The U.S. Preventive Services Task Force (USPSTF) recently issued a recommendation statement advising against the use of prostate-specific antigen (PSA)-based testing for prostate cancer,1 leaving many in the oncology community concerned that decades of clinical progress will be stalled, and setting the stage for another contentious debate in the ongoing controversy over the clinical value of PSA testing. To bring clarity to this important issue, The ASCO Post spoke with several prostate cancer experts and with the Chair and Co-Chair of the Task Force.
Trial Data Pushed Early Recommendation
The Task Force is an independent panel of federally appointed primary care providers who are experts in prevention and evidence-based medicine. After reviewing pertinent scientific data, the panel assigns one of five letter grades to its recommendations, which include “suggestions for practice.” The recent recommendation assigned PSA testing a D grade, which advises providers to “discourage the use of this practice.”
Michael L. LeFevre, MD, Co-Chair of the Task Force, explained that the recommendations are updated about every 5 years unless important data points to an earlier revision. “The reason we updated the 2008 recommendation statement ahead of schedule on PSA screening was because of the U.S. Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial and the European Randomized Study of Screening for Prostate Cancer (ERSPC). After we saw the data, we decided it was time to take another look at PSA recommendations.”
After examining the PLCO and ERSPC trials and other current literature, the Task Force concluded that although there may be benefits associated with routine screening, they were outweighed by the harms. “We found that most of the men who were treated would have lived just as long and as well without the diagnosis and treatment,” said Dr. LeFevre.
Asked about the blanket “regardless of age” clause in the recommendation, Dr. LeFevre responded, “That goes back to the 2008 statement, in which we gave a D rating to screening men aged 75 years and above, recommending against it. The ‘regardless of age’ means that given the latest data, we could not find any age in which the benefits outweighed the harms in PSA screening,” he said.
“The Task Force is charged with making recommendations about what preventive services are most likely to benefit the health of Americans, and the scientific evidence we reviewed sends a different message about PSA screening than the widely held belief that PSA-driven early detection of prostate cancer is a lifesaver with insignificant harms,” said Dr. LeFevre.
Decline in Mortality Misleading
According to Task Force Chair Virginia A. Moyer, MD, MPH, the argument that the drop in prostate cancer mortality over the past decades is largely due to PSA-driven early detection is misleading. “We actually don’t have a solid explanation for the decline in mortality. PSA advocates believe that we should be paying attention to the Göteborg study,2 which shows that if there is benefit, it begins to accrue at about 9 years. However, the decline in prostate cancer mortality began around 1993, at the same time the widespread use of PSA began. If the decline were a result of screening, you would expect to see the curve drop around 2003, but it occurred in 1993. While there may be some benefit in PSA tests, the numbers don’t bear out the theory supporting screening for the decline in mortality,” said Dr. Moyer.
“The bottom line is that science tells us that at most, there is a very small benefit and a significant harm associated with routine PSA screening. Frankly, mass screening is a disaster for the U.S. health-care system, and thoughtless screening in the office is not much better,” said Dr. Moyer. She emphasized that screening should never be initiated without a thoughtful conversation that explains the potential benefits and harms. “Before a man goes ahead with PSA screening, he needs to be fully aware of what he’s getting into, and currently that is not how it’s being done.”
Uneven Evidence For Recommendation
According to Anthony V. D’Amico, MD, PhD, Chief, Genitourinary Radiation Oncology, Brigham And Women’s Hospital, the Task Force’s analyses misread the reality of the disease. “Using the European study, the Task Force found that the absolute benefit (not a hazard ratio) of PSA screening saves only 1 life out of 1,000. That is not the statistic we should use, because screening for prostate cancer with PSA can show a signal of benefit within the first decade, but if you’re screening men in their 40s and 50s who have a life expectancy of 30 to 40 years, the benefits will be multiplied over several decades. So, to perform a risk-vs-reward analysis at a 10-year or 13-year time point is really more of a cost-minded way of looking at the data, not a clinician’s,” said Dr. D’Amico.
Dr. D’Amico continued, “The Task Force has acknowledged that PSA works, but they’re saying that the benefit isn’t large enough to justify the costs to the health-care system, along with the potential toxicities in men who undergo unnecessary screening-induced treatments.”
Commenting further on unnecessary treatment-associated toxicities, Dr. D’Amico said, “The side effects of prostate cancer treatments, such as erectile dysfunction and incontinence, can be clinically managed, but once a man dies we cannot bring him back to life, nor should we discount the suffering he and his family sustain along the road to death. More thought is needed when weighing potential toxicities against potential death.”
Dr. D’Amico stressed that prostate cancers can have a protracted course, and the Task Force’s recommendation is based on studies with follow-up that is too short to make definitive statements about PSA screening benefits during a 40-, 50-, or 60-year-old man’s lifetime. In addition, longer follow-up is needed to assess overdiagnosis-associated toxicities, he asserted.
“The PIVOT study of radical prostatectomy vs active surveillance has followed men for about a decade, the same as the screening studies, which is not long enough to ensure that a healthy man diagnosed and treated in his 40s, 50s, or 60s is going to escape metastasis and death from prostate cancer. Moreover, given the known sampling error associated with prostate biopsy, there is no proof that very low-risk prostate cancer has no meaningful risk for metastatic potential,” commented Dr. D’Amico. The Task Force acknowledged that the European study showed a 21% reduction in death and that the U.S. study had significant flaws, notably a high contamination rate (ie, 85%), he added.
