Download Proposed outline of NCCN Talk

PSA in 2010
James L. Mohler, MD
Chair, NCCN Prostate Cancer Panel
Department of Urology
Prostate Cancer Research Program
Roswell Park Cancer Institute, Buffalo, NY
Every 3 Minutes an American is
Diagnosed with Prostate Cancer
Every 18 Minutes an American
Dies of Prostate Cancer
The Prostate Cancer Challenge
• Complex disease
• Many controversial aspects of management
• Lack of sound data to support most
recommendations
• Several variables must be considered to
tailor prostate cancer therapy to an
individual patient
• Guidelines provide a framework on which to
base treatment decisions
Prostate Cancer:
#1 Incidence
(192,280)
#2 Deaths
(27,360)
Cancer Statistics, 2009
U.S. Annual AgeAdjusted
Incidence Rates
1975 – 2005
Cancer Statistics, 2009
U.S. Annual Age-Adjusted Mortality
Rates, 1930 – 2005 Cancer Statistics, 2009
CaP Screening Recommendations
• American Urological Association
– Annual PSA & DRE
- From age 50 until LE <10 yrs
- From age 40 if high risk (AA or family history)
• American Cancer Society (3/3/2010)
- Annual PSA ± DRE
- From age 50 until LE <10 yrs
- From age 45 if high risk (AA or family history)
- From age 40 if multiple family members
CaP Screening Recommendations
• American College of Physicians; American Academy
of Family Physicians
– Counsel men 50 to 65 regarding risk vs. benefit
• U.S. Preventive Services Task Force
– Routine screening not advocated especially >75
• NCCN (the best recommendation)
– PSA and DRE at 40, if <1, at 45
– PSA and DRE at 45, if <1, at 50
– If high risk because African American, family history or
PSA >1, annual PSA and DRE
– Routine screening less frequent in older men (65-75)
and not advocated especially >75
How reliable is PSA ?
• 70% of men with elevated PSA have
negative biopsies
• PSA can fluctuate by 36% day to day
• Rate of rise more accurate
– PSA Velocity or PSA Doubling Time
– Requires ≥ 3 PSAs over ≥ 18 mo
• PSAV ≥ 0.75 ng/ml or PSADT ≤ 3 yrs
How Reliable is Prostate Biopsy?
• Biopsies sample prostate
• Biopsy detection rate
–
–
–
–
First: 75% of existing cancers
Second: 91%
Third: 97%
Fourth: 99%
• Accuracy of Gleason grade compared to
RP
– 30% grade increases
– 5% grade decreases
PSA and Prostate Cancer
Screening
• PSA increases the detection of organ
confined CaP
• Serial PSA screening improves the ability to
detect organ confined prostate cancer
• PSA detects 2x as many cancers as DRE
Screening Performance
Mammography
PSA
+ Predictive Value
7-17%
33%
Organ Confined
50%
80%
+ Lymph Nodes
20%
2%
“Latent” Cancer
8%
7%
Screening Men with a
Family History
• 2-3 fold increased risk if first-degree relative
with CaP (Keetch, J Urol, 1995; Walsh, Cancer, 1997)
• Younger age at presentation
• Comparable results with RP (Beva, J Urol, 1998)
• Begin screening at age 40
Prostate Cancer Incidence and
Death Rates by Race and Ethnicity,
2001 - 2005
Cancer Statistics, 2009
Caucasian
American
African
American
Asian
American
and
Pacific
Islander
American
Indian and
Alaska
Native
Hispanic
Latino
Incidence
156.7
248.5
93.8
73.3
138
Mortality
24.6
59.4
11.0
21.1
20.6
Use of PSA for Early Detection is
Most Appropriate for:
A) African Americans
B)
C)
D)
E)
Men with CaP in father or brother
Men with life expectancy ≥ 10 yrs
Men with BRAC1 mutation
All of the above
March 26, 2009 CaP Explosion
NEJM 360:1310-19 and 1320-28
ERSPC (European) Trial
• 182,000 men ages 50-74
• Statistics on 162,387 men ages 55-69
• Mean number of PSA tests 2.1
• Median f/u 9 yrs
PSA cutoff
Design
Biopsy
Interval
Finland
4.0
Pop-based
10-12
4
Italy
4.0
Pop-based
6 (transperineal)
4
Netherlands
4.0
Efficacy
6
4
Belgium
4.0 (originally 10) Efficacy
6
4-7
Switzerland
3.0
Efficacy
6
4
Spain
3.0
Efficacy
6
4
Sweden
3.0
Pop-based
6
2
European Trial
Screening
Control
Incidence
8.2%
4.8%
Prostate cancer deaths
214
327
Rate ratio for prostate cancer death
0.80 (p=0.04)
To prevent one death from prostate cancer:
• 1410 men need screened
• 48 additional cases of prostate cancer
need treated
European Trial
PLCO (American) Trial
• 76,693 men ages 55-74 at 10 centers
• Annual PSA screening for 6 yrs vs.
