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!

11 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.

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