Serum Prostate-Specific Antigen for the Early Detection of Prostate Cancer: Always, Never, or Only Sometimes?

VOLUME NUMBER FEBRUARY J OURNAL OF C LINICAL O NCOLOGY E D I T O R I A L S Serum Prostate-Specific Antigen for the Early Detection of Prostate Cancer: Always, Never, or Only Sometimes? Peter R. Carroll, Jared M. Whitson, and Matthew R. Cooperberg, University of California at San Francisco, San Francisco, CA See accompanying articles on pages 355 and 464 Few medical stories have attracted the interest of the media and generated as much confusion and controversy as the issue of prostate- specific antigen (PSA) testing for the early detection of prostate cancer. This story has been building for years, reflecting the widespread use of PSA testing in many developed countries, the ambiguity regarding its benefits, and the uncertainty as to what constitutes the best form of treatment (including nontreatment) for virtually all stages of disease. The recently updated best practice statement of the American Urolog- ical Association recommends that men be counseled regarding the option of PSA testing beginning at age 40 years. 1 Guidelines of other organizations vary markedly in their enthusiasm; the US Preventive Services Task Force guideline—which primary care providers con- sider the most influential 2 —is the most overtly hostile to screening. 3 The controversy reached a head in 2009 when two screening studies with disparate results were published simultaneously in the New England Journal of Medicine. In the PLCO trial (Prostate, Lung, Colorectal and Ovarian Can- cer Screening), men in the United States were randomly assigned to annual PSA screening or usual care; investigators reported that the cumulative risk of death as a result of prostate cancer at 7 to 10 years was low in both screened and unscreened men and did not differ significantly between them. 4 Seven years of follow-up (or even the 10 years of follow-up that two thirds of the cohort received) may still be too short a time to observe a difference, given the long natural history of prostate cancer. Moreover, the high prevalence of pre-enrollment screen- ing and heavy contamination of the control group by PSA screening, togetherwithalowrateoffollow-upbiopsiesamongmenwhocrossedthe predefined PSA threshold of 4.0 ng/mL, 5 severely limited the ability of this study to test the hypothesis fairly, even with longer follow-up. In the ERSPC trial (European Randomized Study of Screening for Prostate Cancer), men in seven countries were randomly assigned to screening at 2- or 4-year intervals, with biopsy thresholds ranging from 2.5 to 4.0 ng/mL. This was a larger study than PLCO, with longer follow-up and much less contamination among control patients, and it demonstrated that screening was associated with a 20% relative risk reduction in prostate cancer–specific mortality. 6 Furthermore, a follow-up analysis demonstrated that with adjustment for compliance with screening in the ERSPC trial, the reduction in mortality rose substantially to 31%. 7 The hazard curves in the ERSPC trial only Journal of Clinical Oncology, Vol 29, No 4 (February 1), 2011: pp 345-354 began to diverge approximately 7 years into the trial; thus, with longer follow-up, the observed benefit of screening would likely be addition- ally magnified. However, the risks of prostate cancer overdetection (ie, detecting a cancer that otherwise would not progress to clinically significant disease during the lifetime of an individual) are substantial and were well highlighted in the ERSPC trial. The authors estimated a number needed to screen (NNS) of 1,410 and number needed to treat (NNT) of 48 to avoid one death as a result of prostate cancer. 6 However, the NNT to avoid metastases was only 24. Because metastases are a har- binger of death resulting from prostate cancer, the absolute risk reduction in prostate cancer–specific mortality between the screened and control arms would presumably become more favorable with time. Two articles in this issue of Journal of Clinical Oncology add some clarity to prostate cancer screening, although they do not resolve all the controversy. Crawford et al 8 reanalyzed the data from the PLCO study, stratifying the analysis by comorbidity and thereby testing the hypothesis that men in good health are those who benefit from early detection strategies. Although other comorbidity scales exist, the au- thors define a comorbid condition as one that could increase the risk of dying as a result of a cancer other than prostate or of cardiovascular disease (leading competing risks of death for US men between ages 55 and 74 years). Minimal comorbidity, according to the definition of Crawford et al, was observed in 35.7% of those in the trial. Consistent with current practice, healthier men were more likely to receive cura- tive rather than noncurative treatment (including androgen depriva- tion therapy). Of note, the analysis did not adjust for this difference in treatment aggressiveness between groups. Perhaps not surpris- ingly, a significant decrease in the risk of prostate cancer–specific mortality was observed in those with few or no comorbidities (hazard ratio, 0.56; P ⫽ .03). The NNS and NNT were 723 and five, respectively. By contrast, among men with more comorbidities, there existed a trend toward an increase in prostate cancer–specific mortality with intensive screening compared with usual care (hazard ratio, 1.43; P ⫽ .08). The authors correctly point out that because analysis was performed post random assignment, the findings are hypothesis generating, and the risks of overdetection and overtreatment remain important issues. Loeb et al 9 reanalyzed the data from the ERSPC trial, noting that although NNS and NNT are useful statistics, they are time dependent; therefore, reporting values at one point in time can be misleading. © 2010 by American Society of Clinical Oncology Information downloaded from jco.ascopubs.org and provided by at UCSF Library on July 29, 2016 from 128.218.42.131 Copyright © 2011 American Society of Clinical Oncology. All rights reserved.