” intermediate risk, which basically means men with a clinical stage of T2b-T2c or a Gleason score of 3 + 4 = 7 (grade group 2) or a PSA level of 10–20 ng/ml and less than 50% of biopsy cores positive for cancer

    — “Unfavorable” intermediate risk, which basically means a clinical stage of T2b-T2c or a Gleason score of 4 + 3 = 7 (grade group 3) or a PSA level of 10–20 ng/mL

    In the case of men with “favorable” intermediate-risk disease, active surveillance is now considered to be an acceptable, initial management option — especially if the patient has clinical stage T1c disease, a PSA of < 10 ng/ml and only a small amount of cancer (such as one or two positive biopsy cores of which only one has a small amount of Gleason 3 + 4 disease).

    So the new member of your group may well be considered, today, as a good candidate for active surveillance.

    Having said that, I have to tell you that if I had been diagnosed with your characteristics back in 2015 and I had only had one or two positive biopsy cores and a small amount of Gleason 3 + 4 disease, I would have simply informed my urologist that I would be going on active surveillance at that time and at that age. Technically, your urologist was probably not wrong in what he told you, and a lot would depend on exactly how many positive biopsy cores you had and how much cancer was in each of those cores.

  3. I would like to know what percent of the men in the control group went on to have a PSA test within, say, the next 6 months, outside of the clinic. Perhaps they were asked to not have a PSA test within a certain time period? I’m guessing there may be a problem in the study design, and I don’t know how to get around it ethically. I assume that PSA testing had to be discussed with all the men in the study before obtaining their consent to participate, whether they were randomized to the PSA clinic or not. This makes them think about PSA and perhaps motivates them to get tested anyway.

  4. Allen:

    See the link to the original information about the study given at the beginning of the commentary. Randomization was not by individual patient. It was by the primary care practice. In other words, all men attending any one of the nearly 600 primary care practices who met the study’s entry criteria either did or did not get invited to go and get a PSA test depending on whether that practice had been randomized as one that offered screening or not. However, anyone who was invited for a PSA test had full power over whether they went for the PSA test or not and, once they attended the testing center, whether they decided to go through with the test or not.

    In many ways I would argue that this was a much more sophisticated form of randomization because it truly randomized patients to “standard care” (i.e., no PSA test) or to the right to decide whether they wanted to have one. You will note that more than half of the men who were given the opportunity to go and have a test did not do so (for whatever reason, which might have been disinterest or sheer laziness).

    You also need to appreciate that in the UK you can’t just walk into a primary care physician’s office and be given a PSA test unless there is some reasonable reason to be given one, and you can’t get to see a urologist without a referral from your primary care physician. Whatever you may think about this as an American who is used to a very different system, this actually allows for a very clear form of randomization as to whether men got screened or not — as opposed to whether they made individual decisions about getting a PSA test purely for risk for prostate cancer.

    There would have been no discussion about the value of the PSA test with men who attended the “standard care” clinics — unless the patient himself brought the subject up, and then if he was given one he wouldn’t have been eligible for participation in the trial. If he wasn’t given one, I think he would still have been eligible.

  5. Thanks for explaining that – I agree that’s a good way of randomizing. So does that mean the controls only got PSA tests after they became symptomatic (eg, getting up several times at night to pee)?

  6. Dear Allen:

    A full description of the original trial design is available on line. Your questions may be answered in that article. I am not going to be able to get to reading it today, sorry.

    I have not seen the full text of the JAMA article. I was going to see if I could get one over the weekend.

    My assumption would be that the men in the control group would have been given a standard PSA test for a whole spectrum of normal reasons that — in addition to the one you mention — might include blood in the urine, a burning sensation on urination, an enlarged prostate on being given a DRE (for whatever reason), etc.

