FDA approved PSA to be used to screen for prostate cancer in 1994,
although it has been so used for many years prior (probably around 1986). But, to screen or not to screen, that is the
question (with no definite answer!) To
illustrate the complexity of the controversy I’ll first mention the most vocal
opponent against using PSA to screen for prostate cancer is Dr. Richard Ablin (see photo, left),
who discovered PSA in 1970. He wrote an
op-ed at NY Times (3/9/2010) “The Great Prostate Mistake”, in which
he chastised the American Urological Association (AUA) for still recommending PSA
screening ‘shamefully’. He also wrote, “If the biopsy showed any
signs of cancer, the patient was almost always pushed into surgery, intensive
radiation or other damaging treatments”.
Patients are “pushed
into surgery” for the “damaging treatments”, that is to say “shame on you, you
urologists!” Drug companies are not
spared, he wrote, “Drug companies continue peddling the tests and advocacy groups push
'prostate cancer awareness' by encouraging men to get screened.” To say ‘peddling’ is equivalent to “咱們的跑江湖賣膏藥的「王樂阿仙」”
Dr. Ablin concluded by saying “I never dreamt that my discovery 4
decades ago would lead to such a profit-driven public health disaster.”
Current U.S. Preventive Services Task Force does not recommend PSA
screening for patients of any age. What’s
wrong with PSA screening? I used it as
one of the examples of “sensitivity and specificity” concept in interpreting
the Lab tests during my talk at the Taiwanese Bible Study last month.
PSA (prostate specific antigen) is produced by the epithelial cells (上皮細胞) of prostate and is released to the blood
stream. PSA increases in the presence of
prostate cancer as its production increases, as does the leakage into the blood
stream. And better yet 90% of prostate
cancer detected by PSA screening show the cancers are confined to prostate or
regional spread (no distant metastasis); the 5-year survival is almost 100%. Prostate cancer diagnosed after patients
become symptomatic (i.e. without PSA screening) are almost always too late.
This makes PSA screening much desirable and medically advisable. No wonder 90% of US men (50 yr-old or older) have
at least one PSA test. However, the
advantages stop here.
Vicious attack on AUA and drug companies notwithstanding, Dr. Ablin also
made many sensible and legitimate comments, such as “American men have a 16%
lifetime chance of receiving a diagnosis of prostate cancer, but only a 3% [2.9%
to be exact] chance of dying from it. That’s because the majority of prostate
cancers grow slowly. In other words, men lucky enough to reach old age are much
more likely to die with
prostate cancer than to die
of it.”
An autopsy study shows two thirds of men (of 80 years of age or older) died of any
illness other than prostate cancer have prostate cancer; these people “die with
prostate cancer than to die of it.”
If you read the Lab report you would see PSA of 4 is the upper normal
limit. But, in realty no one knows what
is the normal upper limit of it.
In a 7-year study of 18,882 patients, 9,459 patients have annual PSA and
digital rectal examination (DRE), 2,950 patients have prostate biopsy at the
end of 7 years and 449 (ages 62-91) turn out to have prostate cancer.
The number of PSA among these prostate cancer patients spread all over
from below 0.5 to way above 4.
PSA 0 - 5 6.6%
0.6
– 1.0 10.1%
1.1
– 2.0 17.0%
2.1
– 3.0 23.9%
3.1
– 4.0 26.9%
---------------------------------------------
74.5%
(with PSA less than 4.0)
greater than 4.0 25.5%
If 100 patients known to have prostate cancer and do PSA test, only
about 25 (1 in 4) have PSA ≥ 4.0, that is to say that PSA test has 25%
sensitivity.
A high sensitivity test is good to rule out disease. For example, D-dimer test (elevated in cases
of deep venous thrombosis or DVT) has nearly 100% sensitivity, that is to say
if one has normal D-dimer, one doesn’t have DVT. But PSA has such a low sensitivity (about 25%
in this study), one has ‘normal’ (i.e. <4.0) PSA still doesn’t guarantee no
prostate cancer.
I mention this dry statistical stuff to make a
point that there is no such a thing as to what is “normal” PSA; setting PSA 4.0
as a cutoff is a “compromised” trade off between sensitivity and specificity.
Setting PSA 4.0 as a cutoff value, sensitivity
is about 21-25%, setting PSA 3.0 as a cutoff value, sensitivity is 32%, so
lower the number, increases sensitivity, but what about specificity?
A high specificity test is good to rule in
disease. If PSA test has a specificity
of 100%, then if one has a PSA>4.0, then one has prostate cancer. However, using PSA 4.0 as a cutoff value, its
specificity is 91%, i.e. 9% of patients with a PSA>4.0 will turn out not to
have prostate cancer. Using PSA 3.0 as a
cutoff value, the specificity is down to 85%.
