1. Modern Management of Prostate Cancer With Active Surveillance PROSTATE CANCER SYMPOSIUM NORTHWESTERN UNIVERSITY FEINBERG SCHOOL OF MEDICINE SEPTEMBER 10, 2011

2. PROSTATE CANCER SYMPOSIUM NORTHWESTERN UNIVERSITY FEINBERG SCHOOL OF MEDICINE SEPTEMBER 10, 2011 Kristian R. Novakovic, MD, FACS Division of Urology NorthShore University HealthSystem

3. OVERVIEW 1. 1.Watchful Waiting Versus Active Surveillance 2. 2.Active Surveillance: Pros and Cons 3. 3.Prostate Cancer Over Diagnosis and Over Treatment 4. 4.Morbidity of Treatment 5. 5.NorthShore University HealthSystem Active Surveillance Clinical Trial 6. 6.Clinical Outcomes 7. 7.Risk Stratification 8. 8.Pathological Outcomes 9. 9.Conclusions

4. WATCHFUL WAITING VERSUS ACTIVE SURVEILLANCE Watchful Waiting Older policy involving no surveillance strategy with palliative treatment only for symptomatic progression Active Surveillance or Expectant Management With Curative Intent Men enrolled with strict criteria and followed closely with goal of identifying men for curative treatment at the first sign of progression

5. ACTIVE SURVEILLANCE PROS AND CONS Pros Screen-detected prostate cancers both over diagnosed and over treatedScreen-detected prostate cancers both over diagnosed and over treated All prostate cancer treatments associated with significant morbidityAll prostate cancer treatments associated with significant morbidityCons Window of curability lost by disease progression during period of active surveillanceWindow of curability lost by disease progression during period of active surveillance Patient anxiety during active surveillancePatient anxiety during active surveillance Morbidity of repeat biopsies every 12-18 monthsMorbidity of repeat biopsies every 12-18 months Increased difficulty of performing radical prostatectomy following multiple biopsiesIncreased difficulty of performing radical prostatectomy following multiple biopsies

6. PROSTATE CANCER OVER DIAGNOSIS AND OVER TREATMENT

7. PROSTATE CANCER PREVALENCE AND MORTALITY Newborn American male has 16% lifetime risk of being diagnosed with prostate cancer – 1 new case every 3 minutesNewborn American male has 16% lifetime risk of being diagnosed with prostate cancer – 1 new case every 3 minutes 1/3 of men over age 60 and 1/2 of men over age 70 have prostate cancer1/3 of men over age 60 and 1/2 of men over age 70 have prostate cancer But lifetime risk of death from prostate cancer is only 3%But lifetime risk of death from prostate cancer is only 3%

8. Prostate Cancer Screening Trials American Trial: 76,693 men between 55 and 74 randomized to either annual screening or usual care76,693 men between 55 and 74 randomized to either annual screening or usual care After 7-10 years of follow-up, death rate from prostate cancer was very low and did not differ significantly between the two study groupsAfter 7-10 years of follow-up, death rate from prostate cancer was very low and did not differ significantly between the two study groups European Trial: 162,243 men between 55 and 69 randomized to either annual screening or no screening162,243 men between 55 and 69 randomized to either annual screening or no screening For first 10 years of follow-up, risk of death from prostate cancer was the same between the two groups, but, after 10 years, there was a 20% decrease in risk of death in the screened groupFor first 10 years of follow-up, risk of death from prostate cancer was the same between the two groups, but, after 10 years, there was a 20% decrease in risk of death in the screened group

9. EUROPEAN TRIAL AMERICAN TRIAL Cumulative Hazard Year American and European Prostate Cancer Screening Trials

10. European Prostate Cancer Screening Trial At median follow up of 8 years, estimated 1410 men needed to be screened (NNS) and 48 men needed to be treated (NNT) to prevent 1 prostate cancer deathAt median follow up of 8 years, estimated 1410 men needed to be screened (NNS) and 48 men needed to be treated (NNT) to prevent 1 prostate cancer death Extrapolating these data:Extrapolating these data: Loeb, S, et al: 2010 American Association of Genitourinary Surgeons Annual Meeting (not presented) Years 91012 NNS1254837503 NNT432918 BUT: Men unselected for active surveillance, and mean life expectancy at age 65 is only 14 years

11. MORBIDITY OF TREATMENT

12. Biochemical Recurrence Rates and Recovery of Urinary and Erectile Function at 1 Year Following Radical Prostatectomy Eastham, J.: AAGUS, May, 2010 Each circle represents a single surgeon, and the size of the circle is proportion to the number of patients treated by that surgeon.