usual care
• Median f/u 11.5 years
American Trial
Screening
Control
PSA testing
86%
40%
Incidence
7.5%
6.1%
No. of advanced cases
122
135
7 years
50
44
10 years (f/u for 67% of subjects)
92
82
312
225
Prostate cancer deaths
Non-prostate cancer deaths (10 yrs)
Possible Reasons for a
Negative Trial
• PSA cutoff 4 ng/ml too high
• Control arm contaminated
- 38% contamination anticipated
- PSA within past year
- 86% in screened group
- 40% in control group
Possible Reasons for a
Negative Trial
• Widespread PSA testing removed
prostate cancer patients from
consideration for enrollment
• Improved treatments for prostate
cancer applied to both arms blunted
effects of screening
• Follow-up too short
PSA Screening?
“ …our results support the validity of the recent
recommendations of the U.S. Preventive Services
TaskForce, especially against screening all men over the
age of 75 years.”
NEJM: Authors of PLCO trial
“The real impact and tragedy of prostate cancer screening
is the doubling of the lifetime risk of a diagnosis of prostate
cancer with little if any decrease in the risk of dying from
this disease,”
Otis Brawley, Chief Medical
Officer, American Cancer Society
What does all this mean?
• PSA was doomed to failure (screened older men and
didn’t include many African Americans or men with
family history of CaP)
• Over-treatment may blunt benefits of treatment
• Even with longer followup, the American study is
unlikely to be positive. Even if it is, the impact of
screening will be so small that it may not be clinically
significant.
• Annual screening may be too frequent
• In the European study, screening was every 4 yrs
• In the American study, the majority of subjects in
the control arm were screened and the control arm
looks rather similar to the q 4 yrs screening arm of
the European study
What does all this mean?
• PSA was doomed to failure (screened older men and
didn’t include many African Americans or men with
family history of CaP)
• Over-treatment may blunt benefits of treatment
• Even with longer followup, the American study is
unlikely to be positive. Even if it is, the impact of
screening will be so small that it may not be clinically
significant.
• Annual screening may be too frequent
• In the European study, screening was every 4 yrs
• In the American study, the majority of subjects in
the control arm were screened and the control arm
looks rather similar to the q 4 yrs screening arm of
the European study
2010 Guideline Updates
1. Defined new risk category: very low risk
CaP
2. Active surveillance only recommendation
for men with
a. low risk CaP and L Exp < 10 yrs
b. very low risk CaP and L Exp < 20 yrs
3. Active surveillance program defined
Preoperative Criteria associated with
Clinically Insignificant Disease in the
Radical Prostatectomy Specimen
•
•
•
•
•
Gleason Sum <7
PSA <10
No. positive biopsy cores <3
CaP <50% in any biopsy
PSAD <0.15
Epstein, JAMA, 1994
2010 NCCN Concerns
• Approximately 3% of all men will die of
prostate cancer (2007)
• Second leading cause of cancer mortality
• Mortality from prostate cancer has declined by
31% over past 13 yrs
- Screening?
- Treatment?
• Any active treatment will significantly
decrease quality of life
2010 Guideline Updates
1. Very low risk CaP
Low Risk
- T1-T2a
- GS 2-6
- PSA<10
Very Low Risk
- T1c
- GS 2-6
- PSA<10
- <3 cores positive
- <50% CaP in any core
- PSAD<0.15
• Incorporates the strictest Epstein criteria from all definitions
for clinically insignificant CaP (Epstein, JAMA, 1994)
• New nomogram may be better (Chun, Cancer, 2008)
2010 Guideline Updates
2. Active surveillance only recommendation for
men with
a. Low risk CaP and L Exp < 10 yrs
b. Very low risk CaP and L Exp < 20 yrs
Concern: “problems of over-treatment related
to the increased diagnosis of early CaP from
PSA testing”
2010 Guideline Updates
3. Active surveillance program
a. PSA as often as every 6 mo
b. DRE as often as every 12 mo
c. Prostate biopsy as often as every 12 mo
when L Exp > 10 yrs
d. Uncertain what the progression criteria
should be to warrant treatment