Modern Management of Prostate Modern Management of Prostate Cancer With Active Surveillance Cancer With Active Surveillance

PROSTATE CANCER SYMPOSIUMPROSTATE CANCER SYMPOSIUMNORTHWESTERN UNIVERSITY NORTHWESTERN UNIVERSITY

FEINBERG SCHOOL OF MEDICINEFEINBERG SCHOOL OF MEDICINESEPTEMBER 10, 2011SEPTEMBER 10, 2011

PROSTATE CANCER SYMPOSIUMPROSTATE CANCER SYMPOSIUMNORTHWESTERN UNIVERSITY NORTHWESTERN UNIVERSITY

FEINBERG SCHOOL OF MEDICINEFEINBERG SCHOOL OF MEDICINESEPTEMBER 10, 2011SEPTEMBER 10, 2011

Kristian R. Novakovic, MD, FACSKristian R. Novakovic, MD, FACSDivision of UrologyDivision of Urology

NorthShore University HealthSystemNorthShore University HealthSystem

OVERVIEWOVERVIEW

1. Watchful Waiting Versus Active Surveillance

2. Active Surveillance: Pros and Cons

3. Prostate Cancer Over Diagnosis and Over Treatment

4. Morbidity of Treatment

5. NorthShore University HealthSystem Active Surveillance Clinical Trial

6. Clinical Outcomes

7. Risk Stratification

8. Pathological Outcomes

9. Conclusions

WATCHFUL WAITING VERSUS WATCHFUL WAITING VERSUS ACTIVE SURVEILLANCEACTIVE SURVEILLANCE

Watchful Waiting Watchful Waiting Older policy involving no Older policy involving no surveillance strategy with surveillance strategy with palliative treatment only for palliative treatment only for symptomatic progressionsymptomatic progression

Active Surveillance or Active Surveillance or Expectant Management Expectant Management With Curative Intent With Curative Intent

Men enrolled with strict criteria Men enrolled with strict criteria and followed closely with goal and followed closely with goal of identifying men for curative of identifying men for curative treatment at the first sign of treatment at the first sign of progressionprogression

ACTIVE SURVEILLANCEACTIVE SURVEILLANCEPROS AND CONSPROS AND CONS

ProsPros• Screen-detected prostate cancers both over diagnosed and Screen-detected prostate cancers both over diagnosed and

over treatedover treated• All prostate cancer treatments associated with significant All prostate cancer treatments associated with significant

morbiditymorbidity

ConsCons• Window of curability lost by disease progression during period Window of curability lost by disease progression during period

of active surveillanceof 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 Increased difficulty of performing radical prostatectomy

following multiple biopsiesfollowing multiple biopsies

PROSTATE CANCER PROSTATE CANCER OVER DIAGNOSIS AND OVER TREATMENTOVER DIAGNOSIS AND OVER TREATMENT

PROSTATE CANCER PREVALENCE AND PROSTATE CANCER PREVALENCE AND MORTALITYMORTALITY

• Newborn American male has 16% lifetime Newborn American male has 16% lifetime risk of being diagnosed with prostate cancer risk of being diagnosed with prostate cancer – 1 new case every 3 minutes– 1 new case every 3 minutes

• 1/3 of men over age 60 and 1/2 of men over 1/3 of men over age 60 and 1/2 of men over age 70 have prostate cancerage 70 have prostate cancer

• But lifetime risk of death from prostate cancer But lifetime risk of death from prostate cancer is only 3%is only 3%

Prostate Cancer Screening TrialsProstate Cancer Screening Trials

American Trial: American Trial: • 76,693 men between 55 and 74 randomized to either 76,693 men between 55 and 74 randomized to either

annual screening or usual careannual screening or usual care• After 7-10 years of follow-up, death rate from prostate After 7-10 years of follow-up, death rate from prostate

cancer was very low and did not differ significantly cancer was very low and did not differ significantly between the two study groupsbetween the two study groups

European Trial: European Trial: • 162,243 men between 55 and 69 randomized to either 162,243 men between 55 and 69 randomized to either

annual screening or no screeningannual screening or no screening• For first 10 years of follow-up, risk of death from For first 10 years of follow-up, risk of death from

prostate cancer was the same between the two groups, prostate cancer was the same between the two groups, but, after 10 years, there was a 20% decrease in risk of but, after 10 years, there was a 20% decrease in risk of death in the screened groupdeath in the screened group

