History of Prostate Cancer Screening and Current CUA Guidelines

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1 History of Prostate Cancer Screening and Crrent CUA Gidelines COLIN LUNDEEN FEBRUARY 7, 2018 Objectives Review the history of prostate cancer (PCa) screening History of Prostate Specific Antigen (PSA) Major screening trials Controversy over screening Otline crrent CUA gidelines on PCa screening and early diagnosis 1

2 DRE Initially the gold standard for detection of prostate cancer Asymmetry, nodlarity, indration Many patients presented with late stage disease and symptoms 1987 stdy indicated that DRE was more efficient than PSA, TRUS, acid phosphatase or aspiration cytology for detection of prostate cancer 1 Ginan et al. Prog Clin Biol Res 1987 Transrectal Ultrasond (TRUS) Research into transrectal ltrasond began in the 1960s Initial images of very poor qality TRUS entered mainstream practice in the US in the 1980s Lee et al showed that TRUS cold detect Pca 1 Tmors are anechoic to hypoechoic Early stdies showed a sensitivity of 77% for TRUS 2 Specificity 89% Positive predictive vale only 15% 1. Lee et al. Prostate Mettlin et al. Cancer 1991 Watanabe et al. Ultrasond in Med & Biol

3 Prostate Specific Antigen (PSA) aka Hman kallikrein peptidase 3 (hk3) discovered 1979 Serine protease: liqefies semen throgh actions on seminogelin and fibronectin Released from prostatic epithelim highly organ specific Prodced by prostatic lminal epithelial cells Fond in seminal flid and serm (10 6 fold higher concentration in seminal flid) Also benign/malignant breast tisse, breast milk, adrenal/renal carcinomas (rare) PSA is NOT cancer specific Benign and malignant prostate tisse have similar, per cell, PSA expression 1 Elevated release of PSA into serm related to disrption of basement membrane and basal layers Prostate disease (prostate cancer, BPH, prostatitis) Prostate maniplation (prostate biopsy, prostatic massage, instrmentation) Falsely elevated PSA can be seen with: Ejaclation retrns to baseline within 48 hors 2 Cycling 10% increase with rides over 55km 3 Black men have higher PSA per prostate volme than white men 4 5α redctase inhibitors associated with ~50% decrease in PSA 5 1. CWU Tchetgen et al. Urology Mejak et al. PLoS One Fowler et al. Urology Gess et al. Prostate

4 PSA Stamey et al NEJM 1987 Compared PSA with prostatic acid phosphatase Findings: PSA elevated in newly diagnosed prostate cancer PSA increases with advancing stage and increasing tmor volme PSA drops to ndetectable levels following radical prostatectomy PSA sefl for detecting residal disease and early recrrence PSA cold be sed to monitor response to radiation therapy PSA Catalona et al NEJM 1991 Stdy grop: 1653 sbjects nderwent PSA testing If PSA >4.0mcg/L sbjects received DRE and TRUS If abnormality on either exam then TRUS biopsy performed Comparison grop: 300 men with TRUS biopsy de to symptoms or abnormal DRE Reslts Stdy grop: 6.5 % had PSA mcg/l (22% positive biopsy) 1.8% had PSA 10 mcg/l (67% positive biopsy) Cancers missed: DRE alone 32%, TRUS alone 43%, PSA alone 21% PSA had lowest error rate of three tests PSA + DRE was the best combination Similar reslts in Brower et al J Urol 1992 PSA : 26%, PSA > 10: 50% 4

5 Incidence of diagnostic tests Incidence of PCa increased nearly 80% from Prior to 1986 most Pca diagnoses were made with TURP In 1988 only 10% of biopsies were preceded by PSA testing Increased to over 50% by 1991 Potosky et al. JAMA 1995 Incidence of prostate cancer From 1985 to 1992 PCa incidence more than dobled Mortality peaked in 1993 has since been ct in half Siegel et al. CA Cancer J Clin 2017 Howlader et al,

