Is PSA recommended for prostate cancer screening? Nicola Mabjeesh, MD, PhD Deputy Chairman Department of Urology Any form of screening aims to reduce disease-specific and overall mortality, and to improve a person’s future quality of life. Platinum Slide Series Prostate cancer incidence rates for select registries, 2000–2004. Source: Cancer Incidence in Five Continents [4].ASR (W) = age-standardized rate (world); SEER = Surveillance Epidemiology and End Results.*Average of rates for ≤4 yr in the time period 2000–.2004 2/7 Melissa M. Center et al. Eur Urol 2012;6:1079-1092 Rationale to screen…….. PSA Screening and Deaths From Prostate Cancer After Diagnosis- A Population Based Analysis PLCO study • This is the first report from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial on prostate-cancer mortality. • From 1993 through 2001, they randomly assigned 76,693 men at 10 U.S. study centers to receive either annual screening (38,343 subjects) or usual care as the control (38,350 subjects). Results • After 7 years of follow-up, the incidence of prostate cancer per 10,000 person-years was 116 (2820 cancers) in the screening group and 95 (2322 cancers) in the control group (rate ratio, 1.22; 95% confidence interval [CI], 1.16 to 1.29). • The incidence of death per 10,000 person-years was 2.0 (50 deaths) in the screening group and 1.7 (44 deaths) in the control group (rate ratio, 1.13; 95% CI, 0.75 to 1.70). The data at 10 years were 67% complete and consistent with these overall findings. ERSPC • The European Randomized Study of Screening for Prostate Cancer was initiated in the early 1990s to evaluate the effect of screening with prostate-specific–antigen (PSA) testing on death rates from prostate cancer. Methods • 182,000 men between the ages of 50 and 74 years through registries in seven European countries for inclusion in our study. • The men were randomly assigned to a group that was offered PSA screening at an average of once every 4 years or to a control group that did not receive such screening. • The predefined core age group for this study included 162,243 men between the ages of 55 and 69 years. • The primary outcome was the rate of death from prostate cancer. • Mortality follow-up was identical for the two study groups and ended on December 31, 2006. Results • The rate ratio for death from prostate cancer in the screening group, as compared with the control group, was 0.80 (95% confidence interval [CI], 0.65 to 0.98; adjusted P = 0.04). • The absolute risk difference was 0.71 death per 1000 men. This means that 1410 men would need to be screened and 48 additional cases of prostate cancer would need to be treated to prevent one death from prostate cancer. • The analysis of men who were actually screened during the first round (excluding subjects with noncompliance) provided a rate ratio for death from prostate cancer of 0.73 (95% CI, 0.56 to 0.90). Conclusions • To prevent one prostate cancer death, 1410 men (or 1068 men who actually underwent screening) would have to be screened, and an additional 48 men would have to be treated. • PSA-based screening reduced the rate of death from prostate cancer by 20% but was associated with a high risk of over diagnosis. Overdiagnosis • Harms of screening include false positive results, which cause anxiety and lead to unnecessary biopsies. • Biopsies, in turn, carry risk of pain, fever, and urinary tract infections. • But overdiagnosis and overtreatment are the most serious, and least understood, harms of screening. Overdiagnosis • Overdiagnosis, or pseudodisease, is detection of cancer that would not have become clinically important during the patient’s lifetime. • Overdiagnosis leads directly to overtreatment: medical interventions with serious and frequent adverse events, including incontinence and sexual dysfunction. • 5 RCTs: ERSPC; Norrkoping; PLCO; Quebec; Stockholm • All studies reported on prostate cancerspecific mortality as the primary outcome. • Additional reported outcomes included prostate cancer diagnosis, all-cause mortality, clinical stage, Gleason score, and treatment follow-up. Norrkoping • The Norrkoping study recruited men 50 to 69 years of age in Sweden and screened every three years. • During the initial phase of the study, only the DRE was offered, however the screening regimen later evolved to include DRE and PSA. • A PSA level greater than 4.0 ng/mL was deemed the cut-off for biopsy. • Participants were followed up over a 20-year period. Quebec • The Quebec study recruited men 45 to 80 years of age in Canada and provided annual screening with combination DRE and PSA. • A PSA greater than 3.0 ng/mL was deemed the cut-off for biopsy. • Participants were followed up over an 11-year • period. Stockholm • The Stockholm study recruited men aged 55 to 70 years in Sweden for a one-time screening using DRE, PSA, and TRUS. • A PSA greater than 10.0 ng/mL was deemed the cut-off for biopsy, with repeat TRUS performed for PSA greater than 7.0 ng/mL. • Participants were followed up over a 15-year period. Prostate cancer-specific mortality All-cause mortality Prostate cancer diagnosis Tumor stage (localized T1T2, N0, M0) Tumor stage (advanced T3-4, N1, M1) Shared Decision-Making Approach 1. Prostate cancer screening with the PSA test is controversial. 2. Screening with the PSA test can detect prostate cancer, but for most men, the chances of harm from screening with the PSA test outweigh the chances of benefit. 3. A small number of prostate cancer cases are serious and can cause death; however, the vast majority of prostate cancer is slow-growing and does not cause death. 