  7. After publication of my Opinion Editorial “The Great Prostate Mistake” in The New York Times (March 10, 2010) I was interviewed by Victoria Lambert, of the Daily Mail, for a May 4, 2010, article “Why Men Shouldn’t Rely on the Prostate Cancer Test” which describes a similar outcome to the conclusions 8 years later by the CAP randomized clinical trial. My 2014 book with Ron Piana, The Great Prostate Hoax: How Big Medicine Hijacked the PSA Test and Caused a Public Health Disaster (Palgrave Macmillan, NY) further documented the uselessness of the PSA test for screening men with prostate cancer. The question I put to those who continue to try to promote the PSA test for screening: What has been accomplished in the last 8 years save for the continued over-diagnosis and over-treatment of men and their decreased quality of life, not to mention the associated costs of both medical management of patients and of costs of running these clinical studies?

  8. The concept of drawing conclusions on the validity of PSA testing on the basis of a single test is anathema to me personally. It is comparable to making a judgement on the health of an entity over a 10-year period on the basis of reviewing a single balance sheet at the start of that period — a snapshot at one point in time. Could anyone looking at Amazon’s balance sheet in 2008 predict the size of the company in 2018?

    I have to ask what the point of this study really is? And before Sitemaster tells me yet again I am missing the point of the study, I am curious whether Allen and others also see the futility in this study?

    We also need a lot more information on how and whether men in both groups were followed for PSA testing. How many subsequently tested their PSA regularly? Does this contaminate the results? I am as suspicious as I was about the US PLCO trial that subsequently determined men randomized not to be tested were in fact testing. Albeit, in defense of this UK trial, that would be a lot harder to do undetected in the UK system.

  9. Dr Ablin:

    Like many men with whom I dialog daily, I am deeply indebted to you for innovating the PSA test for use post-radical prostatectomy. I doubt I would be writing to you today had my elevated PSA not been available as a diagnostic tool. By the same token, I also doubt I would have undergone extensive hormone therapy had my locally advanced disease been diagnosed sooner with an annual PSA test.

    You ask what has been accomplished over the past 8 years w.r.t. PSA testing and its concomitant downside risks. I respectfully point out that we are now testing fewer men for PSA. Controversially, Fleshner et al. indicated in 2016 that, with reduced testing:

    “Rates of prostate biopsy and prostate cancer incidence have declined in unison, with a notable shift towards higher grade, stage and risk upon detection.”

    The “New” Prostate Cancer InfoLink has also commented on this controversy. While it is still early to see trends, there is reason to believe that the reduction in PSA testing will lead to fewer diagnoses, higher later stage and incurable diagnoses, and higher prostate cancer-specific mortality.

    While many of us take your point that “your” test has been misapplied from its original intent, it has saved many lives — including my own. We all agree that the PSA test is far from ideal, but if we restrict its use to diagnose recurrence alone, what do you recommend we use in its place … or should we use nothing and wait until men are symptomatic, invariably resulting in untreatable disease and all too frequently a painful death?

    Critics of the PSA test’s role in screening confound information with treatment. The test does not result in what you describe as “continued … over-treatment of men and their decreased quality of life.” The test only provides information; it is poor communication between the patient and his medical team, not to mention financial conflicts of interest, that prey on fear of the “C” word, that result in over-treatment and wasted costs. This is where many of us believe your criticism based on well-founded abhorrence of over-diagnosis and over-treatment should be focused — not on the PSA test itself.

  10. Rick-

    I think it answers the question, “Is population-based screening a good idea?” Its answer is resoundingly “No.”

    But that doesn’t address other questions about PSA testing:

    • What is the best way to decide whether a man should get a PSA test?
    • How do we insure that only those who need biopsies get biopsied?
    • Should all African-Americans be screened? What about men with a family history?
    • For men who are tested, how should the PSA pattern over time be used?
    • Are there other PSA-based metrics that are more prognostic (e.g., PSA density)?
    • Are there more specific PSA-based blood tests that should be used instead (e.g., PHI, 4KScore, IsoPSA)?
    • Are there other non-PSA-based markers that should be used for screening or testing (e.g., SelectMDx, ExoDx Prostate Intelliscore, PCA3, etc.)?
    • When can BPH be ruled out if PSA is elevated and rising? How should 5-ARIs be used to enhance diagnostic performance?
    • How can prostatitis be ruled out when PSA is elevated and rising?
    • Should DREs be used? How about ultrasound?

