1. Overdetection of prostate cancer ESMO Brussel 2007 Chris H.Bangma Erasmus University Medical Centre Rotterdam, The Netherlands

2. Increasing Pca incidence with age 225.000 in Europe annually

3. PSA and cancer incidence in men aged 50-75 Proportion Prostate Cancer

4. Clinical incidence over time increases (Netherlands)

5. The diagnosis of low risk prostate cancer is increasing Cooperberg et al, J Urol 2003 Year ‘90 ‘92 ‘94 ‘96‘98‘00 % of patients 20 40 60 80 100 0

6.  Albertsen tables JAMA ‘97  N=767  Clinical stage ≤ T2  Palliative treatment  Dark grey = PCa †  Light grey = nonPCa †  White = survival Natural course of Pca

7. There is more cancer than we can detect currently  Autopsy data (Gosselaer 2005)  Cystoprostatectomy data (Damiano R, Eur Urol 2007) Sakr 1993

8. 5.1 2.5 1.6 2.4 2.6 3.2 1.1 1.7 Pca detection frequency in screening ERSPC first round 260.000 participants aged 50-75 in 8 EC countries

9. Tumor volumes in 550 radical prostatectomy specimens per PSA range detected in round 1 and 2 (ERSPC Rotterdam) minimal tumours: <0.5 ml, Gleason <7 Overdiagnosis estimated to be 54 % in screening (Draisma 2003)

10. Conclusion 1: Big wave of small cancers…big threat of overdiagnosis (and subsequent overtreatment!) Hokusai 1830

11. Can we recognise indolent tumours upfront? (Steyerberg, Kattan, Roobol, et al. J Urol 2007)  247 patients Pca T1-2 >> radical prostatectomy>> step section histology  121 (48 % !) indolent disease (<0.5 ml, no Gleason 4)  Statistic analysis identifies relevant prognostic factors  Age  PSA  Prostate volume  Micturition complaints  Stage  Grade  Cancer volume in biopsies  Number of positive cancer biopsies

13. Predicted probability of indolent cancer according to sum of scores

14. Active surveillance: strategy to deminish overtreatment of minimal cancers Active surveillance: regular monitoring, and delayed invasive treatment on signs of tumour progression Watchful Waiting Active Surveillance

15. PRIAS: free access www.prias-project.org  PRIAS means Prostate cancer Research International: Active Surveillance  It is a web-based tool used to include and follow-up patients considered to have indolent disease  International observational study based on experience in watchful waiting and guided by experts to optimise active surveillance  http://www.urosource.com/congress-television/berlin-2007/ http://www.urosource.com/congress-television/berlin-2007/

16. PRIAS inclusion: conservative approach  Criteria for inclusion in PRIAS: 1. Histologically proven adenocarcinoma of the prostate 2. Men should be fit for curative treatment 3. PSA-level at diagnosis ≤ 10 ng/mL 4. PSA density (PSA D) less than 0,2 5. Clinical stage T1C or T2 6. Adequate biopsy sampling (see 'biopsy protocol') 7. Gleason score 3+3=6 8. One or 2 biopsy cores invaded with prostate cancer 9. Participants must be willing to attend the follow-up visits Exclusion-criteria: 1. Men who can not or do not want to be irradiated or operated 2. A former therapy for prostate cancer

17. Year 1Year 2Year 3 - ~ PSA 4 times 2 times a year DRE 2 times1 time1 time a year Repeat biopsy 1 time At 4, 7 and 10 years, thereafter every 5 years Visit 2 times1 time Schedule active surveillance study Analysing biologic tumour behavior Correcting for sampling errors

