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The PSA Puzzle
Claus G Roehrborn, MD
Professor and Chair
S.T. Harris Family Chair in Medical Science, in Honor of John D. McConnell, M.D.
E.E. Fogelson and Greer Garson Fogelson Distinguished Chair in Urology
Department of Urology
UT Southwestern Medical Center at Dallas
Cancer Statistics 2012
CA: A Cancer Journal for Clinicians
Volume 62, Issue 1, pages 10-29, 4 JAN 2012 DOI: 10.3322/caac.20138
http://onlinelibrary.wiley.com/doi/10.3322/caac.20138/full#fig1
Cancer Statistics 2012
CA: A Cancer Journal for Clinicians
Volume 62, Issue 1, pages 10-29, 4 JAN 2012 DOI: 10.3322/caac.20138
http://onlinelibrary.wiley.com/doi/10.3322/caac.20138/full#fig1
Cancer Statistics 2012
CA: A Cancer Journal for Clinicians
Volume 62, Issue 1, pages 10-29, 4 JAN 2012 DOI: 10.3322/caac.20138
http://onlinelibrary.wiley.com/doi/10.3322/caac.20138/full#fig1
Screening for Prostate Cancer: U.S. Preventive
Services Task Force Recommendation Statement
DRAFT
• The U.S. Preventive Services Task Force (USPSTF)
recommends against prostate-specific antigen (PSA)-based
screening for prostate cancer.
• This is a Grade D recommendation.
• This recommendation applies to men in the U.S. population
that do not have symptoms that are highly suspicious for
prostate cancer, regardless of age, race, or family history.
The Task Force did not evaluate the use of the PSA test as
part of a diagnostic strategy in men with symptoms that are
highly suspicious for prostate cancer. This recommendation
also does not consider the use of the PSA test for
surveillance after diagnosis and/or treatment of prostate
cancer.
http://www.uspreventiveservicestaskforce.org/uspstf12/prostate/draftrecprostate.htm
The Prostate
PSA Fundamentals
• Prostate specific antigen (PSA) is an enzyme,
produced in the glandular epithelial cells of the
prostate, and only there (!)
• It is therefore specific to the prostate (and men)
but not to specific prostate diseases
• Every men has a measurable level of PSA as long
as he has a prostate
– The only exception are men after total prostatectomy
and those who are surgically or medically castrated
Common Disease States of the
Prostate and PSA levels
• Normal prostate in younger men
– usually very low levels of PSA
• Benign prostatic hyperplasia (BPH):
– PSA increases with age and with the size of the gland
• Inflammation/infection (prostatitis):
– Relatively rare, can lead to a temporary increase
• Precancerous lesions in the prostate (HG PIN, atypia
and dysplasia)
– Slight elevation of PSA
• Prostate cancer
– The higher the PSA, the greater the risk of cancer, but
there is NO totally safe range
Prevalence of Prostate Cancer Among Men with a
PSA of < 4.0 ng/ml in PCPT
Thompson et al, NEJM 350 (22), 2004
Uses of PSA
• To screen for prostate diseases in a distinct
population (eg all men over 50, or all men with a
family history)
• To diagnose or find diseases in men presenting to
a health care provider with symptoms/problems
• To monitor diseases of the prostate during or
after treatment
• To verify absence of disease (ie undetectable PSA
after total prostatectomy)
PROSTATE CANCER MORTALITY AFTER INTRODUCTION
OF PROSTATE-SPECIFIC ANTIGEN MASS SCREENING
IN THE FEDERAL STATE OF TYROL, AUSTRIA
Bartsch et al, UROLOGY 58: 417–424, 2001
Mortality Results from a Randomized
Prostate-Cancer Screening Trial
Prostate, Lung, Colorectal, and Ovarian (PLCO)
Andriole et al, N Engl J Med 2009;360:1310-9.
• From 1993 through 2001, 76,693 men at 10 U.S. study centers
were randomized to receive either annual screening (38,343
subjects) or usual care as the control (38,350 subjects).
• Men in the screening group were offered annual PSA testing for 6
years and digital rectal examination for 4 years.
• The subjects and health care providers received the results and
decided on the type of follow-up evaluation.
• Usual care sometimes included screening, as some organizations
have recommended. The numbers of all cancers and deaths and
causes of death were ascertained.