  11. Allen:

    I believe you have hit the nail on the head. We have become obsessed with the idea of the PSA test as a mass, population-based “screening” method as opposed to addressing the more sophisticated questions you have laid out, and I am in complete agreement with you.


    Thanks Sitemaster for giving us a chance to weigh in on this study, which I saw elsewhere.

    I can understand the reasons for the design of the study, but as someone with education in statistics and 18 years of experience as a prostate cancer patient, I am appalled by the horrendous effective non-compliance with actual PSA testing. That’s not a design flaw, but it sure is a massive problem in trying to draw meaningful conclusions for this study. I recognize that the randomized invitations were apparently effectively issued, but only 36% of the men invited to screening were actually screened, and then, per the study design, apparently only once, another glaring flaw in a screening program with any hope of being effective.

    It is no wonder at all that there is such a small difference in overall survival and the grossly premature endpoint: a median of only 10 years of follow-up. In fact, while I would like to endorse the conclusion that, per Sitemaster’s report, “The findings to date do not support single PSA testing for population-based screening”, I cannot do so because of the massive “non-compliance”, for starters. That said, it should be clear for other reasons that single snapshot PSA testing is of very limited usefulness compared to a sound testing program. (I’m with you, Rick!) It is noteworthy that proportionately fewer higher-Gleason cancers were found in the so called invitation to screening group.

    Here are just a couple more points of key context.

    Regarding prematurity: While recognizing that this study involves the UK and not the US, in the US a study cut-off of a median 10 years follow-up would be grossly premature because about 99% of US prostate cancer patients are surviving at that point relative to their age mates. In fact, the percentage drops only a few notches at the 15-year point. It follows that what you would be seeing in the US at the 10-year point would likely be only partly due to a single screening and also be due to things like access to health resources and other variables.

    Single snapshot versus sound program: The prostate cancer that we would most like to detect early is the aggressive kind, of course, the kind that leads to low quality of life even if it doesn’t kill. That kind often is characterized by a short PSA doubling time (PSADT), such as less than 15 months. (My own was about 3 to 4 months.) What that means is that many of the prostate cancers we would really like to catch early can be below the radar at a single screening but grow to be really serious in a year, especially within 4 years, the typical window in the European trial where a substantial benefit was found. I am open to the possibility that annual screening, where there is at least a modest basis for concern, may be too close, but I am convinced that 4 years is too loose, based on the doubling times of aggressive cancers. (It does seem that highly favorable baseline profiles justify relaxed screening intervals.) In my own case, it is probable that another year of waiting for that first-ever PSA test, taking doubling at 4 months, would have given me a PSA of 904 at diagnosis (baseline 113; 4 months after baseline, 226; 8 months after baseline, 452; 12 months after baseline, and putative diagnosis, 904).

  13. Dear Jim:

    One of the reasons that I have not made any personal comments about this study until now is that I have been waiting to see what other had to say about it. And I profoundly disagree agree with you because you are looking at this study from entirely the wrong perspective.

    What this study has actually shown us is the following:

    (1) That in a near to perfectly designed, single PSA test-based screening trial for risk of prostate cancer, and despite all the publicity that has tried to persuade us all that mass, population-based PSA testing is imperative if one is to avoid risk of dying of prostate cancer, 74% of men at hypothetical risk in the UK who were offered such a test never went to get one when it was offered.

    (2) Given this utter lack of interest on the part of 74% of the 189,000 or so men to whom the test it was offered, there was no signal that mass, population-based screening for prostate cancer had an impact on risk for prostate cancer at 10 years of follow-up.

    So my question for you has nothing to do with whether mass, population-based screening works or not. My question for you is whether there is any point to the continued attempts to screen men on a mass population basis — which is very different to being willing to give PSA tests to men who want to be tested (for whatever reason).

