1. Screening and active surveillance Bertrand TOMBAL Division of Urology Cliniques universitaires Saint Luc Brussels, Belgium

2. Introduction Natural History of Prostate Cancer

3. The pathways to death by cancer… Localized PIN 1 Malignant transformation Death Locally advanced 2 Local progression Metastatic 3 Generalization

4. Malignant transformation occurs frequently in the adult prostate Autopsies studies Sanchez-Chapado, Prostate 2003, 54, 238-247 Holund, Scand J Urol Nephrol 1980, 14, 29-35 Kabalin, J.Urol 1989, 141, 1091-4 Ward, Urol.Oncol., 2004, 22; 40-7 Localized PIN 1 Malignant transformation Sanchez-Chapado Holund Kabalin Ward Age 36-94 20-80 31-82 44-92 PSA range 0-2 ng/ml PCa Prevalence (%) 22 18.5 38 23

7. Prostate cancer distribution A 3 compartments model Normal / BPH Prostate cancer Potentially Lethal prostate cancer Ideal diagnostic Test

8. PCa diagnostic strategy DRE PSA Prostate Biopsy

12. Database analysis Baade PD et al., International trends in prostate-cancer mortality: the decrease is continuing and spreading. Cancer Causes Control 15:237–41, 2004. Year of Onset Period (years) Reduction Year (%) Total reduction USA 1994 8 5.1 40.8 Germany 1994 8 3.6 28.8 Australia 1994 8 4.9 39.2 Canada 1991 11 2.9 31.9 Austria 1991 11 2.1 23.1 Italy 1988 14 2.1 29.4 UK 1991 11 2.0 22.0 France 1988 14 1.9 24.7 Spain 1994 11 1.8 14.4

15. Randomized control trials. Screening and Prostate-Cancer Mortality in a Randomized European Study FH Schröder et al. N Engl J Med 2009;360:1320-8. Mortality Results from a Randomized Prostate-Cancer Screening Trial GL Andriole et al. N Engl J Med 2009;360:1310-9 .

17. ERSPC – Cumulative risk of death from prostate cancer PSA-based screening reduced the rate of death from prostate cancer by 20%

21. Distribution of PSA value in a given population aged 50 to 75 years old. Postma R, Schröder FH. Eur J Cancer 2005;41:825-33 From the 1 st Screening Round of the ERSPC (n=19970) 1/3 of healthy men will become patients

22. Incidence of PSA if only men with a + DRE below 3 ng/ml of PSA are receiving a biopsy From the 1 st Screening Round of the ERSPC (n=19970) Postma R, Schröder FH. Eur J Cancer 2005;41:825-33

23. PSA in middle age predicts PCa development in the following 25 years Lilja H, et al. J Clin Oncol 2007;25:431-6 Predicted probability of a prostate cancer diagnosis before age 75 years by total prostate-specific antigen (PSA) measured at age 44 to 50 years, with 95% Cls Probability of prostate cancer (%) 10 20 30 40 50 60 70 80 0 0 2 3 4 PSA at baseline venipuncture (ng/mL) ~38% 1 ~20%

24. Prostate specific antigen concentration at age 60 and death or metastasis from prostate cancer: case-control study A. Vickers et al. BMJ 2010;341:c4521

25. On average 4 biopsies are required to diagnose one PCa Postma R, Schröder FH. Eur J Cancer 2005;41:825-33 First round ERSPC n Biopsies Cancer Excess biopsy PSA 19970 n % n % < 2 ng/ml 13344 695 5% 49 7% 93% 2-4 ng/ml 3934 1013 25% 209 20% 80% > 4 ng/ml 2692 2409 89% 756 31% 69% 4117 1014 75%

28. The surgical imperative Prostate cancer screening: accepting the consequences of PSA testing. Chisholm GD. Br J Urol 1993;71:375–7 ‘ There is now the prospect of a prostatectomy holocaust, unless acceptable data can resolve this debate …’

