1. Prostate Cancer in 2009, part I. Now and the future! Why we have ‘Active surveillance, its purpose, its outcome and other matters. Monique J. Roobol, PhD, MSc

2. Overview  The facts of prostate cancer  Screening for prostate cancer  Tumor characteristics over time  Management of prostate cancer  Active Surveillance  Risk indicator

3. The facts of prostate cancer Sakr 1993

4. The facts of prostate cancer Is PC always a life threatening disease?

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

6. The facts of prostate cancer Cancer death by type of cancer and age, The Netherlands, 2000 www.CBS.nl Cancer mortality increases strongly from 50 years of age onwards, peaking at ages 75-79 years. Prostate cancer is an important health problem.

7. The facts of prostate cancer  Conclusions:  1.Prostate cancer is a major health problem  2.Death from prostate cancer and/or metastatic prostate cancer should be avoided  3.The majority of detectable prostate cancer cases do not give any complaints or will lead to death  Early detection of especially those prostate cancer cases that cause symptoms and/or are life threatening is desirable

8. Overview  The facts of prostate cancer  Screening for prostate cancer  Tumor characteristics over time  Management of prostate cancer  Active Surveillance  Risk indicator

9. Screening for prostate cancer Belgium10.359 Finland80.379 France85.414 Italy14.977 Netherlands42.376 Spain4.278 Sweden19.911 Switzerland10.307 Total268.001 www.erspc.org

10. Screening for prostate cancer 21.166 men in control arm ? ? ? ? ? ? ? 42.376 men 21.210 men in screening arm PSA DRE TRUS Prostate biopsy Prostate cancer Death of prostate cancer Prostate cancer 9.176 2.241933 ? ? ? ? ? ?

11. Screening for prostate cancer  With applying a relatively non aggressive screening algorithm, i.e PSA cut-off value >= 3.0 ng/ml Sextant prostate biopsy a 4 year screening interval  The number of screen detected PC cancers is already more than twice as high as compared to the clinical setting  Conclusion: Screening results in a considerable increase of the incidence of PC  Question: Selective for potentially life threatening PC? 

12. Overview  The facts of prostate cancer  Screening for prostate cancer  Tumor characteristics over time  Management of prostate cancer  Active Surveillance  Risk indicator

13. Tumor characteristics over time Screen detected PC, initial screening 76% of T1C cases has Gleason score 6 Screen detected PC, repeat screenings 87% of T1C cases has Gleason score 6 Percentage of potentially indolent PC increases ERSPC, Rotterdam ( 1993-2009)

14. Tumor characteristics over time 59% of t1C cases has Gleason score 6 Percentage of potentially indolent PC increases, also in the clinical setting ERSPC, Rotterdam ( 1993-2009), PC detected in control arm

15. Tumor characteristics over time  PSA use in the clinical setting is increasing and subsequently also the clinical detection of potentially indolent PC.  PSA based screening is becoming more and more common and is not selective for potentially life threatening prostate cancer

16. Overview  The facts of prostate cancer  Screening for prostate cancer  Tumor characteristics over time  Management of prostate cancer  Active Surveillance  Risk indicator

17. Management of prostate cancer  Albertsen tables JAMA ‘05  N=767  Clinical stage ≤ T2  Palliative treatment  Dark grey = PCa †  Light grey = nonPCa †  White = survival Remember: app 60% of cases had Gleason score <= 6 Much more die with PC than of PC

18. Management of prostate cancer

20. HormonesSurgeryRadio Ther.AS PC cases detected within ERSPC Rotterdam. Clinical stage T1C or T2A. Active treatment in app. 70% of the cases

21. Overview  The facts of prostate cancer  Screening for prostate cancer  Tumor characteristics over time  Management of prostate cancer  Active Surveillance  Risk Indicator

22. Active Surveillance ‘primum non nocere’ ("First, not to harm." ) In the case of prostate cancer : Cure might not be possible in those whom it is needed… … but cure may not be needed in those whom it is possible… (Whitmore 1988)

23. Active Surveillance  Overdiagnosis would not matter if treatment had no adverse effects.   It would be acceptable to treat all cases, including those destined never to cause symptoms.  However, while radical treatment for  prostate cancer may or may not improve  a man’s longevity, it can certainly have  a big impact on his lifestyle.  Ideally, such intervention should  be restricted to those who need it. 

