PSA screening: Controversies and Guidelines John Phillips, MD, FACS Department of Urology Urology Center of Westchester New York Medical College
Historical PerspecGve Cancer of the prostate, although rare, is probably more common than stagsgcs indicate. No radical operagon for permanent cure has yet been devised. Any operagon to be of value must be early and radical. Hunter McGuire, MD Medical Record, 6/8/1895
Historical PerspecGve History shows that carcinoma of the prostate is an inevitably fatal disease When all is said and done, all we can accomplish is to relieve the local condigon J.M Birnie, Springfield MA The only Gme when a prostate carcinoma can be radically (cured) is when one finds, in the course of an operagon for benign growth, so small an area of carcinoma as to be demonstrated only by the pathologist. W.M.C. Quinby, Boston Medical and Surgical Journal, 1-26- 1922
Quest for an Early Marker ProstaGc Acid Phosphatase 1950 Alkaline Phosphatase 1952 The Discoverers of PSA M.C. Wang et al, Roswell Park, 1982
Prostate Specific AnGgen PSA (1979) Tracked with stage of disease Early use in forensic medicine First use in screening: Cooner 1988, Catalona 1991 1,653 volunteers seeking men > 50 years of age Cancer in 2.2%, 32% of which would have been missed American Cancer Society recommends PSA and DRE be used as a screening tool for prostate cancer 1993 established cut- offs for age
ROC performance
PSA performance PSA SensiGvity Specificity 0.5 0.99 0.13 1 0.96 0.44 2 0.78 0.75 3 0.59 0.87 4 0.44 0.92 5 0.33 0.95 10 0.13 0.99 20 0.05 1
Distribution of plasma prostate specific antigen (PSA) concentrations in cases and controls. Holmström B et al. BMJ 2009;339:bmj.b3537
Pre- PSA Prostate Cancer Staging A B C D Incidence of Prostate Cancer 1956-1986 Whitmore- Jeweg ABCD staging A Non- Palpable Disease (derived from TURP) B Palpable Disease (B1/B2 with/without bilateral involvement) C ExtraprostaGc Disease (C1/C2 without/with seminal vesicle involvement) D MetastaGc Disease
Pre- PSA Prostate Cancer Staging T1 T2 T3 T4 Incidence of Prostate Cancer 1989 The T component of the TMN clinical staging of prostate cancer. T1 non- palpable disease (T1a < 5% chips, T1b > 5 % chips) T2 Palpable disease (T2a < 50% one lobe, T2b >50% one lobe, T2c bilateral T3 Extracapsular disease T4 ConGguous involvement
Post- PSA Prostate Cancer Staging T1a T1b T1c T2 T3 T4 Prevalence of Prostate Cancer 1992 TMN ProporGon of new T1c prostate cancer in 1989: 6%. In 1999: 47%
Post- PSA Prostate Cancer StaGsGcs
Clinical Sequellae of PSA tesgng Benefits: Early DetecGon of Cancer Risks: Prostate Biopsy Sepsis (0.4-2.7%) Urinary Tract InfecGon Hematuria Hematochezia Pain DetecGon of Non- Lethal Cancers Anxiety Cost (Prostate Biopsy: $1250-3500)
What are we finding? Donald Gleason 1920-2008 Will Rogers 1879-1935
Trials to Address the Benefits of Screening The Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial PLCO NaGonal Cancer InsGtute (NCI)- sponsored Determine the effects of screening on cancer- related mortality men 55 to 74 Screening component of the trial was completed in 2006 Outcomes including prostate- specific survival assessed Annual Screening versus usual care European Randomized Study of screening for Prostate Cancer ERSPC Screening versus no or ligle screening
PLCO vs ERSPC PLCO: PSA screening contaminagon of up to 44% Underpowered to address organized versus opportunisgc care ERSPC Different PSA intervals, countries Low PSA background screening Study with best esgmate for the effect of screening vs no screening Within 55-69 year age group Quality of data was moderate for benefits Quality of data was high for harms
PLCO vs ERSPC: findings PLCO: No mortality benefit ERSPC 20% mortality benefit increasing to 29% at 10 years Number Needed to Screen = 1,410 Number Needed to Treat=48 (NNT breast 10) NNS 837 decreasing to 503 at 12 year follow up NNT 29 decreasing to 18 at 12 year follow up > 10 years of follow up are required to see benefits of screening
United States PrevenGve Services Task Force (USPSTF) 16 volunteer members experts in prevengon, evidence- based medicine, and primary care The Task Force does not have any members who are urologists. However, several are respected cancer researchers. M. Lefevre, MD K. Bibbins- Domingo, PhD
United States PrevenGve Services Task Force (USPSTF) A large U.S. study showed no benefit from screening A large European study that found the highest reported benefit suggests that no more than 1 man in 1,000 avoids death from prostate cancer because of screening. Other studies found no benefit at all. Based on this work, the Task Force concludes that many men are harmed as a result of prostate cancer screening and few, if any, benefit. RecommendaGon Grade: D There is moderate or high certainty that the service has no net benefit or that the harms outweigh the benefits.
AUA 2012 response RecommendaGons based on flawed or underpowered studies Acknowledges that shared- decision making in the face of uncertainty important USPSTF did not address high risk groups African Americans (H.R. 2.1 [95% CI 1.3-4.6] Family History (H.R. FDR 2.4 [95% CI 1.5-2.8] USPSTF did not address the morbidity of untreated disease USPSTF did not establish a risk- assessment strategy
AUA 2014 PSA Guidelines Recommends against PSA screening men < 40 years of age PSA screening in men 40-54 at average risk PSA screening in men > 70 years of age or < 10-15 years life expectancy Recommends Shared Decision making 55-69 Especially in AA men or FDRs Biannual screening May preserve benefit and reduce false posigves
There must be more than PSA? Free/total PSA PSA kinegcs Velocity VolaGlity doubling PSA density PSA isoforms Urinary PCA- III
A Post- PSA era Ocean of Prevalence versus the Shores of Incidence Risk StraGficaGon Increased Efficacy of Trigger Point Algorithms PCA- III tesgng Fusion MRI based biopsies AcGve Surveillance TMPRSS2:ERG mutagon status Male lumpectomy
Quoteworthy If even one man s life is saved by the PSA test, the work in PSA has been a success. T. Ming Chu, PhD 1996 Although there are many crigcs of PSA screening, there is no quesgon that it is more effecgve than mammography. Patrick Walsh 1994 We encourage clinicians not to screen (because) even a small possibility of benefit outweighs the known risk of harms. Michael LeFevre, MD 2012 If cure is possible, is it necessary; if a cure is necessary, is it possible? Willet H. Whitmore, 1962
Cases J.J. 14 12 10 8 6 4 2 0 Apr- 05 Sep- 05 Feb- 06 Jul- 06 Dec- 06 May- 07 Oct- 07 Mar- 08 Aug- 08 Jan- 09 Jun- 09 Nov- 09 Apr- 10 Sep- 10
Cases 6 5 4 3 2 1 0 K.M. Jul- 09 Sep- 09 Nov- 09 Jan- 10 Mar- 10 May- 10 Jul- 10 Sep- 10 Nov- 10 Jan- 11 Mar- 11 May- 11 Jul- 11 Sep- 11 Nov- 11 Jan- 12