Clinical and Health Affairs
Prostate Cancer Screening
Issues and Controversies
By Matthew O’Shaughnessy, M.D., Ph.D., Badrinath Konety, M.D., M.B.A., and Christopher Warlick, M.D., Ph.D.
Abstract
Prostate cancer is the second leading cause of cancer death among men. Because it has been thought that identifying the disease earlier leads to better outcomes, there has been a great deal of interest in screening for the disease. Since the late 1980s, testing for elevated prostate-specific antigen (PSA) levels in blood has been the most prominent screening tool. Despite widespread adoption of PSA testing, however, it remains controversial. It has been shown that elevated PSA levels do not always indicate cancer and low PSA levels do not ensure that cancer is absent. In addition, there has been conflicting evidence about whether definitive treatment of prostate cancer is always indicated. As a result of the conflicting evidence on the efficacy of PSA testing as a screening tool and the necessity of treatment of prostate cancer in all cases, national organizations have issued various guidelines for screening. Thus, the decision to screen or not to screen remains in the court of the individual patient and physician. This article reviews the current thinking about PSA testing, highlights relevant research findings, and discusses possible changes to screening and treatment that may appear in the near future.
Prostate cancer is the second leading cause of cancer death in men in the United States. Nearly one in six American men will be diagnosed with prostate cancer during their lifetime, and about one in 35 will die from the disease.1 This year, more than 217,000 men in the United States will be diagnosed with and 32,000 will die of prostate cancer.1 The incidence varies by race, with African-American men diagnosed at a rate approximately 1.5 times the rate in Caucasians. The Minnesota Department of Health reported more than 4,100 new cases of prostate cancer in Minnesota in 2008.2
After the advent of widespread prostate-specific antigen (PSA) screening in the late 1980s, the incidence of prostate cancer increased rapidly (by about 10% per year) from 1986 until 1992, when it peaked at 237.2 new cases per 100,000 men (Figure).1 Following this peak, the number of new cases per 100,000 dropped by approximately 10% per year for three years, and the incidence has since remained at approximately 150 cases per 100,000 men per year. Analysis of age-specific data on prostate cancer incidence between 1986 and 2005 reveals a number of trends. There has been a decreased incidence in men 80 years of age and older, little change in men ages 70 to 79 years, and dramatic increases in men 69 years of age and younger.3 Furthermore, there has been dramatic stage migration at the time of diagnosis. Currently, only 4% of men are diagnosed with locally advanced disease compared with 12% before the advent of PSA screening.4 Similarly, the percentage of patients presenting with metastatic disease has decreased from 14% to 3% since the advent of PSA screening.5
A rise in prostate cancer mortality initially followed the rise in incidence. Since the early 1990s, the mortality rate has steadily declined (approximately 2% to 4% annually) (Figure).1 Multiple factors including PSA screening, improved efficacy and broader application of definitive therapy, and increased use of hormone therapy for advanced prostate cancer have likely contributed to this decline.
Despite its widespread adoption, PSA screening remains controversial. Until recently, there was limited evidence suggesting that it was effective at reducing the risk of death from prostate cancer. This led to various professional medical organizations issuing conflicting policy statements regarding PSA screening. Further complicating the debate is the fact that definitive therapy for prostate cancer (the natural end of prostate cancer screening) carries with it a risk of significant side effects such as incontinence and erectile dysfunction that can negatively affect a man’s quality of life without necessarily improving his chance of survival. The recent publication of the results of two randomized controlled trials to determine the efficacy of PSA screening have served to ignite anew the controversy regarding the utility of PSA screening.6,7 This debate is occurring in scientific publications as well as in the lay press. Consequently, patients and physicians continue to receive mixed messages. This article highlights some of the existing evidence relevant to the debate, reviews current screening recommendations, and discusses the future of prostate cancer screening.
PSA as a Screening Tool
Prostate cancer screening typically includes measurement of a serum PSA level and a digital rectal exam (DRE). Prostate- specific antigen is a member of the kallikrein serine protease family. It is secreted in high concentrations from prostate cells into seminal fluid, where it is involved in liquefaction of semen, and it is normally found in low concentrations in blood. An abnormal result of either test leads to a recommendation for needle biopsy of the prostate. This is currently the most common method of detecting prostate cancer in the United States, accounting for more than 80% of diagnoses. The remainder of prostate cancers are diagnosed when men present with symptoms of locally advanced or metastatic disease (urinary obstruction, hematuria, back pain, bone pain, or involuntary weight loss) or incidentally in surgical specimens from procedures such as transurethral resection of the prostate performed for urinary obstruction.
