Page 3 of 8 Medscape, LLC encourages Authors to identify investigational products or off-label uses of products regulated by the US Food and Drug Administration, at first mention and where appropriate in the content. Author(s) Zosia Chustecka Zosia Chustecka is news editor for Medscape Hematology-Oncology and prior news editor of jointandbone.org, a Web site acquired by WebMD. A veteran medical journalist based in London, UK, she has won a prize from the British Medical Journalists Association and is a pharmacology graduate. She has written for a wide variety of publications aimed at the medical and related health professions. She can be contacted at ZChustecka@webmd.net. Disclosure: Zosia Chustecka has disclosed no relevant financial relationships. Editor(s) Brande Nicole Martin CME Clinical Editor, Medscape, LLC Disclosure: Brande Nicole Martin has disclosed no relevant financial relationships. CME Author(s) Charles P. Vega, MD Associate Clinical Professor, Residency Program Director, Prime-LC, University of California- Irvine, Orange, California; Department of Family Medicine, University of California-Irvine, Orange, California Disclosure: Charles P. Vega, MD, has disclosed no relevant financial relationships. CME Reviewer(s) Sarah Fleischman CME Program Manager, Medscape, LLC Disclosure: Sarah Fleischman has disclosed no relevant financial relationships. From MedscapeCME Clinical Briefs One-Time PSA Test at 60 Instead of Routine Screening? CME News Author: Zosia Chustecka CME Author: Charles P. Vega, MD CME Released: 09/22/2010; Valid for credit through 09/22/2011 September 22, 2010 New data suggest that a 1-time prostate-specific antigen (PSA) test at age 60 can pinpoint men who are likely to die from prostate cancer. The results, published online September 14 in BMJ, come from a Swedish study with a 25-year follow-up.

Page 4 of 8 The finding "needs to be validated in additional studies," according to an accompanying editorial. The researchers agree there is a need for replication by an independent team; nevertheless, they are enthusiastic about their results. "This is a key finding," said lead research Andrew Vickers, PhD, from the Department of Epidemiology and Biostatistics at the Memorial Sloan-Kettering Cancer Center in New York City. "We know that screening detects many prostate cancers that are not harmful, leading to anxiety and unnecessary treatment," he said in a statement. Indeed, a separate study published online September 14 in BMJ found no support for routine PSA screening in all men. The approach the study authors propose of testing once at age 60 pinpoints men who are at increased risk for "really aggressive cancers, the sort likely to lead to symptoms or shorten a man's life," Dr. Vickers said. His team found that most of the deaths from prostate cancer were among the 25% or so of men who had, at age 60, PSA levels higher than 2 ng/ml. The team originally started their study with the hope of finding a new biomarker for prostate cancer. "What we found instead was a new way of using an old test," Dr. Vickers said. New Way of Thinking About the PSA Test In an interview with Medscape Medical News, Dr. Vickers suggested that the finding provided "a new way of thinking about the PSA test that offers clear recommendations for clinical practice." "We were surprised by just how strong the associations were," he said. Instead of routine PSA screening for all men, which has led to overdiagnosis and overtreatment, this study suggests that repeat screening can be confined to the 25% or so of men whose PSA level is above 2 ng/ml at age 60. It also suggests that the 50% or so of men with PSA levels below 1 ng/ml at age 60 can be left alone, and need not have any further PSA screening. "The harms of further screening will probably outweigh the benefits in this group," he said. This conclusion about discontinuing screening in men with low baseline PSA levels echoes the conclusion of another study published this week. "We haven't totally solved the problem of overdiagnosis," Dr. Vickers explained. Many patients who have a higher than average PSA at age 60 will develop prostate cancers that are unlikely to lead to death. "Nonetheless, it is clear that risk-stratifying screening will reduce overdiagnosis in men at low risk of prostate cancer death and will improve compliance with screening in those men with most to benefit," he added. It's certainly thoughtprovoking. "It's certainly thought-provoking," was the reaction of Brantley Thrasher, MD, FACS, professor of urology at the University of Kansas in Kansas City, who acts as a spokesperson for the American Urological Association. However, he cautioned against relying too much on a single 1-off measurement of PSA, because it represents just a "snapshot in time." PSA is a "continuous variable," and it is important to have a number of data points, he said. "Another concern I have is that there is no PSA below which you can tell a man that he doesn't have cancer," he added. Dr. Thrasher said he could not agree with the proposal that a man could be told not to worry about prostate cancer ever again on the basis of just 1 test, but he could foresee extending the time period between checks for example, from

