Re: Early Detection of Prostate Cancer: AUA guideline

Letters to the Editor/Errata Re: Early Detection of Prostate Cancer: AUA guideline H. B. Carter, P. C. Albertsen, M. J. Barry, R. Etzioni, S. J. Freedland, K. L. Greene, L. Holmberg, P. Kantoff, B. R. Konety, M. H. Murad, D. F. Penson and A. L. Zietman J Urol 2013; 190: 419 – 426.

To the Editor: The recent publication of this guideline for prostate specific antigen (PSA) testing for prostate cancer by the American Urological Association has done little to clarify the furor arising from the May 2012 publication by the U.S. Preventive Services Task Force (USPSTF) of recommendations that such testing should not be performed at all.1,2 In fact, the AUA guideline has been widely and erroneously interpreted by the lay media as concurring with the USPSTF.3 The AUA guideline document differs from the USPSTF report in providing input from individuals, many of whom are highly knowledgeable about the diagnosis and treatment of prostate cancer, and yet, much of the failing of the AUA document lies in the misinterpretation of their recommendations.

GUIDELINES 1 AND 2 The Panel recommends against PSA screening in men younger than 40 years old and does not recommend screening in men between 40 and 54 years old. The Panel commented “For men younger than age 55 years at higher risk (eg positive family history or African American race), decisions regarding prostate cancer screening should be individualized.” In fact, there are very few data on the benefit or harm of prostate cancer screening in men younger than 40 years because current practice is not to screen men of young age unless there is a strong family history of prostate cancer. In present day practice PSA testing typically begins as early as age 45 years but more often at age 50 years. Having said this, there have been no trials specifically designed to evaluate the potential benefit or harm of testing men in their early to mid-40s. The Panel ignored several retrospective studies showing that baseline PSA measurements at a young age are significant predictors of later prostate cancer diagnosis and disease specific outcomes.4 In the Målmo study baseline PSA levels were obtained in 21,277 men 27 to 52 years old between 1974 and 1984, comprising 74% of the eligible population.5 The authors demonstrated a strong association between this single PSA value, and metastatic disease and prostate cancer specific mortality during a 25-year followup. Similarly, in a cohort of more than 4,500 men followed for approximately 20 years at Duke University Medical Center, those with baseline PSA less than 4 ng/mL had a very low risk of death from prostate cancer (0.6%), whereas those with baseline PSA greater than 4 ng/mL had a much higher risk (5.9%).6 Moreover, the Panel’s statement regarding men at higher risk is arbitrary, inadequate and disrespectful of the health of high risk populations (African Americans and men with a positive family history). The recommended age for initiating testing of African American men has been previously set at 40 years by the AUA and 45 years by the American Cancer Society. SEER (Surveillance, Epidemiology and End Results) data demonstrate an estimated 5 to 8-year lead time to prostate cancer mortality between ages 45 and 70 years among African American men, which is much shorter than in European American men, as well as a 3 times higher mortality rate.7,8

GUIDELINES 3, 4 AND 5 “. . .the Panel strongly recommends shared decision-making for men age 55 to 69 years that are considering PSA screening and proceeding based on a man’s values and preferences.” The Panel does not recommend routine PSA screening in men older than 70 years or in any man with less 0022-5347/13/1903-1134/0 THE JOURNAL OF UROLOGY® © 2013 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION

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http://dx.doi.org/10.1016/j.juro.2013.07.002 Vol. 190, 1134-1142, September 2013 Printed in U.S.A.

