The [U.S. Preventive Services Task Force] policy to stem screening rather than improve upon it disavows the potential benefits of screening and leaves men at risk for delayed diagnosis and poor oncologic outcomes.
Daniel A. Barocas, MD, MPH
In 2012, the U.S. Preventive Services Task Force (USPSTF) issued a recommendation against routine screening for prostate cancer.1,2 The grade D recommendation was considered controversial at the time, and remains so now, because many stakeholders have weighed the same body of evidence and come to different conclusions.
Same Evidence, Different Conclusions
Specifically, there are two large-scale randomized trials that have assessed the survival outcomes of screening vs routine care.3,4 The U.S. trial was a negative study, showing no benefit to screening. However, at least 45% of men in the “usual-care” arm of the U.S. trial had undergone prostate-specific antigen (PSA) testing prior to enrollment, and men in this arm averaged 2.7 PSA tests during the 6-year intervention period of the trial (about 1 every other year).5 This degree of contamination essentially invalidates the trial as a comparison between screening and no screening. Fundamentally, the trial compared regularly scheduled screening with opportunistic screening and found no difference between the two.
The other trial took place in Europe, where screening was much less common, and, consequently, contamination was not significant. They found a 21% to 27% reduction in prostate cancer mortality associated with screening, an effect size comparable to that of mammography and colonoscopy,6,7 and a 30% reduction in metastatic disease.8 Although some critics keyed in on the “high” number needed to screen and the number needed to treat to save a life over the course of the study, these figures are quite reasonable over a lifetime horizon (number needed to screen: 186 to 262; number needed to treat: 2 to 9) and, again, are comparable with other cancer screening measures.5
However, the USPSTF considered the U.S. and European trials as comparably informative. In addition, the USPSTF assessment of the relative benefits and harms of screening used inflated estimates of the harms of screening. For example, the USPSTF used outdated figures for its estimate of mortality following prostatectomy, figures roughly fivefold higher than those found in most modern studies.9 But perhaps most concerning, it grouped the harms of treatment of low-risk cancer among the harms of screening.
To be sure, PSA-based screening has led to an unnecessary surge in the detection and overtreatment of low-risk disease, subjecting men to the harms of treatment without likelihood of benefit. However, the harm associated with overtreatment of low-risk disease could be addressed by promoting active surveillance in appropriately selected patients, rather than withholding screening for all men. Nonetheless, the USPSTF concluded that the harms of mass screening outweigh the benefits and recommended against prostate cancer screening.
Has the Policy Achieved Its Goals?
The availability of cancer registry data allows for ecologic studies of the impact of this major health-care policy—whether the intended goals have been accomplished and whether there have been unintended harms of its implementation. The publication by Jemal et al in JAMA10—reviewed in this issue of The ASCO Post (opposite page)—uses the Surveillance, Epidemiology, and End Results (SEER) database to confirm similar findings published by our group some months prior11 using the National Cancer Database and a similar study from Canada.12
In these studies, one finds that new prostate cancer diagnoses have declined dramatically since the draft guidelines were published in late 2011. Stratified analyses indicate that prostate cancer incidence declined by more than 20% within a year of the draft guidelines, in all strata of disease risk, age, comorbidity, race, and socioeconomic status. In addition, screening rates have declined by 10% or more (absolute decline) since 2008, from between 40% and 50% to between 30% and 35%, depending on age10,13,14 (see review of Sammon et al14 also in this issue of The ASCO Post, page 44). Yet the screening rates remain inappropriately high among American men older than age 75, who are at low risk of prostate cancer death and less likely to benefit from screening than younger men.
In assessing whether the policy has achieved its goals, one can conclude the following: screening rates and the incidence of prostate cancer have declined; the incidence of low-risk prostate cancer (in which the risks of treatment often outweigh the risks of the disease) has declined by 30% or more; and the incidence among older and infirm men has declined significantly, sparing them the harms of treatment when few stand to benefit from it.
On the other hand, one must also recognize that the incidence of intermediate- and high-risk disease has declined nearly as much as low-risk disease and that the delayed or missed diagnoses are as likely to occur among younger, healthier men as they are among older, infirm men. Level 1 evidence clearly demonstrates that treatment (particularly surgery vs watchful waiting) improves overall survival and other oncologic endpoints in the setting of intermediate- and high-risk prostate cancer.15 Thus, under the USPSTF policy, we may be missing opportunities to identify and treat life-threatening prostate cancer. The data are not yet mature enough to demonstrate an increase in the incidence of metastatic disease at presentation or prostate cancer mortality, but the reduction in screening rates and the incidence of localized disease leaves little doubt that we will see the negative impact of this policy upon outcomes in the years ahead.