6 Canadian Task Force on Preventative Health Care 1991 Goldbloom et al CMAJ 1991 Natral History 223 men with Pca No treatment ntil local spread/metastases Treatment once symptomatic with orchiectomy or estrogens All pts with Gleason 8-10 died before 10 years Three fold increase in Pca related death after 15 yrs Updated yr f/ 41% local progression 18% developed metastases 17% death from PCa Johansson et al. JAMA

7 PSA Ctoff 2950 men with PSA < 4 ng/ml Taken from control grop of Prostate Cancer Prevention Trial (PCPT) 2.3% of men had Gleason 7 Pca Risk of high grade disease increases with increasing PSA 6.7% of men with PSA had high-grade PCa Raised qestion to the historically sed PSA ctoff of 4ng/mL Thompson et al. NEJM 2004 USPSTF recommendations 2008 Moderate or high certainty that the service has no net benefit or that the harms otweigh the benefit Discorage se of this service 7

8 Prostate, Lng, Colon and Ovarian screening trial (PLCO) 2009 New England Jornal of Medicine Nmber of sbjects: 76,653 Recritment: Intervention: Reslts: Conclsion: Limitations: centers in the US Men aged Screening vs sal care - PSA yearly x 6 yrs and DRE yearly x 4 years PSA 4 or abnormal DRE triggered biopsy PCa related death: rate ratio 1.13 (95% CI ) at 7 years 22% increase in PCa diagnosis No difference in PCa mortality at 7 years Only 94 total PCa related deaths at 7 years Over 80% of patients in the control arm had PSA testing at some point (compared to 85% in screening grop) average PSA test/pt in control arm 2.7 Over 45% of participants had PSA prior to enrolling Only 35% of men with positive PSA screen nderwent biopsy Andriole et al NEJM 2009 Eropean Randomized Stdy of Screening for Prostate Cancer (ERSPC) 2009 New England Jornal of Medicine Nmber of sbjects: 182,160 Recritment: Intervention: Reslts: Conclsion: Limitations: Mltiple centers from 7 contries Men aged (core age grop 55-69) Screening vs no screening - initially with PSA q4yearly and DRE then jst PSA PSA 3 triggered a biopsy Cmlative incidence of PCa 8.2% screening vs 4.8% control Pca related death: rate ratio 0.80 (95% CI ) rate ratio 0.73 (95% CI ) in men actally screened 1410 men need to be screened and 48 men treated for Pca to prevent 1 death Screening redces Pca specific mortality Variety of ctoffs/screening methods between contries Schroder et al. NEJM

9 Goteborg 2010 Lancet Oncology Nmber of sbjects: 20,000 Recritment: Intervention: Reslts: Conclsion: Limitations: Poplation based registry Age Screening vs no screening - PSA q2yearly ntil age 69 PSA 3.4 ( , 2.9 ( ), 2.5(2005 ) Median follow p 14 yrs Cmlative incidence of PCa 12.7% screening vs 8.2% control PCa related death: rate ratio 0.56 (95% CI ) 293 men need to be screened and 12 men treated to prevent 1 death Screening redces PCa specific mortality Single city, sbset already inclded in ERSPC Hgosson et al Lancet Oncol 2010 Complications Carter et al J Urol

10 Complications Mottet et al Er Urol 2017 USPSTF recommendations

11 ERSPC 2012 & NNS and NNT decrease over time Schroder et al. NEJM 2012 Schroder et al Lancet 2014 Goteborg 2014 Relative risk redction for Pca specific mortality: 0.42 (95% CI ) Risk ratio: 0.58 (previosly 0.56) Nmber needed to screen: 139 Nmber needed to diagnose/treat: 13 Arnsrd Godtman et al Er Urol

12 Goteborg 2014 Significant decrease in NNI and NND with each additional year of follow p Arnsrd Godtman et al Er Urol 2014 Canadian Task Force on Preventative Health Care 2014 Bell et al CMAJ

13 Decline in Screening Both Pca incidence and Pca screening declined post USPSTF recommendations Jemal et al. JAMA 2015 Reslts of USPSTF 2012 recommendations Incidence of metastatic PCa increased by : -1.45%/year : 0.58%/yr : 2.74%/yr : 1.03%/yr predicted Similar findings by Glati et al. Cancer 2014 mpca incidence wold doble if PSA screening was ended Kelly et al. Er Urol Foc in press 13

