NEWSLETTER
ARTICLES
HOW
WE CAME TO BELIEVE THAT THE LOW-FAT DIET IS GOOD AND CHOLESTEROL
IS BAD
By Maryann Napoli
Despite decades of effort and many
thousands of people randomized [into clinical trials], there
is still only limited and inconclusive evidence of the effects
of modification of total, saturated, monounsaturated, or
polyunsaturated fats on cardiovascular morbidity and mortality.
British Medical Journal, March 31,
2001
Yes, the low-fat message is yet-another overrated bit of
medical advice. Haven't we been hearing for years that a
low-fat diet will reduce your odds of dying of a heart attack?
Yet those who assessed all the relevant studies (like the
reviewers quoted above) have concluded that the evidence
supporting the advice boils down to this: Eating a low-fat
diet will not help you live longer, but it may slightly
reduce the odds of having a non-fatal heart attack--if you
are a man.
You may wonder why we have been led to believe otherwise.
It's a long story that begins with the Korean War. Autopsies
done on the young casualties, whose average age was 22 years,
surprised physicians who saw earlly evidence of heart disease
in 77% of them. Next came the Framingham Heart Study, which
began in the early 1950s and followed over 5,000 healthy
men and women. High blood levels of cholesterol emerged
as a major risk factor for heart attack for young and middle-aged
men, but not for women or the elderly. It was, however,
only one of 240 risk factors identified by the Framingham
Heart Study.
Though dietary cholesterol was the assumed culprit in the
development of heart disease, this possibility was disproved
early on, according to an historical account by Thomas J.
Moore for his 1989 book Heart Failure. Moore notes that
the Framingham researchers singled out over 900 men and
women to compare their blood levels of cholesterol with
the amount of cholesterol in their diets. To their surprise,
there was no relationship. As so often happens in other
areas of medicine, opinions became fixed before definitive
studies proved the hypothesis. And in this case, a medical
consensus had already developed: Everyone should be concerned
about the amount of cholesterol in their diets. In time,
the public was told to increase intake of polyunsaturated
fats (e.g., vegetable oils), reduce intake of saturated
fats (e.g., meat and dairy products), and severely restrict
dietary cholesterol (e.g., egg yolks, beef, pork). Total
fat intake was to be kept under 30% of calories.
Many more studies confirmed the Framingham finding of
an association between high blood levels of cholesterol
and heart disease. It is, however, one thing to identify
a factor that puts people at higher risk for heart attack--proving
that a change in the risk factor will lower a person's death
rate is an entirely different matter. This was demonstrated
by the failure of the Multiple Risk Factor Intervention
Trial, sponsored by the National Heart, Lung, and Blood
Institute.
This ten-year, $115 million research project followed
over 12,866 middle-aged healthy but high-risk men who were
randomly assigned to one of two groups. The Special Intervention
Group received intensive instruction on smoking cessation,
reducing consumption of dietary cholesterol and saturated
fats, the need for regular physical activity, and blood
pressure reduction. The other half of the participants formed
the Usual Care Group who received no encouragement to change
their risk factors. At ten years, there was no difference
between the two groups in overall death rate or in the heart
disease death rate.
In three other major trials where diet was used to reduce
cholesterol, the best that could be found was a barely significant
reduction in non-fatal cardiovascular "events."
In cholesterol-lowering drug trials, the heart disease death
rates went down among the drug-treated men, but the reduction
was always offset by a higher rate of death from other causes.
"All we are doing is changing what it says on the death
certificate," Dr. William C. Taylor, told HealthFacts
in 1987. With several other researchers Dr. Taylor had calculated
that a lifelong program of cholesterol reduction adds about
three days to three months to the life expectancy of a low-risk
symptom-free adult (Annals of Internal Medicine, 4/87).
Despite the lack of proof that lowering cholesterol in
people without heart disease has a lifesaving benefit, the
National Cholesterol Education Program began a nationwide
"Know Your Numbers" campaign in 1987 to get all
Americans to have their blood cholesterol measured regularly.
In 1995, a landmark clinical trial proved for the first
time that a cholesterol-lowering drug could prevent heart
disease deaths in healthy but high-risk men without increasing
their odds of dying of something else. The drug used in
this study was from a new class of cholesterol-lowering
medications called statins. Half the 6,000 middle-aged Scottish
men in this trial were given pravastatin and half were given
a placebo. At five years, there was a 3.2% heart disease
death rate among the men on pravastatin (Pravachol) and
a 4.1% heart disease death rate among the men on the placebo.
Several years later, another statin, lovastatin (Mevacor),
became the first drug to benefit healthy men and women with
normal or borderline levels of cholesterol. The heart attack
rate in the placebo group was 5.4%, compared with 3.5% in
the lovastatin-treated group. The overall death rate was
the same for both groups. While these two trials appear
to verify the benefits of lowering blood levels of cholesterol,
a growing number of researchers see another explanation
for the statins' benefit. These drugs appear to have anti-coagulation,
anti-inflammatory, and some other biological effects that
protect the arteries. Many researchers believe that inflammation
plays a role in heart attacks and some forms of stroke,
but the exact mechanism is uncertain. The inflammatory theory
could explain why half the heart attacks occur in people
with normal cholesterol levels. (See "Statins
or Aspirin for Heart Attack Prevention" )
As statin drugs move front and center in the heart attack
prevention picture, the low-fat diet is now under attack
because the lack of supporting evidence was brought to the
public's attention by Gary Taubes, first in a 2001 article
for Science ("The Soft Science of Dietary Fat")
and later in a much-discussed 2002 article for The New York
Times ("What If It's All Been a Big Fat Lie?").
While researchers continue to work out the ways that heart
attacks and stroke can be prevented, it should be noted
that the death rates for both have been declining steadily
since the late 1940s--well before Americans ever heard the
low-fat, lower your cholesterol messages. The nation is
experiencing an epidemic of obesity that some attribute
to the low-fat message which drove people to consume more
refined carbohydrates and to increase their total caloric
intake. Still, the heart disease death rate has dropped
dramatically in the last two decades, a period in which
the nation's fat intake dropped only a pitiful 6%. Better
treatments are thought to be the reason. It could also be
due to the increasing percentage of Americans entering the
middle class, a trend that began after World War II. (High
socioeconomic status is associated with a lower rate of
premature heart disease death, especially for women.) Whatever
the reason, it isn't the low-fat diet, and it isn't reduced
intake of dietary cholesterol.
THE GOOD FAT COOKBOOK By Fran McCullough
(Scribner: New York, 2003)
This book is organized around a simple premise: "Foods
that are really good for you taste really good." And
believe or not, science has begun to back up this appealing
idea. In the last few years, foods once thought to be unhealthy
were judged to be good for us. Among those that have made
a comeback are: eggs (rich in two essential nutrients--choline
and lutein), butter (healthier than margarine which usually
contains trans fatty acids), chocolate (lots of antioxidants)
avocados (contain protein, fiber, antioxidants, monounsaturated
fat), nuts (protect against heart disease and cancer), beef
(see below), and alcohol (moderate daily drinking is good
for the heart). If this trend sounds good to you, this book
will make you even happier. Part I deals with the scientific
evidence; part II provides the recipes.
