Transcript Diapositiva 1

Prof. Francesco Boccardo
Direttore Oncologia Medica B, IST Genova
Professore Ordinario di Oncologia Medica,Università di Genova
FLOW DIAGRAM ERSPC TRIAL
(AGE GROUP 55-69)
FLOW DIAGRAM PLCO TRIAL
(AGE GROUP 55-74)
Randomized 162.387
Dead at R: 144
Randomized 76.693
Intervention arm
72.890
Control arm
89.353
Intervention arm
38.343
Control arm
38.350
Prostate Cancer
N = 5.990
Prostate Cancer
N = 4.307
Prostate Cancer
N = 2.820
Prostate Cancer
N = 2.322
Dead
11.490 (15.8%)
Dead
14.142 (15.8%)
Known dead
3.015 (7.9%)
Known dead
3.122 (8.1%)
Dead of PC
N = 214
3.57% of PC
0.29% of all
1.9% of dead
Dead of PC
N = 326
7.57% of PC
0.37% of all
2.3% of dead
Dead of PC
N = 50
1.77% of PC
0.13% of all
1.66% of dead
Dead of PC
N = 44
1.90% of PC
0.12% of all
1.41% of dead
CRITICISM OF ERSPC
1) ERSPC is not one study, it consists of different studies in 7 (8) centers; a common analysis
in not justified, a meta-analysis might be adeguate. If this were true, ERSPC could no
longer be considered as producing the level 1 evidence assigned to randomized controlled
trials (RCT)
2) Treatment ,as reported in the supplementary appendix, is more aggressive in the screen
arm: the difference seen may be due to treatment and not to screening.
3) The trials use wrong endpoint: overall mortality would be appropriate. This comment is
justified in the sense that even a larger difference in PC mortality will only have a very
small impact on overall mortality.
4) The significance of the mortality difference in ERSPC is marginal at 9 years.
CRITICISM OF PLCO
1) While the total average follow-up is reported to amount to 11.2 years, follow-up is 98%
complete only at 7 years. After this time period ERSPC did not reveal a difference either
2) PLCO used a PSA cut-off value of >= 4.0 ng/ml. Recent data from ERSPC show that the
PSA range 3 – 3.9 ng/ml harbors aggressive prostate cancer.
3) Those men that were pre-screened before being randomized to the screening arm show
a 25% lower prostate cancer mortality as compared to those men that were not
pre-screened before randomization,
Screen or Not?
What Those Prostate Studies Mean
Last week, two major studies from the
United States and Europe found that
P.S.A. testing — the annual blood test
used to screen men for prostate cancer
— saves few if any lives, while exposing
patients to aggressive and unnecessary
treatments that can leave them impotent
and incontinent.
The news was unsettling and confusing to many middle-age men, particularly those
who already have diagnoses of prostate cancer as a result of P.S.A. testing. Doctors
say some men are reconsidering surgery or radiation treatment they have planned.
Others, convinced that their lives were saved by P.S.A. screening, wonder how
anyone could question the value of early detection of prostate cancer.
In the face of all this confusion, what’s a man to think? Here are answers to some
frequently asked questions.
WHAT DID THE STUDIES REALLY SHOW?
The bottom line of both studies is that P.S.A. screening does find more
prostate cancers — but finding those cancers early doesn’t do much to reduce
the risk of dying from the disease.
The American study showed no statistical difference in prostate cancer death
rates between a group of men who had the screening and a control group
who did not. The European researchers found that P.S.A. screening does
reduce the risk of dying from prostate cancer by about 20 percent.
But in terms of individual risk, even that is not a huge benefit. It means that a
man who isn’t screened has about a 3 percent average risk of dying from
prostate cancer. If that man undergoes annual P.S.A. screenings, his risk
drops to about 2.4 percent.
And there is an important tradeoff. P.S.A. testing increases a man’s risk of
being treated for a cancer that would never have harmed him in the first place.
The European study found that for every man who was helped by P.S.A.
screening, at least 48 received unnecessary treatment that increased risk for
impotency and incontinence. Dr. Otis Brawley, chief medical officer of the
American Cancer Society, summed up the European data this way: “The test
is about 50 times more likely to ruin your life than it is to save your life.”
SO DO THESE STUDIES SETTLE THE DEBATE
ABOUT THE VALUE OF P.S.A. SCREENING?
Not necessarily. Both have problems that make it difficult to interpret the
data. The American study found no benefit in P.S.A. screening over a
period of 7 to 10 years. But so far, only about 170 men out of 77,000
studied have died of prostate cancer. Prostate cancer is slow-growing, so
it’s possible that in the next few years, meaningful differences in mortality
rates between the two groups will emerge.