14 How does PCa screening compare? Prostate cancer 1 PSA: relative risk 0.79 (Prostate cancer specific mortality) Based on ERSPC Nmber needed to screen (NNS): 781 Breast cancer 2 Mammography: relative risk 0.81 (Breast cancer specific mortality) all ages, average risk patients NNS: 2108 (age 40-49), 721 (age 50-59) Colon cancer 3 Fecal occlt blood: relative risk 0.82 (Colon cancer specific mortality) Age NNS: Schroder et al Lancet Myers et al JAMA Bacchs et al CMAJ 2016 PLCO 2017 Pinsky et al Cancer

15 USPSTF draft recommendations Clster randomized trial of PSA testing for Prostate cancer (CAP) RCT with over 400,000 patients in the UK (intention to screen) Randomized to one of two arms 1. PSA offered to men age Biopsy offered if PSA 3 Men with clinically localized prostate cancer were asked to participate in ProtecT trial Only 65,000 men in the intervention arm nderwent PSA testing 2. screening based on National Health Service recommendations Info given to men interested in PSA screening only Data not matre Trner et al, BJC

16 CUA Gidelines Prostate Cancer Screening and Early Diagnosis Rendon et al CUAJ 2017 CUA Gidelines Prostate Cancer Screening and Early Diagnosis Rendon et al CUAJ

17 CUA Gidelines Prostate Cancer Screening and Early Diagnosis Rendon et al CUAJ 2017 CUA Gidelines Prostate Cancer Screening and Early Diagnosis Rendon et al CUAJ

18 CUA Gidelines Prostate Cancer Screening and Early Diagnosis Rendon et al CUAJ 2017 CUA Gidelines Prostate Cancer Screening and Early Diagnosis Rendon et al CUAJ

19 CUA Gidelines Prostate Cancer Screening and Early Diagnosis Rendon et al CUAJ 2017 CUA Gidelines Prostate Cancer Screening and Early Diagnosis Rendon et al CUAJ

20 CUA Gidelines Prostate Cancer Screening and Early Diagnosis Increased risk of prostate cancer PSAV greater than 0.75 ng/ml/year PSAD greater than 0.15 ng/ml/cm 3 Free to total ratio less than 0.10 (PSA 4-10) Rendon et al CUAJ 2017 CUA Gidelines Prostate Cancer Screening and Early Diagnosis Rendon et al CUAJ

21 CUA Gidelines Prostate Cancer Screening and Early Diagnosis PCPT prostate cancer risk calclator (PCPT-RC) ERSPC prostate cancer risk calclator (ERSPC-RC) Rendon et al CUAJ 2017 CUA Gidelines Prostate Cancer Screening and Early Diagnosis Rendon et al CUAJ

22 Eropean Association of Urology Gidelines Mottet et al Er Urol 2017 Eropean Association of Urology Gidelines Mottet et al Er Urol

23 American Urological Association Gidelines Carter et al J Urol 2013 American Urological Association Gidelines Carter et al J Urol

24 American Urological Association Gidelines Carter et al J Urol 2013 Conclsions Screening redces PCa specific mortality Offer PCa screening to men with a greater than 10 yr life expectancy Risks of PCa screening mst be discssed with a patient inclding overtreatment, overdiagnosis and potential biopsy and treatment complications PCa screening shold be a shared decision making process mpmri with fsion biopsy is not standard of care for biopsy naïve patients 24

25 Acknowledgements Dr Gleave Dr So Dr Metcalfe Adjnctive strategies Zappala et al Rev Urol

26 Adjnctive strategies Zappala et al Rev Urol 2017 Adjnctive strategies Zappala et al Rev Urol

27 Adjnctive strategies Base test Age, PSA 4K Age, total PSA, free PSA, HK2, intact PSA Prostate Health Index Total PSA, free PSA, [-2]proPSA Zappala et al Rev Urol

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