The low-fat diet has been promoted to the public for over
30 years by government officials and the American Heart
Association. It is considered the ideal way to prevent heart
disease and obesity. Yet despite the proliferation of reduced-fat
products (over 15,000) and a small drop in the nation's
fat intake (34% down from 40%), Americans have become the
fattest people on earth.
Now the low-fat diet is undergoing a major rethink, and
the tide of scientific evidence is changing in favor of
those who have challenged the conventional medical wisdom.
Two population groups are frequently cited to support the
contention that certain fats are so healthy that they should
be consumed in high quantities: The Greenland Eskimos with
their high consumption of fatty fish (rich in heart-healthy
omega-3 oil) and people living in Mediterranean regions
where the diet is high in olive oil, a healthy monounsaturated
fat. Both groups have a total fat intake that is just as
high or higher than that of the average American, but the
Eskimos have virtually no heart disease and the Mediterranean
people have low rates of heart disease and some cancers.
Citing studies of such populations, a 1998 international
conference convened by the Harvard School of Public Health,
reached a consensus that a healthy diet need not be restricted
in total fat.
In The Good Fat Cookbook, Fran McCullough gathers the
latest scientific evidence to show there are healthy and
unhealthy fats. Her findings are likely to surprise. "The
best fat of all is coconut and the worst fat of all is soy,"
she writes. Canola and soy oils are so highly processed
that the good nutrients are lost and trans fatty acids develop
(80% of cooking oil used in the U.S. is soy oil). The biggest
surprise comes in the section on the health benefits of
coconut. As anyone who has tried to keep up with the latest
nutrition information knows, tropical fats (coconut and
palm oil) are extremely unhealthy and should be banished
from the diet. Not so, says McCullough. Coconut has numerous
health virtues: It protects against heart disease and cancer;
stimulates metabolic activity and gives you a burst of energy;
provides high levels of antioxidants; contains lauric acid,
the protective substances in mother's milk; and has strong
antiviral, antimicrobial, antibacterial, antifungal, and
antiinflammatory activity.
Coconut oil used to be the predominant fat used in cookies,
crackers, and most baked goods. In 1986, writes McCullough,
the soy industry mounted a campaign to discredit coconut
oil and warn the public of its dangers. The campaign was
successful, according to McCullough, because "there
is no Coconut Council to fund research and send out press
kits, take journalists on junkets, and lobby Washington
for favorable treatment in the way other elements in the
agribusiness food industry cooked up the Dietary Guidelines."
Some foods are innately healthy but become much less so
due to human interference. When cattle and sheep are allowed
to slowly fatten on grasses, as they are meant to, their
meat has a healthy ratio of omega-3 to omega-6 fats. But
that has changed with the mass production feedlots that
supply most of America's meat. The animals are fed corn
that disrupts their digestive systems because they weren't
meant to eat grain, which, in turn, creates major health
problems that necessitates antibiotics. Furthermore, their
meat often undergoes irradiation to be sure that infections
are not passed on to us.
The book has a resource section with web sites and 800
#s for finding high quality products, such as meat from
grass-fed animals, high quality oils, and omega-3 supplements.
(February
2003)
PSA
Screening Test for Prostate Cancer:
An Interview with Otis Brawley,
MD
By
Maryann Napoli
The prostate-specific antigen (PSA) screening test for
early prostate cancer has been surrounded by controversy
ever since it was introduced over 15 years ago. The test
can indicate the presence of cancer, but many men have a
form of prostate cancer that will remain dormant or is so
slow-growing that it will never cause symptoms. Neither
this test, nor any other can distinguish which prostate
cancer will become lethal. Furthermore, there is no proof
that the use of the PSA blood test to screen symptom-free
men will spare anyone a prostate cancer death, yet it is
associated with a considerable amount of unnecessary treatment
with aftereffects that can be both severe and permanent.
All of the treatments for early prostate cancer carry the
risk of impotence and incontinence. In short, cancer researchers
do not know whether PSA screening saves more lives than
it ruins.
Otis W. Brawley, MD, is the brains behind the ongoing
National Cancer Institute Prostate Cancer Prevention Trial,
which is designed to answer questions about the effectiveness
of screening and the causes of prostate cancer. After leaving
the National Cancer Institute, Dr. Brawley became the Director
of the Georgia Cancer Center and Professor of Medicine,
Oncology, and Epidemiology at Emory University School of
Medicine. He is interviewed about the ever-increasing use
of PSA screening in the face of so much uncertainty about
its value.
Napoli: Does the popularity of PSA screening concern
you?
Dr. Brawley: First of all, I'm not against prostate
cancer screening. I'm against telling people that it is
well established; and that it works; and that it saves lives
when the evidence that supports those statements simply
does not exist. I'm a tremendous supporter of the real American
Cancer Society (ACS) recommendation, which is: Within the
physician-patient relationship, men should be offered PSA
screening and should be informed of the potential risks,
as well as the potential benefits and be allowed to make
a choice.
Napoli: Do you think fully informing men about PSA
screening happens very often?
Dr. Brawley: I think it rarely happens. Many doctors
are uninformed, and that's a big problem. My great concern
is people being misled. I routinely follow the prostate
cancer screening recommendations of 18 organizations in
the U.S., Canada, and Western Europe. The two most pro-screening
recommendations are those of the ACS and the American Urologic
Association. Both of whom say it should be offered to men;
men should be informed of the potential risks and the potential
benefits; and they be allowed to make a choice. The ACS
does not recommend that men of normal risk be offered mass
screening. There's a distinction between what is done within
a doctor/patient relationship at a doctor's office and mass
screening.
Napoli: What is the difference?
Dr. Brawley: Mass screening takes place at a booth
at a mall where screening is offered to anyone who comes
by and wants screening. In the last few years, there has
been screening on the floor of the Republican National Convention,
health fairs at the mall, [TV] channel this or channel that
will have a health fair with prostate cancer screening.
Yet there is no organization that endorses mass screening
because of the concern that you can't have informed consent.
Napoli: If policy makers aren't promoting the test,
who is?
Dr. Brawley: The British Medical Journal recently
published an article about how several of the leading prostate
cancer survivor organizations [based in the U.S.] that do
a lot of the pushing of screening are funded by the makers
of the PSA screening kits. And, indeed, [these survivor
organizations] do things that the Food and Drug Administration
won't let the manufacturers do--like make promises that
there are only benefits from prostate cancer screening.
Many of these prostate survivor organizations that I'm critical
of--that take drug company money--offer mass screening.