EUROPEAN TRIALAMERICAN TRIAL

C

um

ula

tive H

aza

rd

Year

American and European American and European Prostate Cancer Screening TrialsProstate Cancer Screening Trials

European Prostate Cancer Screening TrialEuropean Prostate Cancer Screening Trial

• At median follow up of 8 years, estimated 1410 men At median follow up of 8 years, estimated 1410 men needed to be screened (NNS) and 48 men needed to be needed to be screened (NNS) and 48 men needed to be treated (NNT) to prevent 1 prostate cancer deathtreated (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

9 10 12

NNS 1254 837 503

NNT 43 29 18

BUT: Men unselected for active surveillance, and mean life expectancy at age 65 is only 14 years

MORBIDITY OF TREATMENTMORBIDITY OF TREATMENT

Biochemical Recurrence Rates and Biochemical Recurrence Rates and Recovery of Urinary and Erectile Recovery of Urinary and Erectile

Function at 1 Year Following Radical Function at 1 Year Following Radical ProstatectomyProstatectomy

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.

RANDOMIZED TRIAL OF WATCHFUL RANDOMIZED TRIAL OF WATCHFUL WAITING VERSUS RADICAL WAITING VERSUS RADICAL

PROSTATECTOMYPROSTATECTOMY• Scandinavian randomized trial of 695 men found Scandinavian randomized trial of 695 men found

absolute risk reduction of 6.1% in prostate cancer absolute risk reduction of 6.1% in prostate cancer deaths at 15 years in men undergoing radical deaths at 15 years in men undergoing radical prostatectomy vs watchful waitingprostatectomy vs watchful waiting– Number needed to treat to prevent 1 prostate cancer death Number needed to treat to prevent 1 prostate cancer death

– 15– 15• Benefit more pronounced in men < 65 years of ageBenefit more pronounced in men < 65 years of age

– Number needed to treat – 7Number needed to treat – 7• Men in “low risk” group also derived benefitMen in “low risk” group also derived benefit

– 4.2% reduction4.2% reductionBill-Axelson, A, et al, Radical prostatectomy versus watchful Bill-Axelson, A, et al, Radical prostatectomy versus watchful

waiting in early prostate cancer: NEJM 364:18 (1708-1717), waiting in early prostate cancer: NEJM 364:18 (1708-1717), 2011.2011.

NORTHSHORE UNIVERSITY NORTHSHORE UNIVERSITY HEALTHSYSTEM HEALTHSYSTEM

ACTIVE SURVEILLANCE CLINICAL TRIALACTIVE SURVEILLANCE CLINICAL TRIAL

NORTHSHORE UNIVERSITY HEALTHSYSTEM ACTIVE NORTHSHORE UNIVERSITY HEALTHSYSTEM ACTIVE SURVEILLANCE CLINICAL TRIAL ELIGIBILITY CRITERIASURVEILLANCE CLINICAL TRIAL ELIGIBILITY CRITERIA

• Age Age >> 60 years 60 years• Men meeting the six following clinical and pathologic criteria:Men meeting the six following clinical and pathologic criteria:

1.1. Clinical stage T1c or T2a prostate cancer, verified by a NorthShore Clinical stage T1c or T2a prostate cancer, verified by a NorthShore University HealthSystem urologist. University HealthSystem urologist.

2.2. Biopsy Gleason Score Biopsy Gleason Score << 6, with no primary or secondary 4 or 5 tumor 6, with no primary or secondary 4 or 5 tumor pattern; pathology verified by NorthShore University HealthSystem pattern; pathology verified by NorthShore University HealthSystem pathologist. pathologist.

3.3. Diagnosis of prostate cancer made on at least a 12 core needle biopsy Diagnosis of prostate cancer made on at least a 12 core needle biopsy with with << 3 cores positive for cancer. 3 cores positive for cancer.