Number of Diagnoses of All Prostate Cancers (Panel A) and
Number of Prostate-Cancer Deaths (Panel B)
Conclusions After 7 to 10 years of follow-up, the rate of death
from prostate cancer was very low and did not differ
significantly between the two study groups
Andriole G et al. N Engl J Med 2009;10.1056/NEJMoa0810696
Screening for Prostate Cancer: U.S. Preventive
Services Task Force Recommendation Statement
DRAFT
• The U.S. Preventive Services Task Force (USPSTF)
recommends against prostate-specific antigen (PSA)-based
screening for prostate cancer.
• This is a Grade D recommendation.
• This recommendation applies to men in the U.S. population
that do not have symptoms that are highly suspicious for
prostate cancer, regardless of age, race, or family history.
The Task Force did not evaluate the use of the PSA test as
part of a diagnostic strategy in men with symptoms that
are highly suspicious for prostate cancer. This
recommendation also does not consider the use of the PSA
test for surveillance after diagnosis and/or treatment of
prostate cancer.
http://www.uspreventiveservicestaskforce.org/uspstf12/prostate/draftrecprostate.htm
What is the current commotion all
about?
• Screening studies:
– Allocate one half of men to have annual PSA
testing and biopsies if elevated, then treat
– Allocate one half of men to NOT have annual PSA
or PSA testing at all for the duration of the study,
except if they have an abnormal examination,
symptoms etc; then test, biopsy and treat
• Endpoint: death from prostate cancer
PSA Screening Studies
• Hypothesis:
–
–
–
–
–
If PSA elevated prostate cancer is more likely
TRUS biopsy will find the cancer if it is there
If cancer is found, patient will have treatment
Treatment is effective in curing the cancer
Patients thus diagnosed with elevated PSA and
cancer on biopsy will less likely die from prostate
cancer over the course of the study
Better sleep leads to greater
productivity
• Hypothesis:
– Certain mattresses allow for a deeper sleep
– A deeper sleep will cause a person to be better
rested for the next day
– A better rested person will be more productive at
work
– Greater productivity at work will increase
efficiency and thus the financial bottom line of a
factory
Better sleep leads to greater
productivity
• Study design:
– Allocate one half of the workers to sleep on a new
mattress purchased for them
– Allocate one half of workers to sleep on their old
mattress, ask them not to buy any new mattress
or change it during the study
• Endpoint: productivity measures and financial
bottom line comparing the two groups of
workers
What did men in the PLCO study actually do
in terms of PSA testing?
• Compliance with the screening protocol in the screen
population overall was 85% for PSA testing and 86%
for digital rectal examination.
• In the control group, the rate of PSA testing was 40%
in the first year and increased to 52% in the sixth year
• They did not really follow the rules of the study!
What might the factory workers do?
• Results:
– Of the 38,000 workers who were given the new
mattress 15% did not like it and did not use it
– Of the 38,000 workers told to use their old mattress,
45% heard about the new mattress and bought it at
some time during the two years to sleep on it
– More workers who slept on the new mattress (in both
group) said they felt they slept better
– There was not demonstrable difference in
productivity measures between the two groups
Better sleep leads to greater
productivity
100%
80%
100%
17000
Bought
new
60%
40%
80%
21000
20%
Used old
60%
32000
Used new
40%
20%
Used old
6000
0%
0%
Old Mattress
Group
New
Mattress
Group
Let’s
compare
the workers
who
Better
sleep leads
to greater
actually used
new vs old mattresses
productivity
50000
50000
40000
Got new
but used
old
40000
Used old
20000
30000
6000
20000
10000
21000
0
17000
Assigned to
old but
bought
new
32000
Used new
30000
10000
0
Old
Mattress
New
Mattress
How would the results be if we compare the
workers actually using the new versus the old
mattresses?
• This logical and seemingly legitimate question cannot
be asked – it is called ‘per protocol’ analysis
• The analysis has to be as intention to treat
– Ie, you were told to sleep on the old mattress and –
whatever you actually did – that is how we analyze you, as
an old mattress user
– You did not like the new mattress? Too bad, we will
analyze you as though you used it anyway
Did we answer the question(s)
• What do you think now? Buy everybody a new
mattress? No new mattresses for anybody?
