Pre-test Audience Response Screening and Treatment of Prostate Cancer: The 2013 Perspective 1. I do not offer routine PSA screening, and the USPSTF D recommendation will not change my practice. 2. In light of the new USPSTF D recommendation, I plan to reduce / stop PSA screening in my practice. 3. The USPSTF D recommendation is not strongly evidence-based, and will not change my practice. Nicholas A. Daniels, MD, MPH Department of Medicine Declaration of full disclosure: No conflict of interest 4. I am unaware of the USPSTF D recommendation. 2 Prostate Cancer 2012 Urologic cancer: Cases and Deaths American Cancer Society Siegel et al. CA Cancer J Clin 2012; 62:10 3 4 1
The Good News: Prostate Cancer Screening Controversy 40% drop in ageadjusted prostate cancer mortality since early 1990s Siegel et al. CA Cancer J Clin 2012; 62:10 Moyer et al. Ann Intern Med, epub 2012. 5 6 Other Prostate Cancer Screening Recommendations Prostate cancer is heterogeneous American Cancer Society Informed decision making for prostate cancer screening at age 50 years American Urological Association Recommends annual screening with both PSA and DRE starting at age 40 if life expectancy > 10 years American College of Physicians Informed decision making and discussion of potential benefits and harms of PSA screening with men >50 years Esserman et al. JAMA 2009; 302:1685 7 8 2
The Changing Face of Prostate Cancer PLCO Prostate, Lung, Colorectal, & Ovarian Cancer Screening Trial Cooperberg et al. J Urol 2007; 178:S14 Andriole et al. NEJM 2009; 360:1310 9 10 PLCO 76,693 men aged 55-74 randomly assigned to annual PSA screening for 6 years vs. usual care at 10 U.S. centers Any prior screening allowed; no more than 1 PSA within past 3 years 44.1% of control group had 1 PSA in past 3 years; 53.9% had 1 DRE PSA >4.0 ng/ml considered abnormal Andriole et al. NEJM 2009; 360:1310 PLCO Screening compliance 85% in screening arm Rate of screening in control arm 40% in first year, 52% in sixth year Rate of biopsy among those with PSA >4 fell from 40% in first year to 30% by third year At 7 years, prostate cancer diagnosed in 2820 screening pts and 2322 controls, RR 1.22 (1.16-1.29) 96.0% vs 94.3% of screened vs control tumors were stage I-II; 32% vs 39% were GS 7 At 7 years, 50 cancer-specific deaths in screening group, 44 in control group, RR 1.13 (0.75-1.70) Andriole et al. NEJM 2009; 360:1310 11 12 3
PLCO: Level of Contamination PLCO: the contamination problem Data from surveys of the control arm of the PLCO study: Given the high level of contamination in PLCO, one way of interpreting the trial is that it is a study of an active (organized) program of screening versus passive (opportunistic) screening, that is, the current level of screening ongoing in the community a finding of no benefit implies that an organized program does not confer significantly greater mortality benefit for prostate cancer than opportunistic screening as currently carried out in the US. However, the study interpreted in this manner would not be able to answer the question of whether that level of opportunistic screening is conveying a mortality benefit over no screening. Pinsky et al. Clin Trials 2010; 7:303 Pinsky et al. Clin Trials 2010; 7:303 13 14 PLCO: Update ERSPC European Randomized Study of Screening for Prostate Cancer PLCO was not a trial of screening vs. no screening Andriole et al. J Natl Cancer Inst 2012; 104:1 Schröder et al. NEJM 2009; 360:1320 15 16 4
ERSPC ERSPC Population-based study at 7 European centers 182,160 men age 50-74 randomized (162,387 in core age 55-69) 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 Some variation in thresholds for biopsy (3.0 ng/ ml vs 4.0 with ancillary tests (DRE/fPSA/TRUS) for values between 2.5 or 3.0 and 4.0 82% compliance with screening in screening arm 86% compliance with biopsy recommendations Incidence 4.8% in control, 8.2% in screening arm 27.8% vs 45.2% of screened vs. control tumors were Gleason 7 Adjusted mortality rate ratio 0.8 (0.67-0.95) in favor of screening. Mortality rates begin diverging at 7 years (20% reduction in mortality rate) Schröder et al. NEJM 2009; 360:1320 Schröder et al. NEJM 2009; 360:1320 17 18 Other findings from ERSPC ERSPC: Adjusting for compliance No substantial heterogeneity among different centers in Europe (mortality reduction varies from 16-26%) Absolute mortality risk reduction 7 per 10,000 men screened NNS: 1,410 NNT: 48 in excess of control group at 9 years NNT to prevent metastasis: 24 Schröder et al. NEJM 2009; 360:1320 Roobol et al. Eur Urol 2009; 56:584 19 20 5
ERSPC: Update The Göteborg trial 20% risk reduction for cancer-specific mortality with screening (up to 38% in years 10-11) 29% risk reduction with adjustment for noncompliance Men 50-64 (median 56) in a single Swedish city randomized to biannual screening until age 69 vs. no screening 9952 men in each arm Referral to urologist at PSA 3.4, later reduced to 2.9 then to 2.5 ng/ml. Biopsies used sextant template 76% of men in screening arm were screened at least once; 93% of men with elevated PSA had at least one biopsy Schröder et al. NEJM 2012; 366:981 Hugosson J. Lancet Oncol 2010; 11:725 21 22 The Göteborg randomized trial The Göteborg randomized trial Hugosson J. Lancet Oncol 2010; 11:725 Hugosson J. Lancet Oncol 2010; 11:725 23 24 6