A significant limitation of using PSA to screen for prostate cancer stems from the fact that elevated serum levels of PSA can result from a number of common nonmalignant conditions including benign prostatic hyperplasia, prostatitis, transurethral instrumentation, or urinary retention. Because of this, screening results in a relatively low cancer-detection rate. For men with normal digital rectal exams and a PSA between 4 and 10 ng/mL, the likelihood of detecting cancer on a prostate biopsy is approximately 25%.
Further insight into the performance of PSA as a screening test can be gained through analysis of secondary endpoints from the Prostate Cancer Prevention Trial.8,9 This study randomized nearly 19,000 men aged 55 years and older with a normal DRE and PSA level less than 3.0 ng/mL to receive finasteride (a 5-alpha reductase inhibitor that may reduce prostate cancer risk) or a placebo for seven years. Men in both groups underwent PSA testing and biopsy at the end of the study. Of 5,587 men in the placebo group with a PSA level less than 4.0 ng/mL, 21.9% were diagnosed with prostate cancer. Twenty-five percent of these subclinical prostate cancers were intermediate or high-grade (Gleason 7 or higher). Furthermore, prostate cancer was even detected in approximately 6% of men with PSA values between 0 and 0.5 ng/mL. Data from this study have been used to calculate sensitivity (the likelihood that if cancer is present, the PSA test will be abnormal) and specificity (the likelihood that if cancer is not present, the test will be normal) characteristics of the PSA test for a range of PSA cut-off values. Using a PSA cutoff of 1.1 ng/mL provided sensitivity of 83.4% and specificity of 38.9%. Increasing the cut-off point to 2.1, 3.1, or 4.1 ng/mL reduced the sensitivity of the test to 52.6%, 32.2%, and 20.5% and increased the specificity to 72.5%, 86.7%, and 93.8%, respectively. Thus, two important observations become evident: There is no PSA level below which there is no risk of prostate cancer; and the risk of prostate cancer increases with increasing PSA levels. As such, the appropriate threshold value can be set depending on whether the purpose is to maximize sensitivity or specificity. Attempts to improve the sensitivity and specificity of PSA testing have included adding analysis of the percent of free PSA in human serum, PSA velocity or doubling time, and PSA density (PSA value divided by the prostate volume measured by transrectal ultrasound), and use of age-specific cut-offs. No consensus exists on the optimal use of these additional tests.
Overdiagnosis and Overtreatment
Although prostate cancer is the second leading cause of cancer death in men in the United States, most prostate cancer demonstrates an extended natural history, which results in most men dying with their prostate cancer and not because of it. Autopsy studies have detected subclinical prostate cancer in men in their 20s, with prevalence increasing with age such that nearly half of men in their 70s have at least a single focus of prostate cancer.10,11 Given the large reservoir of subclinical prostate cancer and the lack of specificity of PSA levels for cancer, many are concerned that screening for PSA may detect many cancers that would have remained clinically silent during a man’s lifetime in the absence of screening (in other words, PSA screening leads to overdiagnosis).
