Dr. Ron’s Research Review – March 16, 2011

This week’s research review focuses on an article about the controversy over PSA screening tests. This is a complicated issue. Here are some relevant quotes.

The debate over prostate cancer tests. By Chris Woolston, Los Angeles Times, Link

There's a growing fear that PSA testing ends up harming far more men than it helps.

Some men choose to skip the test. Richard Ablin of Tucson is 70 and has never had his PSA checked. Not once. And it's not because he's uninformed. Quite the opposite: He's the scientist who discovered PSA more than 40 years ago.

The recent controversy followed an article published in NEJM that compared usual care and annual screening. After 7 to 10 years of follow-up, the rate of death from prostate cancer was very low and did not differ significantly between the two study groups. (Andriole, Crawford et al. 2009)

A recent meta-analysis concluded that the existing evidence from randomized controlled trials does not support the routine use of screening for prostate cancer with prostate specific antigen with or without digital rectal examination. (Djulbegovic, Beyth et al. 2010)

Two recent studies, however, found benefit in PSA screening tests in Europe and Sweden.

European men who received annual PSA tests were 20% less likely to die of prostate cancer than those who weren't tested. (Schroder, Hugosson et al. 2010)

A 2010 follow-up of this study that tracked more than 19,000 Swedish men for 14 years suggested that screening reduced cancer deaths by 44%. (Vickers, Cronin et al. 2010)

Dr. Ron


PSA Abstracts

© 2011

Mortality results from a randomized prostate-cancer screening trial

            (Andriole, Crawford et al. 2009) Download

BACKGROUND: The effect of screening with prostate-specific-antigen (PSA) testing and digital rectal examination on the rate of death from prostate cancer is unknown. This is the first report from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial on prostate-cancer mortality. METHODS: From 1993 through 2001, we randomly assigned 76,693 men at 10 U.S. study centers to receive either annual screening (38,343 subjects) or usual care as the control (38,350 subjects). Men in the screening group were offered annual PSA testing for 6 years and digital rectal examination for 4 years. The subjects and health care providers received the results and decided on the type of follow-up evaluation. Usual care sometimes included screening, as some organizations have recommended. The numbers of all cancers and deaths and causes of death were ascertained. RESULTS: In the screening group, rates of compliance were 85% for PSA testing and 86% for digital rectal examination. Rates of screening in the control group increased from 40% in the first year to 52% in the sixth year for PSA testing and ranged from 41 to 46% for digital rectal examination. After 7 years of follow-up, the incidence of prostate cancer per 10,000 person-years was 116 (2820 cancers) in the screening group and 95 (2322 cancers) in the control group (rate ratio, 1.22; 95% confidence interval [CI], 1.16 to 1.29). The incidence of death per 10,000 person-years was 2.0 (50 deaths) in the screening group and 1.7 (44 deaths) in the control group (rate ratio, 1.13; 95% CI, 0.75 to 1.70). The data at 10 years were 67% complete and consistent with these overall findings. CONCLUSIONS: After 7 to 10 years of follow-up, the rate of death from prostate cancer was very low and did not differ significantly between the two study groups. (ClinicalTrials.gov number, NCT00002540.)

Screening for prostate cancer: systematic review and meta-analysis of randomised controlled trials

            (Djulbegovic, Beyth et al. 2010) Download

OBJECTIVE: To examine the evidence on the benefits and harms of screening for prostate cancer. DESIGN: Systematic review and meta-analysis of randomised controlled trials. DATA SOURCES: Electronic databases including Medline, Embase, CENTRAL, abstract proceedings, and reference lists up to July 2010. Review methods Included studies were randomised controlled trials comparing screening by prostate specific antigen with or without digital rectal examination versus no screening. Data abstraction and assessment of methodological quality with the GRADE approach was assessed by two independent reviewers and verified by the primary investigator. Mantel-Haenszel and inverse variance estimates were calculated and pooled under a random effects model expressing data as relative risks and 95% confidence intervals. RESULTS: Six randomised controlled trials with a total of 387 286 participants that met inclusion criteria were analysed. Screening was associated with an increased probability of receiving a diagnosis of prostate cancer (relative risk 1.46, 95% confidence interval 1.21 to 1.77; P<0.001) and stage I prostate cancer (1.95, 1.22 to 3.13; P=0.005). There was no significant effect of screening on death from prostate cancer (0.88, 0.71 to 1.09; P=0.25) or overall mortality (0.99, 0.97 to 1.01; P=0.44). All trials had one or more substantial methodological limitations. None provided data on the effects of screening on participants' quality of life. Little information was provided about potential harms associated with screening. CONCLUSIONS: The existing evidence from randomised controlled trials does not support the routine use of screening for prostate cancer with prostate specific antigen with or without digital rectal examination.