LETTERS TO THE EDITOR/ERRATA

than a 10 to 15-year life expectancy. In contrast to the AUA guidelines, the new European Association of Urology guidelines recommend a baseline PSA test at age 40 to 45 years with followup testing for all men with a greater than 10-year life expectancy (Eur Urol 2013; Jul 9. doi:pii:s0302-2838(13)00666-0). To reduce the harms of screening, a routine screening interval of 2 years or more may be preferred over annual screening for those men who have participated in shared decision making and decided on screening. There is increasing recognition that the natural history of “indolent” prostate cancer is one of slow progression over the course of several decades. The 2 major studies upon which the USPSTF based their recommendation against prostate cancer screening were the PLCO (Prostate, Lung, Colorectal, and Ovarian) Cancer Screening Trial and the ERSPC (European Randomised Study of Screening for Prostate Cancer). As acknowledged by the Panel, the PLCO trial had only a 7-year followup and was highly flawed by testing as many as 83% of control subjects for PSA outside the protocol.9 The ERSPC, with age limits precisely at 55 to 69 years, was more successful in excluding such “contamination” of PSA testing by control subjects. The cumulative incidence of prostate cancer diagnosis was 8.2% in the screened group vs 4.8% in the control group. However, after a median followup of 11 years in the core age group, the relative reduction in the risk of death from prostate cancer in the screening group was 21% (rate ratio 0.79, 95% CI 0.68 to 0.91, p ⫽ 0.001) and 29% after adjustment for noncompliance, and in men followed for 10 to 11 years this risk decreased to 0.62 (95% CI 0.45 to 0.85, adjusted p ⫽ 0.003).10 There were 9, not 1 as stated in the AUA guidelines, lives saved per 1,000 men screened. Hence the clear positive benefit of PSA testing in the 55 to 69-year age group studied in the ERSPC trial on prostate cancer mortality is irrefutable but the study was not powered to explore the benefit outside this age range. After a median 14-year following in the Göteborg Randomised Population-Based Prostate Cancer Screening Trial of 20,000 men 50 to 64 years old, the cumulative incidence of prostate cancer was 12.7% in the PSA screened group and 8.2% in the control group (hazard ratio 1.64, 95% CI 1.50 –1.80, p ⬍0.0001).11 Yet despite the higher incidence, the rate ratio for prostate cancer death for the screened group was 0.56 (95% CI 0.39 – 0.82, p ⫽ 0.002), a reduction of 44%. The number of men needed to screen to save 1 life for this study was estimated at 208 (ie 4.8 lives saved per 1,000 men screened). The realization that the benefit of PSA testing must be measured for a far longer duration than a 10-year study leads us to question the attempt of the AUA Panel to impose arbitrary age limits on the recommendation for testing. The current expected life span for white and black men 45 to 50 years old in the United States is about 30 years and 27 years, respectively.12 Certainly, younger men with undiagnosed prostate cancer have a longer potential life span and, therefore, are at greater risk for eventual progression and mortality from this disease. The most persuasive results favoring testing emanate from the ERSPC data whose protocol specified PSA testing every 4 years. No study has evaluated the ideal testing interval. The PSA test itself is relatively inexpensive and has no significant adverse consequences, so the arguments about appropriate intervals go to the question of what shall be done with a suspicious result. Here we face the real issue, which is the presumption that the harms of testing and treatment are greater than those attributable to cancer. The great fallacy in the arguments of the USPSTF and the AUA Panel arises from incomplete premises of comparison of harm. The harms of testing for prostate cancer arise not from the measurement of PSA but, rather, from the ensuing biopsy and side effects of potential treatment. The USPSTF erred in assuming that a positive PSA test inevitably leads to biopsy which then leads to either surgery or radiotherapy. On the contrary, the trend following diagnosis has moved more toward the practice of active surveillance, which means following patients with localized, well differentiated prostate cancer, monitoring repeat PSA levels and performing biopsies when levels increase. Triggers for definitive treatment in most active surveillance protocols include an increase in the Gleason grade, rapidly rising PSA level and digital rectal examination findings suspicious for cancer.13–15 Although the practice of active surveillance incurs repeat prostate biopsies at varying intervals, with possible side effects, it does permit deferral of definitive therapy in most men with low risk disease, thus avoiding overtreatment. The USPSTF and AUA Panel erred in focusing on prostate cancer specific mortality benefits without considering avoidance of metastatic disease. It is concerning that the list of harms did not include the well-known and feared consequences of advanced prostate cancer. Local spread of prostate cancer in the pelvis causes pain and urinary obstruction as well as hemorrhage.