A recent study estimated that more than 1.3 million men in the United States have been diagnosed with prostate cancer and 1 million have undergone definitive treatment because of PSA testing.3 Models estimate the rate of overdiagnosis as ranging from 23% to 66% of all screen-detected cancers.12,13 Furthermore, up to 29% of prostate cancers detected by screening have a low likelihood of progression based on pathological review of surgical specimens (criteria include low-grade and low-volume cancer).14 This suggests many men with low-risk disease undergo what may be unnecessary definitive therapy.15 In an observational study of 1,886 men with localized prostate cancer, 310 (16%) met criteria for very low-risk disease, but only 28 (9%) of them chose surveillance.16
Further complicating matters is evidence showing that definitive therapy improves prostate cancer survival in non- PSA-screened populations. Bill-Axelson et al. reported on a randomized trial of observation versus surgery in men diagnosed in the absence of PSA screening.17 At 12 years of follow-up, there were prostate cancer deaths in 12.5% of the surgery group compared with 17.9% of the observation group for a relative risk of 0.65. Of note, the survival advantage of the surgical arm of the study was restricted almost entirely to men younger than 65 years of age, suggesting that older men may not benefit as readily from definitive therapy. However, one must use caution when interpreting this finding, as the number of men older than 65 years of age in this study was small and the study was not intended to assess the benefits of surgery versus observation relative to the age of the patient. Similarly, a survival advantage was noted in men undergoing treatment (surgery or radiation therapy) versus observation in an analysis of Medicare patients, all of whom are by definition older than 65 years.18 A report from the Connecticut Tumor Registry on 13-year outcomes after treatment for clinically localized prostate cancer in 1,618 patients who underwent surgery, external beam radiation, or observation found that men who had surgical treatment had significantly higher prostate- cancer-specific survival than men who received radiation therapy or observation regardless of whether they had low-, intermediate-, or high-risk disease.19 Thus, there is an advantage to definitive therapy over observation for many men, and this would support the use of a screening test that can detect cancer earlier, when there may be a higher likelihood of cure. Furthermore, one cannot ignore the 2% to 4% annual decrease in prostate cancer mortality that has been observed since the early 1990s. Although PSA screening alone is certainly not responsible for this trend, mathematical models estimate that between 45% and 70% of this effect is the result of PSA screening.13
Prostate Cancer Screening Trials
Two large randomized controlled trials designed to measure the effects of prostate cancer screening on mortality were published in 2009. The Prostate, Lung, Colorectal, and Ovarian (PLCO) trial enrolled 76,693 men at 10 U.S. study centers between 1993 and 2001.6 Men were randomized to receive either screening or “usual care.” Men in the screening group received annual PSA tests for six years and DREs for four years. A PSA value greater than 4.0 ng/mL was designated as a positive screen for prostate cancer. These men were then advised to seek diagnostic information and treatment if indicated. Men in the “usual care” arm were not actively screened and received their routine health care over the course of the study but were not prevented from receiving a PSA test outside of the confines of the study. The authors concluded that while more cancers were detected in the screened patients, there was no statistical difference in prostate cancer mortality after seven to 10 years of follow-up between the usual care group and the screened group (82 versus 92 deaths). Although the study had excellent follow-up rates, one significant flaw in its design was the very high rate of screening in the usual care group (men not originally intended to receive screening), which reached 52% by the sixth year. This is likely because PSA screening was becoming an increasingly widespread practice in the United States during the course of enrollment in the study. This may have significantly mitigated any advantage conferred by screening. Because of this, this study really amounted to an analysis of the benefit of more screening versus less screening rather than a comparison between screening and no screening (which would be the ideal and intended comparison). It remains to be seen if a difference between these two groups becomes evident with further follow-up.
The results from another large screening trial, the European Randomized Study of Screening for Prostate Cancer (ERSPC), were published simultaneously with the results from the PLCO trial.7 In this study, more than 162,000 men between the ages of 50 years and 74 years in several European countries were enrolled between 1991 and 2003 and randomly assigned to receive PSA screening every four years on average or no screening. PSA values above 3.0 ng/mL were generally considered positive and patients were subsequently referred for prostate biopsy. During median follow-up of nine years, the incidence of prostate cancer was 8.2% in the screening group and 4.8% in the control group. The number of prostate cancer-specific deaths was 214 in the screening group compared with 326 in the control group, resulting in a 20% relative risk reduction with screening. Additional analysis of these results suggests that 1,410 men need to be screened and 48 men need to be treated for prostate cancer to prevent one man from dying from prostate cancer.
The contrasting results of the PLCO and the ERSPC trials do not definitively answer the question of whether population-based screening for prostate cancer should be performed. Although it does appear that PSA screening can prevent deaths from prostate cancer, it appears to also carry a significant risk of overdiagnosis and, therefore, overtreatment as well. Both studies may benefit from continued follow-up as more significant benefits from screening may be realized after a longer interval is observed. Importantly, neither study addressed quality of life, which could be adversely affected not only by complications of treatment but also by symptoms of advanced prostate cancer caused by delayed diagnosis.