The Göteborg randomized trial The Göteborg randomized trial biannual PSA testing can lower the risk for prostate cancer-specific mortality by at least 40 percent Göteborg vs. PLCO & ERSPC Younger mean age at start of screening Lower PSA threshold for referral Q2 year interval Higher rate of biopsy among those with high PSA Lower rate of pre- and intra-study PSA contamination Longer follow up (though still relatively short) Hugosson J. Lancet Oncol 2010; 11:725 Hugosson J. Lancet Oncol 2010; 11:725 25 26 From: Screening for Prostate Cancer: U.S. Preventive Services Task Force Recommendation Statement Ann Intern Med. 2012;157(2):120-134. doi:10.7326/0003-4819-157-2-201207170-00459 Is screening itself harmful? Figure Legend: Relative risk of prostate cancer death for men screened with PSA versus control participants, by country. ERSPC = European Randomized Study of Screening for Prostate Cancer; PLCO = Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial Copyright The American College of Physicians. All rights reserved. Heijnsdijk et al. N Engl J Med 367:595, 2012 27 28 7
An interesting perspective USPSTF: Assessment of harms What seems to be missing from most of the PSA discussion is that the majority of men will have a normal PSA value and they will be reassured A normal PSA level offers peace of mind, a valued commodity in a world that is frequently full of troubling news. Detsky et al. JAMA 307:1035, 2012 Adequate evidence shows that up to 5 in 1000 men will die within 1 month of prostate cancer surgery and between 10 and 70 men will have serious complications but survive. Radiotherapy and surgery result in long-term adverse effects, including urinary incontinence and erectile dysfunction in at least 200 to 300 of 1000 men treated with these therapies. Radiotherapy is also associated with bowel dysfunction Moyer et al. Ann Intern Med, epub 2012. 29 30 The real problem: overtreatment? Treatment by risk and age Prostate Cancer Risk Assessment Score Cooperberg et al. J Clin Oncol 2010; 28:1117 Bechis et al. J Clin Oncol 2011; 29:235 31 32 8
Do PCPs care about the USPSTF? Do PCPs care about the USPSTF? Tasian et al. Urol Oncol 30:155, 2012 Prasad et al. JAMA 307:1692, 2012 33 34 RaGonale for earlier screening (AUA) Establishing a baseline PSA A baseline PSA level above the median for age 40 is a strong predictor of prostate cancer The age adjusted mortality rate for prostate cancer between ages 55 and 64 is significant. Younger men are more likely to have curable cancer PSA is a more specific test for cancer in younger men Earlier and less frequent testing might reduce mortality and costs compared to annual testing beginning later Patients at risk for, but who do not have, cancer may be candidates for chemoprevention PSA at 60 predicts long-term prostate cancer mortality Analysis of 1167 samples from Malmö registry data 11.4% diagnosed, 2.7% died of prostate cancer If PSA <1.0 at age 60, likelihood of prostate cancer death <0.3% 90% of prostate cancer deaths occurred in men with PSA >2.0 (top quartile) Greene et al. J Urol 2009; 182:2232 Vickers et al. BMJ 341, 2010 35 36 9
MulGvariable risk assessment PCA3 and Positive Prostate Biopsy http://tinyurl.com/caprisk Gittelman M, Journal of Urology, Feb 2013 37 38 Radical Prostatectomy vs. Watchful Waiting Risk Assessment and Risk- Adapted Management Diagnosis Treatment Bill-Axelson et al. New Engl J Med 2011; 364:1708 39 40 10
PIVOT Trial PIVOT Trial Wilt T et al. NEJM 2012; 367:203 Wilt T et al. NEJM 2012; 367:203 41 42 Prostate Cancer Risk Assessment Prostate cancer Current treatment trend in US Goal: informed physician-patient decisions about optimal initial treatment approach and timing 43 44 11
So what explains this graph? Treatment Changes Explain Only a Fraction of the Mortality Decline No treatment Treatment Siegel et al. CA Cancer J Clin 2012; 62:10 Cancer, in press. Courtesy of Ruth Etzioni 45 46 Mortality Trends Suggest a Clear Role for PSA Screening What if we followed the USPSTF recommendation? No treatment Treatment Treatment and screening ERSPC benefit Cancer, in press. Courtesy of Ruth Etzioni 47 48 12
D is the wrong conclusion? D is the wrong conclusion? 49 50 Conclusions Prostate Cancer screening saves lives The USPSTF recommendation downplays benefits D is the wrong conclusion. Guidelines should avoid recommending for or against PSA screening Shared decision making with individual patient Overtreatment is a major public health problem Answers lie in smarter screening, better treatment decisions, not cessation of screening. Future DirecGons: smarter screening, avoid overtreatment, chemopreven7on Focus on populations at highest risk Consider screening earlier (e.g., 40) Screen less frequently if baseline is low (<2.5) Screen for high-risk prostate cancer, don t over-treat low-risk disease Embrace active surveillance Change nomenclature (e.g., PIN and low risk cancer) Continued development of novel biomarkers (PCA3) Consider finasteride chemoprevention 51 52 13
Post-test Audience Response 1. I will not offer prostate cancer screening to any men 2. I will only offer prostate cancer screening to men who specifically ask for it 3. I will discuss screening with men with a long life expectancy, and individualize the decision to screen 4. I will screen most men over 40 in good health 5. I am more confused than I was an hour ago. Acknowledgements UCSF Department of Urology Matthew Cooperberg, MD MPH Katsuto Shinohara, MD UCSF Department of Medicine Oanh Nguyen, MD San Francisco Primary Care Focus Group on Prostate Cancer Screening and Treatment 53 54 14