Contemporary Approaches to Screening for Prostate Cancer

Contemporary Approaches to Screening for Prostate Cancer Gerald L. Andriole, MD Robert K. Royce Distinguished Professor Chief of Urologic Surgery Siteman Cancer Center Washington University School of Medicine St. Louis, Missouri

Prostate Cancer Stage Migration (USA) % Organ Confined % Regionally Advanced % Metastatic 1985 37 19 42 2009 91 4 4

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Oliver et al. IJC 2002

Impact of screening on CaP Mortality SEER 10 yr study comparing age-matched men in Seattle & Connecticut Seattle: 5.4x higher PSA test rate 2.2x higher Bx. rate 4.2x higher RP rate CaP death rate = identical (Shaw, 2004) Nested case-control study @ 10 VAMC in New England Men with CaP and/or death between 1991 and 1999 matched to living controls by factors including age, PSA screening intensity No difference in overall or cause specific mortality (Concato, 2006)

Effect of PSA screening on prostate cancer mortality Tyrol study Rates (x100000) 300 100 50 CaP mortality in Austria excluding Tyrol CaP mortality in Tyrol (PSA testing mandated) CaP incidence in Tyrol (PSA testing mandated) 10 1970 1975 1980 1985 1990 92 94 96 98 00 Year Horninger et al. Can J Urol 2005; 12 (Suppl 1): 7 13

Effect of Screening Simultaneous randomized prospective trials USA: PLCO Europe: ERSPC

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Geography of PLCO and ERSPC

PLCO ERSPC Age Group 55-74 50-74; 55-69 (Core) Enrolled 77,000 1993-2001 162,000 1991-2001 Locations 10 U.S. Centers 7 Eur. Countries Randomization Individual Population PSA Cutoff 4 ng/ml; community standard Pre- or post-consent 3 ng/ml (usual) DRE All men Some men Testing Biopsy Treatment Annual (PSA 6X; DRE 4X) Community Standard both arms Community Standard both arms Year 0 & 4 (usual) Year 0, 2 and 4 (1 center) Center v. Community Center v. Community

Screening and Biopsy in PLCO and ERSPC PLCO ERSPC Received 1 Screen 90% 82% Mean no. PSA tests 4.5 2.1 PSA Positivity 8% 16% Biopsy Rate (following suspicious test) 69% (@ 4 yrs.) 85% resolved 85% (1 st round; within 4 years) Biopsy PPV 33% 24% Cancers Screen Detected 73% 71% Contamination (approx.) 50% 15%

Prostate Biopsy in PLCO Pinsky, Andriole et al: J Urol: 173:746 (2005)

HR for Bx within 3 years in PLCO if T0 PSA>4 J Natl Cancer Inst 2005;97:433 8 Bx More Likely HR (p) Young Age 1.4 (0.04) Fam. Hx. CaP 1.2 (0.04) Bx Less Likely Hx. Prostate Sx 0.89(0.04) Prior Bx. 0.77(0.0006) Prior PSA 0.79(0.002)

Resolution by Study year if Positive screen BJUI 102:1524 (Dec. 2008) T0 (%) T1 (%) T2 (%) Cancer 34.7 24.0 18.0 Negative Biopsy Lower Repeat PSA/DRE nl 34.3 27.2 27.3 12.5 28.4 39.1 Unresolved 30.9 20.3 15.7

Probability of CaP and HG-CaP Based on Initial reaction to PSA >4 BJUI 102:1524 (Dec. 2008) % CaP (% Gleason >7) Overall 28.4 (29.9) 8.7 Repeat PSA 33.8 (29.7) 9.4 Repeat < 4 10.6 (22.1) 23.5 Repeat > 4 38.2 (30.9) 7.6 Direct to Bx 44.7 (30.1) 2.6 F/up > 1yr 18.4 (29.5) 24.9 Median Time to Dx. (Mos.)

