published online 04 April 2011.
Article Outline
In some respects, prostate-specific antigen (PSA) screening has fallen victim to its own success. From 1990–1991 to 2006, death rates from cancer in general have decreased by 21.0% among U.S. men [1]. Nearly 80% of this decrease in the cancer death rates can be explained by declining mortality rates from lung, prostate, and colorectal cancers. Overall, there has been approximately a 40% reduction in the age-specific prostate cancer mortality rates during the PSA era. In 2010, 32,050 deaths from prostate cancer are projected, compared with approximately 27,360 in 2009 [2]. Although this increase likely reflects an aging population and variability in the model projections, these figures nevertheless demonstrate that prostate cancer continues to represent a major public health threat.
Rather than applauding the progress made in early prostate cancer detection, recent emphasis has been largely focused on concerns regarding overtreatment of screen-detected tumors that would not have caused harm. The purpose of this article is to highlight some of the key pitfalls in this controversy.
(1)Screening itself is not the problem, but may be problematic without careful patient selection. For example, a major problem is inappropriate patient selection for screening. Walter et al. reported that 36% of men aged ≥85 years in the worst health underwent PSA testing [3]. If applied to the wrong patient population, there is no doubt that screening will unearth tumors unlikely to cause symptoms during life and engender more harm than good. However, when applied judiciously to men with a long life expectancy, the true benefits of screening may be realized. For example, in the Goteborg randomized screening trial with a median age of 56 years, Hugosson et al. reported a 44% relative reduction in prostate cancer-specific mortality with screening compared with controls with a 14 year (median) follow-up [4].
(2)The benefits of screening cannot be realized without appropriate follow-up. In the U.S. Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO), there was no difference in prostate cancer-specific mortality between the “screening” and “control” groups with 5 to 6 years (median) of follow-up [5]. However, a minority of men from the screening group with abnormal screening results underwent prompt prostate biopsy [6]. Among men with an abnormal PSA result, the cumulative probability of biopsy was 34% to 41% at 1 year. An even lower 19% to 22% 1-year probability of prostate biopsy was reported for men with a suspicious DRE and normal PSA. At the same time, there was heavy prescreening in the U.S. (>40% of participants were screened within 3 years of study entry, and nearly 10% had 2 or more PSA tests), as well as correspondingly high rates of opportunistic PSA testing in controls during the study period (“contamination”). Since most screenees did not get prompt biopsy, and >50% of controls got screened, it is not surprising that the trial failed to show a difference in mortality between the groups.
(3)The full mortality benefit of screening is not realized until well beyond 10 years. In the European Randomized Study of Screening for Prostate Cancer, Schroder et al. reported that PSA reduced prostate cancer-specific mortality by 20% at 9 years in the intent-to-treat analysis [7]. However, the authors reported that 1,410 men needed to be screened (NNS) and 48 needed to be treated (NNT) to prevent 1 prostate cancer death at a median follow-up of 9 years. However, due to the lengthy natural history of screen-detected prostate cancer, the survival curves in the screening and control arms had just begun to separate at 7 to 8 years follow-up. Our research group subsequently developed a statistical model to project the NNT in the ERSPC over longer follow-up using extrapolated data [8]. By 12 years, only 503 needed to be screened and 18 treated to prevent 1 prostate cancer death. In the Goteborg randomized prostate cancer screening trial, the number-needed-to-treat was only 12 to prevent a prostate cancer death at a median of 14 years follow-up [4], which compares favorably with breast cancer screening (NNT = 10 to prevent 1 breast cancer death with mammography at 10 years). It is also noteworthy that NNT is somewhat of a misnomer in that not all men diagnosed with prostate cancer undergo definitive treatment.
(4)Reduced mortality is not the only benefit of screening. Within the ERSPC, screening led to a 41% reduction in metastatic disease at diagnosis in the intent-to-treat analysis [7]. In a follow-up study, Van Leeuwen et al. compared the screening arm from the Rotterdam section of the ERSPC with the population of northern Ireland where screening is rare [9]. In this analysis, screening was associated with a relative risk for 0.47 (95% CI, 0.35–0.63, p < 0.001) “for metastatic disease” compared with the non-screening control population. Overall, metastatic prostate cancer has a profound impact on quality of life, with limited treatment options. Accordingly, a reduction in metastatic disease—not just mortality—through screening should also be considered as a critical endpoint.
(5)Diagnosis does not mandate treatment. In the aforementioned Goteborg study, screening was associated with a substantial mortality benefit despite the fact that 30% of men with screen-detected cancers remained on active surveillance at last follow-up [4]. As was eloquently stated by Dr. Joseph Smith Jr., “Treatment or non-treatment decisions can be made once a cancer is found but not knowing about it in the first place surely burns bridges” [10]. In addition, treatment itself continues to evolve, with considerable ongoing advances in both surgery and radiation therapy. As the morbidity of treatment continues to decrease, the risk to benefit ratio of early prostate cancer diagnosis will continue to improve.
(6)Screening protocols continue to evolve. Both randomized trials of PSA screening used the total PSA level to determine the need for biopsy [5], [7]. Although serum PSA levels reflect the full spectrum of prostate cancer risk, several adjunctive PSA-based measures may further increase the specificity of screening for clinically significant prostate cancer [11]. In particular, PSA velocity has been shown to predict the risk of life-threatening prostate cancer >10 years prior to diagnosis at a time when total PSA levels were low [12]. More recently, there is investigation on the incorporation of PSA isoforms (such as [-2]proPSA) into screening protocols [13]. The future holds considerable promise, as we learn more about the ability of these and other markers to enhance the specificity of screening for clinically significant prostate cancer.
In summary, there is finally level 1 evidence proving that PSA screening saves lives and reduces the burden of metastatic disease [4], [7]. Judicious patient selection for screening, informed management decisions after diagnosis, and continuing refinements in prostate cancer treatment are all important strategies that will maximize the benefits and minimize the potential harms of prostate cancer screening in the future.
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