Lead time and overdiagnosis in prostate-specific antigen screening: importance of methods and context

            (Draisma, Etzioni et al. 2009) Download

BACKGROUND: The time by which prostate-specific antigen (PSA) screening advances prostate cancer diagnosis, called the lead time, has been reported by several studies, but results have varied widely, with mean lead times ranging from 3 to 12 years. A quantity that is closely linked with the lead time is the overdiagnosis frequency, which is the fraction of screen-detected cancers that would not have been diagnosed in the absence of screening. Reported overdiagnosis estimates have also been variable, ranging from 25% to greater than 80% of screen-detected cancers. METHODS: We used three independently developed mathematical models of prostate cancer progression and detection that were calibrated to incidence data from the Surveillance, Epidemiology, and End Results program to estimate lead times and the fraction of overdiagnosed cancers due to PSA screening among US men aged 54-80 years in 1985-2000. Lead times were estimated by use of three definitions. We also compared US and earlier estimates from the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer (ERSPC) that were calculated by use of a microsimulation screening analysis (MISCAN) model. RESULTS: The models yielded similar estimates for each definition of lead time, but estimates differed across definitions. Among screen-detected cancers that would have been diagnosed in the patients' lifetimes, the estimated mean lead time ranged from 5.4 to 6.9 years across models, and overdiagnosis ranged from 23% to 42% of all screen-detected cancers. The original MISCAN model fitted to ERSPC Rotterdam data predicted a mean lead time of 7.9 years and an overdiagnosis estimate of 66%; in the model that was calibrated to the US data, these were 6.9 years and 42%, respectively. CONCLUSION: The precise definition and the population used to estimate lead time and overdiagnosis can be important drivers of study results and should be clearly specified.

Screening and prostate-cancer mortality in a randomized European study

            (Schroder, Hugosson et al. 2010) Download

BACKGROUND: The European Randomized Study of Screening for Prostate Cancer was initiated in the early 1990s to evaluate the effect of screening with prostate-specific-antigen (PSA) testing on death rates from prostate cancer. METHODS: We identified 182,000 men between the ages of 50 and 74 years through registries in seven European countries for inclusion in our study. The men were randomly assigned to a group that was offered PSA screening at an average of once every 4 years or to a control group that did not receive such screening. The predefined core age group for this study included 162,243 men between the ages of 55 and 69 years. The primary outcome was the rate of death from prostate cancer. Mortality follow-up was identical for the two study groups and ended on December 31, 2006. RESULTS: In the screening group, 82% of men accepted at least one offer of screening. During a median follow-up of 9 years, the cumulative incidence of prostate cancer was 8.2% in the screening group and 4.8% in the control group. The rate ratio for death from prostate cancer in the screening group, as compared with the control group, was 0.80 (95% confidence interval [CI], 0.65 to 0.98; adjusted P=0.04). The absolute risk difference was 0.71 death per 1000 men. This means that 1410 men would need to be screened and 48 additional cases of prostate cancer would need to be treated to prevent one death from prostate cancer. The analysis of men who were actually screened during the first round (excluding subjects with noncompliance) provided a rate ratio for death from prostate cancer of 0.73 (95% CI, 0.56 to 0.90). CONCLUSIONS: PSA-based screening reduced the rate of death from prostate cancer by 20% but was associated with a high risk of overdiagnosis. (Current Controlled Trials number, ISRCTN49127736.)

Prostate specific antigen concentration at age 60 and death or metastasis from prostate cancer: case-control study

            (Vickers, Cronin et al. 2010) Download

OBJECTIVE: To determine the relation between concentrations of prostate specific antigen at age 60 and subsequent diagnosis of clinically relevant prostate cancer in an unscreened population to evaluate whether screening for prostate cancer and chemoprevention could be stratified by risk. DESIGN: Case-control study with 1:3 matching nested within a highly representative population based cohort study. SETTING: General population of Sweden taking part in the Malmo Preventive Project. Cancer registry at the National Board of Health and Welfare. PARTICIPANTS: 1167 men aged 60 who provided blood samples in 1981 and were followed up to age 85. MAIN OUTCOME MEASURES: Metastasis or death from prostate cancer. RESULTS: The rate of screening during the course of the study was low. There were 43 cases of metastasis and 35 deaths from prostate cancer. Concentration of prostate specific antigen at age 60 was associated with prostate cancer metastasis (area under the curve 0.86, 95% confidence interval 0.79 to 0.92; P<0.001) and death from prostate cancer (0.90, 0.84 to 0.96; P<0.001). The greater the number for the area under the curve (values from 0 to 1) the better the test. Although only a minority of the men with concentrations in the top quarter (>2 ng/ml) develop fatal prostate cancer, 90% (78% to 100%) of deaths from prostate cancer occurred in these men. Conversely, men aged 60 with concentrations at the median or lower (</=1 ng/ml) were unlikely to have clinically relevant prostate cancer (0.5% risk of metastasis by age 85 and 0.2% risk of death from prostate cancer). CONCLUSIONS: The concentration of prostate specific antigen at age 60 predicts lifetime risk of metastasis and death from prostate cancer. Though men aged 60 with concentrations below the median (</=1 ng/ml) might harbour prostate cancer, it is unlikely to become life threatening. Such men could be exempted from further screening, which should instead focus on men with higher concentrations.


References

Andriole, G. L., E. D. Crawford, et al. (2009). "Mortality results from a randomized prostate-cancer screening trial." N Engl J Med 360(13): 1310-9.

Djulbegovic, M., R. J. Beyth, et al. (2010). "Screening for prostate cancer: systematic review and meta-analysis of randomised controlled trials." BMJ 341: c4543.

Draisma, G., R. Etzioni, et al. (2009). "Lead time and overdiagnosis in prostate-specific antigen screening: importance of methods and context." J Natl Cancer Inst 101(6): 374-83.

Schroder, F. H., J. Hugosson, et al. (2010). "Screening and prostate-cancer mortality in a randomized European study." N Engl J Med 360(13): 1320-8.

Vickers, A. J., A. M. Cronin, et al. (2010). "Prostate specific antigen concentration at age 60 and death or metastasis from prostate cancer: case-control study." BMJ 341: c4521.