4. Most men who choose not to have PSA testing will not be diagnosed with prostate cancer and will die of something else. Shared Decision-Making Approach 5. Patients who choose PSA testing are much more likely than those who decline testing to be diagnosed with prostate cancer. 6. The PSA test often does not distinguish between serious cancer and nonserious cancer. However, men with markedly elevated PSA levels (10 g/L) may have a reduced chance of dying from prostate cancer by having surgical treatment. 7. The small potential benefit of prostate cancer screening corresponds to preventing, at most, 1 death caused by prostate cancer per 1000 men screened after 11 years of follow-up. Shared Decision-Making Approach 8. There are many potential harms of screening. There may be problems in interpreting test results: The PSA test result may be high because of an enlarged prostate but not because of cancer, or it may be low even though cancer is present. Prostate biopsy, if needed is also not free from risk. It involves multiple needles being inserted into the prostate under local anesthesia, and there is risk for infection or clinically significant bleeding and hospitalization (1.4%). Shared Decision-Making Approach 9. The PSA test is not “just a blood test.” It is a test that can open the door to more testing and treatment that a man may not actually want and that may actually harm him. A man’s chances of being harmed are much greater than his chances of benefiting from the PSA test. Thus, each man should have the opportunity to decide for himself whether to have the PSA screening test. 10. Studies are ongoing, so clinicians expect to learn more about the benefits and harms of screening, and recommendations may change over time. Men are also welcome to change their minds at any time by asking for screening that they have previously declined or discontinue screening that they have previously requested. Cost effectiveness How We Do Harm: A Doctor Breaks Ranks About Being Sick in America • Otis Brawley writes, “I believe that a man should know what we know, what we don’t know, and what we believe about prostate cancer. • I have been concerned that many patients and physicians have confused what is believed with what is known.” • I agree. Common sense is what we believe. Does common sense trump science? Did the US Preventive Services Task Force (USPSTF) get it wrong? • I don’t think so. What don’t we know about the benefits? • We don’t know whether following screened and nonscreened men for 15 or 20 years or longer will demonstrate a larger difference in mortality. • Competing causes of mortality make it progressively less likely that men who are screened will actually live longer. • The average age of death from prostate cancer is 80 years, and 70% of all deaths occur after age 75. • Contrast those statistics to breast cancer, for which the average age of death is 68 years and 63% of all deaths occur before age 75.5 What do we believe about the benefits? • Some certainly believe the trials must be wrong; common sense tells us that early detection and treatment must provide more benefit than what the evidence has shown. • Common sense tells us that the decline in prostate cancer mortality over the past 2 decades must be due to screening, although the ERSPC results clearly show that neither the magnitude nor the timing of the decline can be attributed to screening. What do we know—and not know—about the harms? • We know that much of the suffering from prostate cancer is a consequence of the diagnosis and management of the disease, rather than the disease itself. • Complications of both diagnosis and treatment of prostate cancer are frequent and serious. • We also know that many screen-detected cancers would never become apparent in a man’s lifetime without screening. PCPT long-term results • The recently published long-term results from the Prostate Cancer Prevention Trial are enlightening. • Finasteride reduced the incidence of screendetected cancers by 30%, with no impact on allcause mortality at 18 years. • If those screen-detected cancers had been a significant threat to health, then after 18 years we would have expected some mortality benefit from finasteride. What do we believe about the harms of screening? • In the United States 90% of men found to have prostate cancer are treated (including about 75% of men with low-risk cancers). • And although we hope to be able to reduce harms without changing benefits, we do not know what impact more conservative management of screen-detected cancers would have on the already small effect of screening on prostate cancer mortality. Science trumps common sense. • For every 1000 men screened, at most, one will avoid a prostate cancer death at 10 years. • But 30 to 40 will have erectile dysfunction, urinary incontinence, or both due to treatment, men will experience a serious cardiovascular event, one will have a venous thromboembolic event, and one in 3000 screened will die from complications of surgical treatment. FUTURE DIRECTION AND RESEARCH NEEDS • Further, improved tools for estimating life expectancy would help identify those men more likely to benefit from screening. • Assessment of the absolute benefits of PSAbased prostate cancer screening relative to the rates of overdiagnosis and over treatment of disease among different populations is an important area for future research. To screen or NOT to screen? NOT to screen. Not exactly…… …………”individualized” screening!