Why is it so? the answer lies in the fact that there are many other
conditions that will raise PSA, most commonly benign prostate hyperplasia; the
list is as long as your arm, like Dr. Albin wrote, “Infections,
over-the-counter drugs like ibuprofen, and benign swelling of the prostate can
all elevate a man’s P.S.A. levels.”
Not all prostate cancer behave the same way; most are slow growing, but
some can be aggressive. One wrote in a letter-to-the-editor in NY Times claimed “roughly 30-40% of all
prostate cancers are aggressive.” (see photo below). I am not sure all urologists would agree with the number of 30-40%, though. Unfortunately, PSA screening cannot
differentiate between indolent and lethal [aggressive] prostate cancer.”
The urologists have many tools at their disposal in predicting which
will be more aggressive and treated accordingly; these evaluations are helpful, but by no means
perfect.
^ Gleason score (after prostate
biopsy)
^ PSA velocity (rate of increase)
^ ratio of free over bound PSA
^ PSA density (PSA divided by
volume of prostate)
^ age
^ comorbidity
^ life expectancy
There are two major trials study the impact of treatment outcome of PSA
screening. One is from Europe: ERSPC (European Randomized Study of
Screening for Prostate Cancer), the other from the U.S.: PLCO (prostate, lung, colo-rectal &
ovary trial). The ERSPC involves 182,000
patients in 7 European countries over 9 years period, whereas the PLCO involves
76,693 patients at 10 U.S. centers over 7-10 years period. Both studies were published in the same issue
(3/26/2009)
of New England Journal of Medicine (NEJM).
The result is not favorable in pursuing PSA screening. The ERSPC shows small absolute survival benefit
after 9 years follow up. Although there
is 20% decrease in prostate cancer mortality in the group of ages 55-69, the
absolute survival benefit is very small (a decrease in 0.7 death per 1,000
patients after 9 years follow up), and 1,410 patients have to be screened and
48 patients have to be diagnosed to have prostate cancer to prevent one death.
The “over diagnosed” issue comes into play. If one’s prostate cancer never would have
caused any problem during his life time, and it is picked up because of doing
PSA tests and is therefore subject to surgery (radical prostatectomy) or
radiation therapy, resulting in complication or undesirable consequence, such
as erectile disorder (20-70%) or urine incontinence (15-50%), then this is
“over diagnosed”. Over diagnosed may lead to unnecessary treatment and the potential complications.
The PLCO study shows no mortality benefit from annual PSA screening in
7-10 years of follow up.
This is what led the U.S. Preventive Services Task Force to recommend no
PSA screening. However, American Cancer
Society still recommends the PSA screening begins at age of 50, while AUA at
age of 40 (see photo below).
PSA is very good in monitoring the progress of prostate cancer treatment
or recurrence; there is no controversy about it.
The way Dr. Ablin criticizes the AUA is not fair. The urologists are the ones seeing all the
troubles, complications and suffering of prostate cancer patients. This is not 飯碗的問題 (not a matter of making a living); in fact,
the urologists end up making more money in taking care of complicated prostate
cancer patients.
Keep in mind that Dr. Ablin is a Ph.D., not an M.D., let alone an
urologist. A super scientist though he
may be, he may lack the knowledge and understanding of the relevant clinical
problems and idiosyncrasy of individual patient.
USPSTF is supposed to be a government (federal) agency; one may wonder
their stand and recommendation put more weight on the cost than the benefit of
individual patient. They caused an
uproar two years ago when they announced the mammogram can be done every two
years, instead of every year, and begins at age of 50, instead of 40. Is this the Obama Care to come?
One thing for sure is that a PSA test shouldn’t be requested (by
patients) or ordered (by doctors) without a through counseling, which will be a
daunting task. The photo is the cover of
the British Medical Journal illustrating the importance of physician patient
partnership. It is not as graceful as
the image implies.
上醫醫未病之病
中醫醫將病之病
下醫醫已病之病
This is from 黃帝內經. Prevention is not as easy as it seems. It is not easy to be a 上醫.
The issue of PSA screening also demonstrates the wisdom of 黃帝內經.
This writing is to help you understand the complexity and dilemma of a
medical controversy. Is a PSA test right
for you? Only you and your doctor can
make the decision. The last slide of my
talk quoted what Enrico Fermi said in 1938,
“Before I came here I was
confused about this subject, but now having heard your lecture I am still
confused, but at a higher level.”
After reading this, if you’re still confused, hopefully at a higher
level, then the purpose of this writing is served.
Dr. Wang (王炯珵) was a research fellow at UPMC about six years ago. When he came to attend the annual American Urology Association meeting at Washington, D.C. this past May, he made a side trip to Mount Vernon with us—a fond memory. The photo shows Dr. Wang and Katy at the back yard of George Washington’s House at Mt. Vernon, overlooking the majestic Potomac River in Northern Virginia.
No comments:
Post a Comment