Napoli: You were once quoted in The New York Times
saying that 30-40% of men whose cancers appear to have been
confined to the prostate at diagnosis will recur soon after
treatment.
Dr. Brawley: Yes, this [brings up] one of the lies
perpetrated about prostate cancer. If you look at the prostate
cancer outcomes from a huge study conducted by the National
Cancer Institute, close to 40% of men who undergo a radical
prostatectomy will have a PSA relapse within two years.
This means that they had disease that was outside of the
prostate that was not obvious to the surgeon or the pathologist.
It means that if the man lives long enough, metastatic disease
will kill him.
Napoli: The public is always told that early detection
is lifesaving. How true do you think that is for prostate
cancer?
Dr. Brawley: If you have a group of men diagnosed
as a result of PSA screening, 30-40% don't need to know
that they have prostate cancer because it's meaningless
in terms of risk to their health. And for somewhere between
30% and 40% of the men with prostate cancer, no matter what
[treatment is given], the disease is not curable. And then
maybe there are about 20% who actually benefit.
Napoli: And there's no way to know which type of
prostate cancer you have.
Dr. Brawley: That's right.
Napoli: What about African American men, who as
a group, are at a particularly high risk for prostate cancer?
PSA testing is thought to be advisable for them at an earlier
age.
Dr. Brawley: The proportion of black men in Rocky
Feuer's paper [for the Journal of the National Cancer Institute]
who don't need to know they have prostate cancer was over
40%, compared to 30% of white guys. The reason it's higher
for black men is that they have so many other competing
causes of death. The other issue is this: It's a principle
of cancer screening that, unfortunately, many of the advocates
of screening just don't comprehend, and that is, the more
aggressive cancers are less likely to benefit from screening.
There are people out there who say we must screen black
men because they have more aggressive prostate cancer. [These
screening proponents] do not realize that they are saying,
in effect, because prostate cancer screening is less likely
to benefit black men, then we must screen black men.
Napoli: You recently published a medical journal
article about informed consent and the PSA test.
Dr. Brawley: Yes, the problem I have is that people
are not open and honest about all the controversies, and
this extends to people being not open and honest about the
treatments, once prostate cancer is diagnosed. Men tend
to get railroaded toward radical prostatectomy or to external-beam
radiation, or to seed implants.
Napoli: Since there's no evidence that any one of
these treatments is superior to another or superior to no
treatment, for that matter, where do you suggest men go
for unbiased information?
Dr. Brawley: First of all, I think we should tell
men what is scientifically known and what is scientifically
not known and what is believed and label them accordingly.
[As for credible sources of information,] the National Cancer
Institute's PDQ treatment statements at www.cancer.gov are
good [call 800/4-CANCER]. So is the ACS's information. And
by the way, we at Emory have figured out that if we screen
1,000 men at the North Lake Mall this coming Saturday, we
could bill Medicare and insurance companies for $4.9 million
in health care costs [for biopsies, tests, prostatectomies,
etc]. But the real money comes later--from the medical care
the wife will get in the next three years because Emory
cares about her man, and from the money we get when he comes
to Emory's emergency room when he gets chest pain because
we screened him three years ago.
Napoli: You're saying that screening creates long-term
customers. So, did Emory Healthcare decide to go ahead with
the free PSA screening on Saturday?
Dr. Brawley: No, we don't screen any more at Emory,
once I became head of Cancer Control. It bothered me, though,
that my P.R. and money people could tell me how much money
we would make off screening, but nobody could tell me if
we could save one life. As a matter of fact, we could have
estimated how many men we would render impotent...but we
didn't. It's a huge ethical issue.
(May
2003)
Should
You Be Tested For C-Reactive Protein?
By Maryann Napoli
The revised view of heart disease got a boost recently.
Over the last ten years, a research case has been building
for the possibility that chronic inflammation within the
coronary artery walls plays a strong role in the development
of heart disease. This hypothesis received some support
from a new study showing that inflammation is a better predictor
of who will have a heart attack than high cholesterol (The
New England Journal of Medicine, 11/14/02). Nearly 28,000
healthy women were tested and followed for eight years;
those whose blood tests showed high levels of C-reactive
protein (CRP), an indicator of inflammation, were twice
as likely to have a heart attack or a stroke as the women
with high levels of LDL cholesterol, also known as the "bad
cholesterol." Similar findings are showing up in an
ongoing study of 22,000 men.
Media reporting of this study generally gave the impression
that many doctors did not think people should seek CRP testing,
though it is readily available. And the leading guidelines-setting
organizations like the American Heart Association have yet
to take an official position about whether the CRP test
should become part of the standard battery of tests routinely
administered to all adults. But a New York Times editorial
was downright enthusiastic, "The test could be a boon,
if not for every American then at least for all those whose
weight, age, smoking or other factors make them wonder about
their cardiovascular prospects."
It would be premature to start screening all adults for
CRP, according to Lori Mosca, MD, who is the Director of
Preventive Cardiology at New York Presbyterian Hospital.
"We don't yet know how to use this information, even
though we do know that statistically CRP has been shown
to predict cardiovascular events-just like 300 other risk
markers for heart disease." Dr. Mosca wrote the editorial
that accompanied the new study, entitled, C-Reactive Protein-to
Screen or Not to Screen? "People are calling my office
to ask, 'should I have a stress test or an angiogram' because
their CRP is elevated. I think there's a real risk that
this information is going to be misused," she warned
in a telephone interview. "And until science can figure
what to do with the information, I think that screening
every American is not appropriate at this point." What's
more, gingivitis, bronchitis and many other possibilities
can raise CRP levels.
That view was seconded by David Atkins, MD, chief medical
officer at the Center for Practice and Technology Assessment
at the U.S. Agency for Heathcare Research & Quality.
To Dr. Atkins, the known major risk factors for heart disease-high
blood pressure, diabetes, smoking, being overweight or obese,
high LDL, and a sedentary lifestyle-already allow doctors
to do a good job at identifying the people who should be
treated with drugs. "Taken together these risk factors
can probably catch the large majority [of people headed
for] heart attacks," said Dr. Atkins in a telephone
interview.
After doing a call-in show for National Public Radio,
Dr. Mosca worried that people got the wrong impression from
news reports. "Consumers might misinterpret this new
study to mean that LDL cholesterol is not important because
it has been shown statistically that CRP is a little bit
better predictor," she said. "Well, we can say
the same thing about hundreds of other risk factors. But
LDL reduction has been shown to reduce death and disability,
and CRP reduction has not."
But half of all heart attacks occur in people with normal
cholesterol levels-doesn't that suggest high cholesterol
isn't such an important risk factor? "The reason why
so many people with heart disease have so-called normal
cholesterol levels is that normal is too high in the U.S.,"
answered Dr. Mosca. "If our LDLs were cut in half [to
the level] they are in Asia, we wouldn't have so much heart
disease," she emphasized. "There is virtually
no heart disease in countries where the total cholesterol
is less than 150."
