Age and PSA level at initial testing may significantly impact prostate cancer-specific mortality

In early 2009 the European Randomized Study of Screening for Prostate Cancer (ESRPC) reported a reduction of 20 percent in prostate cancer-specific mortality in a screened cohort of men aged between 55 and 74 years of age — as opposed to an unscreened cohort with the same age constraints. Median follow-up of patients in this study had been for 9 years as of December 31, 2006. Further analysis suggested that the mortality benefit might actually be as high as 30 percent after adjustments for contamination in the unscreened cohort and non-attendance of patients in the screening arm of the study.

What the ERSCP could not do, however, was provide insight into patient risk based on individual PSA levels at the time of initial diagnosis. This was because blood samples were not collected from the men in the unscreened cohort of men in the ERSPC trial at the time of randomization to the trial. (In other words, we did not know the baseline PSA for all the men in the study, prior to a diagnosis.)

A new article by van Leeuwen et al., published today in Cancer, provides us with insights into the relative outcomes of men who were screened or not screened for prostate cancer and the impact of their PSA level on their outcome at the time of diagnosis. The article is based on the analysis of data from two cohorts of men:

  • An “intervention” cohort, comprising 43,987 men (aged between 55 and 74 years) of age from the Netherlands, Sweden, and Finland who participated in the national screening cohorts of the ERSCP
  • A “clinical” cohort, comprising 42,503 men (also aged between 55 and 74 years of age) from Northern Ireland who had a first PSA test between January 1994 and December 1999 and whose PSA was < 20.0 ng/ml.

There was no systematic use of the PSA test to identify early-stage prostate cancer in Northern Ireland during this time period. However, data in the Northern Ireland Cancer Registry made it possible to identify data from all routinely performed PSA tests carried out after 1994 and subsequently to identify those patients who had an actual diagnosis of prostate cancer and those who died of their disease.

The primary purpose of the research was to explore whether it was possible to categorize men by risk at baseline (based on their age and their PSA level) into groups that required no further PSA tests because their risk of prostate cancer-specific mortality was minimal, and groups who has a significant risk for prostate cancer-specific mortality and should be encouraged to undergo continued testing and early treatment if necessary. We should also be very clear that this study is a restrospectivce data analysis and not a randomized clinical trial.

The paper contains a great deal of highly detailed information. We shall restrict this report to the major results provided by the authors, and we should emphasize that these results are based on access to the full text of the article, not just the abstract:

  • The men in the intervention group were younger than the men in the clinical group (median ages of 61 and 65 years respectively).
  • Median baseline PSA levels were lower in the intervention group than in the clinical group (1.18 vs. 1.60 ng/ml, respectively).
  • The vast majority of the men in both groups had initial PSA levels of between 0.0 and 1.99 ng/ml
    • 32,035/43,987 (72.8 percent) in the intervention group
    • 25,555/42,503 (60.1 percent) in the clinical group
  • Prostate cancer was diagnosed in 4,339 men (9.9 percent) in the intervention group and 1,522 men (3.6 percent) in the clinical group.
  • Men diagnosed with prostate cancer in the intervention group were younger than men diagnosed with prostate cancer in the clinical group (median ages of 66 and 71 years, respectively).
  • Median PSA levels at the time of diagnosis of prostate cancer were lower in the intervention group than in the clinical group (5.0 vs. 12.8 ng/ml, respectively).
  • By the end of 2006, the overall mortality rate was 25.5 percent in the clinical group and 14.5 percent in the intervention group.
  • By the end of 2006, the prostate cancer-specific mortality rate was 0.6 percent in the clinical group and 0.2 percent in the intervention group.
  • The prostate cancer-specific mortality rates increased with increasing baseline PSA level in both groups
  • The prostate cancer-specific mortality rate for men with an initial PSA level of < 2.0 ng/ml was 0.05/10,000 person-years.
  • The prostate cancer-specific mortality rate for men with an initial PSA level of between 10.0 and 19.99 ng/ml was 8.88/10,000 person-years.

The bottom line to this study is that for men aged between 55 and 74 years of age, a PSA value of < 2.0 ng/ml was associated with almost no risk for prostate cancer-specific mortality at up to 12 years of follow-up and that for men with a PSA value of < 4.0 ng/ml the risk for prostate cancer-specific mortality was only minimally higher (also at 12 years of follow-up).

Now the authors are very careful to point out that “longer follow-up is needed to provide clinical recommendations.” This is a justifiable reservation. We probably need a median 20 years of follow-up (as opposed to the roughly 9.0 years in this study) to know whether this statistical result translates into an actual clinical recommendation. What is very evident at the present time, however, is that there is a massive difference between the numbers of patients who need some form of work-up to establish a diagnosis (i.e., a biopsy and other tests) and the number of men who need to be treated to save a life within 12 years if you take patient age and PSA levels into consideration at the time of an initial PSA.

Here are the data from the number needed to investigate (the NNI) and the number needed to treat (NNT) per life saved:

  • For men with a PSA < 2.0, the NNI was 24,642 and the NNT was 724.
  • For men with a PSA between 2.0 and 3.99, the NNI was 2,393 and the NNT was 427.
  • For men with a PSA between 4.0 and 9.99, the NNI was 492 and the NNT was 152.
  • For men with a PSA between 10.0 and 19.99, the NNI was 133 and the NNT was 60.

At its bluntest, this means that (based on up to 12 years of follow-up), 13,517 men between 55 and 74 years of age with a PSA of < 4.0 ng/ml would need at least a biopsy and 553 of those men would need to be treated to save a single life, and all of those men would be at risk for the harms of prostate cancer diagnosis and treatment.