Current Screening Practices and Guidelines
Prostate cancer screening has become common in the United States over the last 20 years partly because it is recommended by the American Urological Association (AUA) and the American Cancer Society (ACS). Recent reviews of screening practice in the United States indicate that as many as 49% of men 40 years of age and older had received a PSA test in the previous two years, including 16% of men aged 40 to 49 years, 58% of men aged 50 to 64 years, and 71% of men aged 65 years and older.20,21 Screening practices appear to reflect previously described guidelines as more young (aged 40 to 49 years) black men had undergone PSA screening than their white counterparts (23% versus 16%). However, some studies indicate widespread use of PSA screening among elderly patients who are the least likely to benefit from it. In one study, as many as 56% of men older than 70 years received PSA screening within the VA system.22
The heterogeneity of screening practices around the country reflects the active controversy surrounding the topic and the often conflicting recommendations published by various professional medical organizations. The U.S. Preventative Services Task Force and American Academy of Family Physicians do not endorse screening for men younger than 75 years and recommend against screening in men older than 75.23,24 The ACS recommends that physicians offer PSA and DRE screening to men aged 50 years and older if they have at least a 10-year life expectancy.25 They also recommend that high-risk men (African Americans and men with first-degree relatives with prostate cancer) be offered screening at younger ages. Furthermore, they recommend that repeat screening be done yearly if the PSA level is 2.5 ng/mL or higher but suggest it could be done every two years if the level is lower than 2.5 ng/mL.
The National Comprehensive Cancer Network (NCCN) guidelines support offering PSA screening starting at age 40 and that if the PSA is less than 1.0 ng/mL that it be done every five years until age 50, when it should be done annually.26 If the baseline PSA level is greater than 1.0 ng/mL or the patient is at high risk for prostate cancer, the NCCN recommends annual screening. The NCCN also recommends individualized screening assessment in men older than 75 years of age.
The AUA recently revised its screening recommendations.27 Previously, it recommended that physicians offer men screening with PSA tests and DRE annually beginning at age 50 and at a younger age if a man was at high risk. The 2009 guideline recommends obtaining a baseline PSA/DRE at age 40 if life expectancy is more than 10 years, with rescreening intervals based on individual risk criteria including initial PSA value, age, family history, and comorbidities. For example, if the initial PSA value is below the median level for age (0.7 ng/mL for men in their 40s, 0.9 ng/mL for men in their 50s, 1.2 ng/mL for men in their 60s, and 1.5 ng/mL for men in their 70s), men may not need annual screening. However, men who have both initial low PSA levels and risk factors including a positive family history of prostate cancer may benefit from continued annual screening. The rationale for lowering the age of initial testing is based on data showing that having a baseline PSA value greater than 1 ng/mL before the age of 50 is associated with a seven-fold increased chance of developing prostate cancer up to 25 years later28 as well as a higher incidence of locally advanced or metastatic prostate cancer at diagnosis.29 The PSA test is also more specific for cancer in younger men because prostatic enlargement is less likely to confound the results. Furthermore, early screening provides a baseline PSA value that can be compared with others going forward. Earlier screening also may identify men at increased risk of prostate cancer who may be candidates for chemoprevention. Importantly, the AUA recommends that the risk of overdiagnosis and overtreatment be discussed with all men prior to screening.
The Future of Prostate Cancer Screening
There is clearly a need to improve screening protocols and develop improved prostate cancer biomarkers, particularly ones that can help distinguish indolent from aggressive disease. Until that happens, the focus will be on improving the PSA test. A number of changes to protocols have already been proposed and as more data become available may become part of official screening recommendations. These include:
■ Using Baseline PSA Levels to Identify Men Who Are at Risk
The first change likely to improve screening is reflected in the recently updated AUA and NCCN guidelines. Establishing a baseline PSA value and comparing that with age-adjusted PSA values has been shown to predict prostate cancer risk in younger men.30 Identifying men at risk for prostate cancer earlier may allow us to minimize screening those less likely to develop prostate cancer as well as to treat those with potentially life-threatening, high- Gleason-grade disease during the period when cure may still be possible. Analyses from one observational cohort demonstrated that men aged 75 years and older with PSA values less than 3.0 ng/mL were unlikely to die from prostate cancer (particularly if they have other comorbidities) or develop high-risk disease,31 although it should be noted that the incidence of high-Gleason-grade disease is higher in older men in general. Efforts to develop uniform approaches to the diagnosis and management of prostate cancer in elderly men have called for factoring comprehensive geriatric assessment and assessment of functional status into decisions about screening and treatment.32
■ Having Longer Intervals Between Screenings
The ERSPC was a randomized, controlled trial that showed decreased mortality from PSA screening of patients every four years on average.7 Because some benefit from screening was seen at this interval, it is thought that annual screening may be unnecessary. Recent changes to screening guidelines reflect this idea. The ACS now recommends PSA screening every two years for men with PSA levels less than 2.5 ng/mL, and the NCCN and AUA recommend that screening intervals be based on the results of the initial PSA test.27 In addition to minimizing overdiagnosis and overtreatment of prostate cancer, this approach is also likely to reduce costs.
