Prostate Cancer Screening: Con Laurence Klotz Professor of Surgery, Sunnybrook HSC University of Toronto
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Why not PSA screening? Overdiagnosis Overtreatment Risk benefit ratio unfavorable Flaws of PSA (cutpoint, etc.) Morbidity of diagnostic biopsy Uneconomic (cost per life year)
US Preventive Services Task Force summary on PSA screening 10/2011: small to no reduction in 10 year prostate cancerspecific mortality; harms related to false-positive test results, subsequent evaluation, and therapy, including overdiagnosis and overtreatment. optimal screening intervals and PSA thresholds remain uncertain. The Task Force recommends against PSA-based screening a Grade D recommendation.
Factors promoting overdiagnosis of cancer Welch H G, Black W C JNCI J Natl Cancer Inst 2010;102:605-613 Existence of a silent disease reservoir Activities leading to its detection, ie screening Long natural history hence modest cancer specific mortality
Over diagnosis in ERSPC Screening until age 75 q 4 years: 57% over diagnosis Screening q 1 year until 70: 49% over diagnosis EAM Heijnsdijk et al. BJC 2009
Management of Favorable Risk Prostate Cancer in the US--Overtreatment Hamilton AS et al, BJU Int 2010 (Data from SEER)
Prostate Cancer Screening Trials Norrköping Quebec Study (RCT) 1998 Swedish Study (RCT) 2004 Tyrol Study Population comparison (+ screen effect) PLCO ERSP Göteborg CAP and ProtecT (UK) are ongoing Deviations / limitations In statistical methods
Three Largest Randomized PSA ERSPC Screening Trials PSA every 4 yrs in 182,000 men PLCO USA trial testing PSA every yr vs. no PSA screening in 76,693 men analyzed in ITT analysis Göteborg Randomized 20,000 man screening trial showed 44% reduction in death (not much press!) ERSPC = European Randomized Study of Screening for Prostate Cancer; PLCO = prostate, lung, colorectal, ovarian; ITT = intent-to-treat. Schroder et al, 2009; Andriole et al, 2009. Hugosson J, 2010
ERSPC: Cumulative Risk of Death From Prostate Cancer ERSPC demonstrates 20% reduction in prostate cancer death after 8.8 yrs of follow-up. The adjusted rate ratio for death from prostate cancer in the screening group was 0.8 (95% CI, 0.65 0.98; p =.04). CI = confidence interval. Schroder et al, 2009.
PLCO: No Difference at 13 years.
Pick level 1 evidence to make any point Two Conflicting Studies (PLCO/ERSPC) Published Together = Great Press!! No PLCO: No reduction in prostate cancer mortality Yes ERSPC: 20% reduction in mortality 25% reduction in metastatic disease Yes Göteborg Trial: 44% reduction in mortality Andriole G, et al. N Engl J Med. 2009;360:1310-1319. Schröder F, et al. N Engl J Med. 2009;360:1320-1328.
Study Over Treatment of Prostate Cancer is Common Age, yrs Follow Up, yrs No. Needed to Treat Prostate Cancer Metastases Death ERSPC (Schroder, N Engl J Med 2009) Mean 61 9 48 22 Goteborg (Hugosson, Lancet Oncol 2010) Mean 56 14 15 SPGS-4 (Bill Axelson, N Engl J Med 2011) Mean 65 15 17 8 Subgroup Absolute >65 33 20
Prospective cohort study 1147 men, 8 centres Side Effects of Biopsy: BMJ 2012 Jan 9:344 Pain in 44% (serious in 7%) Fever, chills 17.5% (serious in 5%) Hematuria 66% Hematochezia 37% Hematospermia 93% Overall 2% no sympotms 65% minor symptoms 32% moderate to severe symptoms
Change
US: 241,000 versus 28,000
Health Canada Web Site, 2010 PSA finds 3 Clinically Insignificant cases
Who Would And Would Not Benefit From Routine PSA Screening Groups who benefit Men who would have died from CaP but are cured owing to earlier detection / screening Groups who do not benefit (and may be harmed) Men with a false negative result Men with a false positive result Men who die from a PSA detected CaP Men who survive CaP without screening (die with/not of disease) Men whose CaP would never have been detected (overdiagnosis) Men whose quality of life was reduced out of proportion to the mortality reduction (even if they were spared a prostate cancer death)
Screening scenario 30% chance of elevated PSA 17% risk of positive biopsy Negative predictive value only 75% 4% chance of urosepsis, (fatal > 0%) Biopsy positive: 50% chance clinically insignficant 90% chance of radical treatment (US) If treated: 50% chance significant erectile dysfunction, 20% some incontinence Benefit: 20-30% mortality reduction At best, 1% absolute risk reduction in mortality Side effects are now; death avoided is in 10 or more years
Screening and overdiagnosis are selfreinforcing Screening exam Normal False positive Clinically significant disease Overdiagnosis Feel good Increased health related anxiety Outcome unaffected Outcome improved Owe their life to early detection
Patient Preferences are Critical Life quality vs quantity Treatment side effects Risk tolerance Value placed on present versus future
Prostate Cancer Cost Trends Average Annual Costs ($) Per Patient $80,000 $70,000 $60,000 $50,000 $40,000 $30,000 $20,000 $10,000 WW Surgery Radiation Hormone Chemo Miscellaneous $0 2000 2001 2002 2003 2004 Crawford ED, et al. Prostate Cancer Prostatic Dis. 2010;13(2):162-167. 30
The benefits of screening for Pca are uncertain The balance of risks and harms cannot be determined. Men should be informed of risks and benefits before PSA testing done. American Cancer Society AUA NCCN American College of Preventive Medicine US Dept Health and Human Services
How to reduce impact of over diagnosis with screening a) restrict testing to high risk groups b) Don t test if life expectancy short or comorbidity c) Accept there will be significant over diagnosis even if screening restricted to high risk groups d) Strive to avoid overtreatment Adjust for comorbidity and tumor factors Better tools: biomarkers for significant disease Active Surveillance Prevention strategies