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Widespread metastases, particularly to bone, cause terrible suffering. Our argument has been eloquently summarized in the recent editorial, “There is More to Life than Death” by Hartzband and Groopman.16 If the frequency of advanced cancer were not influenced by PSA testing, then an assessment of benefit and harm based upon disease specific mortality alone would be acceptable. However, the ERSPC data showed that the cumulative risk of metastatic disease at 9 to 11 years of followup was 31% to 33% lower in the screened arm than the control arm.17 Factoring in the harms due to diagnosis and treatment procedures, their analysis showed 56 quality of life adjusted years gained by PSA screening.18 The recommendation not to screen men older than 70 years would appear sensible if prostate cancer were always slow growing and only resulted in health deterioration after 15 years. Yet, not all prostate cancer is indolent. Aggressive prostate cancer can proceed to metastases and death within 10 years or less. The expected life span in the U.S. for a 75-year-old man is more than 10 years but it is nearly 15 years for men 70 years old.12 The question becomes what testing is justifiable in the so-called “elderly” population. Does it make sense to test for chronic diseases such as diabetes or kidney disease or, in fact, any form of malignancy in individuals alleged to be entering senescence. Certainly, age 70 may be considered “old” by some, but not so by men still vigorous and healthy in their eighth decade of life. We recognize that the AUA Panel sought to remedy a drastic rejection of prostate cancer testing by the USPSTF, which does not include individuals who typically diagnose and treat prostate cancer. It is to the credit of the AUA Panel that they have challenged the USPSTF call to terminate testing for prostate cancer. Unlike the USPSTF, they attempted to avoid arbitrary conclusions, and within their recommendations they allowed for opposing views. It is extremely important that they emphasize shared decision making between physicians and their patients. It is ethically unsound to pursue PSA testing without discussion with patients as to the possible consequences of a positive result, including possible side effects of treatment such as incontinence and erectile dysfunction. The word “screening” tends to imply testing without explanation. We agree that it is improper to test an uninformed patient. However, it is also highly improper to deny patients the benefit of prostate cancer testing, as proposed by the USPSTF, to prevent metastatic disease and prostate cancer death. An important failing of the AUA guideline was not so much of the Panel’s own doing but, rather, the interpretation accorded to their recommendations. In USA TODAY the guidelines were reported as “Urology group stops recommending routine PSA.”3 This interpretation is, of course, incorrect. What the Panel did was to not recommend any action when hypotheses had not been confirmed or even tested in published randomized controlled trials. Hence, they accorded evidence level C to PSA testing outside the age range of 55 to 69 years. They most certainly did not assign an evidence level of D as did the USPSTF. Where the Panel went wrong was by not sufficiently clarifying the deficiencies of their approach, not the least of which is the inability to make use of rapidly accumulating evidence, such as the ERSPC results recently published. Furthermore, it is difficult to properly design and execute trials. For example, the USPSTF dismissed screening the African American population claiming that there were adequate numbers in PIVOT (Prostate Cancer Intervention Versus Observation Trial), which they claimed showed no benefits of treatment.19 As it was, PIVOT was markedly underpowered as a result of failure to reach the planned enrollment and totally inadequate to study the African American subgroup. Randomized clinical trials are necessary to determine whether interventions are beneficial. Yet, when trials are not designed with the power to evaluate hypotheses, it is not correct to state that the interventions are not beneficial. The Panel should have said, “Since there are insufficient trials, we cannot recommend for or against screening men under age 55 for individuals with familial cancer, nor for African American men, or for what screening interval should be used.” Instead, they said, “We do not recommend screening men aged 40 –55” and “We recommend a 2-year screening interval.” The establishment of recommendations has serious ramifications in modern day medical practice, driven primarily by issues of reimbursement. The U.S. Center for Medical Services can easily use such recommendations to limit payments for testing and for treatment of prostate cancer. More than 50% of medical care reimbursement comes from the Department of Health and Human Services, which funds the USPSTF. Currently, as a result of the 2008 USPSTF recommendations, PSA testing in men younger than 50 years is frequently denied by third party payers irrespective of family