Page 5 of 8 having a PSA test yearly to having it every 5 years. This view was echoed by Andrew Wolf, MD, associate professor of medicine at the University of Virginia School of Medicine in Charlottesville, who was also approached for independent comment by Medscape Medical News. "I don't think you can make a dichotomous decision to continue to screen or not on the basis of 1 test," he said. "In particular, I don't think you can leap to the conclusion that you are good for life if your level is below 1 ng/ml." "It would be premature to change our practice on the basis of these findings," he added. But the study is "intriguing" and it does add to the literature. It also adds fuel to the ongoing discussions about extending intervals between PSA tests, he said. Initially, in the United States, this was seen as an annual test, but there is a move toward longer intervals now, especially in low-risk men. The American Cancer Society recently recommended testing every 2 years for men with a PSA value below 2.5 ng/ml, he noted. One-Time Test Predicts Mortality The study involved reanalyzing blood samples that had been collected more than 25 years previously for the Malmö Preventive Project. Originally, these blood samples were collected from 60-year-old Swedish men for cardiovascular studies. But Dr. Vickers and colleagues, including senior author Hans Lilja, MD, PhD, also from Sloan-Kettering, analyzed the stored blood samples for PSA. They collected this information for 1167 men. Then they scoured the Swedish Cancer Registry for details of men who had been diagnosed with prostate cancer (n = 126), and identified 43 men who developed prostate cancer metastases and 35 who died from the disease. Conditional logistic regression analysis showed that it was the men with the highest levels of PSA in their blood at age 60 who were most likely to die from prostate cancer. "As an example, men with a [PSA] concentration 2 ng/ml at age 60, have, on average, 26 times the odds of dying from prostate cancer than men with a concentration <2 ng/ml," the researchers write. It was rare to find prostate cancer metastases or death from prostate cancer among men who had a PSA concentration below 1 ng/ml at age 60, the researchers note, but the risk rose rapidly as the concentrations increased. Risk Stratification Men aged 60 with a PSA concentration below 1 ng/ml (about half of the men in this study) should be considered at low risk for prostate cancer death and might not need to be screened in the future, the researchers suggest. They might go on to develop prostate cancer, but "even if they do harbor cancer, it is unlikely to become apparent during their lifetime and even less likely to become life-threatening," they add. In contrast, men with a PSA concentration above 2 ng/ml (about 25% of men in this study) should be considered at increased risk for aggressive prostate cancer and should continue to be screened regularly, they conclude. But the raised PSA level is "far from being an inevitable harbinger of advanced prostate cancer," they point out. Even among the highest levels of PSA (5.2 ng/ml), only 1 in 6 men will die of prostate cancer by age 85. Limiting screening to a 1-time PSA test is "likely to shift the ratio of harms to benefits," the researchers note. They argue that it would also "lead to increased acceptance of screening among patients." In addition, it could increase the uptake of chemoprevention with drugs like finasteride, they suggest. Currently, few men take up this option, but they might be more willing to do so if they were identified as being at high risk.

Page 6 of 8 The researchers wonder whether these results can be replicated by an independent group, and whether the risk stratification would be similar in other populations. This study involved white Swedish men, but the incidence of prostate cancer is lower in Asian and higher in African American people than in white people. This point was also raised by Dr. Wolf, who pointed out that the study was conducted in one town in Sweden, where the men are likely to be genetically similar, and that they were all 60 years old. Hence, these findings cannot be extrapolated to other populations or other age groups, he cautioned. Another prostate cancer researcher, Lars Holmberg PhD, MD, from the Division of Cancer Studies at King's College Medical School in London, United Kingdom, said the study is "well done by a very competent group and on good quality data." "Everything that can be done to help use PSA testing in a more rational way, minimizing the side effects of testing on wide indications, is worthwhile," Dr. Holmberg told Medscape Medical News. "The strategy they propose may diminish testing and anxiety and unnecessary diagnoses," he said. However, "it is unclear how much their proposed limitation of PSA use would really affect the major (and very serious!) problem with screening overdiagnosis." The strategy... may diminish testing and anxiety and unnecessary diagnoses. The study was funded by grants from the National Cancer Institute, the Swedish Cancer Society, the Swedish Research Council, and several other foundations. Dr. Lilja reports holding a patent for free PSA and hk2 assays. BMJ. Published online September 14, 2010. Clinical Context Besides skin cancer, prostate cancer is the most common cancer among men worldwide, and it is the secondleading cause of cancer-related death among men in the United States. To forestall the morbidity and mortality burden of prostate cancer, screening tests have been developed. A meta-analysis by Djulbegovic and colleagues published in the current issue of the BMJ examines the usefulness of PSA testing as a means to screen men for prostate cancer. In the meta-analysis, PSA screening was associated with an increased probability of a diagnosis of prostate cancer and stage I prostate cancer specifically. However, screening did not significantly reduce the risk for death from prostate cancer or the overall mortality rate, regardless of men's age at the time of screening. There was limited information regarding the potential harms of screening, although PSA testing was associated with false-positive rates for prostate cancer that exceeded 70%. This meta-analysis calls into question the practice of PSA screening for prostate cancer. The current case-control study by Vickers and colleagues, which appears in the same issue of the BMJ, examines outcomes related to PSA testing among men 60 years old. The study results are summarized in the "Study Highlights" section. Study Highlights Study data were drawn from the cohort of the Malmö Preventive Project. This cohort includes 1167 men born in 1921. These men completed a health examination, including blood work, in 1981.