4.4. Maximum tumor length < 50% of any core. Maximum tumor length < 50% of any core. 5.5. Total tumor volume Total tumor volume << 5% of biopsy volume. 5% of biopsy volume. 6.6. Men must undergo a repeat, confirmatory, 12 core ultrasound-guided Men must undergo a repeat, confirmatory, 12 core ultrasound-guided

prostatic needle biopsy by a NorthShore University HealthSystem prostatic needle biopsy by a NorthShore University HealthSystem urologist using 3-dimensional, color Doppler equipment. These urologist using 3-dimensional, color Doppler equipment. These confirmatory biopsies will also be reviewed by a NorthShore University confirmatory biopsies will also be reviewed by a NorthShore University HealthSystem pathologist. HealthSystem pathologist.

NORTHSHORE UNIVERSITY HEALTHSYSTEM NORTHSHORE UNIVERSITY HEALTHSYSTEM ACTIVE SURVEILLANCE CLINICAL TRIAL ACTIVE SURVEILLANCE CLINICAL TRIAL

PROTOCOL SCHEDULEPROTOCOL 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

X X ◙ ◙ X + ◙ X ◙

Every 3 months X ◙

Every 6 months ◙ X ◙

Every 12 months X + ◙

Time of Prostate Surgery

X + ◙

NORTHSHORE UNIVERSITY NORTHSHORE UNIVERSITY HEALTHSYSTEM HEALTHSYSTEM

ACTIVE SURVEILLANCE CLINICAL TRIALACTIVE SURVEILLANCE CLINICAL TRIAL

Patients considered for enrollmentPatients considered for enrollment 152152

Number of patients entered into trialNumber of patients entered into trial 9595

Number of patients not entered into trialNumber of patients not entered into trial 5656

Approached but did not consentApproached but did not consent 2626

Consented but disqualified by confirmation biopsyConsented but disqualified by confirmation biopsy 1414

Other medical problemsOther medical problems 44

Consented and awaiting confirmation biopsyConsented and awaiting confirmation biopsy 1414

CLINICAL OUTCOMESCLINICAL OUTCOMES

ACTIVE SURVEILLANCEACTIVE SURVEILLANCECLINICAL OUTCOMESCLINICAL OUTCOMES

Study

No. Participa

nts

Median

Follow-Up

(mo)

No. Treated (%)

Disease-Specific Survival

(%)

No. of Metastatic

Disease

Overall Surviv

al

UCSF 321 43 24 100 None identified

100%

Toronto 299 64 34 99.3 After 8 y

2 (Resulted in 2 deaths)

85%

Johns Hopkins

407 41 25 100 None reported

99%

MSK and Baylor

88 44 35 Not reported Not reported Not reported

Royal Marsden Hospital

326 22 20 100 0 98%

Newcomb, LF: Urology 75:407-413, 2010

RISK STRATIFICATIONRISK STRATIFICATION

RISK STRATIFICATION RISK STRATIFICATION CUMULATIVE INCIDENCE OF DISEASE CUMULATIVE INCIDENCE OF DISEASE

PROGRESSION AT INITIAL SURVEILLANCE PROGRESSION AT INITIAL SURVEILLANCE BIOPSYBIOPSY

376 Patients: 376 Patients:

Tseng, KS, et al., J Urol 183:1779-1785, May 2010

RiskRisk

Low Risk:Low Risk: % Serum Free PSA >15 AND % Serum Free PSA >15 AND

<35% involvement of any core<35% involvement of any core

7.6%7.6%

High Risk:High Risk: % Serum Free PSA <15 AND/OR % Serum Free PSA <15 AND/OR >35% involvement of any core>35% involvement of any core

29.2%29.2%

CUMULATIVE INCIDENCE OF DISEASE CUMULATIVE INCIDENCE OF DISEASE PROGRESSION 3 YEARS AFTER INITIAL PROGRESSION 3 YEARS AFTER INITIAL

SURVEILLANCE BIOPSYSURVEILLANCE BIOPSY

Tseng, KS, et al., J Urol 183:1779-1785, May 2010

RiskRisk

Low Risk:Low Risk: PSADPSAD11 <0.08 AND Negative Surveillance <0.08 AND Negative Surveillance BiopsiesBiopsies

11.1%11.1%

Int Risk:Int Risk: PSAD > 0.08 OR Positive Surveillance PSAD > 0.08 OR Positive Surveillance BiopsiesBiopsies

25.0%25.0%

High Risk:High Risk: PSAD > 0.08 AND Positive Surveillance PSAD > 0.08 AND Positive Surveillance BiopsiesBiopsies

