Wednesday, December 12, 2012

Cancer epidemiology 101 for urologists (and others)

I've had many Twitter conversations with prostate cancer screening advocates who fear that the U.S. Preventive Services Task Force's "D" (don't do it) recommendation against PSA-based screening for prostate cancer will lead to a dramatic spike in prostate cancer deaths as primary care physicians screen more selectively, or perhaps stop screening at all. I seriously doubt these apocalyptic forecasts (for one thing, prostate cancer causes only 3% of deaths in men, and the decline in the U.S. prostate cancer mortality rate since 1990 hasn't had any appreciable effect on overall life expectancy). However, I recognize that reasonable people disagree with my review and the USPSTF's interpretation of the evidence. The American Cancer Society, for example, continues to support screening if men are adequately informed of the known risks and uncertain benefits. But it's one thing to argue from evidence, and quite another to argue from ignorance. Many of the tweets I've seen from urologists, unfortunately, represent the latter.

When I went to medical school, biostatistics and epidemiology was the course that no one took seriously. Things have changed for the better over the years - today I teach a rigorous course in evidence-based medicine and population health at Georgetown University School of Medicine - but there's still an appalling lack of basic knowledge about these topics among practicing physicians of all specialties. Below are a few key concepts in cancer epidemiology that anyone should understand before getting into a dispute about the value of prostate cancer screening.

Lead-time bias - "Prostate cancer survival has improved since we started PSA screening, so screening must work!" The first clause of this sentence is absolutely true: in the 1970s, about 70 percent of men diagnosed with prostate cancer were still alive 5 years after diagnosis, while today that figure is closer to 99 percent. The second clause could be true, but does not invariably follow from the first. By finding prostate cancers in men long before they become symptomatic (if they ever become symptomatic), screening advances the time of diagnosis, but could have no impact on mortality. In other words, 5-year survival always increases when a screening test is implemented, but its effect might only be giving patients an earlier cancer diagnosis without affecting their disease course. See chest x-ray screening for lung cancer (which was unfortunately a common practice for years) for an example of this phenomenon.

A variation on the above statement is the observation made by older urologists that "Before PSA testing, we used to see men with prostate cancer only when they came in with metastatic disease; today we see them with much less advanced tumors so that they can be cured." Much of this clinical experience reflects the effect of lead time, as well as overdiagnosis of cancer that didn't need to be found in the first place. In the words of urologic oncologist Willet Whitmore, "For a patient with prostate cancer, if treatment for cure is necessary, is it possible? If possible, is it necessary?"

Association does not equal causation - "Prostate cancer mortality has declined by 30 percent since 1990, which must be due to PSA screening." It's tempting to make sweeping conclusions based on observational data - the press has been doing this forever, linking caffeine use to cancer today, then reversing itself when a new headline is needed tomorrow. It's certainly possible that some of the decline in mortality is due to screening, but it's just as likely that some other factor is responsible. For example, men who smoke are less likely then male non-smokers to die from prostate cancer. Does that mean that tobacco use has a protective effect? Of course not; these men are dying prematurely from heart attacks and chronic obstructive pulmonary disease, and therefore not dying of prostate cancer. Also, the temporal association between the mortality decline and the PSA screening doesn't make any sense, since the only randomized trial to show that PSA screening reduces prostate cancer mortality (more on this later) found that it takes at least 9 years to do so. Since PSA screening was not widespread in the U.S. until the early 1990s, any benefit of screening wouldn't have changed the mortality statistics until 2000. But that's not what happened.

The most favorable study represents "the truth" - "Prostate cancer screening reduces prostate cancer mortality by 20 percent." If you only speak to urologists, you might come away thinking that there's only been one randomized trial of PSA screening: the European Randomized Study of Screening for Prostate Cancer (ERSPC), which reported this result in 2009 and again in 2012 after 11 years of follow-up. The usual description of the ERSPC as a single "trial" is problematic (it's actually a combined analysis of screening results from 7 European countries), but even allowing for that, it's only one of 5 randomized trials of screening, and (guess what?) the only one of the 5 to show a benefit.