    I would point out that a true screening trial like this has never, ever been carried out anywhere else in the world, but it wouldn’t surprise me at all to discover that a very typical result of sending a letter or other communication to 100 males aged between 50 and 69 years of age anywhere in the world that offered them a free PSA test would be that only about 35 of them turned up to have a test.

    In other words, the reason that mass, population-based screening for prostate cancer is never going to work is that most healthy men do not see prostate cancer as a significant risk for them personally. The fact that activist prostate cancer patients like yourself may think that this is a terrible thing is, of course, unsurprising. However, this is a critical part of the underlying problem with trying to use a grossly inaccurate test to screen for a disease in which, as you are correct to point out, what we really should be trying to find is the men with or at risk for clinically significant prostate cancer!

    Bad test; most men have little to no interest — and I can entirely understand that perspective. (And I would point out that I am someone who has been having annual health check-ups for most of the past 30+ years, i.e., since I turned 40 years of age. In that entire time I have had thee PSA tests, at my doctors recommendation, for related reasons and never to “screen” myself for risk of prostate cancer.)

    You use the term “non-compliance” in your discussion above. However, there was no “no-compliance”. What there was was utter disinterest on the part of 74% of the 189,000 men who were offered the test. The “failure” of the study to show any benefit was not a consequence of any design factor related to the trial. There was no benefit given the structure of the trial.

    So, let’s say one did the study all over again, and the men randomized (through their physicians’ practices) to testing were offered a test every 2 years for the next 10 years and they were then followed for 20 years. What do you think the “compliance” rate would be then? Is that going to change the number of men who turn up for the PSA tests they are offered but have no interest in having? Or are you suggesting that these 200,000 or so men be required to have a PSA test every 2 years? That sounds like Tuskegee to me!

    It’s high time we all stopped having this silly conversation about the appropriate use of “screening” for risk of prostate cancer with the PSA test. For those who want to have PSA tests, let them. For those who couldn’t care less, they are completely entitled to flip a coin, to say “No thank you”, and to accept that the consequences can sometimes be serious. All we need is a large sign in the doctor’s waiting room that says, “If you are between 40 and 70 years of age and are interested in being tested for risk of prostate cancer, please let the doctor know when you see him/her.”

  14. A Sound Alternative to Mass Population Based Screening

    As always, thank you for your thoughtful reply. I would like to clarify the position toward screening that I’m convinced we should take, and add some points about the study and its impact, particularly the editorial by Dr. Barry in a second post.

    No to mass screening: My impression is that few if any of us who participate in this blog space favor mass population based screening; I certainly do not. While I am convinced that PSA screening is the best existing, practical way to prevent death or a heavy burden from the disease (as when it metastasizes substantially), but I recognize that mass screening would trigger a rush to overtreatment in so many men, often spurred on by their loved ones, who do not understand that prostate cancer that is “the little c” should not be managed like prostate cancer that is “the big C”.

    The solution that makes sense: educate men (and their loved ones) that there is a common form of prostate cancer that is mild and best managed by active surveillance; then, for men who can appreciate that, screening should be encouraged and backed up by sound data as needed for those who want the numbers (not PLCO or the CAP study results on overall survival for sure!). That way, overtreatment can be minimized, and death from prostate cancer or a heavy disease burden can also be minimized.

    When unsound and misinterpreted data are presented by doctors, guidelines groups and health “educators”, as they so often were, as an example, after the New England Journal of Medicine published the severely premature PLCO (which was also severely flawed) and ERSPC trials in 2009, men are going to be misled, and naturally they are going to downplay the value of a PSA test. I have taken some delight in seeing the number needed to invite/screen to avoid one death plummet with each update that added additional years of follow-up. I have taken some satisfaction, with others, in confidently predicting at the time of the 2009 publication that this would happen in the ERSPC. (PLCO was obviously, at least to many of us, a lost cause.)