The point that cholesterol levels shouldn't be viewed
in isolation was underscored by Dr. Atkins. "People
hear that half of all heart attacks occur in people with
normal cholesterol levels and think 'that could be me,'
but the reality is that many of those people have diabetes,
they smoke, or have hypertension," he explained. "Only
a very small percentage of heart attacks occur in people
who don't have multiple cardiac risk factors." Dr.
Atkins is concerned that most doctors still focus too narrowly
on elevated cholesterol levels, when they should step back
and look at the big picture-that is, the full range of major
established risk factors for heart disease-and then target
the intensity of the therapy accordingly.
Statins are the cholesterol-lowering drugs of choice.
Lipitor and Zocor, the two top-selling statins, accounted
for $4.5 billion and $2.7 billion in retail sales, respectively,
in 2001 and the largest increase in prescription drug sales
for that year. Low-dose aspirin therapy is another, far
less expensive, standard drug recommended for heart attack
prevention. There's pretty good evidence that both drugs
are effective even in people without high cholesterol, explained
Dr. Atkins. Aspirin's anti-inflammatory effect may account-at
least, in part-for its success as a heart attack preventive,
and statins have an anti-inflammatory effect as well as
a cholesterol-lowering effect.
Learning that a person has elevated CRP levels isn't-in
most cases-going to change the treatment plan once a doctor
assesses the patient's other risk factors. "If the
person is at low risk, it is unlikely that the CRP results
will change our recommendations to the patient, we would
still recommend exercise, maintaining weight, avoiding smoking,
eating well, etc.," said Dr. Mosca.
"For the very high-risk individual, that is, the person
with heart disease, we already know they should be on statin
and aspirin therapy, unless it's contraindicated,"
she continued. "For the middle-risk individual, the
decision to test should rest on whether or not the treatment
is going to be altered by the results," she continued.
"I've certainly screened some patients for CRP when
I'm on the border for using certain kinds of therapy--after
I have got them as good as I can in terms of lifestyle."
Dr. Mosca said that after the New England Journal of Medicine
published her editorial advising against routinely screening
all adults for CRP, she received many congratulatory calls
and e-mails from cardiologists around the country. All are
concerned that CRP testing will be used routinely before
research proves its worth.
"Look at hormone therapy," said Dr. Mosca, referring
to the trial that was stopped last summer because the combination
of estrogen and progestin was deleterious to the health
of older women. "Hormones became the standard of care
for the prevention of heart disease, and when the clinical
trial showed that the drugs not only didn't prevent heart
disease but caused heart disease in some women, we still
have doctors who refuse to believe the information. We need
to wait for the clinical trials before we make general public
health recommendations to screen every American."
(December
2002)
Read
This Before You Have A Mammogram
In
2001, yet another mammography controversy was triggered
by two Danish researchers who, after an in-depth assessment
of all mammography-screening clinical trials, found the
test leads to more aggressive treatment; increases the detection
of cancers that do not progress; and might not save lives.
In this review, conducted by Ole Olsen and Peter Gotzsche
of the Nordic Cochrane Centre, mammography-screened women
showed a slight increase in heart-related deaths. The deaths
are believed to be related to radiation therapy, a standard
treatment for early breast cancer. To read more about this
review, click into: Olsen &
Gotzsche Review For
a 2004 update on Summary of the Evidence.
Another controversy is brewing among researchers over the
cause of the slight increase in breast cancer deaths among
women in their forties shown in all mammography screening
trials. This topic was addressed in two interviews conducted
in 2002 by Maryann Napoli.
Mammography's
Risk to Younger Women
by
Maryann Napoli
Last month, the Canadian National Breast Screening Study
published follow-up results showing, once again, that mammography
screening did not reduce the breast cancer death rate for
women in their 40s (Annals of Internal Medicine,
9/3/02). The Study's findings have challenged the prevailing
belief that early breast cancer detection saves lives. Worse,
they show that mammography screening leads many more women
to be treated unnecessarily with mastectomy or radiation
therapy. Though 40 more cases of non-palpable invasive breast
cancer were detected in the mammography-screened women,
their breast cancer death rate was no different from that
of the women who did not get mammograms. Similarly, there
were 42 more cases of ductal carcinoma in situ, a non-invasive
cancer, detected in the mammography-screened women. This
shows that mammography screening causes a significant number
of younger women to suffer treatment-related harm without
reducing their odds of dying of breast cancer.
Mammography proponents have criticized the Canadian Study
ever since it first published results more than a decade
ago. The Study now has 11 to 16 years worth of follow-up
for women in their 40s. Its deputy director, Cornelia J.
Baines, MD, was interviewed about the fact that---in the
early years of this trial---there were more breast cancer
deaths among women given mammograms. This was initially
thought to be a statistical fluke when it first showed up.
Now some researchers are having second thoughts.
MN: When you published your seven-year results, there
were more breast cancer deaths (38) in the mammography-screened
women, compared with those in the control group who had
no mammograms (28). Were there any surprises now that you
have 11-16 year results?
Dr. Baines: No, I knew by 1983 that more breast
cancer deaths were occurring in the mammography-screened
group rather than the control group. Of course, that's not
what we expected. When we started out, we were sure that
we were going to show a major benefit. After all, the HIP
Study [the first mammography trial conducted in the 1960s]
had shown a benefit to women ages 50-69, and we assumed
that the only reason a benefit wasn't shown for younger
women was that the mammography was archaic by today's standards.
MN: When I interviewed you at the time you published
the seven-year results, you said that the excess of ten
breast cancer deaths was not statistically significant.
I thought that meant it could be ignored.
Dr. Baines: You are quite right it's not statistically
significant, but what is disturbing is that this excess
has happened in all screening trials in three different
countries. 1985 was a landmark year for mammography screening
trials. A Swedish study headed by Laszlo Tabar was published
in The Lancet (4/13/85). When you read the abstract
[summary] of that study, it says that women ages 40-74 showed
a 31% reduction in breast cancer deaths. But if you look
in the text of the article, you see that the number of deaths
in the [small subset of] women in their 40s given mammograms
was higher than in the control group. Similar results were
observed in the Stockholm and HIP trials. The consistency
of this trend demands further evaluation.
MN: Is anyone looking into it?
Dr. Baines: When we published our first results
in 1992, it never entered my head that the people who have
been promoting mammography would try to completely destroy
the credibility of our study and ignore this phenomenon
which had been clearly shown in Tabar's study and which
had also been shown in the HIP study. I started out saying
that this needs investigating at the basic science level
and believing that screening researchers would pay attention
to these trends. Well, was I ever out to lunch. People,
when they strongly believe in something, don't waste time
looking at evidence that challenges their beliefs. That's
just not human nature.