24. Active Surveillance  Aims to individualise the management of PC by offering curative treatment in those cases with evidence of biochemical or histological progression. Watchful waiting, a policy of observation with the use of palliative treatment for symptomatic progression. I would have been here sooner

25. Active Surveillance  Prostate Cancer Research International: Active Surveillance  Spin off from the European Randomized Study of Screening for Prostate Cancer (ERSPC)  Initiative of the Department of Urology of the Erasmus Medical Centre  Based on available literature  Prospective study design, ongoing evaluation, aid in decision making  Main goal is to reduce over treatment  It also provides an ideal setting for research to identify new markers, which, in the future, could improve our ability to determine which men need, and which men do not need, treatment for their prostate cancer.  Web based study, accessible for urologists all over the world

26. Active Surveillance

27.  Inclusion criteria:  PSA  10  PSA density <0,2   T2  Gleason  3+3=6   2 positive biopsies

28. Active Surveillance  Follow-up criteria:  PSA doubling time (DT) >3 yr   T2  Gleason  3+3=6   2 positive biopsies  If PSA >20: Bonescan  If PSA DT 3-10 yr: Yearly rebiopsies

29. Active Surveillance  Timetable:  PSA (1x / 3 mo) (1x / 6 after na 2 yr)  DRE (1x / 6 mo) (1x / 12 mo after 2 yr)  Rebiopsies (standard after 1, 4 and 7 yr)

31. Active Surveillance

33. Active surveillance Baseline characteristics (N=500)

34. Active Surveillance PSA-DT and rebiopsy findings

35. Active Surveillance Deferred active therapies and reasons for treatment change

37. Active Surveillance Anxiety and distress during active surveillance (N=129)

38. Management of prostate cancer Outcomes of PC eligible for Active Surveillance who were managed expectantly (ERSPC, N=616) Van den Bergh et al. Eur urol 2008. PSA < 10.0 ng/ml PSA-density <0.2 ng/ml per ml Stage T1C/T2 Gleason score 3 + 3 = 6 <= 2 positive biopsy cores

39. Management of prostate cancer  The calculated (Kaplan-Meier) 10-yr PCa-specific survival was 100%, which sharply contrasted with 77% overall survival. Men still alive showed favourable PSA characteristics.  The calculated 10-yr treatment-free survival was only 43%, objective signs of progression often did not indicate the shift to radical treatment.  Conclusions: AS seems justified in selected men. Prospective protocolbased AS programs are necessary to optimise selection criteria and to find the appropriate trigger points for switching to active therapy.

40. Follow-up regimen and preliminary results (Klotz et al 2007, Choo et al 2002)  Visits every 3 months for 2 years, later 6 monthly, PSA, DRE, one biopsy month 18  Active treatment: either PSADT < 2 years (later < 3 years), upgrade biopsy or clinical progression  331 men, follow-up 5.8 years, 34% are off surveillance  15% had PSA progression  3% clinical progression  4% histological progression  3 patients died of PC after treatment (99% DSS) at 7 year follow-up

41. Follow-up regimen and preliminary results (Carter et al 2007)  Biannual visits, annual biopsy (>= 12 core), PSA and DRE  Active treatment: biopsy decisive, Gleason pattern 4 or 5, > 2 cores+, more than 50% PC in one core, PSA change no trigger  407 men, follow-up 3-4 years, 103 (25%) treated  10/49 treated by RP (20%) potentially non curable

42. Active Surveillance  Make the PRIAS website accessible for more (European) countries  Inclusion based on nomogram use?  Inclusion and/or follow-up based on new biomarkers?  Establishment of biorepository ( PROCABIO)  Individual active surveillance protocol, depending on comorbidity and age?  Quality of Life on long term?  Is delay in radical treatment dangerous? ( evaluations ongoing)  Costs?  PRIAS will be a important source of information with respect to application and safety of active surveillance

43. Overview  The facts of prostate cancer  Screening for prostate cancer  Tumor characteristics over time  Management of prostate cancer  Active Surveillance  Risk Indicator

44. Prostate Cancer Risk Indicator  A decision aid for lay men and urologist to help them in the question prostate cancer screening yes or no  www.urosource.com www.urosource.com  Gives balanced information on pro’s and con’s  Gives risk estimates on having a biopsy detectable prostate cancer on 5 different levels  Gives risk estimate on potentially indolent prostate cancer  Validated for understanding and effect.

50. PRIAS, THE study for Active Surveillance  Questions ? Interested in future participation ?  Protocol and PIF’s can be translated into own language (Europa Uomo)  Always acces to own data  Participation in scientific research  www.prias-project.org  r.vandenbergh@erasmusmc.nl  m.roobol@erasmusmc.nl