Page 7 of 8 Researchers used a national Swedish cancer registry to identify participants with prostate cancer diagnosed before 2007. Each case patient with prostate cancer was matched with 3 control individuals without prostate cancer. The main study outcome was the relationship between PSA results and the risks for any prostate cancer, metastatic prostate cancer, and death from prostate cancer. Researchers also compared total PSA levels vs free PSA levels and kallikrein-related peptidase 2 levels in these outcomes. 126 men were diagnosed with prostate cancer, and 43 had either metastatic disease or died of prostate cancer. The median PSA concentration for the entire cohort was 1.06 ng/ml. There were low rates of prostate cancer screening during follow up. Most prostate cancer was diagnosed during investigation for urinary tract symptoms. PSA level at age 60 years was significantly associated with the risk for a diagnosis of prostate cancer at age 85 years (area under the curve, 0.76; 95% CI, 0.71-0.81). The respective areas under the receiver operating characteristic curve for prostate cancer metastases and death from prostate cancer were 0.86 and 0.90. The risk for prostate cancer increased in a linear fashion with rising PSA values. However, metastases and death related to prostate cancer were rare among men with a PSA level of less than 1 ng/ml at age 60 years (0.5% and 0.2% probability, respectively). Men with a PSA value of 2 ng/ml or more at age 60 years experienced a relative risk for prostate cancerspecific mortality that was 26 times that of men with lower PSA values. 90% of deaths from prostate cancer were among men with a PSA level of 2 ng/ml or more. Total PSA level appeared superior as a marker of prostate cancer vs free PSA level, the free:total PSA ratio, and kallikrein-related peptidase 2 levels. Clinical Implications A meta-analysis finds that screening for prostate cancer with PSA testing is associated with increased rates of finding stage I prostate cancer and any prostate cancer, but PSA screening did not reduce rates of overall or prostate cancer-specific mortality. A case-control study suggests that a PSA level of less than 1 ng/ml at age 60 years is associated with a very low risk for prostate cancer metastases or mortality. CME Test You are discussing prostate cancer screening with a 60-year-old asymptomatic man without a family history of any cancer. According to the current meta-analysis by Djulbegovic and colleagues, what can you tell him regarding the outcomes of PSA screening? It does not improve the detection of prostate cancer It only increases the rate of detection of high-grade prostate cancer It reduces prostate cancer-specific mortality risk It does not significantly reduce total mortality rates The patient from Question #1 decides to undergo PSA screening. His result is a PSA level of 0.8 ng/ml. According to the current case-control study by Vickers and colleagues, what can you tell him about his risk for prostate cancer outcomes in the future? He will almost certainly never go on to have prostate cancer His risk for prostate cancer is low for the next 3 years only

Page 8 of 8 He is at a very low risk for prostate cancer metastases or mortality His age and PSA value should prompt referral to a urologist Save and Proceed This article is a CME certified activity. To earn credit for this activity visit: http://cme.medscape.com/viewarticle/729169 MedscapeCME Clinical Briefs 2010 Medscape, LLC Disclaimer The material presented here does not necessarily reflect the views of Medscape, LLC or companies that support educational programming on www.medscapecme.com. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or employing any therapies described in this educational activity. Send press releases and comments to news@medscape.net. This article is a CME certified activity. To earn credit for this activity visit: http://cme.medscape.com/viewarticle/729169