MN: Dr. Tabar is a recipient of an American Cancer
Society award for his promotion of mammography screening
and a teacher of Continuing Medical Education courses for
American radiologists. He and the other mammography researchers
might not want to look at the "why" behind the
increase in breast cancer deaths, but haven't some researchers
begun to investigate a possible underlying biological mechanism
for the deaths?
Dr. Baines: Yes, Michael Retsky, PhD, at Harvard
Medical School, and Romano Demicheli and William Hrushesky.
They studied the relapse patterns of 251 premenopausal women
with node-positive breast cancer who had been treated only
with surgery only and followed for 16-20 years. Retsky and
colleagues found that the breast cancer mortality rates
show two peaks: one occurs three years after diagnosis,
the other at nine years, and after that, women seem to survive
quite well. This, of course, corresponds with what we have
been observing in mammography screening trials. Increasingly,
researchers like Michael Retsky and Michael Baum speculate
that something associated with the biopsy or surgery stimulates
growth factors. In some women with micrometastases [undetectable
spread of cancer outside the breast], these growth factors
may stimulate the micrometastases, and the woman goes on
to die. This is consistent with the suggestion made along
time ago by Bernard Fisher [America's leading breast cancer
researcher]---that micrometastases has already occurred
in 90% of all breast cancers before clinical or radiological
detection.
MN: Are you talking only about women in their 40s?
Dr. Baines: The finding was more prominent in younger
women, but Tabar's study showed a breast cancer mortality
increase in older women as well.
(October
2002)
Surgeon
Who Headed a UK Mammography Program Becomes One of Its Strongest
Critics
by Maryann
Napoli
Michael Baum, MD, emeritus professor of surgery at University
College in London, U.K., has been a breast cancer surgeon
for 30 years. After leaving the Breast Screening Programme
for the National Health Service in the southeast of England,
Dr. Baum became an outspoken critic of mammography screening,
particularly for women in their 40s.
In this interview, Dr. Baum was asked to comment on the
Canadian Study results. In doing so, he argues for a new
paradigm for how and why breast cancer spreads. Dr. Baum
champions the ideas of the famed Boston-based researcher,
Judah Folkman, who did the pioneering work on angiogenesis.
This natural process, which is controlled by certain chemicals
produced in the body, leads to the formation of new blood
vessels. In adults, angiogenesis is involved in wound healing
and menstruation. But angiogenesis can also have negative
effects. The newly formed blood vessels bring the blood
and oxygen that encourage tumor growth; they also provide
the means for cancer cells to travel to distant organs and
form new tumors.
MN: What do you make of the increase in breast cancer
deaths shown in the women given mammograms in the Canadian
Study?
Dr. Baum: I believe that it is a real phenomenon
and not simply an artifact of this one study. It appears
in all the studies.
MN: There were more than twice as many cases of
ductal carcinoma in situ [Latin for cancer in place]
in the mammogram group. What do you make of that?
Dr. Baum: I'm very influenced by Judah Folkman's
work. He believes that in situ is probably not a
good word, and we should call it latent cancer. These latent
cancers, particularly in premenopausal women, are grossly
over-represented in women given mammograms--something like
five times more, compared to what you would expect. This
suggests that if left to their own devices, these latent
cancers might never trouble a woman. But if you identify
these latent cancers and biopsy them, you have traumatized
the area. You immediately trigger the natural healing mechanisms,
and natural healing mechanisms involve angiogenesis. So,
effectively, the biopsy could be considered an angiogenic
switch. You take a latent cancer that would never hurt a
woman, biopsy it, turn on the angiogenic switch, and it
ceases to be latent. A latent disease becomes an aggressive
disease.
MN: Is this true only for breast cancer?
Dr. Baum: You see this in other cancers. The most
notorious is renal cell cancer. If you find a symptomless
renal tumor by chance, and operate, [then] in no time the
patient is riddled with metastasis. This happened to a dear
friend of mine. I think that an angiogenic switch might
be an explanation. It's really scary.
MN: And this is what you suspect happened to some
women in the mammography trials.
Dr. Baum: My explanation sounds a bit farfetched,
but it is strongly supported by basic science that is coming
out of the work on angiogenesis. There are profound cyclical
changes going on in the premenopausal breast, and these
changes can also be seen in premenopausal breast cancer.
So just by happenstance, you might get a surgical insult
at a time in the menstrual cycle that favors the cancer
cells. It's all quite alarming.
MN: In the Canadian Study, 71 cases of ductal
carcinoma in situ (DCIS) were diagnosed in the mammogram
group, compared to 29 in the no-mammogram group.
Dr. Baum: That tells you two things: 1) It emphasizes
the quality of the study. If they had not detected so many
cases of DCIS, then the screening zealots would say that
the screening techniques in the Canadian Study were bad;
2) It demonstrates, yet again, that all screening programs
will show an excess of cancers. And the excess is mostly
DCIS. In women given a manual breast exam, only about 3%
of cancers detected are DCIS; whereas in mammography-screened
women, 20% of the cancers are DCIS.
MN: The breast cancer death rate was the same for
both groups in the Canadian Study. Doesn't that indicate
that early detection is of no benefit to any women with
DCIS, even those with the type of DCIS destined to become
invasive?
Dr. Baum: Yes, I think so. I don't know if any lives
are saved by screening, frankly. But the one argument about
which I cannot be shaken is that women invited to screening
should know these things. I was one of the people given
the job of setting up a screening program in 1987-88 in
the U. K. Then it gradually dawned on me that this was state
interference with public health, and it was coercion. I
resigned in disgust from the National Screening Committee
because they were intentionally deceiving women [about the
harms]. They went on record saying, "We mustn't let
women know this because it might deter them from coming
to be screened." So I decided to work outside the system
to inform women about the truth of screening. I can see
how some women, fully informed, would accept screening over
the age of 50, but to promote mammography to women under
the age of 50 is absolutely unethical.
MN: The American Cancer Society has been promoting
mammography starting at age 40 for over 30 years.
Dr. Baum: Either the ACS is funded by the screening
industry, or they've backed themselves into a corner and
can't admit they've been wrong all this time. The message
is so seductive: "The secret to cancer is catching
it early." That's rubbish. It's so naïve. The
only thing that influences cancer mortality is better treatment,
as far as I'm concerned. The word "early" has
no meaning to a scientist.
MN: Do you have an equivalent to the ACS in your
country overselling the early detection message?
Dr. Baum: No, but we have "Black October,"
which is what I call Breast Cancer Awareness Month, when
lots of fine young women have these campaigns with runway
models advising breast self-examination every month. And
that gets across two false messages: 1) that self-examination
is of any value; and 2) that the role model for breast cancer
patients is a skinny girl of 23.
MN: Any parting thoughts about the current state
of mammography research?