53.6%53.6%

PSADPSAD1 1 = PSA Density defined by Serum PSA/Prostate Weight= PSA Density defined by Serum PSA/Prostate Weight

376 Patients: 376 Patients:

PATHOLOGICAL OUTCOMESPATHOLOGICAL OUTCOMES

PATHOLOGICAL FINDINGS IN MEN IN PATHOLOGICAL FINDINGS IN MEN IN WHOM ACTIVE SURVEILLANCE FAILSWHOM ACTIVE SURVEILLANCE FAILS

• 51/470 men (10.9%) underwent radical 51/470 men (10.9%) underwent radical prostatectomyprostatectomy

• Radical prostatectomy slides available for review in Radical prostatectomy slides available for review in 48 of 51 48 of 51

Organ-confined Organ-confined 65%65%Extracapsular tumor extension Extracapsular tumor extension 35%35%Positive surgical marginsPositive surgical margins 15%15%Seminal vesicle involvementSeminal vesicle involvement 2% 2%Lymph node involvementLymph node involvement 4% 4%

Duffield, AS, et al. J Urol 182, 2274-2279, November 2009

• Mean tumor volume Mean tumor volume 1.4 cm1.4 cm33

• Most progression occurred 1-2 years after Most progression occurred 1-2 years after enrollment into active surveillance, enrollment into active surveillance, suggesting undersampling of more suggesting undersampling of more aggressive tumor rather than progression of aggressive tumor rather than progression of indolent tumorindolent tumor

• All 10 tumors with a dominant tumor nodule > All 10 tumors with a dominant tumor nodule > 1 cm 1 cm 3 3 were located anteriorly confirming a were located anteriorly confirming a need for improved imaging. need for improved imaging.

PATHOLOGICAL FINDINGS IN MEN IN PATHOLOGICAL FINDINGS IN MEN IN WHOM ACTIVE SURVEILLANCE FAILSWHOM ACTIVE SURVEILLANCE FAILS

Duffield, AS, et al. J Urol 182, 2274-2279, November 2009

IS ACTIVE SURVEILLANCE – DELAYED IS ACTIVE SURVEILLANCE – DELAYED RADICAL PROSTATECTOMY ASSOCIATED WITH RADICAL PROSTATECTOMY ASSOCIATED WITH

A HIGHER RISK OF UNFAVORABLE A HIGHER RISK OF UNFAVORABLE OUTCOMES?OUTCOMES?

Van den Bergh, RCN, et al. Cancer, 116:1281-90, March, 2010

Outcomes After RP Immediate RP

Delayed RP p Value

Number of Patients 158 69 -

Gleason score >6 22.7% 27.9% .404

Capsular penetration 8.0% 11.8% .372

Positive margins 20.0% 20.6% .920

Tumor volume, mL (mean, median, SD) 0.7, 0.5, 0.7 0.8, 0.5, 0.8 .602

Total follow-up time since diagnosis, y (mean, median, SD) 5.7, 5.5, 3.2 5.8, 5.4, 3.2 .737

Total follow-up time since surgery, y (mean, median, SD) 5.2, 4.9, 3.1 3.2, 2.1, 3.0 <.001

CONCLUSIONS CONCLUSIONS

• Active surveillance is different from watchful waiting with Active surveillance is different from watchful waiting with strict enrollment criteria and close surveillancestrict enrollment criteria and close surveillance

• Rationale of active surveillance is to avoid over treatment Rationale of active surveillance is to avoid over treatment and morbidity of treatmentand morbidity of treatment

• Clinical outcomes generally favorable but largely dependant Clinical outcomes generally favorable but largely dependant on variable inclusion criteria on variable inclusion criteria

• Risk stratification possible based on initial and surveillance Risk stratification possible based on initial and surveillance biopsies, but there is a need for improved imaging and biopsies, but there is a need for improved imaging and biomarkers to predict and monitor disease progression biomarkers to predict and monitor disease progression

• Pathological outcomes in men failing active surveillance who Pathological outcomes in men failing active surveillance who undergo radical prostatectomy are similar to men undergoing undergo radical prostatectomy are similar to men undergoing immediate radical prostatectomyimmediate radical prostatectomy

• Quality of life issues and patient personality important Quality of life issues and patient personality important considerations in decision of whether or not to enroll in active considerations in decision of whether or not to enroll in active surveillancesurveillance