    Viewpoint for seeing the worth of PSA regarding death and burdensome disease: PSA should be regarded as any of the numerous tests, scans and exams we undergo that address relatively unlikely but potentially severely debilitating or deadly illnesses and conditions that can be effectively prevented or treated. Not testing with PSA is kind of like playing Russian roulette with a 100 chamber revolver. (We can argue about the number of chambers, but this illustrates the concept.) Now that’s a pretty low risk, and arguably the risk is going to be too low for some to be motivated to get the test. However, logically, such a person should also be unmotivated to get a cholesterol test. Again, the risk is fairly low, but you are putting another many chambered revolver to your head an additional time. We can add more tries with the revolver with blood pressure checking (granted, that’s a revolver with a lot fewer chambers), with fasting glucose, with each of the elements of a complete blood count or metabolic panel, etc. Like many of these low-likelihood but high stakes checks, one periodic blood draw that also covers PSA does it all. When you aggregate the risks for each of these elements, the risk level is not so small anymore. If a person looks at it that way – seeing the full risk, they are a lot more likely to be motivated.

  15. Dear Jim:

    I think you are missing the point again. Men are horrible at looking after their health. By comparison with all of the other things they already do to help ensure an earlier than necessary death (smoking, excessive drinking, poor diets, lack of exercise, the list goes on and on … even in the UK), their risk of death from prostate cancer is really very small. We have largely failed to address even the simplest of these.

    The age-adjusted death rate for men in America was ~ 400 per 100,000 in 2015 (1.4 times that of women). The age-adjusted death rate from prostate cancer was ~ 20 per 100,000. Thus the average man in America is about 20 times less likely to die of prostate cancer than he is to die of something else.

    Educating the average American male to understand the value of PSA testing, given that contextual issue, is not going to get us very far. As I said before, if someone wants to have a PSA test to assess their risk for prostate cancer, I am all in favor of letting them have one … but we aren’t going to be able to “educate” our way out of this risk. Most men aren’t listening; they don’t care; and they don’t go to see a doctor until they are sick enough to really need one.

    Do you really think “educating men (and their loved ones)” is going to make a difference to prostate cancer when we have failed with much simpler health challenges?

  16. The Education Challenge

    Once again thank you, Sitemaster, for your thoughtful reply and its important observations. In the last 2 years especially I too have come to have great doubts about the average American male’s capacity to think about unfamiliar issues, and I understand your point that we have failed with much simpler health challenges, the obesity and opioid “epidemics” being just two examples. You certainly put the challenge in perspective!

    But I’m keeping in mind the well-known story of the man who approaches the boy on the beach who is throwing starfish that are stranded on the hot sand, one by one, back into the ocean, rescuing them. The puzzled man considers the multitude of stranded starfish and asks the boy what difference he thinks he is making. The boy chucks another starfish back into the surf and tells the man: “Looks like I made a difference for that one!”

    We can “rescue” people who do have a capacity to care for their health and are trying to do so, but who do not understand some of the risks, including prostate cancer. People who invest time in their own fitness, who read health sections in their newspapers, who subscribe to health newsletters, and their doctors come to mind. (I was one of these people back in the late 1990s when I was getting the message that screening for prostate cancer wasn’t so important, so I did not get screened for several years, and that nearly cost me my life. That’s probably the main reason I find Dr. Ablin’s book so upsetting and dangerous!) And maybe all of these people, once they get the word, can help their less able friends who don’t think so well but are good at other things.

    At least we can do what we can to counter bad information and foster good information, a mission to which you are so effectively dedicated.

  17. Jim:

    I agree … but that’s why the simple answer is the sign in the doctor’s office …

  18. Apparently your sitemaster is not alone in his interpretation of the results of the CAP trial. See this commentary just published on the MedPage Today web site, in which two physicians conclude as follows:

    “On the whole, these findings suggest that most men, after being properly informed, will likely decide that PSA screening is more trouble than it’s worth. Still, we support shared decision making, and believe some appropriately educated men may opt to be screened if they have a strong family history of prostate cancer or another compelling reason to seek screening.”

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