• Did this long and large study answer your
question regarding the connection from
mattress to sleep to productivity?
• Did the PLCO study answer the question
regarding the connection between PSA testing
and cancer diagnosis and mortality?
Mortality results from the Göteborg randomised
population-based prostate-cancer screening trial
Risk of prostate cancer
In Sweden there is not much PSA screening outside
the study, and thus, there is little contamination!
The results of a per protocol vs intention to treat
are therefore quite similar!
Hugosson Lancet Oncol 2010; 11: 725–32
Mortality results from the Göteborg randomised
population-based prostate-cancer screening trial
Risk of death from prostate cancer
The rate ratio of death from prostate cancer for
attendees compared with the control group was
0·44 (95% CI 0·28–0·68; p=0·0002).
Overall, 293 (95% CI 177–799) men needed to be
invited for screening and 12 to be diagnosed to
prevent one prostate cancer death.
Hugosson Lancet Oncol 2010; 11: 725–32
Screening and Prostate-Cancer Mortality
in The European Randomized Study of Screening for Prostate Cancer
Schröder et al, N Engl J Med 2009;360:1320-8.
Conclusions PSA-based screening reduced the rate
of death from prostate cancer by 20% but was
associated with a high risk of overdiagnosis
Schroder F et al. N Engl J Med 2009;10.1056/NEJMoa0810084
Adjusting
for Cancer Mortality Reduction by Prostate-Specific
Prostate
contamination
or Screening Adjusted for Nonattendance and
Antigen–Based
Contamination in the European Randomised Study of Screening
nonattendance
increased the risk for Prostate Cancer (ERSPC)
UROLOGY 5 6 ( 2 0 0 9 ) 5 8 4 – 5 9 1
reduction toEUROPEAN
30%
Cumulative Hazard of Death from Prostate Cancer among Men 55 to
69 Years of Age.
•
The European Randomized Study of
Screening for Prostate Cancer
continues to show a 21% reduction in
prostate-cancer mortality in the
screening group, after 11 years of
follow-up.
•
The number of cancers that would
need to be detected to prevent one
prostate-cancer death is 37.
Schröder FH et al. N Engl J Med 2012;366:981-990
Nothing about the evaluation process is
inevitable, and all decisions are shared!
1. Decision to go to a physician or health
provider
2. Whether to get a PSA test
3. How to interpret the results
4. Whether to do a biopsy
5. If the biopsy is positive, whether to treat,
and if so how to treat the cancer
Cancer Statistics 2012
CA: A Cancer Journal for Clinicians
Volume 62, Issue 1, pages 10-29, 4 JAN 2012 DOI: 10.3322/caac.20138
http://onlinelibrary.wiley.com/doi/10.3322/caac.20138/full#fig1
Original Article
Radical Prostatectomy versus Watchful Waiting in
Early Prostate Cancer
Anna Bill-Axelson, M.D., Ph.D., Lars Holmberg, M.D., Ph.D., Mirja Ruutu, M.D., Ph.D.,
Hans Garmo, Ph.D., Jennifer R. Stark, Sc.D., Christer Busch, M.D., Ph.D., Stig
Nordling, M.D., Ph.D., Michael Häggman, M.D., Ph.D., Swen-Olof Andersson, M.D.,
Ph.D., Stefan Bratell, M.D., Ph.D., Anders Spångberg, M.D., Ph.D., Juni
Palmgren, Ph.D., Gunnar Steineck, M.D., Ph.D., Hans-Olov Adami, M.D., Ph.D., JanErik Johansson, M.D., Ph.D., for the SPCG-4 Investigators
N Engl J Med
Volume 364(18):1708-1717
May 5, 2011
Cumulative Incidence of Death from Any Cause, Death from Prostate Cancer, and
Development of Metastases.
Bill-Axelson A et al. N Engl J Med 2011;364:1708-1717
Cumulative Incidence of Death from Prostate Cancer and Development of Metastases among
Men with Low-Risk Prostate Cancer.