A larger concern is what statisticians call “contamination” in the unscreened
control group. Because it would have been unethical to tell men in the
control group that they could not be screened, many either sought the test
or were offered it by their doctors.
Investigators initially estimated that 20 percent of the control group would
fit in this category, but the numbers ended up being far higher —38 to 52
percent. As a result, the study doesn’t really compare the risks and benefits
of screening and no screening. It compares aggressive screening and
some screening.
The fact that so many men in the nonscreening group “dropped in” to the
screening category “is a serious concern,” said Dr. Eric A. Klein, chairman
of the Glickman Urological and Kidney Institute at the Cleveland Clinic,
who added:
“The argument for screening today is no different than before. These
studies do not settle the issue definitively one way or another.”
The American investigators said that while contamination did complicate
the interpretation of the data, they were still confident in the finding that
there is little or no benefit to P.S.A. screening. “Our statisticians still felt the
power of the study to detect a medically meaningful benefit was retained,”
said Dr. Barnett S. Kramer, co-author of the study and associate director for
disease prevention at the National Institutes of Health.
The European research has its own set of problems. Although the finding
that P.S.A. screening reduces cancer deaths by 20 percent is statistically
significant, experts say it’s on the borderline, and a few more years of data
could weaken the result. Finally, parts of the study were not “blinded,”
meaning that biases could have crept into the interpretation of the data.
DOES THIS MEAN MEN SHOULD NOT
RECEIVE PROSTATE CANCER SCREENING?
No. Before the studies were released, most major medical groups said
P.S.A. testing was a personal decision that a man should discuss with his
doctor. The two new studies are unlikely to change that advice, experts
say; instead, they give men and their doctors more information with which
to make the decision.
For older men, the screening decision should be easier. P.S.A. screening
is already not advised for those 75 and older. And the American research
confirms that P.S.A. testing is not helpful for men with 10 years or less of
life expectancy. In the European study, among men 70 or older, there were
more deaths in the P.S.A. screening group, although the trend could be
caused by chance.
The advice is murkier for middle-age men. In the European study, 50- to
54-year-olds didn’t benefit from screening. But men ages 55 to 69 were 20
percent less likely to die from prostate cancer than those who weren’t
screened. (Still, men in that age group must decide whether the high risks
of unnecessary treatment are worth it.)
A co-author of the American study, Dr. Gerald L. Andriole Jr., a surgeon at
Washington University, says that while every man shouldn’t get a P.S.A.
test, he also doesn’t recommend “wholesale stoppage.”
Middle-age men or older men with a life expectancy of 10 years or more
“need to be informed about the potential pros and harms of screening,” he
said, adding:
“If they want to embark on it, that’s fine. I’m still open to accepting that we
learn a lot about a man’s prostate and about the probability of him getting
or having prostate cancer by measuring P.S.A..”
Dr. Brawley of the American Cancer Society agreed that individual men
might come to different decisions after talking with their doctors.
“There is a guy out there whose personal experience is such that he’s very
frightened of prostate cancer, so maybe he should be screened,” Dr.
Brawley said. “Then there are the guys out there who see that 48-to-1 ratio
and say, ‘I don’t want to be screened.’ It’s an individual personal decision.
You can’t criticize guys who want it versus guys who don’t want it.”
WHAT IF I’M IN A HIGH-RISK GROUP, LIKE AFRICANAMERICANS OR MEN WITH A STRONG FAMILY HISTORY
OF PROSTATE CANCER?
The studies don’t include enough data to make definitive recommendations for either
group. Dr. Andriole said men at higher risk who receive a diagnosis of prostate
cancer as a result of screening should be reassured by the data that they don’t have
to rush into aggressive treatment. Bear in mind that prostate cancer is usually not
fatal.
“It’s a terrific tool for helping a man assess his risk for having prostate cancer,” Dr.
Andriole said. “Does it necessarily mean it’s a killer cancer? The answer is no. We
should be more judicious. We should modify the way we’re reacting to the abnormal
screens in light of what we now know.”
SHOULD MEN STILL UNDERGO A DIGITAL RECTAL EXAM?
Neither study offers insights into the value of this traditional test, in which a doctor
feels the prostate for hardness or bumps that may signal risk for prostate cancer. The
American study looked at a combination of P.S.A. and rectal screening and found no
benefit. The European study provides no specific evidence about the exam.
DO THE NEW STUDIES MEAN I SHOULD
CANCEL SURGERY OR RADIATION?
The study data speak only to the risks and benefits of P.S.A. screening in healthy
men without symptoms. If your cancer was detected as a result of symptoms,
nothing in the study should change the medical advice you have already received.
Early signs of prostate cancer may include difficulty urinating or blood in the
semen or urine.