18. Flowchart for follow-up PSA kinetics can indicate a biopsy or treatment shift

19. Unique protected individualised entry

21. Modification of follow- up data feasible: curves

22. Is active surveillance safe?  Natural course of disease of Gleason 6 cancer after 20 years 85-96 %  Lead time of 12 years in screening setting  D’Amico: low risk population (PSA<10, Bx Gleason <7 and T1-2): 5 year cancer specific survival after therapy of 98%  Klotz 2005: PSADT< 2 years as an indication for active therapy after active surveillance misses few progressive tumours over 8 years (1 % metas)  ERSPC: 100% tumour specific survival in 61 patients over 4 years of active surveillance (Roemeling 2006)  Delayed radical prostatectomy does not increase tumor stages (Carter 2003, Roemeling 2007)

23. Overall and cancer specific survival minimal (cGleason  6, PSA  10, T1c) versus relevant cancers (> Gleason 6, cT2) Overall survival Pca specific survival months 10 year

24. What can we offer European men? Men want to know their risks….how can we reduce overdiagnosis?  Level 1: Man age 55 – 74: do I need to screen?  Level 2: PSA known: shall I visit a urologist?  Level 3: Levels 1+2, DRE, TRUS, and prostate volume known: do I need a biopsy?  Level 4: Biopsy result known: do I need a therapy? PRIAS?  Level 5: first biopsy shows no cancer: do I need a second screen?  Level 6: in case of cancer: what is my risk to get metastases?

25. Future: reducing overdiagnosis will reduce overtreatment. Risk calculators  We may offer risk analysis to decrease wild screening / rescreening in low-risk groups  Avoid screening of asymptomatic cancers in the elderly: only 0.09% of men aged 70-75 in ERSPC died in six years of Pca (Roobol 2007)  Avoid rescreen within 5 years in men with PSA< 1.0 (Roobol, Prostate. 2006, Crawford, J Urol. 2006)

26. Conclusion 2: overdiagnosis in Europe Can men be protected?  Overtreatment of indolent tumours can be avoided with active surveillance (www.prias-project.org)www.prias-project.org  Introduction of step-wise risc-calculation will likely reduce overdiagnosis in men aware of prostate cancer (EAU- website:www.urolog.org)www.urolog.org  Active Surveillance policies should be improved with respect to patient inclusion and monitoring by validated markers

27. Europe as a scaffold to integrate research for prostate cancer patients Industry Biomarker research: P-MARK, PROCABIO Patient organisations: Europa Uomo Health care professionals: EAU Research programs: ERSPC, EORTC

28. year 1years 2-4 WP1: Biorepository management Management serum and tissue validation set Management prospective biomaterials from active surveillance study WP2: Proteomics biomarkers & WP3: Genomics biomarkers Marker validation for discrimination indolent and progressive PCa Clinical implementation selected markers in active surveillance study Marker format optimisation Active surveillance biorepository outcome Marker implementation in treatment policies WP4: Clinical study Preparatory phase participating clinical centres European multi-centre active surveillance study Cohort A: entry by set parameters Cohort B: entry by risk calculator Evaluation intermediate endpoints WP5: Public relations Informing stakeholders on active surveillance Informing stakeholders on progress and outcome active surveillance study and marker implementation Guidelines on active surveillance year 1years 2-4 WP1: Biorepository management Management serum and tissue validation set Management prospective biomaterials from active surveillance study WP2: Proteomics biomarkers & WP3: Genomics biomarkers Marker validation for discrimination indolent and progressive PCa Clinical implementation selected markers in active surveillance study Marker format optimisation Active surveillance biorepository outcome Marker implementation in treatment policies WP4: Clinical study Preparatory phase participating clinical centres European multi-centre active surveillance study Cohort A: entry by set parameters Cohort B: entry by risk calculator Evaluation intermediate endpoints WP5: Public relations Informing stakeholders on active surveillance Informing stakeholders on progress and outcome active surveillance study and marker implementation Guidelines on active surveillance Tailored treatment (Active Surveillance) by PROstate CAncer BIOmarkers: PROCABIO

29. Detection of indolent cancers PSAirways …risk of flying…