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history or ethnicity. It would be tragic if the USPSTF opposition to PSA screening and denial of reimbursement for PSA testing or outright prohibition sent us back to the 1980s when prostate cancer was typically discovered only in advanced and incurable stages.5,20 –26 Respectfully, Judd W. Moul Duke Prostate Center at the Duke Cancer Institute and Department of Surgery, Division of Urology, Duke University School of Medicine, Durham, North Carolina

Patrick C. Walsh Department of Urology, The Johns Hopkins Medical Institutions, Baltimore, Maryland

Marc S. Rendell Department of Medicine

Henry T. Lynch Departments of Medicine, and Preventive Medicine and Public Health

Stephen W. Leslie Division of Urology, Department of Surgery

Omofolasade Kosoko-Lasaki Departments of Surgery (Ophthalmology), and Preventive Medicine and Public Health and

William P. Fitzgibbons Department of Family Practice Creighton University School of Medicine, Omaha, Nebraska

Isaac Powell Department of Urology, Wayne State University/Karmanos Cancer Institute, Detroit, Michigan

Anthony V. D’Amico Department of Radiation Oncology, Brigham and Women’s Hospital and Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts

William J. Catalona Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, Illinois

Reply by Authors. The American Urological Association guideline panel on the detection of prostate cancer (DPC) began deliberations 1 year before the U.S. Preventive Services Task Force recommendation to discourage use of the PSA test for prostate cancer screening1 and, thus, was not a reaction to the USPSTF report. The Panel was asked to develop an evidence-based approach to the diagnosis of prostate cancer, and chose to focus on the average risk asymptomatic man because there is no evidence to inform decisions for “high risk” men whether because of family history or race. The process involved a systematic review of the evidence available today with interpretation of the balance of benefit and harms of PSA based prostate cancer detection, which is the most common method for diagnosing prostate cancer. The Panel recognized that there will be evidence forthcoming to clarify the balance of benefit and harm, and that as this evidence accrues the guideline will be updated at 12 to 18-month intervals as are all AUA guidelines. Moul et al imply that the Panel should have assumed that the benefits of screening outweigh the harms outside the age range for which there is clear evidence of benefit (age 55 to 69 years). For men younger than 55 years, they believe that benefits will outweigh harms based on low quality evidence from retrospective studies that indicate a PSA level is predictive of future outcomes.4-6 While a PSA measurement before age 55 years may risk stratify men, it is not evidence that men who receive a PSA test before age 55 years will have improved health outcomes compared to those who begin testing at age 55 years. The Panel did not recommend against use of the PSA test in men younger than 55 years, especially those at high risk, but rather recommended against routine screening of the average risk man because the evidence review did not show that benefits outweighed harms for this age group.

