Transcript Slide 1

Modern Management of Prostate
Cancer With Active Surveillance
PROSTATE CANCER SYMPOSIUM
NORTHWESTERN UNIVERSITY
FEINBERG SCHOOL OF MEDICINE
SEPTEMBER 10, 2011
PROSTATE CANCER SYMPOSIUM
NORTHWESTERN UNIVERSITY
FEINBERG SCHOOL OF MEDICINE
SEPTEMBER 10, 2011
Kristian R. Novakovic, MD, FACS
Division of Urology
NorthShore University HealthSystem
OVERVIEW
1.
2.
3.
4.
5.
6.
7.
8.
9.
Watchful Waiting Versus Active Surveillance
Active Surveillance: Pros and Cons
Prostate Cancer Over Diagnosis and Over Treatment
Morbidity of Treatment
NorthShore University HealthSystem Active
Surveillance Clinical Trial
Clinical Outcomes
Risk Stratification
Pathological Outcomes
Conclusions
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
ACTIVE SURVEILLANCE
PROS AND CONS
Pros
• Screen-detected prostate cancers both over diagnosed and
over treated
• All prostate cancer treatments associated with significant
morbidity
Cons
• Window of curability lost by disease progression during period
of active surveillance
• Patient anxiety during active surveillance
• Morbidity of repeat biopsies every 12-18 months
• Increased difficulty of performing radical prostatectomy
following multiple biopsies
PROSTATE CANCER
OVER DIAGNOSIS AND OVER TREATMENT
PROSTATE CANCER PREVALENCE AND
MORTALITY
• Newborn 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 cancer
• But lifetime risk of death from prostate cancer
is only 3%
Prostate Cancer Screening Trials
American Trial:
• 76,693 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 groups
European Trial:
• 162,243 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 group
American and European
Prostate Cancer Screening Trials
AMERICAN TRIAL
Cumulative Hazard
EUROPEAN TRIAL
Year
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 death
• Extrapolating these data:
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
Loeb, S, et al: 2010 American Association of Genitourinary Surgeons Annual
Meeting (not presented)
MORBIDITY OF TREATMENT
Biochemical Recurrence Rates and
Recovery of Urinary and Erectile Function
at 1 Year Following Radical Prostatectomy
Each circle represents a single surgeon, and the size of the circle
is proportion to the number of patients treated by that surgeon.
Eastham, J.: AAGUS, May, 2010
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 waiting
– Number needed to treat to prevent 1 prostate cancer death –
15
• Benefit more pronounced in men < 65 years of age
– Number needed to treat – 7
• Men 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.
NORTHSHORE UNIVERSITY
HEALTHSYSTEM
ACTIVE SURVEILLANCE CLINICAL TRIAL
NORTHSHORE UNIVERSITY HEALTHSYSTEM ACTIVE
SURVEILLANCE CLINICAL TRIAL ELIGIBILITY CRITERIA
•
•
Age > 60 years
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.
NORTHSHORE UNIVERSITY HEALTHSYSTEM
ACTIVE SURVEILLANCE CLINICAL TRIAL
PROTOCOL SCHEDULE
Visit
Schedule
Study
start
Every 3
months
Every 6
months
Testosterone
blood tests
PSA
blood
test
Research
blood
sample
Research
Urine
sample
Prostate
Biopsy*,
including
additional
specimen
for
research◙
X
X
◙
◙
X+◙
X
◙
◙
Every 12
months
X+◙
Time of
Prostate
Surgery
X+◙
Digital
Rectal
Exam
Research
Questionnaires
X
◙
X
◙
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
26
Consented but disqualified by confirmation biopsy
14
Other medical problems
Consented and awaiting confirmation biopsy
4
14
CLINICAL OUTCOMES
ACTIVE SURVEILLANCE
CLINICAL OUTCOMES
Study
No.
Participants
Median
FollowUp
(mo)
No.
Treated
(%)
DiseaseSpecific
Survival (%)
No. of
Metastatic
Disease
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
Overall
Survival
RISK STRATIFICATION
RISK STRATIFICATION
CUMULATIVE INCIDENCE OF DISEASE
PROGRESSION AT INITIAL SURVEILLANCE
BIOPSY
376 Patients:
Risk
Low Risk:
% Serum Free PSA >15 AND
<35% involvement of any core
7.6%
High Risk:
% Serum Free PSA <15 AND/OR
>35% involvement of any core
29.2%
Tseng, KS, et al., J Urol 183:1779-1785, May 2010
CUMULATIVE INCIDENCE OF DISEASE
PROGRESSION 3 YEARS AFTER INITIAL
SURVEILLANCE BIOPSY
Risk
376 Patients:
Low Risk:
PSAD1 <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%
PSAD1 = PSA Density defined by Serum PSA/Prostate Weight
Tseng, KS, et al., J Urol 183:1779-1785, May 2010
PATHOLOGICAL OUTCOMES
PATHOLOGICAL FINDINGS IN MEN IN
WHOM ACTIVE SURVEILLANCE FAILS
• 51/470 men (10.9%) underwent radical
prostatectomy
• Radical prostatectomy slides available for review in
48 of 51
Organ-confined
Extracapsular tumor extension
Positive surgical margins
Seminal vesicle involvement
Lymph node involvement
65%
35%
15%
2%
4%
Duffield, AS, et al. J Urol 182, 2274-2279, November 2009
PATHOLOGICAL FINDINGS IN MEN IN
WHOM ACTIVE SURVEILLANCE FAILS
• Mean tumor volume 1.4 cm3
• Most 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.
Duffield, AS, et al. J Urol 182, 2274-2279, November 2009
IS ACTIVE SURVEILLANCE – DELAYED RADICAL
PROSTATECTOMY ASSOCIATED WITH A
HIGHER RISK OF UNFAVORABLE OUTCOMES?
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
Van den Bergh, RCN, et al. Cancer, 116:1281-90, March, 2010
CONCLUSIONS
• Active 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 treatment
• Clinical 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 progression
• Pathological 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
surveillance