PLCO Biopsy Analysis Validates that men are undergoing evaluation in accord with reasonable practice standards in the community

Prostate Cancer Incidence PLCO ERSPC* Screened Arm Usual Care Arm Screened Arm Usual Care Arm Cancers 3452 2974 5990 4307 Rate** (per 10,000 person years) 103 88 93 55 Rate Ratio (95% CI) 1.17 (1.11 to 1.22) 1.71 (1.32 to 2.33) * Core age group ** Rates for ERSPC estimated from paper Rates in screened are almost comparable as contamination and frequency of testing were greater in PLCO but greater rates of biopsy in ERSPC.

Prostate Cancer Mortality PLCO ERSPC* Screened Arm Usual Care Arm Screened Arm Usual Care Arm Deaths 92 82 214 326 Rate* (per 10,000 person years) 2.7 2.4 3.5 4.1 Rate Ratio (95% CI) 1.11 (0.83 to 1.50) 0.80 (0.65 to 0.98) *Core age group

My concerns about PLCO Pre-screening relatively high Biopsy/Evaluation takes 2-3 years Contamination in control arm Few overall deaths Tiny number of CaP deaths (92 v. 82)

My concerns about PLCO Pre-screening relatively high Biopsy/Evaluation takes 2-3 years Contamination in control arm Few overall deaths Tiny number of CaP deaths (92 v. 82) BUT, pre-screening and slow biopsy same in BOTH arms Trial remains powered to find a 20% mortality reduction (>90% still alive)

Concerns about ERSPC Variable screening protocols It may be more appropriate to analyze as a meta-analysis than as a single trial (Boyle and Brawley, Cancer, 2009)

Concerns about ERSPC Variable screening protocols It may be more appropriate to analyze as a meta-analysis than as a single trial (Boyle and Brawley, Cancer, 2009) 20% mortality reduction seen only on 3rd Interim analysis of core group P value 0.04 and upper confidence interval of 0.98 For all men: 15% mortality reduction and upper confidence interval equal to 1

Concerns about ERSPC Variable screening protocols It may be more appropriate to analyze as a meta-analysis than as a single trial (Boyle and Brawley, Cancer, 2009) 20% mortality reduction seen only on 3rd Interim analysis of core group P value 0.04 and upper confidence interval of 0.98 For all men: 15% mortality reduction and upper confidence interval equal to 1 Variable outcome by age strata

Benfit NS

Concerns about ERSPC Center v. community treatments (Appendix 7) RP rate 2.8x and XRT rate 1.8x higher in screened arm Small number of CaP deaths 214 v. 326 (162,000 men)

Treatment in ERSPC Wolters, et al: Int J Cancer Most information concerns primary therapy only More missing information in control arm Study arm was predictive of therapy (p=0.018) Control arm had reduced rate of RP, increased rates of AS, RT and HT Screened arm pts. 5x more likely to be treated at University hospital Largest differences observed in high-risk nonmetastatic men

Treatment of High-Risk non-met. CaP in ERSPC Wolters, et al: Int J Cancer Screen Control RP 34.2% 19.6% HT 14.7% 29.5%

Why concern about treatment effects in ERSPC? It is now clear that drop in CaP mortality in 1990s was due to treatment changes Too early for screening per both trials Radical Prostatectomy rates increased 10x between 1980 and 1990 (Lu-Yao, J Urol 1997)

Why concern about treatment effects in ERSPC? Overall CaP death rates in ERSPC higher than PLCO ERSPC: Screened 3.3 (66.4% known treated) PLCO: Screened 2.7 (90% treated) The control arm of ERSPC (4.1 CaP deaths) has less intense treatment screened arm? Due to prevailing attitudes in the community Most benefit occurred in countries with a high baseline CaP death rate

Age-Adjusted CaP Mortality per 100,000 men Sweden 20.4 Finland 15.2 Netherlands 15.1 Switzerland 14.9 USA 10.8 Spain 10.8 Italy 10.5

ERSPC If 1410 men are serially screened 226 will undergo a prostate biopsy 48 with cancer potentially need to be treated (e.g, Radical Prostatectomy) 1 CaP death will be averted Absolute mortality reduction of 0.5% For 1000 men, 25 instead of 30 will die of prostate cancer