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For men 55 to 69 years old, the Panel found clear evidence of benefit in terms of prevention of prostate cancer death with PSA based screening from the ERSPC trial10 and, therefore, recommended shared decision making for those considering screening, with the recognition that there are harms. The Göteborg study (1 of 7 countries in the ERSPC) is highlighted by Moul et al as evidence for the increased benefits of PSA screening with time.11 However, it is also possible that the findings from Göteborg are, in part, a result of screening a population (Sweden) in which death rates are the highest of any country participating in the ERSPC. In the Finnish section of the ERSPC, which was larger than the Göteborg study and not cited by Moul et al, there was no evidence of a reduction in prostate cancer mortality.20 Moul et al indicate that the PSA test itself is not harmful, and that the harms of treatment should not have been included as harms of screening. They support this view with their statement that “the trend following diagnosis has moved more toward the practice of active surveillance, which means following patients with localized, well differentiated prostate cancer, monitoring repeat PSA levels and performing biopsies when levels increase.” However, they do not provide any supporting evidence for this statement. In fact, the trend is to discourage use of PSA changes as a trigger for identifying aggressive prostate cancer21 and the increased use of advanced technology treatments for men at low risk of dying of prostate cancer.22 In the PLCO trial approximately 10% of patients in the screening and control arms were not treated23 compared to 30% in the Göteborg study,11 suggesting that most patients receive treatment after diagnosis in the U.S. health care system. Low rates of surveillance prevail among those with a limited life expectancy,22,24 despite strong evidence of a lack of benefit for treatment of older men.19,25 In our current system we do not believe it is rational to ignore the downstream consequences of PSA screening when virtually everyone (approximately 90%) is treated after a new diagnosis of prostate cancer,23 even those least likely to benefit from treatment.22,24 To do otherwise is to ignore the facts. Moul et al believe that the Panel ignored the reduction in metastatic disease that occurs with screening. The Panel fully acknowledged the population data and that from the ERSPC which demonstrate a reduction in the rate of metastatic disease at diagnosis.10 However, the Panel also recognized that a reduction in metastatic disease could be a result of lead time, whereby with further followup after diagnosis the rates of metastatic disease are similar for those screened and not screened as reported in the ERSPC.17 If further followup reveals that the rates remain similar in the screened and unscreened groups, then measuring the rates of metastatic disease at diagnosis in screened and unscreened men may not be an appropriate end point for assessing the benefits of screening.17 The Panel recommended against routine screening of men 70 years old or older, recognizing that some healthy men older than 70 years may benefit from screening and that for others a 70-year cutoff for screening may be too early. Thus, the Panel recommended for the healthy man who is well informed and chooses to be screened beyond this age that higher PSA thresholds be used for biopsy referral and that those with low PSA levels consider discontinuing screening in an effort to reduce over diagnosis and overtreatment. Moul et al have confused the AUA guideline recommendation against routine screening of asymptomatic average risk men outside the age range 55 to 69 years, with a recommendation against screening in general for younger and older men. The AUA guideline statements are not a recommendation against screening, but a call for an approach to screening that targets those most likely to benefit from a diagnosis and treatment of prostate cancer. Moul et al ignore the fact that PSA based screening is a form of prevention in which the bar for ensuring that benefits outweigh harms should be high before a blanket recommendation is issued, similar to the Food and Drug Administration recommendation against the use of 5-alpha reductase inhibitors for the prevention of prostate cancer.26 It is ironic that investigators who were in charge of the largest screening trials demonstrating the benefits of prostate cancer screening continue to caution against recommendations that go beyond the evidence,10 whereas in the U.S. some continue to argue that if screening is beneficial for some, then it must be beneficial for all. 1. Moyer VA: U.S. Preventive Services Task Force. Screening for Prostate Cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2012; 157: 120.

2. Catalona WJ, D’Amico AV, Fitzgibbons WF et al: What the U.S. Preventive Services Task Force missed in its prostate cancer screening recommendation. Ann Intern Med 2012; 157: 137.

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3. Szabo L: Urology group stops recommending routine PSA. USA Today, May 3, 2013. 4. Loeb S, Carter HB, Catalona WJ et al: Baseline prostate-specific antigen testing at a young age. Eur Urol 2012; 61: 1. 5. Vickers AJ, Ulmert D, Sjoberg DD et al: Strategy for detection of prostate cancer based on relation between prostate specific antigen at age 40 –55 and long term risk of metastasis: case-control study. BMJ 2013; 346: f2023. 6. Tang P, Sun L, Uhlman MA et al: Baseline PSA as a predictor of prostate cancer-specific mortality over the past 2 decades: Duke University experience. Cancer 2010; 116: 4711. 7. Powell IJ, Bock CH, Ruterbusch JJ et al: Evidence supports a faster growth rate and/or earlier transformation to clinically significant prostate cancer in black than in white American men and influence racial progression and mortality disparity. J Urol 2010; 183: 1792. 8. Surveillance, Epidemiology, and End Results (SEER) Program (www. seer.cancer.gov) SEER*Stat Database: Incidence - SEER 9 Regs Limited-Use, Nov 2007 Sub (1973–2005) ⬍Katrina/Rita Population Adjustment⬎ - Linked To County Attributes - Total U.S., 1969 –2005 Counties, National Cancer Institute, DCCPS, Surveillance Research Program, Cancer Statistics Branch, released April 2008, based on the November 2007 submission.