13. RANDOMIZED TRIAL OF WATCHFUL WAITING VERSUS RADICAL PROSTATECTOMY Scandinavian randomized trial of 695 men found absolute risk reduction of 6.1% in prostate cancer deaths at 15 years in men undergoing radical prostatectomy vs watchful waitingScandinavian randomized trial of 695 men found absolute risk reduction of 6.1% in prostate cancer deaths at 15 years in men undergoing radical prostatectomy vs watchful waiting –Number needed to treat to prevent 1 prostate cancer death – 15 Benefit more pronounced in men < 65 years of ageBenefit more pronounced in men < 65 years of age –Number needed to treat – 7 Men in “low risk” group also derived benefitMen in “low risk” group also derived benefit –4.2% reduction Bill-Axelson, A, et al, Radical prostatectomy versus watchful waiting in early prostate cancer: NEJM 364:18 (1708-1717), 2011.

14. NORTHSHORE UNIVERSITY HEALTHSYSTEM ACTIVE SURVEILLANCE CLINICAL TRIAL

15. NORTHSHORE UNIVERSITY HEALTHSYSTEM ACTIVE SURVEILLANCE CLINICAL TRIAL ELIGIBILITY CRITERIA Age > 60 yearsAge > 60 years Men meeting the six following clinical and pathologic criteria:Men meeting the six following clinical and pathologic criteria: 1.Clinical stage T1c or T2a prostate cancer, verified by a NorthShore University HealthSystem urologist. 2.Biopsy Gleason Score < 6, with no primary or secondary 4 or 5 tumor pattern; pathology verified by NorthShore University HealthSystem pathologist. 3.Diagnosis of prostate cancer made on at least a 12 core needle biopsy with < 3 cores positive for cancer. 4.Maximum tumor length < 50% of any core. 5.Total tumor volume < 5% of biopsy volume. 6.Men must undergo a repeat, confirmatory, 12 core ultrasound-guided prostatic needle biopsy by a NorthShore University HealthSystem urologist using 3-dimensional, color Doppler equipment. These confirmatory biopsies will also be reviewed by a NorthShore University HealthSystem pathologist.

16. NORTHSHORE UNIVERSITY HEALTHSYSTEM ACTIVE SURVEILLANCE CLINICAL TRIAL PROTOCOL SCHEDULE Visit Schedule Testosterone blood tests PSA blood test Research blood sample Research Urine sample Prostate Biopsy*, including additional specimen for research ◙ Digital Rectal Exam Research Questionnaires Study start XX ◙◙ X + ◙ X ◙ Every 3 months X ◙ Every 6 months ◙ X ◙ Every 12 months X + ◙ Time of Prostate Surgery X + ◙

17. NORTHSHORE UNIVERSITY HEALTHSYSTEM ACTIVE SURVEILLANCE CLINICAL TRIAL Patients considered for enrollment 152 Number of patients entered into trial 95 Number of patients not entered into trial 56 Approached but did not consent Approached but did not consent26 Consented but disqualified by confirmation biopsy Consented but disqualified by confirmation biopsy14 Other medical problems Other medical problems4 Consented and awaiting confirmation biopsy Consented and awaiting confirmation biopsy14

18. CLINICAL OUTCOMES

19. ACTIVE SURVEILLANCE CLINICAL OUTCOMES Study No. Participants Median Follow- Up (mo) No. Treated (%) Disease- Specific Survival (%) No. of Metastatic Disease Overall Survival UCSF3214324100None identified 100% Toronto299643499.3 After 8 y2 (Resulted in 2 deaths) 85% Johns Hopkins 4074125100None reported99% MSK and Baylor 884435Not reported Royal Marsden Hospital 3262220100098% Newcomb, LF: Urology 75:407-413, 2010