Dr. Baum: It
ceases to be medical science now---it's egos. A proper scientist
should learn that you go through life being humiliated again
and again. You have to prepare yourself to admit you were
wrong. That's the very mechanism of science. Scientific
truths are only temporary expressions of reality that serve
us for the time being. There's no such thing as scientific
truth. It's all an approximation to reality. A true scientist
has to accept that his version of reality will be overturned
in the fullness of time. If you can't accept that, you're
not a scientist.
(October
2002)
Surgery
for Early Prostate Cancer
By Maryann Napoli
When a man is diagnosed with early
prostate cancer, he faces several options but no clear answer
to the most crucial of all questions: Is treatment better
than no treatment at all? A new Swedish study showed that
surgical removal of the prostate does, in fact, reduce a
man's odds of dying of prostate cancer, but worsens his
quality of life.
Unfortunately, the finding has little relevance to most
American men because prostate cancer screening has become
so popular in this country that the majority are diagnosed
before they have any signs or symptoms of the disease. This
was not true of the majority of the Swedish men who participated
in the study published last month in The New England Journal
of Medicine (9/12/02).
Americans Diagnosed Earlier
The term early means that the cancer has not spread beyond
the prostate gland. But there are degrees of "early."
The majority of the Swedish participants had tumors that
could be felt by a digital rectal examination, and many
had symptoms, such as difficulty urinating. Whereas 75%
of American men with prostate cancer do not have a tumor
that can be felt, nor do they have symptoms. They are diagnosed
after a biopsy performed as a result of a PSA screening
test. The Prostate-Specific Antigen (PSA) test identifies
a protein in the blood that can indicate the presence of
a cancer too small to be felt. Originally intended as a
follow-up test for men who had been treated for prostate
cancer, the PSA test has been promoted to symptomless men
for over a decade.
The relatively small group of newly diagnosed American men
who fit the profile of the 695 participants in the Swedish
Study should take note: The results of this study are a
wash. At six years, the men who had a prostatectomy (surgical
removal of the prostate) had a lower death rate from prostate
cancer, but it was canceled out by a higher death rate from
other causes. If the aim is solely to reduce the odds of
dying of prostate cancer within the next six years, then
surgery is the way to go. Only 4.6% of the men died of prostate
cancer after undergoing a radical prostatectomy; where 8.9%
of the untreated men died of the disease.
If, however, the goal is to lower the odds of dying from
any cause, then no treatment may be the way to go. The overall
death rate in both groups was exactly the same. It is possible
that the surgically treated men died of treatment-related
causes, such as an infection. In that case, their deaths
would not be counted as prostate cancer deaths. All the
men were under the age of 75, with an average age of 64
years.
By counting the overall death rate-that is, the deaths from
all causes-the authors of this study are following an important
new trend in research. They are stepping back and looking
at the big picture, as opposed to looking solely at the
question of whether X medical treatment lowers the death
rate from Y disease. Too often, the treatment itself will
cause deaths, but they go uncounted by most researchers.
Here is the conclusion of the Swedish study: "…there
was no significant difference between surgery or watchful
waiting in terms of overall survival," wrote Lars Holmberg,
MD, and colleagues at the Scandinavian Prostatic Cancer
Group Study.
The Swedish research team noted that there were 37 deaths
from other causes in the surgically treated group and 31
in the untreated group. "This difference could be due
to chance or to long-term but hitherto unknown adverse effects
of prostatectomy."
While it is unusual for researchers to address the overall
death rate in the conclusion of their study, the finding
itself is not. There are already several examples of medical
interventions that reduced the death rate from cancer but
failed to lower the overall death rate. For example, several
randomized controlled trials showed that screening tests
for colon cancer reduce the rate of deaths from this disease,
but inexplicably increase the death rate from heart disease.
More recently, a review of all the best mammography clinical
trials came to a similar conclusion about the overall death
rate.
Symptoms Worsen After Surgery
Now for the question of quality of life. It's certainly
possible that a prostatectomy could improve a man's life
without prolonging it. Consequently, the Swedish research
team sent questionnaires to the 326 men who had symptoms
at the start of the study to see how they fared four years
later. The percentage of men suffering the following symptoms
was consistently higher among the surgically treated, as
compared to the untreated: impotence (80% vs 45%), "distress
from compromised sexuality" (55% vs 40%), urinary leakage
(49% vs 21%), "distress from all urinary symptoms"
(27% vs 18%).
The clinical trial with the most relevance to American men
is currently in progress, and results will not be available
until 2008. It is sponsored by the Department of Veterans
Affairs, the National Cancer Institute and the U.S. Agency
for Health Research and Quality. The 731 participants had
cancer that was confined to the prostate, and most were
diagnosed initially with a PSA test. The men were randomly
assigned to have their prostates removed or to remain untreated.
The lead researcher, Timothy J. Wilt of the Minneapolis
VA Medical Center, recently told The New York Times that
five years into the study, no survival advantage has been
shown for either group.
Although there are other treatment options for men with
localized prostate cancer, such as radiation therapy and
radiation seed implants, no head-to-head comparison study
has ever been done.
(October
2002)
How
Well Tested Are New Cancer Drugs?
by Maryann Napoli
With a certain amount of regularity a new cancer drug
makes headlines, generating an enormous amount of hope,
as well as pressure to make the product swiftly available.
In time, we usually learn that the drug's benefit is much
more modest than originally portrayed in the media, and
soon oncologists (cancer specialists) begin to prescribe
the drug for other forms of cancer without waiting for clinical
trials to prove effectiveness. This recurring scenario merits
a closer look at the U.S. Food and Drug Administration (FDA)
and the basis upon which it approves new cancer drugs.
Tumor Shrinkage
Contrary to popular belief, drug companies are not required
to prove that their drugs prolong survival. Until the mid-1980s,
all cancer drugs were approved solely on the basis of what
researchers call the "tumor response." In other
words, the testing required of a drug company need only
show that the drug caused a tumor to shrink, not necessarily
to disappear.
Years ago, a change in the approval process was recommended
by the FDA's own Oncologic Drug Advisory Committee. The
Committee members, all primarily cancer experts unaffiliated
with any government agency, knew that tumor shrinkage often
has little or no relation to survival. The Committee proposed
the novel idea that a drug company should be required to
prove that a drug provides some benefit that is meaningful
to the patient, such as increased survival or improvement
in symptoms. The Committee argued further that the potential
benefit of tumor shrinkage did not necessarily outweigh
the substantial toxicity of cancer drugs.
This recommendation was made in the mid-1980s, but change
at the FDA comes slowly, as a recent assessment of new drug
approvals has demonstrated. From 1990 through 2001, the
FDA approved 66 new cancer drugs. Prolonged survival was
not proven for 48 drugs. And tumor response was the basis
of approval for 35 drugs.