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14. Dall’Era MA, Albertsen PC, Bangma C et al: Active surveillance for prostate cancer: a systematic review of the literature. Eur Urol 2012; 62: 9763. 15. Loeb S, Metter EJ, Kan D et al: Prostate-specific antigen velocity (PSAV) risk count improves the specificity of screening for clinically significant prostate cancer. BJU Int 2012; 109: 508. 16. Hartzband P and Groopman J: There is more to life than death. N Engl J Med 2012; 367: 987. 17. Schröder FH, Hugosson J, Carlsson S et al: Screening for prostate cancer decreases the risk of developing metastatic disease: findings from the European Randomized Study of Screening for Prostate Cancer (ERSPC). Eur Urol 2012; 62: 745. 18. Heijnsdijk EA, Wever EM, Auvinen A et al: Quality-of-life effects of prostate-specific antigen screening. N Engl J Med 2012; 367: 595. 19. Wilt TJ, Brawer MK, Jones KM et al: Radical prostatectomy versus observation for localized prostate cancer. N Engl J Med 2012; 367: 203. 20. Kilpeläinen TP, Tammela TL, Malila N et al: Prostate cancer mortality in the Finnish randomized screening trial. J Natl Cancer Inst 2013; 105: 719. 21. Vickers AJ: Prostate cancer: Why is PSA velocity such a sticky concept? Nat Rev Urol 2013; 10: 189.

9. Pinsky PF, Blacka A, Kramer BS et al: Assessing contamination and compliance in the prostate component of the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Clin Trials 2010; 7: 303.

22. Jacobs BL, Zhang Y, Schroeck FR et al: Use of advanced treatment technologies among men at low risk of dying from prostate cancer. JAMA 2013; 309: 2587.

10. Schröder FH, Hugosson J, Roobol MJ et al: Prostate-cancer mortality at 11 years of follow-up. N Engl J Med 2012; 366: 981.

23. Andriole GL, Crawford ED, Grubb RL III et al: Mortality results from a randomized prostate-cancer screening trial. N Engl J Med 2009; 360: 1310.

11. Hugosson J, Carlsson S, Aus G et al: Mortality results from the Göteborg randomised population-based prostate-cancer screening trial. Lancet Oncol 2010; 11: 725.

24. Raldow AC, Presley CJ and Yu JB: The relationship between clinical benefit and receipt of curative therapy for prostate cancer. Arch Intern Med 2012; 172: 362.

12. Arias E: United States Life Tables, 2006. National Vital Statistics Reports 58, No. 21, June 28, 2010.

25. Bill-Axelson A, Holmberg L, Ruutu M et al: Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med 2011; 364: 1708.

13. Carter HB: Management of low (favourable)-risk prostate cancer. BJU Int 2011; 108: 1684.

26. Justman S: Do No Harm. Chicago: Ivan R. Dee 2008.

Re: To Biopsy or Not to Biopsy: Minimizing the Risk of Prostate Needle Biopsy A. S. Kibel J Urol 2013; 189: 796 –797.

To the Editor: Kibel notes in his editorial a 1.1% incidence of clinical infection following prostate biopsy. These infections (8 documented deaths) are unnecessary if the original transperineal route is used. When the transrectal ultrasound guided biopsy approach spread throughout the developed world in the early 1980s, I did not join the throng. I found the prospect of first dipping my needle in feces and then sticking it into the prostate theoretically unsound. I have not observed a clinical infection following prostate biopsy in 40 years of practice, 15 of which were in the Veterans Administration system during the peak of World War II veteran attendance. I say bring back the perineal route nationally and let us be done with this complication. Respectfully, Anthony H. Horan Alpine Urology 1205 Garces Hwy., Ste 303 Delano, California 93215