In this population-based study of 380 prostate cancer deaths and 380 matched controls, we found no evidence that PSA screening, as used clinically in the 1990s, reduced prostate cancer mortality. In view of the widespread use of PSA screening and the morbidity, expense, and worry experienced by patients needing biopsies and surgery related to screening, this result is disturbing. Case-control studies have successfully identified the benefits of fecal occult blood screening and colonoscopy for colon cancer17–19
, cytological screening for cervical cancer20,21
, and mammography for breast cancer22
Our results are nearly identical to those found by Concato et al. using a similar population-based, case-control design11
. Both their study and this one use “ever screened” as the metric of exposure, rather than tabulating screening in specific short intervals before diagnosis. This is important because screening can affect the date of diagnosis. In a patient with preclinical prostate cancer, the occurrence of screening has a high probability of leading to the diagnosis. Such patients will usually not have been screened in the years immediately before diagnosis because had they been tested earlier, the diagnosis would likely have been made then. Tabulating screening as ever/never largely avoids this problem.
Interpretation of a third case-control study of PSA screening is complicated by this issue. Kopec et al.12
found no difference in the proportion of cases and controls that had ever been screened, in agreement with the negative findings cited above. However, these authors apparently counted PSA tests in controls during the period of clinical suspicion in the cases and also stratified their analysis of PSA tests by time period before diagnosis in a manner that likely overweighted the experience in prior years when a deficit of screening in the cases was to be expected. These procedures produced an adjusted result showing a benefit of screening that we believe may have been spurious.
The most significant potential limitation of all the observational studies is in determining what constitutes a “screen”. Some PSAs identified in medical records with little documentation may be interpreted as a screen when, in fact, they may have been ordered for suspicion of cancer or for urinary symptoms related to early cancer. However, three investigators blinded to case/control status reviewed all PSAs done within 6 months of the index case’s date of clinical suspicion (or the comparable time for the control). We obtained very similar results using different thresholds for classifying a PSA as a screen, and the PSA frequencies of our controls were similar to those reported in the New Jersey BRFSS. However, it is still possible we missed some PSAs. If more PSAs were missed in controls than in cases, the study results would be biased against the efficacy of screening. This seems unlikely as we directly interviewed controls about providers who might have ordered a PSA, whereas for cases, we relied on other medical records and the spouse to identify providers. We only counted documented PSAs. The impact of excluding non-married subjects on ascertainment of PSA screens is unknown.
The confidence intervals are wide, and although a lower 95% bound of 0.76 includes a possible protective effect of 24%, we believe that the consistency of the point estimates around unity makes a protective effect less likely. We chose prostate cancer-specific mortality as our outcome. Overall mortality is also a relevant outcome in a population of men with prevalent comorbidity and the possibility of misclassification of the cause of death and the increased potential for treatment side-effects. However, using all-cause mortality as an outcome may make it difficult to show an effect of screening because the majority of these men will die of comorbidity rather than prostate cancer.
Evidence supporting the efficacy of PSA screening has been limited to date. Although the benefit of prostatectomy has been demonstrated for early prostate cancer, the studies thus far have depended on traditional, clinical detection of prostate cancer9,10
. One would expect that most of the cases in the randomized trial of surgery vs watchful waiting9
would have been detected by a PSA screen (had it been commonly used in the source population), but such screening would also have detected many slowly progressive cases. Many cases would not be expected to benefit from surgery thus diluting the overall benefit. Indeed, a competing risk analysis of watchful waiting for men diagnosed with prostate cancer in the pre-PSA era has demonstrated that for low and moderate grade tumors (Gleason
6), the risk of dying from the disease within 15 years is small23
Two randomized studies on PSA screening are still a few years away from completion24,25
. However, the results of the case-control studies suggest that any benefit of PSA screening identified in these trials is likely to be modest. Pending results from the trials, a conservative stance on PSA screening seems justified26,27
. Even if PSA testing is shown to have a modest, protective effect on mortality from prostate cancer, it will still be incumbent on the clinician to help the patient understand the trade-offs of this imperfect test. The high rates of prostate cancer incidence and mortality in black men and the protective odds ratio found for these men in the current study (albeit not statistically significant), may argue for more liberal use of testing in that group, but this needs further study with a larger sample size. We, along with others, await better methods for detecting prognostically ominous forms of this ubiquitous cancer.