20. RISK STRATIFICATION

21. RISK STRATIFICATION CUMULATIVE INCIDENCE OF DISEASE PROGRESSION AT INITIAL SURVEILLANCE BIOPSY 376 Patients: Tseng, KS, et al., J Urol 183:1779-1785, May 2010 Risk Low Risk: % Serum Free PSA >15 AND <35% involvement of any core 7.6% High Risk: % Serum Free PSA 35% involvement of any core 29.2% 29.2%

22. CUMULATIVE INCIDENCE OF DISEASE PROGRESSION 3 YEARS AFTER INITIAL SURVEILLANCE BIOPSY Tseng, KS, et al., J Urol 183:1779-1785, May 2010 Risk Risk Low Risk: PSAD 1 <0.08 AND Negative Surveillance Biopsies 11.1% Int Risk: PSAD > 0.08 OR Positive Surveillance Biopsies 25.0% High Risk: PSAD > 0.08 AND Positive Surveillance Biopsies 53.6% PSAD 1 = PSA Density defined by Serum PSA/Prostate Weight 376 Patients:

23. PATHOLOGICAL OUTCOMES

24. PATHOLOGICAL FINDINGS IN MEN IN WHOM ACTIVE SURVEILLANCE FAILS 51/470 men (10.9%) underwent radical prostatectomy51/470 men (10.9%) underwent radical prostatectomy Radical prostatectomy slides available for review in 48 of 51Radical prostatectomy slides available for review in 48 of 51 Organ-confined 65% Extracapsular tumor extension 35% Positive surgical margins15% Seminal vesicle involvement 2% Lymph node involvement 4% Duffield, AS, et al. J Urol 182, 2274-2279, November 2009

25. Mean tumor volume 1.4 cm 3Mean tumor volume 1.4 cm 3 Most progression occurred 1-2 years after enrollment into active surveillance, suggesting undersampling of more aggressive tumor rather than progression of indolent tumorMost progression occurred 1-2 years after enrollment into active surveillance, suggesting undersampling of more aggressive tumor rather than progression of indolent tumor All 10 tumors with a dominant tumor nodule > 1 cm 3 were located anteriorly confirming a need for improved imaging.All 10 tumors with a dominant tumor nodule > 1 cm 3 were located anteriorly confirming a need for improved imaging. PATHOLOGICAL FINDINGS IN MEN IN WHOM ACTIVE SURVEILLANCE FAILS Duffield, AS, et al. J Urol 182, 2274-2279, November 2009

26. IS ACTIVE SURVEILLANCE – DELAYED RADICAL PROSTATECTOMY ASSOCIATED WITH A HIGHER RISK OF UNFAVORABLE OUTCOMES? Van den Bergh, RCN, et al. Cancer, 116:1281-90, March, 2010 Outcomes After RPImmediate RP Delayed RPp Value Number of Patients15869- Gleason score >622.7%27.9%.404 Capsular penetration8.0%11.8%.372 Positive margins20.0%20.6%.920 Tumor volume, mL (mean, median, SD)0.7, 0.5, 0.70.8, 0.5, 0.8.602 Total follow-up time since diagnosis, y (mean, median, SD)5.7, 5.5, 3.25.8, 5.4, 3.2.737 Total follow-up time since surgery, y (mean, median, SD)5.2, 4.9, 3.13.2, 2.1, 3.0<.001

27. CONCLUSIONS Active surveillance is different from watchful waiting with strict enrollment criteria and close surveillanceActive surveillance is different from watchful waiting with strict enrollment criteria and close surveillance Rationale of active surveillance is to avoid over treatment and morbidity of treatmentRationale of active surveillance is to avoid over treatment and morbidity of treatment Clinical outcomes generally favorable but largely dependant on variable inclusion criteriaClinical outcomes generally favorable but largely dependant on variable inclusion criteria Risk stratification possible based on initial and surveillance biopsies, but there is a need for improved imaging and biomarkers to predict and monitor disease progressionRisk stratification possible based on initial and surveillance biopsies, but there is a need for improved imaging and biomarkers to predict and monitor disease progression Pathological outcomes in men failing active surveillance who undergo radical prostatectomy are similar to men undergoing immediate radical prostatectomyPathological outcomes in men failing active surveillance who undergo radical prostatectomy are similar to men undergoing immediate radical prostatectomy Quality of life issues and patient personality important considerations in decision of whether or not to enroll in active surveillanceQuality of life issues and patient personality important considerations in decision of whether or not to enroll in active surveillance