An additional consideration in assessing the potential harm of this policy is its impact on men at increased risk for prostate cancer and related mortality. African American men bear a disproportionate burden of prostate cancer, with a 65% higher incidence of disease and a more than twofold higher mortality compared with white men.16 The randomized screening trials contain too few African American men to permit accurate estimation of the risk-benefit ratio of screening in this population. Nonetheless, it seems inaccurate to assert that harms outweigh benefits of screening in high-risk populations—at most we can say there is insufficient evidence (grade I). Similar concerns exist for men with a family history, genetic risk, and socioeconomic vulnerability.
Opportunities for Improvement
As a society, what should we do about an imperfect cancer screening test that leads to widespread detection of indolent cancers and treatment associated with significant harm? The lack of specificity of the PSA test and the overtreatment of low-risk cancers are major public health problems that the USPSTF policy attempts to address. However, this policy to stem screening rather than improve upon it disavows the potential benefits of screening and leaves men at risk for delayed diagnosis and poor oncologic outcomes.
There are several opportunities to improve upon the risk-benefit ratio of prostate cancer screening and detection. First, it must acknowledged that in at least some settings, prostate cancer screening is associated with a substantial reduction in prostate cancer mortality.8 Enthusiasm for this potential benefit must be tempered by recognition of the potential harms associated with the poor specificity of the current screening paradigm and the overtreatment of low-risk disease.17,18
Second, the patient must be involved in the decision of whether to pursue screening in a shared decision-making process.19,20 Although the decision-making process may be nuanced and time-consuming, patients and providers must be empowered by the available knowledge and entrusted to work together to identify the approach aligned most closely with the patient’s values, risk factors, and life expectancy.
Third, we must target screening efforts to men most likely to benefit from screening and detection. For example, a life expectancy below 10 years is a clear contraindication to screening, whereas men in the age range in which a survival benefit has been demonstrated (55–69 years) are appropriate candidates for a shared decision-making process around screening. It may be particularly important to engage men at higher-than-average risk (eg, African American men, and those with a family history or a genetic susceptibility) in screening discussions.
Fourth, it is absolutely necessary to make efforts to improve upon the specificity of PSA-based screening, in which only 30% to 40% of biopsies based on an elevated PSA yield a cancer diagnosis (many being low-grade, indolent tumors). Using a screening interval of 2 years instead of 1 year and reducing reliance on PSA velocity are simple examples.19,21 In addition, some tools for deciding whether to biopsy men with an elevated PSA level are already in place, such as nomograms and calculators predicting the likelihood of significant cancer based on PSA level, age, race, family history, and other factors.22,23
Similarly, there are new biomarkers, such as kallikrein panels (4K Score and Prostate Health Index) and urine biomarkers (PCA3 and TMPRSS2-ERG), which improve further upon PSA and existing tools.24 The implementation of these biomarkers as secondary screening tools (or perhaps even primary screening tests) could improve specificity markedly, sparing as many as half of men with an elevated PSA level the need to undergo biopsy. Although we may have some trepidation about delaying or missing diagnoses of significant cancers in a small proportion of patients with such a strategy, it would represent a reasonable compromise to the “screen all and biopsy all” modality of the past and the “screen none and biopsy none” policy of the USPSTF.
Finally, magnetic resonance imaging (MRI) may also play a role in improving the specificity of PSA-based prostate cancer detection.25 Currently valued for its sensitivity for high-grade disease, MRI also demonstrates excellent specificity in the hands of expert readers, markedly reducing the proportion of negative biopsies and the detection of low-grade disease.
As we gain confidence in secondary screening studies (new biomarkers and imaging) through further research and clinical experience, we have the opportunity to address some of the well-founded concerns regarding the poor specificity of the current approach to prostate cancer screening.
A second and equally important goal toward decreasing the harms associated with screening and prostate cancer detection is to reduce overtreatment of low-risk disease. Over the past 20 years, the safety of active surveillance has been demonstrated in large North American cohort studies, with metastases in only 1.5% and disease-specific mortality in 1.3% of men out to 15 years.26 Whereas the USPSTF evidence review considered the harms of overtreatment of low-risk disease an inevitable consequence of screening, emerging evidence indicates rising adoption of active surveillance in the United States.27-29 Furthermore, the data are clear that the benefits of screening accrue even in settings in which up to 45% of men diagnosed by screening undergo initial active surveillance.30
Thus, using participatory decision-making, being strategic about targeting those most likely to benefit from screening, employing secondary screening tests to improve risk stratification and specificity, and promoting active surveillance in appropriate clinical settings could substantially improve the risk-benefit ratio of prostate cancer screening.
