In this article, the authors have done an excellent job in reviewing recent findings regarding prostate-specific antigen (PSA) and other methods for the early detection of prostate cancer. This is a fast-moving field, with new results being reported on a weekly basis. Indeed, it is an exciting time to be conducting research in prostate cancer. At the same time, however, it is far too easy to lose sight of some of the basic principles by which we should judge evidence to make research or clinical decisions. Specifically, there are hard-learned epidemiologic lessons about which we need to constantly remind ourselves.
In this article, the authors have done an excellent job in reviewingrecent findings regarding prostate-
specific antigen (PSA) and other methods for the early detection of prostatecancer. This is a fast-moving field, with new results being reported ona weekly basis. Indeed, it is an exciting time to be conducting researchin prostate cancer. At the same time, however, it is far too easy to losesight of some of the basic principles by which we should judge evidenceto make research or clinical decisions. Specifically, there are hard-learnedepidemiologic lessons about which we need to constantly remind ourselves.
Source Population Variables
The first of these is to keep in mind the patient population to whichwe are trying to draw inference. Results can vary from study to study dependingon the source population. As a consequence, comparing results from studieswith markedly different source populations may be likened to comparingapples and oranges. For example, studies of the characteristics of serumPSA determinations conducted in urology practices can provide importantinferences about similar populations. Nevertheless, it is likely that theproportion of men with benign prostatic hyperplasia (BPH) or prostatitiswould be greater in these practices than in the general population. Becauseserum PSA levels are elevated with either of these noncancerous conditions,the distribution of serum PSA levels would be different in studies basedon these practices than in the general population. As a consequence, thespecificity of this test for any given serum PSA level would most likelybe much worse in a urology practice than in a screening program conductedin the general population. Thus, the results of any study evaluating thediagnostic characteristics of serum PSA determi nations, free PSA determinations,PSA messenger RNA, human kallikrein 2, or any other marker must take intoaccount the appropriate target population.
The second point I wish to raise concerns the predictive power of apositive or negative test. The predictive power is a function of not onlythe diagnostic characteristics of the test (sensitivity and specificity)but also the prevalence of the undiagnosed condition (prostate cancer)in the source population. Consequently, for a given sensitivity and specificity,the predictive value of a positive test will be greater in populationswith a higher prevalence or lower in populations with a lower prevalence.
This becomes more complicated when the diagnostic characteristics ofa test change as a function of the population setting. As noted above,the specificity of serum PSA determinations decreases in a urology practicewhen those determinations are compared to the general population. Likewise,the prevalence of prostate cancer will differ between these two groups.Consequently, judgmental statements about levels of predictive value ofa positive test become extremely difficult to interpret without knowledgeof the prevalence of the disease in the target population.
This latter aspect was highlighted in our recent publication describingthe test characteristics of serum PSA determinations in the community setting.In this paper, we discuss the trade-off in sensitivity and specificityfor serum PSA determinations in the diagnosis of prostate cancer in population-basedcases of prostate cancer from Olmsted County vs controls from the OlmstedCounty Study of Urinary Symptoms and Health Status among Men. The receiver-operator-receiver-operator-characteristic(ROC) curve that summarizes the predictive power of the test demonstratedan area under the curve of 0.94. This is much greater than the area underthe curve for practice-based studies (Figure1). This shows why an evaluation of PSA based on a urology practicemay indicate a need for better markers; whereas from a population perspective,total serum PSA levels are powerful indicators in the diagnosis of prostatecancer in the community setting. In fact, there is little room left forimprovement with the additional knowledge gained by measuring free PSA.Unfortunately, many of the studies that have reported the ROC curves forthe addition of free PSA did not provide a summary curve that includedall the information (a negative test for total PSA levels less than 2.5ng/mL or positive test for serum PSA level greater than 10 ng/mL) givenby the testing cascade. Nevertheless, these results suggest that we alreadyhave extremely powerful tools for detecting prostate cancer in the population.
Finally, while it is clear that we can detect prostate cancer, it isnot so clear that we should be detecting all cases of prostate cancer.Some of those opposed to general screening point to the disparity betweenincidence and mortality rates. For example, for 1997, the American CancerSociety projects that 334,500 men will be diagnosed with prostate cancerand 41,800 will die from the disease. Those opposed to screening pointto the known probability of side effects in some proportion of the menfor whom no treatment should have been undertaken. Consequently, it isdisappointing to see that efforts are still being directed towards findingall prostate cancers. Rather, it seems that it would be more importantto identify those men with prostate cancer in whom the lack of treatmentwould result in death or a decrement in quality of life and not identifythose for whom treatment is unnecessary or futile.
In summary, these are exciting times in prostate cancer research. Thepace at which we are accruing knowledge is fantastic. We do, however, needto remain mindful of how to interpret and use this information as it becomesavailable.
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