33. Selectively eradicate cancers needing treatment avoiding collateral damages

36. Insignificant Prostate Cancer and Active Surveillance: From Definition to Clinical Implications PJ. Bastian et al. European urology 55 ( 2009) 1321–1332 Author cT PSA (ng/ml) Gleason PSA density Pos. cores Max % per core Epstein, 1994 T1c Gr. < 3 < 0,15 <3 <50 Dall’Era, 2008 ≤ T2a ≤ 10 Gr. < 3 < 0,15 <33% Soloway, 2008 ≤ T2 <15 Gr. < 3 <2 <50 PRIAS, 2007 ≤ T2b <10 Gr. < 3 < 0,20 <3 Van Ass, 2008 ≤ T2a <15 Sc < 7(3+4) <50% Klotz, 2010 < 10 <15 (>70 y.o) Sc < 7 Sc ≤ 3+4 Stattin, 2010 ≤ T2 < 20 ≤ 7

42. Insignificant Prostate Cancer and Active Surveillance: From Definition to Clinical Implications PJ. Bastian et al. European urology 55 ( 2009) 1321–1332 Study DRE PSA Rebiopsy TRUS Van As et al., 2008 Every 3 mo for 2 yr, then every 6 mo Year 1: monthly Year 2: every 3 mo Afterwards: every 6 m At 18–24 mo, then biannually No mention Dall’Era et al., 2008 Every 3 mo Every 3 mo Every 12–24 mo 6–12-mo interval Carter et al., 2006 Every 6 mo Every 6 mo Yearly No mention Klotz et al., 2005 Every 3 mo for 2 yr, then every 6 mo if PSA level is stable Every 3 mo for 2 yr, then every 6 mo if PSA level is stable At 12–18 mo Optional Patel et al., 2004 Every 3 mo for 1 yr, then every 6 mo Every 3 mo for 1 yr, then every 6 mo At 6 mo At 6 mo Soloway et al., 2008 Every 3 mo Every 3 mo for 2 yr At 6–12 mo, afterwards when indicated No mention Hardie et al., 2005 Every 3–6 mo for 2 yr, then every 6 mo Every 3–6 mo for 2 yr, then every 6 mo if PSA is stable Not routine Not routine

43. Insignificant Prostate Cancer and Active Surveillance: From Definition to Clinical Implications PJ. Bastian et al. European urology 55 ( 2009) 1321–1332 Study Median age yr (range) Median Fup mo Treatment criteria Van As et al., 2008 67 (50–79) 22 PSAV >1 ng/ml per year; Gleason score ≥4 + 3; >50% cancer per core Dall’Era et al, 2008 63.4 (40–86) 24 Gleason score ≥7 on rebiopsy, rising PSA, increase in volume by biopsy parameters Carter et al., 2006 65.7 (45.8–81.5) 23 Gleason score ≥7; any pattern 4, 5; >2 cores involved; >50% any single core involved. Klotz et al., 2005 NA 64 PSA DT <2 yr; Gleason score ≥8; Gleason score ≥7 (4 + 3) Patel et al., 2004 Mean: 65.3 (44–79) 44 Gleason score increase, PSAV >0.75/yr, increase DRE/TRUS detected lesion, increase biopsy volume Hardie et al., 2005 70.5 (59–81) 42 Rising PSA, clinical judgment Roemeling et al., 2007 69.8 (25–75) 40 PSA DT Ercole et al., 2008 68 (52–75) 48 Increase in tumour volume, Gleason score progression, urinary symptoms, change of DRE, patient preference Soloway et al., 2008 67 (mean: 66.02) 45.3 (mean) Gleason score increase, PSA and PSA DT increase, stage progression, increase biopsy volume, patient preference

53. Outcome of Primary Versus Deferred Radical Prostatectomy in the National Prostate Cancer Register of Sweden Follow-up Study B. Holmström, J.Urol Vol. 184, 1322-1327, 2010

55. ‘… an encounter with a urologist and, subsequently, his biopsy gun is the most powerful risk factor for its [prostate cancer] diagnosis.’ Rebalancing ratios and improving impressions: later thoughts From the prostate cancer prevention trial investigators J Clin Oncol 2005;23:7388–90 Talcott JA, et al. J Clin Oncol 2005;23:7388–90