Addressing the potential impact on access, Dr. D’Amico said, “If Medicare adopts the Task Force’s recommendation and stops reimbursing for a screening PSA, large private insurers might follow, creating a health-care disparity problem among financially challenged populations and, in particular, men known to be at high risk for aggressive and life-threatening prostate cancer—namely, men of African American, Latino, or Hispanic heritage. This is an important issue, with huge downstream consequences that need to be identified and addressed,” said Dr. D’Amico.
Stratifying Risk
Judd W. Moul, MD, FACS, Director of the Duke Prostate Center, voiced concern that the Task Force’s blanket recommendation against PSA testing limits clinical flexibility in a disease with multiple biologic behaviors. “I think the new American Urological Association (AUA) guidelines that, for example, recommend a risk-stratified PSA test at age 40, make sense, because there’s evidence that baseline PSA measurements in certain age groups can predict aggressive prostate cancers, metastases, and disease-specific mortality years down the road. Over the past few years, we’ve learned how to better use PSA as a risk-assessment tool, which the Task Force didn’t consider. So, I’m concerned that this policy might harm at-risk groups of men.”
Dr. Moul pointed to emerging nuances in the use of PSA testing that escaped the Task Force. “If a 40-year-old man has a baseline PSA of less than 1 ng/mL, that dictates a low future risk of prostate cancer, he can probably go on 5-year testing intervals. On the other hand, a 40-year-old with a PSA greater than 1.5–2.5 ng/mL should be followed more closely. Data from two randomized trials paint too narrow a picture of the value of PSA, especially in risk assessment,” said Dr. Moul.
Experts agree that men with low-volume, low-risk disease have been aggressively overtreated, but Dr. Moul warned against unintended consequences of the recommendation. “President Obama had a screening PSA test as part of his annual physical at Walter Reed earlier in 2012. Presumably, he was counseled on the pros and cons of testing and chose to be tested. Wouldn’t it be a shame if that choice was now taken away from other American men,” said Dr. Moul. He added that using PSA as a risk-stratification tool will reduce the amount of overdiagnosis and help detect potentially aggressive cancers.
“Prostate cancer is viewed as a disease of older men, many of whom might die of other causes. However, when you factor in the human and financial costs of metastatic disease, it would be best not to return to a pre-PSA era,” said Dr. Moul.
Middle Ground Needed
“The major urological associations argue that PSA plays a valuable role in early detection. However, other factions contend that mass screening does not provide adequate results based on the number of tests needed to detect one cancer. Both opinions have valid points. What we need is to find common ground,” said E. David Crawford, MD, who presented a study at the recent AUA Annual Meeting on the potential implications of the USPSTF recommendations against PSA screening.
Using the PLCO Cancer Screening Trial, Dr. Crawford and associates estimated the clinical and economic effects of increasing the current 1-year PSA screening interval by 1 to 4 years. They found significant financial savings, particularly for the 5-year screening interval, with an estimated national savings of $3.9 billion. However, when factoring in the amount of missed prostate cancers, the investigators concluded that a “no screening” policy would be a bad investment on the societal level.
“The ultimate goal is to detect and treat only those prostate cancers that will kill men. I began my career in an era when most men walked into the clinic with advanced disease. We simply don’t see that today and I think the Task Force is missing the precise economic impact of treating advanced prostate cancer. We should continue to screen, but in a rational manner that uses PSA to separate out high-risk from low-risk patients, and we should screen at appropriate intervals.”
Dr. Crawford made it clear that policymakers should consider both the risks and benefits of the USPTF recommendations on prostate cancer screening. “Hopefully, this study will help find common ground to employ PSA in a cost-effective and thoughtful manner that saves lives. The USPSTF findings should be used as an opportunity to begin that process,” said Dr. Crawford.
Recommendation Reconsidered
After reviewing data from several randomized clinical trials, the Task Force concluded that PSA screening benefits do not outweigh the harms. Further, they resolved that mass PSA screening is deleterious to our health-care system and should therefore be discouraged. Nevertheless, the Task Force’s recommendation begs the question: What are the societal consequences of a sea change in the detection and diagnosis of a disease with an estimated 240,000 new cases per year?
Dr. D’Amico countered that prostate cancers can have a protracted course and the follow-up studies that the Task Force used for its risk-to-reward analysis were too short; he also pointed out flaws in the studies. Dr. Moul added that the data analyzed by the Task Force missed the nuanced potential of PSA, such as a risk-assessment and stratification, warning about unintended consequences of a one-size-fits-all approach to screening.
Dr. Crawford concluded that a “no screening” policy would markedly decrease prostate cancer health expenditures but would be a bad investment at the societal level. He advised a more rational policy, screening appropriate men and treating only those with significant cancers, adding that the USPSTF findings should be viewed as an opportunity to help resolve the important debate over PSA screening for prostate cancer. ■
Disclosure: Drs. LeFevre, Moyer, D’Amico, and Moul reported no potential conflicts of interest. Dr. Crawford is an advisor for Felling (also an employee), Janssen, Dendreon, Bayer, and Amgen; and an investigator for Precision Biopsy.
References
1. U.S. Preventive Services Task Force: Screening for prostate cancer: Current recommendation. Available at www.uspreventiveservicestaskforce.org/prostatecancerscreening.htm. Accessed June 7, 2012.
2. Hugosson J, Carlsson S, Aus G, et al: Mortality results from the Göteborg randomised population-based prostate-cancer screening trial. Lancet Oncol 11:725-732, 2010.