The Public Health Impact
Of course, since primary care providers are on the front lines of health-screening activities, their buy-in and education will be critical. However, busy primary care providers are apt to be more responsive to the USPSTF recommendations (particularly those as easy to comply with as a grade D recommendation) than to other sources of information. How to disseminate this message remains a significant challenge. The options include working within the current framework to propose changes to USPSTF or to work more directly with patients, patient advocacy groups, providers, provider groups, health systems, and payers.
We must continue to remain vigilant for any efforts to oversimplify this nuanced topic into a ‘screen all’ or, worse, ‘screen none’ policy.— Daniel A. Barocas, MD, MPH
In addition to the public health issue at hand, there is also an important political issue to address. Namely, the USPSTF is a powerful organization that makes recommendations affecting hundreds of millions of American lives (and its recommendations are often adopted in other nations as well), but it lacks an appropriate degree of stakeholder involvement and oversight. The entire process of developing and implementing the grade D recommendation against screening for prostate cancer took place without input from patient advocates, oncologists, radiation oncologists, or urologists. This process simply must change, and there is currently legislation proposed in both houses of Congress to address these concerns. Individuals can get involved in this issue by voicing their support for the USPSTF Transparency and Accountability Act and by contacting their own representatives and senators.
The public health impact of the USPSTF grade D recommendation against prostate cancer screening could be compounded if it is incorporated into payment models and quality assessment/reporting, as was proposed to the Centers for Medicare and Medicaid Services (CMS) this past year.31 A misguided proposal to make compliance with the grade D recommendation a quality measure was presented by Mathematica Policy Research and CMS for public comment and, through advocacy and public outcry, was defeated. We must continue to remain vigilant for any efforts to oversimplify this nuanced topic into a “screen all” or, worse, “screen none” policy.
Adjusting the intensity of prostate cancer screening and detection efforts to balance potential benefits with potential harms remains a challenge. The USPSTF policy of 2011 to 2012 is associated with large declines in screening and incidence, which undoubtedly reduce the known harms of screening but also its known benefits. There are better ways to improve upon the risk-benefit ratio of screening—shared decision-making, screening only those likely to benefit, using secondary screening tests to improve specificity, and decoupling screening from treatment. The USPSTF policy should be actively opposed to reduce its harmful impact on men’s health. This strategy will entail direct outreach to patients, providers, and payers, as well as advocacy and legislative action. ■
Disclosure: Dr. Barocas reported no potential conflicts of interest.
5. Gulati R, Mariotto AB, Chen S, et al: Long-term projections of the harm-benefit trade-off in prostate cancer screening are more favorable than previous short-term estimates. J Clin Epidemiol 64:1412-1417, 2011.
8. Schröder FH, Hugosson J, Roobol MJ, et al: Screening and prostate cancer mortality: Results of the European Randomised Study of Screening for Prostate Cancer (ERSPC) at 13 years of follow-up. Lancet 384:2027-2035, 2014.
11. Barocas DA, Mallin K, Graves AJ, et al: Effect of the USPSTF grade D recommendation against screening for prostate cancer on incident prostate cancer diagnoses in the United States. J Urol 194:1587-1593, 2015.
12. Bhindi B, Mamdani M, Kulkarni GS, et al: Impact of the U.S. Preventive Services Task Force recommendations against prostate specific antigen screening on prostate biopsy and cancer detection rates. J Urol 193:1519-1524, 2015.
13. Drazer MW, Huo D, Eggener SE: National prostate cancer screening rates after the 2012 US Preventive Services Task Force recommendation discouraging prostate-specific antigen-based screening. J Clin Oncol 33:2416-2423, 2015.
20. Makarov DV, Fagerlin A, Chrouser K, et al: AUA white paper on implementation of shared decision making into urological practice, 2015. Available at https://www.auanet.org/common/pdf/education/clinical-guidance/Shared-Decision-Making.pdf. Accessed March 16, 2016.
31. Non-recommended PSA-based screening, 2015. Available at http://cqrcengage.com/aacu/file/yc3eNmm9F28/CMS-PSA-Quality-Measure_PSA Screening_Framing Document.pdf. Accessed March 16, 2016.