■ Increasing Use of PSA Kinetics
Recently, it has been proposed that determination of the point when the rate of increase in a man’s PSA levels begins to dramatically change can help identify men with life-threatening prostate cancer.33 In the retrospective analysis that generated this hypothesis, the transition point was more than 15 years before diagnosis in more than half of the men; in 75% of men, it was when their PSA levels were less than 1.6 ng/mL.33 Monitoring PSA velocity, therefore, may help identify men at higher risk of developing life-threatening prostate cancer who would likely benefit from definitive therapy or closer surveillance. Although this represents an interesting new approach to early identification of men with significant prostate cancer, it remains untested in prospective studies.
■ Identifying Prostate Cancer Biomarkers
The recent discovery of the presence of a stable gene translocation in more than 50% of prostate cancers resulting in the fusion of androgen-regulated genes and transcription factors, TMPRSS:2ERG, may result in the development of a new biomarker as well as a possible therapeutic target.34 Another new biomarker for prostate cancer is the overexpression of DD3/PCA3 (likely a noncoding gene expressed in prostate cancer cells) in a urine polymerase chain reaction (PCR) test. In one study, this test was found to have a negative predictive value of 90% in men with PSA greater than 3.0 ng/mL who underwent prostate biopsy.35 Therefore, use of the DD3/PCA3 marker may prevent unnecessary prostate biopsies. Future screening strategies may rely on these biomarkers or on combinations of biomarkers.
■ Using Shared Decision-Making
Most current PSA screening guidelines recommend informed consent and shared decision-making. The shared decision-making process provides an opportunity for patients and physicians to discuss the pros and cons of screening and the possible risks of overdiagnosis and overtreatment as they pertain to each patient’s health status and value system. Well-informed patients may decide for or against screening; but there is at least one report that shared-decision making decreases the frequency of PSA testing in controlled trials.36 Of note, this study was published prior to the results of the PLCO and ERSPC screening trials.
■ Increasing Role for Active Surveillance
Active surveillance may be widely underused especially with very low-risk prostate cancer that is unlikely to progress.16 With data from the PLCO and ERSPC trials highlighting the extent of overdiagnosis and overtreatment, it is likely that in the future there will be increased promotion of active surveillance or focal therapy strategies for managing low-risk prostate cancer. As technology improves, the risks of incontinence and erectile dysfunction, as well as other side effects of therapy for prostate cancer, will decrease. As this occurs, and with more acceptance of active surveillance, overdiagnosis will become less of an issue.
■ Changing the Role of Primary Care Providers
As the complexity of screening recommendations increases, the role of primary care providers may change with regard to prostate cancer screening. One important aspect of nearly every screening recommendation is that screening should be reserved for men with at least a 10-year life expectancy. Because a primary care physician often has knowledge of a patient’s overall health status, he or she may be in the best position to make an assessment of the patient’s life expectancy. However, PSA values need to be interpreted in light of the patient’s age, family history, baseline PSA, PSA velocity or transition points, and new biomarkers. Thus, decisions about care and treatment will need to be made by urologists, primary care providers, and patients working together.
Prostate cancer screening is currently evolving. Efforts to develop new tools to help us balance the benefits of PSA screening with the potential risks of overdiagnosis are underway. These tools will improve our ability to better guide our patients to the decisions that are best for them. MM
Matthew O’Shaughnessy is a resident, Badrinath Konety is professor and chair, and Christopher Warlick is an assistant professor in the department of urologic surgery at the University of Minnesota.
References
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