In the old days, the process of writing reviews and guidelines went as follows: write up recommendations that you already know to be correct from clinical experience, then go to the literature to select evidence that supports your positions. A less biased approach is to evaluate all of the available evidence, regardless of one's preexisting biases, which is what my colleagues and I did and what independent reviewers did for the both the Cochrane Collaboration and BMJ. Here's what the Cochrane reviewers concluded: "Prostate cancer screening did not significantly decrease all-cause or prostate cancer-specific mortality in a combined meta-analysis of five RCTs."

Specialist-authored guidelines are superior to generalist-authored guidelines - "The USPSTF guidelines are invalid because there were no urologists on the panel." Let's put aside for the moment the fact that more prostate cancer diagnoses invariably lead to more business for urologists, and that guidelines authored by specialty societies are of lower quality than those authored by generalists. Dismissing the USPSTF recommendation on the basis of its primary care membership is still nonsense, pure and simple. The vast majority of prostate cancer screening occurs in primary care settings, and therefore primary care clinicians are the most appropriate experts to evaluate and weigh the evidence about screening. (The same can be said about mammography guidelines and radiologists.) Several urologists were, of course, consulted at multiple stages during and after the writing of our evidence review to make sure that no important studies were missed.

As I've said, I welcome debates with well-informed advocates of PSA screening, who tend to view this imperfect test as a glass half-full rather than half-empty (or shattered beyond repair). For the less-informed, I get it that you don't have time to go back to medical school for remedial epidemiology lessons. So consider this post your Cliff's Notes.


  1. "'s one thing to argue from evidence, and quite another to argue from ignorance".
    You betcha. When you argue from ignorance, you don't have to worry about those pesky facts getting in your way!

  2. Agree! But to be clear, I'm not calling out all urologists here, and primary care physicians can be just as clueless when it comes to benefits and harms of cancer screening. Although earlier this year I had promised myself that I would stop giving talks on PSA testing (, it seems that the message just isn't getting through. Test first, ask questions later remains the default prostate cancer screening strategy, which continues to drive up health costs and lead to thousands of unnecessary procedures and suffering. Meanwhile, the focus on prostate cancer crowds out discussions about the many other preventable causes of morbidity and mortality in men. Make me want to get back up on that soapbox again.

  3. What then can be done to detect Prostate Cancer or doesn't it exist anymore?

    Could we fully trust that a negative family history, adecuate diet and exercise, can fully free us from it? Rectal exams, that are not carefully done and not al lthe time,and usually don't reach the most frequent location of the initial tumor in the prostate and need of an examiner well trained to be able to differentiate between an enlarged smooth organ and the lumpy hard or the one with a hard area that can be more telltale. the call of the EMR can distract the physician that also has to ask for symptoms that direct him in the direction of benign Prostatic Hypertrophy. Keep in mind, that like teenagers that refuse testicular exams,a number of patients do the same with the Digital Rectal exam.

    What is then left? Why not to improve the value of the idea of the PSA? I believe an step in the right direction can be to consider the result of the free fraction of it, or combine this one with other biomarkers of PC tissue, there is a test being tried the Prostate Health index that uses these principles. The Scandinavians and Dutch have developed at least 3 different examples.

    I am 72, worry me, a simple ignorant retired pediatrician that several Urologists that I know talk about equivocal results of the screen for risk factors or mention the case of the negative DRE in patients with cancer of the prostate already invading the capsule. To do an MRI of the prostate could be defining, but because cost and difficulty has to be selective, one of the test that I mentioned, could perhaps help. What do you think?.

    1. While I readily agree with Dr Lin's view that there is way too much test-first-question-later going on, I think an unfortunate byproduct of recent discussions has been to equate testing with the PSA (and to equate any PSA testing with blind/stupid PSA testing), when there are finally many efforts going on to find good ways of testing, whether those involnve PSA, PCa3, or any number of genetic markers.