Bill-Axelson A et al. N Engl J Med 2011;364:1708-1717
Survival Among Men With Clinically Localized Prostate
Cancer Treated With Radical Prostatectomy or Radiation
Therapy in the Prostate Specific Antigen Era
Source: Journal of Urology, The 2012; 187:1259-1265 (DOI:10.1016/j.juro.2011.11.084 )
Copyright © 2012 American Urological Association Education and Research, Inc. Terms and Conditions
Learning curve for cancer control after radical
prostatectomy stratified by preoperative risk group
Low
Intermediate
High
Klein et al J Urol 2008 Jun;179(6):2212-6
Effects of surgeon experience on outcome by preoperative
risk group and in 5,038 patients treated after 1995
Klein et al J Urol 2008 Jun;179(6):2212-6
2006 period life table for the
Social Security area population
80
70
60
50
40
30
20
10
20.7
17.0
13.6
10.5
7.8 5.6
0
5
10
15
20
25
30
35
40
45
50
55
60
65
70
75
80
85
90
95
100
105
110
115
0
http://www.ssa.gov/OACT/STATS/table4c6.html
Use of PSA in men with voiding symptoms and
benign prostatic growth or BPH
• I use PSA in men with voiding symptoms and BPH to
–
–
–
–
–
–
Estimate prostate size
Determine the risk of worsening of symptoms
Determine the risk of requiring surgery in the future
Determine the risk of not being able to urinate at all
Monitor disease activity over time
Monitor response to certain types of drugs (5 alpha
reductase inhibitors [Avodart, Jalyn, Proscar])
AGE VERSUS LOG SERUM PSA AND LOG
VOLUME
Means ± 95% CI for age categories and linear
regression lines
3.8
1
3.0
50
3.7
Log Prostate Volume, cc
Log Serum PSA, ng/ml
0.8
0.6
0.4
0.2
0
-0.2
-0.4
-0.6
3.5
3.4
3.3
3.2
3.1
-0.8
-1
3.6
20
0.5
< 30
3
30 - 39
40 - 49
50 - 59
Age, years
60 - 69
70 +
< 30
30 - 39
40 - 49
50 - 59
Age, years
60 - 69
70 +
SERUM PSA VERSUS PROSTATE VOLUME
CONFIDENCE BANDS FOR DIFFERENT AGE GROUPS
85
25 30 35 40 45 50 55 60 65 70 75 80 85
85
50-59
60-69
80
75
70
70
70
60
55
50
45
Prostate Volume (cc)
75
65
65
60
55
50
45
65
60
55
50
45
40
40
40
35
35
35
30
30
30
25
25
25
0
1
2
3
4
5
6
7
8
9 100
1
2
3
4
5
6
70+
80
75
Prostate Volume (cc)
Prostate Volume (cc)
80
85
7
8
9 010 1
2
3
4
5
6
7
8
9
10
CUMULATIVE INCIDENCE OF AUR, SURGERY AND
EITHER ONE FOR PLACEBO TREATED PTS
IN 4-YR PLESS STUDY BY INCREASING PSA
30
Cumulative Incidence (%)
25
Either
Surgery
AUR
20
15
10
5
0
.0
>0
.5
>0
.0
>1
.5
>1
.0
>2
.5
>2
.0
>3
.5
>3
.0
>4
.5
>4
.0
>5
.5
>5
.0
>6
.5
>6
.0
>7
.5
>7
.0
>8
47
Monitor PSA in men after treatment
• After radiation therapy the PSA decreases usually to
a level of < 1.0.
– Monitoring is important
– If the PSA increases from the lowest measured level , and
that increase is confirmed by a second measurement, the
cancer has recurred and additional treatment is needed
• During hormone therapy the PSA usually drops, and
an increase is indicative of the cancer not responding
to the treatment any longer
Monitor PSA in men after prostatectomy
• After total prostatectomy the PSA should be
undetectable (<0.05)
• Monitoring over time is important:
– If PSA becomes detectable it indicates persistent or
recurrent cancer
– The rate of increase over time indicates how aggressive
the recurrent cancer is
– Additional treatments such as radiation and/or hormone
therapies can be monitored by a subsequent decrease in
PSA levels
Urology Clinic at UTSW
9th Floor Aston Center
214 645 8765 (UROL)
Or
Request an Appointment
214-645-8300 or online
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Claus G Roehrborn MD
Cell 214 649 2941
Claus Roehrborn Urology Blog