Variations in Endpoints
"The FDA has a certain amount of regulatory flexibility
to make an assessment of the side effects versus the efficacy
of new products," said the FDA's Richard Pazdur, MD,
in a telephone interview. He had been asked why so few new
drugs have been proven to prolong survival. "The drug
company must prove that its product provides a longer life,
a better life, or a favorable effect on an established endpoint
for a better life," he explained. The FDA's flexibility
comes into play on the last point about "an established
endpoint for a better life." One example of an established
endpoint, says Dr. Pazdur, is a complete response in leukemia-that
is, the bone marrow is normal, the blood count have normalized.
Even so, there is a hierarchy of established endpoints.
"Survival is the gold standard of endpoints because
it is the most meaningful to all people," cautioned
Dr. Pazdur, who is the Director of Oncology Drug Products
at the FDA's Center for Drug Evaluation and Treatment. He
explained that there can be no misinterpretation where it
concerns survival-the patient is either dead or alive. "Whereas,
the other endpoints, such as tumor response rate, are usually
determined by x-rays or scans," he continued. "There
can be variations in the radiologists, the techniques of
how the x-rays or scans are obtained, which can make it
confusing and unreliable. Also, there is a subjective judgment
in reading these x-rays and scans."
Accelerated Approval
These cautions notwithstanding, the FDA still allows the
use of tumor shrinkage as the sole endpoint in the approval
of certain drugs. In 1992, the agency introduced an accelerated
approval (AA) process. The idea behind AA is to get drugs
quickly to advanced cancer patients in whom all available
options had failed. Consequently, tumor shrinkage was the
sole basis of the AA for 10 of 11 new drugs. The rationale:
Shrinking a lung tumor might, in the FDA's view, be "reasonably
likely" to alleviate breathing difficulties.
The testing for AA is minimal. The new drug is given to
about 30 or so participants who have run out of options.
In what is called a Phase II trial, there is no comparison
group-everyone in the study gets the new drug. Consequently,
this type of trial is not likely to provide a true picture
of the drug's toxicity or efficacy. That's why a drug given
AA must continue to be studied to see if it provides any
benefit in terms of increased survival or symptom improvement.
"The drug companies usually do a large trial in which
the new drug is compared to the standard drug," said
Dr. Pazdur. "This usually takes two to four years,
and the proof comes from a usually large trial that compares
the new drug to the standard drug." And what if the
drug company does not comply? "We have a process for
rapidly removing the drug from the market," replied
Dr. Pazdur.
Still, some not-so-well tested drugs are available for
several years following an AA, and oncologists are free
to prescribe them for cancers other than the type for which
the products received approval. Or, more often, oncologists
can add the new product to a multiple-drug regimen, which
in itself has never been studied. "Yes, this is called
off-label use, which is fairly common in the practice of
oncology in the U.S.," agreed Dr. Pazdur. "But
this involves the practice of medicine, and the FDA does
not control the practice of medicine."
Unless their oncologists tell them, cancer patients would
not know whether they are being given a drug off-label.
"We would like patients to read the drug label to see
the approved indications and contraindications," advised
Dr. Pazdur, who said that the information is freely available
at the FDA's Web site.
For more information:
- To read a drug label, go to www.fda.gov
or to the Physicians' Desk Reference (PDR), which
is updated yearly and available at most local libraries
and large bookstores. The label is daunting for its extensive
length, tiny type and medical jargon-ridden style. It is,
however, the only source for results of the FDA-required
tests. The section entitled "Indications" will
identify the purpose(s) for which the drug has been proven
beneficial.
If you can't find your type and stage of cancer listed
under "Indications," this signals off-label use.
Unfortunately, only the rare cancer patient well versed
in clinical trials will be able to discern whether the label
is identifying a drug that has gone through the less-rigorous
AA process. For example, capecitabine was given AA (on the
basis of tumor response) for advanced breast cancer in 1998.
The 2002 Physicians' Desk Reference describes capecitabine's
testing as a "phase II, single-arm trial," which
signals AA.
Another clue can be found under "Indications,"
where response rate is described as the basis for the drug's
use for metastasized breast cancer. However, the much watered-down
patient version of the capecitabine label (which appears
after the information aimed at professionals) does not include
an explanation of these terms. The patient's label makes
no mention of the fact that the drug was approved through
the accelerated process. Capecitabine is sold under the
brand name: Xeloda.
- Go to the Web site of the National Cancer Institute (www.cancer.gov),
click into the following succession of options: "treatment,"
"chemotherapy," and "newly approved cancer
treatments." You will find explanations of phase II
trials, off-label drug use (complete with Q and A: "Can
off-label drug use be harmful?"), and many other relevant
terms. People without access to the Internet can call the
National Cancer Institute at 1 (800) 4-CANCER to get this
information mailed to them.
When recommending a new cancer drug to a patient, oncologists
will often quote "response rate" without explaining
what it means. Ask. This article has addressed how new drugs
receive FDA approval. But once on the market, they are often
studied eventually in large randomized, controlled trials
as part of a multiple-drug regimen.
- Ask for the evidence to support a proposed chemotherapy
regimen. Here's one way to phrase the question: "Can
you give me a citation for the studies that show this drug
or drug-combination will benefit people with my stage and
type of cancer? The citation will allow you to do a Medline
search (ask the librarian at your local public library)
to locate the study and determine the exact nature of the
benefit.
Medline is a service available through the National Library
of Medicine (www.nlm.gov).
It provides free access to the abstracts, or summaries,
of the studies published in a large proportion of the world's
medical journals. Some public libraries will retrieve the
entire article at no charge, but the article can also be
purchased on-line.
A Drug that Proved Meaningful Benefits to Patients
When gemcitabine (brand name: Gemzar)
was approved by the FDA in 1996 for pancreatic cancer, it
was particularly momentous to people diagnosed with this
disease. In most cases, pancreatic cancer is advanced at
the time of diagnosis, and the treatment options offer little
in the way of increased survival.
The process required for gemcitabine's approval also came
at time of change within the FDA regarding how success is
determined. For regular, as opposed to accelerated, approval
of its drug, the manufacturer Eli Lilly had to prove "clinical
benefit" in two large randomized clinical trials (RCTs)
comparing its new drug with the standard chemotherapy drug
(5-FU).
The first trial proved that the drug not only prolonged
life, but also provided a better life for some of the participants.
The 63 pancreatic cancer patients, who had been randomly
assigned to take gemcitabine lived nearly six months*, compared
with four months for the 63 patients who had taken 5-FU.
The "better quality of life" benefit was determined
by consumption of painkillers, pain intensity, performance
of everyday activities, or weight change. Fourteen of the
63 people on gemcitabine showed this benefit, compared with
only three taking 5-FU.
In time, oncologists began prescribing gemcitabine off-label
to people with non-small cell lung cancer. Though drug companies
are not required to conduct additional studies just because
their drugs are being prescribed off-label, some manufacturers
might do so when oncologists report encouraging results.