Let s put a 20% reduction in Prostate cancer mortality in perspective Prior to PSA (1985) 8.5% chance CaP diagnosis and 2.5% CaP death 2005 in USA 16.6% chance of diagnosis (half men getting screened) and 3.0% CaP death If widespread screening and treatment ~20% chance of diagnosis and 2.4% chance of death We are back to 1985, except 2-3 fold increase of diagnosis For 1000 men, 24 instead of 30 would die of CaP

CaP Incidence: 1985 and 2009 Prostate 25% Lung & bronchus 15% Colon & rectum 10% Urinary bladder 7% Melanoma of skin 5% Non-Hodgkin 5% lymphoma Kidney & renal pelvis 5% Leukemia 3% Oral cavity 3% Pancreas 3% All Other Sites 19%

CaP Death: 1985 and 2009 Lung & bronchus 30% Prostate 9% Colon & rectum 9% Pancreas 6% Leukemia 4% Liver & intrahepatic 4% bile duct Esophagus 4% Urinary bladder 3% Non-Hodgkin lymph. 3% All other sites 25%

Proportion of men considered to have an abnormal PSA Proportion abnormal 50% 40% PSA >2.5 ng/ml 30% PSA >4 ng/ml 20% 10% PSA >6 ng/ml PSA >8 ng/ml PSA >10 ng/ml 0% 40 49 50 59 60 69 70 79 80 Age groups (years) 10-year risk of prostate cancer death Welch et al. J Natl Can Inst 2005; 97: 1132 7

The ratio of incidence to mortality is high for PCa Ratio of incidence to mortality is high 1,2 Thus, more cases of cancer are diagnosed than will ever cause death 7 6 5 4 3 2 1 0 Incidence to mortality ratio 3.9 EU 6.1 US 1 2 1. Ferlay et al. Ann Oncol 2007;18:581 92. 2. http://seer.cancer.gov/statfacts/html/prost.html

Risk Migration: US Men, 1990-2007 Patients, % 100 80 60 40 20 27.4 16.5 26.5 29.6 21.7 19.5 25.1 33.7 13.2 15.8 24.0 47.0 13.1 10.7 27.6 48.6 13.7 10.3 30.0 46.0 High Intermediate/High Intermediate Low 0 1990-94 1995-99 2000-01 2002-03 2004-07 Risk Distribution by Year of Diagnosis Cooperberg MR, et al. World J Urol. 2008;26:211-218.

Tumour volumes and % insignificant* tumours in 386 men screened in round 1 of ERSPC (Rotterdam) Percent insignificant tumours 70% 60% 50% 40% 30% 20% 10% 0% 3.0 2.5 2.0 1.5 1.0 0.5 0.0 <3.0 3.0 3.9 4.0 9.9 10 *Insignificant according to Epstein criteria PSA (ng/ml) Volume (ml) Schröder et al. EAU-EBU Update 2006;4(2):71 81.

Copyright 2009 American Cancer Society FIGURE 3 Annual Age-adjusted Cancer Incidence Rates among Males for Selected Cancers, United States, 1975-2005 From Jemal, A. et al. CA Cancer J Clin 2009;0:caac.20006v3

Most Men Diagnosed with CaP are Treated

Making sense of PLCO and ERSPC Don t screen if life expectancy is <10 years Await longer follow up of PLCO Evaluate sub-groups Test new markers in biorepository Must explain impact of treatment difference on the mortality benefit in ERSPC Acceptance that there is significant overdiagnosis and treatment associated with screening Must find ways to reduce overdiagnosis Risk Reduction strategies Must find ways to reduce overtreatment Molecular markers to ID significant disease and define those appropriate for AS or focal ablation

PLCO Prostate Subcommittee Urologists NCI G. Andriole, Chair C. Berg C. Amling R. Hayes D. Crawford G. Izmerlian R. Grubb B. Kramer D. Levin Westat A. Miller D. Carrick P. Pinksy B. O Brien L. Ragard Others T. Riley D. Chia T. Church IMS D. Reding J. Ciapp B. Wilcox