And even if the cancer was detected as a result of P.S.A. screening, the data have
limited applicability to one’s personal situation. The two studies look at the
average risk and benefits across a large group of men, but they don’t take into
account the specific factors that influence a man’s individual risk.
What is your Gleason score — a measure of the cancer’s aggressiveness? What
is your family history? How much cancer was in each biopsy? Did you do a repeat
biopsy to confirm your case? The answers to those questions will give a man
better information about how to proceed. At the same time, even those answers
can’t reliably predict a man’s risk for having a serious cancer.
“The regrettable truth of the matter is we don’t have really good tools to determine
from the sea of cancers we discover, which ones are the bad ones,” Dr. Andriole
said. “A man who has surgery scheduled tomorrow who is now not sure what to
do, we don’t have a whole lot to tell him right now.”
RICHARD J. ABLIN
The Great Prostate Mistake
By RICHARD J. ABLIN
Published: March 9, 2010
EACH year some 30 million American men
undergo testing for prostate-specific antigen, an
enzyme made by the prostate. Approved by the
Food and Drug Administration in 1994, the P.S.A.
test is the most commonly used tool for detecting
prostate cancer.
The test’s popularity has led to a hugely
expensive public health disaster. It’s an issue I am
painfully familiar with — I discovered P.S.A. in
1970. As Congress searches for ways to cut costs
in our health care system, a significant savings
could come from changing the way the antigen is
used to screen for prostate cancer.
Americans spend an enormous amount testing for prostate cancer. The annual bill for
P.S.A. screening is at least $3 billion, with much of it paid for by Medicare and the
Veterans Administration.
Prostate cancer may get a lot of press, but consider the numbers: American men
have a 16 percent lifetime chance of receiving a diagnosis of prostate cancer, but
only a 3 percent 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.
Even then, the test is hardly more effective than a coin toss. As I’ve been trying to
make clear for many years now, P.S.A. testing can’t detect prostate cancer and,
more important, it can’t distinguish between the two types of prostate cancer — the
one that will kill you and the one that won’t.
Instead, the test simply reveals how much of the prostate antigen a man has in his
blood. Infections, over-the-counter drugs like ibuprofen, and benign swelling of the
prostate can all elevate a man’s P.S.A. levels, but none of these factors signals
cancer. Men with low readings might still harbor dangerous cancers, while those with
high readings might be completely healthy.
In approving the procedure, the Food and Drug Administration relied heavily on a
study that showed testing could detect 3.8 percent of prostate cancers, which was a
better rate than the standard method, a digital rectal exam. Still, 3.8 percent is a
small number.
Nevertheless, especially in the early days of screening, men with a reading over four
nanograms per milliliter were sent for painful prostate biopsies. If the biopsy showed
any signs of cancer, the patient was almost always pushed into surgery, intensive
radiation or other damaging treatments.
The medical community is slowly turning against P.S.A. screening. Last year, The
New England Journal of Medicine published results from the two largest studies of
the screening procedure, one in Europe and one in the United States.
The results from the American study show that over a period of 7 to 10 years,
screening did not reduce the death rate in men 55 and over.
The European study showed a small decline in death rates, but also found that 48
men would need to be treated to save one life. That’s 47 men who, in all likelihood,
can no longer function sexually or stay out of the bathroom for long.
Numerous early screening proponents, including Thomas Stamey, a well-known
Stanford University urologist, have come out against routine testing; last month, the
American Cancer Society urged more caution in using the test. The American
College of Preventive Medicine also concluded that there was insufficient evidence
to recommend routine screening.
So why is it still used? Because drug companies continue peddling the tests and
advocacy groups push “prostate cancer awareness” by encouraging men to get
screened.
Shamefully, the American Urological Association still recommends screening, while
the National Cancer Institute is vague on the issue, stating that the evidence is
unclear.
The federal panel empowered to evaluate cancer screening tests, the
Preventive Services Task Force, recently recommended against P.S.A.
screening for men aged 75 or older. But the group has still not made a
recommendation either way for younger men.
Prostate-specific antigen testing does have a place. After treatment for
prostate cancer, for instance, a rapidly rising score indicates a return of
the disease. And men with a family history of prostate cancer should
probably get tested regularly. If their score starts skyrocketing, it could
mean cancer.
But these uses are limited. Testing should absolutely not be deployed to
screen the entire population of men over the age of 50, the outcome
pushed by those who stand to profit.
I never dreamed that my discovery four decades ago would lead to such
a profit-driven public health disaster. The medical community must
confront reality and stop the inappropriate use of P.S.A. screening. Doing
so would save billions of dollars and rescue millions of men from
unnecessary, debilitating treatments.
Richard J. Ablin is a research professor of immunobiology and pathology at the University of
Arizona College of Medicine and the president of the Robert Benjamin Ablin Foundation for
Cancer Research.