Prostate Cancer Screening Eric Shreve, MD Bend Urology Associates
University of Cincinnati Medical Center
University of Iowa Hospitals and Clinics
PSA Human kallikrein 3 Semenogelin is substrate Concentration in semen is a million-fold higher than found in serum Discovered 1979 Clinical application 1980s-1990s
PSA Prostate cancer cells secrete less PSA Elevated PSA likely result of destabilization of prostate histological architecture 5a reductase inhibitors
Screening DDx: cancer, BPH, inflammation Trauma DRE Instrumentation ejaculation Variation Age, race, medication, sunlight
Rising PSA Without BPH 0.04 ng/ml / year BPH 0.07-0.27 ng/ml / year Disruption of cellular architecture loss of basal layer
Positive predictive value <4 <2.5 ng/ml -- <2% 2.5 4 ng/ml -- 18% 4-10 25% >10 67%
PSA density For PSA between 4-10 (normal DRE) PSA / prostate volume PSAD >0.15 suggestive of cancer May fail to detect 50% of cancers
PSA velocity PSA between 4-10 >0.75 ng/ml per year 72% of men with cancer, 5% of men without cancer had elevated velocity Specificity 90% Sensitivity 79% (11% when total PSA<4)
Age-specific levels
Age-specific levels
%Free PSA
% Free PSA May also suggest aggresiveness Factors that do not change %free: Race Sunlight finasteride
Prostate cancer screening Cancer rarely causes symptoms 80% asymptomatic, based on PSA or DRE 50-70% decline in distant disease at diagnosis between 1986-1999
Criteria for use as a screening test Significant burden of disease Preclinical stage is prevalent Screening tests are acceptable, inexpensive, and accurate Effective treatment is available Early detection improves outcomes with acceptable morbidity
Benefit of screening? Does it extend life expectancy? Does screening lead to health problems? Do the benefits outweigh the harm?
Controversy Lifetime risk of death from prostate cancer 3% Lifetime risk of prostate cancer dx 17% Screening WILL result in overdiagnosis Screening is higher in older men 48% in age 50-59 56% in age >80
SEER database PSA>4 7.6% (760) Positive biopsy 25% (190) High grade 19% (36) PSA<4 92.4% (9240) Positive biopsy 15% (1386) High grade 15% (208)
PLCO, 2009 77,000 males, age 55-74 Randomized to annual PSA and DRE vs usual care 7 year followup 17% more cancers detected in screening arm No difference in cancer-specific death 50 vs 44 at 7 years 92 vs 82 at 10 years
PLCO criticisms 2/3 of men randomized received prior prostate cancer screening May have eliminated high risk patients 85% of men in screening arm were not compliant 57% of men in control arm underwent screening 31% of men with abnormal DRE and PSA >4 received biopsy
ERPC, 2009 182,000 males, age 59-69 Randomized to DRE and PSA every 4 years vs control (no screening) 9 year followup 39% more cancers detected in screening group 20-31% reduction in prostate cancer death in screening group
ERPC criticisms Very few (no data) were screened prior to study Contamination of control group 15% Compliance with biopsy 85% NNS = 1400 NNT = 48 at 9 years
Goteborg (Swedish) study 20,000 males, age 50-64 Screening (PSA every 2 years) vs usual care Median f/u 14 years More cancers detected in screening arm 1138 vs 718 Fewer prostate cancer deaths in screening arm 44 vs 78 40% lower risk of prostate cancer death in screening arm
Goteborg trial, 2010 No difference in overall mortality 1981 vs 1982 Mortality benefit not seen for 7-8 years To prevent one prostate cancer death 293 screened 12 treated 40% chose surveillance over treatment
Goteborg criticisms Low threshold for biopsy Initially 3, decreased to 2.5
Scandinavian Prostate Cancer Group 4 trial surgical management of localized, clinicallydetected prostate cancer was associated with about a 6% absolute reduction in prostate cancer and all-cause mortality at 12 15 years' followup; benefit appeared to be limited to men younger than age 65 years J Natl Cancer Inst. 2008 August 20; 100(16): 1144 1154. Published online 2008 August 20. doi: 10.1093/jnci/djn255
PIVOT trial 731 males with localized prostate cancer Randomized to surgery vs observation After 12 years, intention to treat with radical prostatectomy resulted in nonstatistically significant differences in disease-specific and allcause mortality compared with observation that were less than 3% in absolute terms Wilt et al. Radical Prostatectomy versus Observation for Localized Prostate Cancer N ENGL J MED 2012; 367:203-213July 19, 2012DOI: 10.1056/NEJMOA1113162
PIVOT trial Subanalysis Low risk Intermediate risk PSA>10 Only group with PSA>10 showed benefit to RP (ARR 7%)
Screening downside Anxiety, depression Diagnosis significantly increases death from cardiovascular events Diagnosis significantly increases rates of suicide For every 1000 screened 1 DVT, PE 2 MI 40 incontinent, impotent
US Services Preventative Task Independent agency Force Preventative and primary care physicians Grade D recommendation Recommended against screening at any age
Table 1: What the Grades Mean and Suggestions for Practice A B C D Grade I Statement Definition The USPSTF recommends the service. There is high certainty that the net benefit is substantial. The USPSTF recommends the service. There is high certainty that the net benefit is moderate or there is moderate certainty that the net benefit is moderate to substantial. Note: The following statement is undergoing revision. Clinicians may provide this service to selected patients depending on individual circumstances. However, for most individuals without signs or symptoms there is likely to be only a small benefit from this service. The USPSTF recommends against the service. There is moderate or high certainty that the service has no net benefit or that the harms outweigh the benefits. The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of the service. Evidence is lacking, of poor quality, or conflicting, and the balance of benefits and harms cannot be determined. Offer/provide this service. Offer/provide this service. Suggestions for Practice Offer/provide this service only if other considerations support offering or providing the service in an individual patient. Discourage the use of this service. Read "Clinical Considerations" section of USPSTF Recommendation Statement. If the service is offered, patients should understand the uncertainty about the balance of benefits and harms.
USSPTF 90% of men with localized prostate cancer undergo treatment Up to 5 in 1000 men die within one month of prostate cancer surgery 10-70 in 1000 will have serious complications Chou R. Ann Intern Med. 2011 Oct 7.
Affordable Care Act (Health Care Reform) Requires medicare and insurances to cover preventative services recommended by USSPTF May cover those not recommended by USSPTF Department of Health and Human Services PSA still covered
Update AUA recommendations AUA annual meeting, 2013 Recommendations for not-at-risk individuals Asymptomatic No family history Not African American Men aged 40-54, without risk factors Screening not encouraged (not recommended against) Men over 70 or <10-15 year life expectancy Screening not encouraged (exceptions)
Update AUA recommendations AUA annual meeting, 2013 Men aged 55-69 Recommends shared decision making and screening based on values and expectations Guidelines now recommend biannual screening Prevents prostate cancer mortality in 1 of 1000 men screened over a decade AUA remains in disagreement with USSPTF recommendations
Does prostate cancer screening save lives? Higher rate of early stage detection Prostate cancer deaths have fallen during PSA era Due to screening? Due to increased awareness of disease and diagnostic testing?