Someone may want to suggest that The “New” Prostate Cancer InfoLink is downplaying the value of screening for prostate cancer. What we are actually doing is reporting the data published by the research community. But it is certainly a fair question for every man of 55-74 years of age and a PSA of < 4.0 ng/ml whether he wants to have treatment for prostate cancer based on a 553 to 1 chance that treatment will actually affect his long-term survival, and given the well-known side effects of treatment. We do believe that these data add emphasis to the value of expectant management as a method of caring for men with low-risk prostate cancer.

13 Responses

  1. At least in Europe they are having a healthy debate about how PSA should be used. It seems that what we read here in the US is opinion that PSA should not be done.

  2. If you are referring to the piece in the New York Times over the weekend, let’s be clear. That is non-medical opinion (inclusive of Richard Ablin, who is not a clinician). Even Dr. Brawley doesn’t think we should throw out the PSA test. He “just” thinks it is over-used.

  3. I completely agree that a man needs to consider whether he wants to follow up the diagnosis and whether to be treated or not, but in the absence of better markers, one MUST have a PSA test to decide if he is in the 724 NNT or the 60 NNT group.

    Isn’t that so?

  4. That is certainly true. But for the 5 out of every 6 men who will never get diagnosed with prostate cancer (as opposed to the 1 in 6 who will), the first question that needs an answer is, “How frequently does one need that PSA test?”

  5. How do you know if you get diagnosed or not if you don’t take a PSA test?

    Bear in mind that people do blood tests all the time, e.g. to check their cholesterol level. I can’t see the inconvenience of doing a PSA test once a year. The question is what do you do with the results? When do you decide to have a biopsy? When does a biopsy trigger a more drastic treatment such as surgery or radiation?

  6. Reuven:

    No one is saying people shouldn’t have a PSA test, but people at no known risk for heart disease do not get cholesterol tests “all the time.” I do, but then I have had a heart attack. I still don’t advocate that everyone else over 40 years of age should have a cholestrol test every year if they have no other known risk. And heart disease has a far higher risk for mortality (about 6 times as high) as prostate cancer. As I have said before, the question is how often should a man with no known risk for prostate cancer get a PSA test. There are costs associated with all of this — and they run into the billions per annum.

  7. Just my opinion … The PSA test is not over used. The information from a PSA may be misused, but it is a helpful test. The overall problem is education not “over-diagnosis”, which I first heard from Dr. Brawley. In fact even the term “over-diagnosis” can be dangerous to some men who grasp the PSA debate information incorrectly.

  8. I can only repeat what i said yesterday — we still have to address how to diagnose the 20,000-30,000 men initially diagnosed with high risk disease. M<any of these men, myself included, do not identify as an at-risk group, though some clearly do.

    The sitemaster and I have debated the issue of costs before. I am not sure where the "billions" comes from, nor what costs it includes; costs are more than just that of treatment. Neither am I sure whether the sitemaster has considered the full social costs of failing to test high-risk men; there are social and economic costs associated with their treatment and their loss of life — is this sum greater or less than the medical cost of adminstering the PSA test on a widespread basis?

    How many lives saved make it worth spending "billions" on PSA testing and its repercussions?

    I do not know the answer, but it is a valid question for study — and if we throw out "billions" as a cost of administering the test, we should know how that compares to the costs of NOT testing. This is the essence of cost-benefit analysis.

  9. I am 82 years old. … My doctor just checked my prostate and said it is very small. However, my PSA has gone from 4.2 ng/ml 5 years ago to 7.9 ng/ml. … Any comments on this?

  10. Dear Bill,

    There are all sorts of reasons why your PSA might have risen by this amount over 4 years. However, this is by no means a rapid increase in your PSA.

    You could ask about a biopsy, but it does not seem particularly likely that a man with a PSA level that has taken 4 years to (roughly) double from 4.2 to 7.9 ng/ml is at any great risk for clinically significant prostate cancer. On the other hand, if your family history is one in which most of the males live well into their 90s, then you might want to talk to your doctor some more about this because the real issue is your long-term life expectancy and whether a slow grown of cancer in your prostate could become problematic over time.

  11. Hmmm … All relatives on mother’s side lived into 90s except her mother, who died of cancer in her late 40s. … All relatives on father’s side died in their 60s except father’s mother, who lived to be 87?

  12. No one ever said this sort of decision is simple!


  13. One aspect of looking at risk and benefit is the benefit from treatment in preventing the need for long-term hormone therapy.

    Having been a physician experiencing both eras (screened and not screened) and treating the disease as a specialist for 25 years, I can tell you that long-term hormone therapy is no picnic and mortality is not the only consideration for treatment. Patients with late disease will almost certainly need long-term hormone therapy. Two personal examples are my Dad and his best friend, both with prostate cancer.

    My dad was treated with seeds and never had a recurrence. His best friend was treated with external beam radiation therapy and failed almost immediately. Both men lived for longer than 15 years. By mortality consideration they both did exactly the same. However my Dad’s friend had a much worse life because he was on hormone therapy forever, and it wrecked many aspects of his life. Be aware that the Goteborg study, which followed patients much longer than the poor American study, showed a dramatic improvement in mortality with screening.

Leave a Reply

Fill in your details below or click an icon to log in: Logo

You are commenting using your account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s

This site uses Akismet to reduce spam. Learn how your comment data is processed.

%d bloggers like this: