Download PSA Screening: A Modern Medical and Societal Dilemma

PSA Screening and Cancer
Treatment
Douglas S. Scherr, M.D.
Assistant Professor of Urology
Clinical Director, Urologic Oncology
Weill Medical College-Cornell
University
Criteria of a Screening Program
• The Disorder
• The Test
• The Treatment
• The Screening Program
Criteria of a Screening Program
• The Disorder -Prostate Cancer
• The Test
• The Treatment
• The Screening Program
PROSTATE CANCER
Highest in Incidence and Second in Cause of Death
from Cancer in American Males
Incidence
Cause of Death
Melanoma of Skin 5%
3% Esophagus
Oral Cavity & Pharynx 3%
Lung & Bronchus 14%
31% Lung & Bronchus
5% Pancreas
Pancreas 2%
3% Kidney
Colon & Rectum 11%
3% Liver
Kidney 3%
10% Colon & Rectum
Prostate 30%
11% Prostate
Urinary Bladder 7%
Leukemia 3%
3% Urinary Bladder
4% Leukemia
Non-Hodgkin’s Lymphoma 4%
5% Non-Hodgkin’s Lymphoma
All Sites 637,500
189,000 New Cases
288,200 All Sites
2002 Estimates
30,200 Death
U.S. Incidence and Mortality of
Prostate Cancer
Prevalence of Prostate Cancer
45
40
35
% Men
With PIN
Or CaP
30
25
PIN
Prosate Cancer
20
15
10
5
0
2nd
3rd
4th
Decade
Sakr et al., J Urol, 150: 379, 1993
5th
Criteria of a Screening Test
The Disorder
“Prostate Cancer”
• Natural history understood:
-To die of prostate cancer or die with prostate
cancer?
-Conservative Treatment:
a.) Gleason 2-4: 4-7% chance of death
b.) Gleason 6:
18-30% chance of death
c.) Gleason 8-10: 60-80% chance of death**
Frankel et al. Lancet, 361: 1122, March 2003
**Albertsen et al., JAMA, 280: 975, 1998
Lifetime Risk of Developing or Dying of Prostate
Cancer for a 50-Year-Old Man in the United States
Lifetime Risk of
Risk
Risk Ratio
Developing histologic cancer
42 %
11.7
100
Developing clinical cancer
16 %
4
38
Dying of prostate cancer
3.6 %
1
8.6
Modified from Scardino PT. Urol Clin N Am 1989 and Hum Path 1992;
and from CA Cancer J Clin Jan-Feb, 2000.
Proportional
Risk
Criteria of a Screening Program
• The Disorder
• The Test
• The Treatment
• The Screening Program
Criteria of a Screening Test
The Test
• Simple, safe and precise
• Distribution in target population should be known
• Appropriate cut-offs and age defined ranges
• Test should be acceptable to the population
Diagnostic tests performed when a positive test
is found should be agreed upon
Criteria of a Screening Test
The Test
“DRE and PSA”
Bangma et al., Urology, 46(6): 773, 1995
Rate of Detection of Prostate Cancer by Needle Biopsy
Positive Predictive Value of DRE and PSA (n=6630)
PSA (ng/ml)
0-2
2-4
4-10
>10
DRE-
1%
15%
25%
>50%
DRE+
5%
20%
45%
>75%
Modified from Catalona et al: J Urol 1994: 151:1283.
Positive Predictive Value of
PSA and DRE for Prostate
Cancer
50
45
40
35
30
25
20
15
10
5
0
46.6
31.6
25.5
23.2
24.6
14.6
DRE+
PSA >4 PSA <4 & PSA >4 & PSA >4 & PSA >4
DRE+
DREDRE+ or DRE+
PREDICTIVE MODELING TABLES TO CALCULATE RISK OF POSITIVE BIOPSY
BASED ON DRE, PSA, F/T PSA RATIO AND PSA DENSITY IN MEN WITH PSA < 10
NG/ML
Tewari, Boorjan, Bartsch, 2005
NOT SUSPICIOUS FOR CANCER
SUSPICIOUS FOR CANCER
DRE FINDINGS
AGE GROUPS
<40
YEARS
41-50
YEARS
51-60
YEARS
61-70
YEARS
>70
YEARS
<40
YEARS
41-50
YEARS
51-60
YEARS
61-70
YEARS
>70
YEARS
F/T PSA
RATIO
PSA
DENSITY
PROBABILITY OF FINDING CANCER FOLLOWING SYSTEMIC SEXTANT BIOPSY OF THE
PROSTATE
MEAN PROBABILITY (95 % UPPER AND LOWER CONFIDENCE LEVELS)
FREE
VERSUS
COMPLE
X PSA
RATIO
>15%
<.15 (Large
prostate)
5 (3-6)
7 (6-9)
11 (10-13)
17 (15-20)
25 (22-29)
11 (7-16)
17 (12-22)
24 (19-30)
34 (28-41)
46 (39-54)
.15-.2
(Medium
prostate)
8 (6-11)
12 (9-16)
19 (15-22)
27 (23-32)
38 (32-43)
18 (12-26)
26 (19-34)
36 (29-45)
48 (40-56)
60 (52-68)
>.20 (Small
prostate)
10 (7-14)
15 (12-20)
23 (19-27)
33 (28-38)
44 (38-50)
22 (15-31)
31 (24-41)
43 (34-51)
55 (47-63)
66 (58-73)
FREE
VERSUS
COMPLE
X PSA
RATIO
<15%
<.15 (Large
prostate)
7 (6-9)
11 (10-13)
17 (15-19)
25 (22-28)
35 (31-40)
16 (12-22)
24 (19-31)
34 (28-41)
46 (39-53)
58 (50-65)
.15-.2
(Medium
prostate)
12 (9-16)
18 (15-22)
27 (23-31)
37 (33-42)
49 (43-55)
26 (18-35)
36 (28-45)
48 (40-56)
60 (52-67)
71 (64-77)
>.20 (Small
prostate)
15 (12-20)
23 (19-27)
32 (28-36)
44 (39-48)
56 (50-61)
31 (23-41)
42 (34-51)
54 (47-62)
66 (59-72)
76 (70-81)
PSA density should be calculated by ultrasound. A new model will be available soon if PSA density
is not available)
Serum PSA Levels Rise Prior to
the Development of Significant
Cancer
From Carter HB et al. JAMA 267:2215,1992
Criteria of a Screening Test
The Test
“DRE and PSA”
AUA Best Practice Policy
• PSA detects more tumors than does DRE
and it detects them earlier
• Most Sensitive method uses both DRE
and PSA
PSA Best Practice Policy, Oncology, 14(2), Feb. 2000
Factors That Affect PSA
•
•
•
•
•
•
Prostatitis
Benign Prostatic Hyperplasia (BPH)
Prostate Cancer
Physical Activity
Infection
Medications – finasteride (Proscar/Propecia)
•
•
•
•
Herbal Medicines – Saw Palmetto, PC-SPES,
Ejaculation
Rectal Examination
Urinary Retention/Cystoscopy
Sensitivity/Specificity of PSA
• Sensitivity: 67.5-80%
(20-30% tumors will be missed if PSA<4.0 ng/ml used)
Ways to Improve Sensitivity:
a.) age-adjusted PSA
b.) PSA velocity
• Specificity: 60-70% (if PSA>4.0 ng/ml)
(only ¼ prostate biopsies reveal CaP)
Ways to Improve Specificity:
a.) Age adjustment
b.) Free-to-total PSA
c.) PSA density
Improvements on PSA
• Age-adjusted PSA
Age
• Free-to-Total PSA
(14-28%)
PSA
Cutoff
(ng/ml)
<40-50
2.5
50-60
3.5
60-70
4.5
>70
6.5
• PSA Velocity
(>0.75ng/ml/yr)
Criteria of a Screening Program
• The Disorder
• The Test
• The Treatment
• The Screening Program
Criteria of a Screening Test
“The Treatment”
• Watchful Waiting
• Hormonal Deprivation Therapy
• Radiation Therapy
• Radical Prostatectomy
Criteria of a Screening Program
• The Disorder
• The Test
• The Treatment
• The Screening Program
Policies of Prostate Cancer
Screening
Group
Policy Statement
AUA
Screen annually at age
50
Take personal decision
after consultation
ACS
Screen annually at age
50
Provide risk and benefit
information
AMA
Mass screening is
premature
Allow “well informed”
decision
ACP
Routine PSA is
“inappropriate”
Counsel patient
Introduction as policy is
premature
Provide risk and benefit,
await randomized trials
EU
Recommendations
Evidence for the Effectiveness of
Screening
• PSA screening initiated in 1989
• A decrease in prostate cancer mortality
has been demonstrated in the U.S. by
4.4%/year from 1994-97
• Total decrease in mortality of 17.6%
Cost per annual adjusted life year for annual Prostate cancer screening
Howard. J Health Econ., 24(5): 891-906, Sept. 2005
Practice Patterns of General Practitioner
Howard. J Health Econ., 24(5): 891-906, Sept. 2005
Practice Patterns Amongst General Practitioners
Question
n (%)
95% CI for%
Do you perform a DRE in all males with
LUTS?
220 (76)
67.2–84.0
Do you measure PSA in all males with
LUTS?
82 (28)
19.3–37.0
Is the decision to refer the patient to a
urologist affected by the patient's PSA
value?
230 (79)
71.1–87.0
Is the decision to refer affected by the
patient's age?
190 (65)
55.9–74.6
Is the decision to refer affected by the
patient's symptoms?
272 (93)
88.5–98.5
Is the decision to refer affected by the
findings of DRE?
254 (87)
80.7–93.9
151 (52)
42.1–61.7
Do you measure PSA as part of a general
health check-up?
29 (10)
4.1–15.8
If you perform PSA testing, do you tell the
patient what a PSA test can show?
247 (85)
77.9–91.9
Do you perform PSA
screening for PC?
41 (14)
7.2–21.0
Would you refer asymptomatic
patients with elevated PSA?
Jonler et al., Scan J Uol Nephol, 39: 214-218, 2005
Side effects of screening
Flip side: Screening cause harm
Impact of treatment on overall survival
Gain in LE (Mo)
Myocardial revascularization
1 vessel
2 vessels
3 vessels
Heart Transplantation
Cholecystectomy
Appendectomy
Treatment of prostate cancer (Fleming)
Gl 5-7
Gl 8-10
Wright & Weinstein NEJM 1998:339:380-6
7
0-8
4-14
31-99
2-3
2-31
1-11
30-60
Controversies in Screening
• Decline in mortality since 1989 is too rapid
given the indolent natural history of
prostate cancer
• Improvements in locally advanced disease
could explain decline in mortality
• Decline in mortality has been seen in
countries where screening is not prevalent
Quebec City Screening Study
Quebec City Screening Study
• November 1988-Decmeber 1996
• 46,193 men randomized
screening vs. non-screening
• Screening Group: 8,137 were screened
• Relative risk of dying of CaP was 3.7 times
higher in the control group
• 69% reduction in mortality with screening
Labrie et al., Prostate, 38(2): 83-91, 1999
Tyrol Prostate Cancer Screening Group
• 1993-1998, PSA
screening offered to
65,123 men in Tyrol,
Austria
Mortality Rates
• 42% reduction in
prostate cancer
mortality
Bartsch et al., Urology, 58(3): 417-24, 2001
Incidence by Stage
Olmstead County Screening Trial
• Retrospective
analysis of death
record between 19801997
• Decline in mortality of
22% between the
earliest and most
recent time periods
Roberts et al., J Urol, 161: 529, 1999
Trends in Prostate Cancer Mortality
Cost Effectiveness of PSA Screening
Intervention
Liver Transplantation
Screening Mammography (age
<50)
Worst Case – CaP Screening
CABG-2 vessels (angina)
Captopril for HTN
HCTZ for HTN
Best Case- CaP Screening
Stop Smoking-MD Message
Thompson et al., Oncology, 9: 141-5, 1995
Cost Per Quality-Adjusted LifeYear Gained
$237,000
$232,000
$145,000
$106,600
$82,600
$23,500
$8,700
$1,300
Problems with Screening
Lead Time Bias
Length Time Bias
Thompson, Recent Advances in Prostate Cancer
Breast Cancer vs. Prostate Cancer
1998
PROSTATE CA
New Cases/Yr.
Deaths/Yr.
Deaths/Cases
Lifetime risk of Developing
Mets at Diagnosis
Mortality Rate Trend (22 yr.)
5 Yr. Relative Survival Rate
Median Age at Diagnosis
Median Age at Death
Scardino, MSKCC
184,500
39,200
21%
17%
9%
+ 17%
93%
71 yr
77 yr
BREAST CA
180,300
43,900
24%
14%
6%
- 3%
85%
64 yr
68 yr
Ongoing Randomized Screening
Trials
•
Prostate, Lung, Colon and Ovarian (PLCO) Trial of the NCI
Q: Does screening decrease mortality?
•
European Randomized Study of Screening for Prostate Cancer (ERSPC)
Q: Difference in CaP mortality in screened vs. unscreened
patients?
Q: Quality of life differences in screened population?
•
Prostate Cancer Intervention Vs. Observation Trial (PIVOT)
Q: Does early, aggressive treatment decrease
mortality?
•
Prostate Cancer Prevention Trial (PCPT)
Q: Can finasteride prevent prostate cancer?
Prostate, Lung, Colorectal and Ovarian
(PLCO) Trial
Men (74,000) and women (74,000) ages 55 to 74
years will be randomized to a control arm (routine
medical care) or a screening arm which includes:
•
•
•
•
Prostate:
Lung:
Colorectal:
Ovarian:
PSA and DRE
CXR
Flexible sigmoidoscopy
Pelvic exam, CA125,
Transvaginal ultrasound
ERSPC Trial
• Large, International cooperative study initiated in
1994
• Goal is to compare prostate cancer mortality
between screened and control arms
• With 165,000 men age 55-69 with a 20%
contamination rate, the trial will reach a power of
86% to show a 20-25% mortality reduction
• Results expected in 2008
ERSPC Trial
Impact of PSA on Survival
Tsodikov et al. UC Davis
What Can We Do While we Await
the Results?
• Improve diagnostics:
1.) Imaging
2.) More sensitive PSA
• Improve Treatment Stratification:
1.) Nomograms
• Improve Surgical Technique
(lower morbidity)
1.) nerve sparing
2.) nerve grafts
3.) Laparoscopic Prostatectomy
Improved Cancer Detection
Through Imaging
Endorectal MRI/Spectroscopy
• Potential improvement over ultrasound
• Biochemical gradients to decipher cancer
from benign
• Remains investigational
• Possible role in high risk patients
MRN 309468
Endo-rectal coil MRI
* *
*
Image 8 I 54.44 mm
Image 9 I 57.56 mm
H
H
H
H
H
H
H
H
H
H
sc vc
H
H
H
H
H
H
H
H
H
vc
H
H
H
H H
H
H
Treatment Stratifications
• Allow for improvement in patient
understanding
• More objective in guiding treatment
decisions
• Less physician bias
Preoperative Nomogram for Prostate Cancer Recurrence
Points
PSA
0
10
0.1
30
T1c
40
T2c
60 Month Rec. Free Prob.
9 10
12
70
80
90
100
16 20 30 45 70 110
T1ab T2b
Biopsy Gleason Grade 2+  2
0
60
T3a
 2+3 3+  2
Total Points
50
2 34 6 7 8
1
T2a
Clinical Stage
20
20
 4+
 3+ 4
3+3
40
.96
60
.93 .9
80
100
.85 .8
120
.7
140
160
.6 .5 .4 .3 .2
180
200
.1 .05
Instructions for Physician: Locate the patient’s PSA on the PSA axis. Draw a line straight upwards to the Points axis to determine how many
points towards recurrence the patient receives for his PSA. Repeat this process for the Clinical Stage and Biopsy Gleason Sum axes, each time
drawing straight upward to the Points axis. Sum the points achieved for each predictor and locate this sum on the Total Points axis. Draw a line
straight down to find the patient’s probability of remaining recurrence free for 60 months assuming he does not die of another cause first.
Note: This nomogram is not applicable to a man who is not otherwise a candidate for radical prostatectomy. You can use this only on a man who
has already selected radical prostatectomy as treatment for his prostate cancer.
Instruction to Patient: “Mr. X, if we had 100 men exactly like you, we would expect between <predicted percentage from nomogram - 10%> and
<predicted percentage + 10%> to remain free of their disease at 5 years following radical prostatectomy, and recurrence after 5 years is very rare.”
Kattan MW et al: JNCI 1998; 90:766-771.
 1997 Michael W. Kattan and Peter T. Scardino
3D Conformal Radiation Therapy Nomogram for PSA Recurrence
0
Points
Pretreatment PSA
10
20
0.3
Bx.Gl.Sum
Dose (gy)
40
1
50
60
2
3
80
100
4
70
5
80
6 7
9 10
90
100
25 50 100
T3ab T3c
T2a
Clinical Stage
30
T2b T2c
T1c
3 35
7
9
2 24 6
88
8
72
10
68
64
No
Hormones
Total Points
Yes
0
20
40
60-Month Recurrence Free Prob.
0.99
60
0.98
0.95
0.9
0.8 0.7
120
0.5
140
0.3
0.1
160
0.01
180
Palm Pilot Nomogram Software
• Includes pretreatment and postoperative
predictions.
• Uses published nomograms in prostate cancer.
Postoperative Nomogram for Prostate
Cancer Recurrence
0
Points
Preop PSA
0.1
4
Gleason Sum
Extraprostatic Ext.
Surgical Margins
10
20
0.2
30
0.3
40
0.5
50
0.7
6
60
1
70
2
8
3,5
80
3
4
90
6
100
8 10 100
10
7
9
Inv.Capsule
Established
None
Focal
Pos
Neg
Yes
Seminal Ves. Invasion
Lymph Nodes
No
Pos
Neg
Total Points
84-Month Rec. Free Prob.
0
40
80
0.99 0.98
120
0.95 0.9
160
200
240
280
0.8 0.7 0.5 0.3 0.1 0.01
 1998 Michael W. Kattan and Peter T. Scardino
Technical Improvements in Surgery
• Cavernosal nerves necessary for postoperative erectile functions
• In advanced disease, nerves may need to
be resected to obtain a negative margin
• Sural nerve or genitofemoral nerve serve
as sources of nerve grafts in this setting
Laparoscopic/Robotic
Prostatectomy
• Minimally invasive form of prostatectomy
• Shorter hospital stay, less blood loss,
improved optical visualization
• No long data regarding cancer control,
potency or quality of life
Conclusion
• Prostate cancer screening is controversial
• More cost-effective means at targeting high risk
populations may be more reasonable
• We await results of randomized screening trials
• While we await results of screening trials, we
continue to improve prostate cancer treatment
with cancer control and quality of life as our
primary aims.