Eli Lilly conducted an RCT comparing cisplatin, the standard
chemotherapy drug for non-small cell lung cancer, with the
combination of cisplatin and gemcitabine. Results showed
that the people taking the combination lived six more weeks*
than those taking the older drug alone.
Now oncologists are adding gemcitabine to a multiple-drug
regimen for advanced breast
cancer.
*This is median survival, which means
that half the cancer patients lived longer and half lived
less.
(September
2002)
Post
Menopausal Hormones: A Cautionary Tale
By Maryann Napoli
Always read the information that comes with your prescription
drug. That's the take-home message from the recent announcement
that postmenopausal hormones cause more harm than good.
The woman who took the time to wade through the multiple
pages of tiny type in the "patient packet insert"
included* within her estrogen/progestin prescription would
not have been surprised at the recent news that this combination
causes far more harm than good.
For well over a decade, there had been an informal consensus
building among gynecologists who seemed to think that virtually
all women should consider lifelong hormone therapy, primarily
to prevent heart disease. It's doubtful that many doctors
took the time to explain the uncertain safety of combining
estrogen with progestin or the iffy nature of the heart
protective effects. But the patient packet insert that comes
with Prempro, the most widely prescribed estrogen/progestin
combination, contains the following information listed under
Precautions: "A causal relationship between estrogen
replacement therapy and reduction of cardiovascular disease
in postmenopausal women has not been proven. Furthermore,
the effect of added progestins on this putative [reputed]
benefit is not yet known." Yes, it could have been
written in a jargon-free style, but the key information
about the "unknowns" is there.
Estrogen was approved by the Food and Drug Administration
in 1942 to alleviate the symptoms of menopause. Ironically,
the whole point of adding progestin to the regimen was to
overcome an adverse reaction to estrogen (an increased risk
of endometrial cancer) that was identified 35 years later.
Now the combination has been shown to be far more dangerous
than estrogen alone.
The story of postmenopausal hormones provides yet another
illustration of how long a drug must be in use before a
full picture of its safety and effectiveness becomes clear.
It also shows the importance of randomized clinical trials.
The National Institutes of Health-sponsored trial, called
the Women's Health Initiative (WHI) is the first large study
ever to compare hormones with a placebo. The 16,608 healthy
participants, aged 50 to 79 years, had been randomly assigned
to take Prempro or a placebo. Those who had had a hysterectomy
were randomly assigned to take estrogen or a placebo.
The main part of the WHI was stopped three years short of
its intended goal because the women taking Prempro showed
a higher rate of heart attacks, breast cancer, stroke, and
blood clots than the women taking the placebo. These risks
showed up after only four years on the drug. Though the
women taking Prempro had a decreased risk of colon cancer
and fractures, these benefits were far outweighed by the
harms. The WHI continues to study the women without a uterus
who presently show no significant benefit or risk from taking
estrogen alone.
You might wonder why the heart-protective benefit remained
so fixed within the belief system of the average gynecologist.
For example, a small increase in the number of heart attacks,
strokes, and blood clots in the lungs showed up in the first
one to two years of use of estrogen and progestin. But doctors
reasoned that this small risk (less than 1% altogether)
would disappear after two years, so the trial was allowed
to continue. But, in the next years, the women on the hormone
combination showed a continued increase in heart attacks,
strokes, and blood clots. The same disturbing results showed
up in an earlier randomized trial that explored the question
of whether hormones could prevent heart attacks in women
with heart disease.
But gynecologists, as a group, had managed to convince themselves
that the heart benefits would eventually be verified. Previous
trials did show estrogen's good effect on what doctors call
"markers" for heart disease, such as cholesterol.
And there were many observational studies, indicating that
women who took hormones had a lower incidence of heart disease.
But upper-income women tend to have lower rates of heart
disease, and this is the same group that was more likely
to take hormones. As Susan M. Love, MD, author of Dr. Susan
Love's Hormone Book, is fond of saying, "We don't know
whether the hormones made the women in these observational
studies healthy, or whether healthy women took hormones."
Definitive information did not arrive until the WHI announced
its findings last month in the Journal of the American Medical
Association (JAMA, 7/17/02).
The same issue of that journal included another study that
reported an increased risk of ovarian cancer to be associated
with the use of estrogen alone. The risk was especially
relevant to women who took estrogen for ten or more years.
This study, however, was not a randomized trial, so it is
possible that the ovarian cancer risk will not be confirmed
in future, well-designed clinical trials.
There are many women who take hormones solely for the purpose
of alleviating menopausal symptoms or osteoporosis prevention.
For these women, both pharmaceutical and non-pharmaceutical
alternatives are described in one of the Web sites listed
below.
Resources:
-Consult the Physicians' Desk Reference, which is available
at most community libraries, before taking any prescription
drug. Though quite daunting in language and format, the
PDR is the only source of accessible information for consumers
who want the most complete information about any prescription
drug they are about to take. The book is updated yearly
and can be purchased at most major chain bookstores. The
patient packet insert referred to in this article is the
same information provided in the PDR. Unlike other drug
reference books, the PDR describes what has been proven
in terms of effectiveness in the pre-approval clinical trials
and how long the trials followed the participants.
-For alternatives to hormone therapy, including supplements
and other drugs, visit the Web site of the North American
Menopause Society (www.menopause.org).
NAMS has received funding over the years from Wyeth, makers
of Prempro, Premarin, and other estrogen drugs, and it has
been the prime force behind the inappropriate promotion
of these drugs for prevention of heart disease. At this
Web site you can also read the organization's position papers
and expert comments on the WHI findings.
-The Food and Drug Administration Web site (www.fda.gov)
has prescription drug information, but it is better at providing
it for newly approved drugs. If you can find your way to
"advisory committee transcripts," that is where
the pre-approval discussions of a drug's pros and cons can
be found.
-Our Web site (www.medicalconsumers.org)
grants free access to the March 2002 HealthFacts article
on postmenopausal hormones.
*Hormone drugs are in a rare category of prescription drugs.
Their manufacturers are mandated by law to include written
information for consumers in their products. How well they
comply has yet to be studied. To find this important information
for all prescription drugs, see "Resources."
(August
2002)
Hip
Fracture Prevention
By Maryann Napoli
Hip fractures are a serious concern for the frail el-derly,
and much of the relevant research to date has centered upon
the use of estrogen, calcium, vitamin D, exercise, and drugs
to strengthen bones. More attention of late has turned to
the question of why elderly people fall and how these falls
can be prevented. Swedish researchers studied the effects
of a program of different strategies to prevent falls and
resulting injuries in elderly people living in residential
care facilities (Annals of Internal Medicine, 5/21/02).
The 11-week program involved educating the staff, modifying
the environment (e.g., lighting), adjusting medications
(e.g., eliminating drugs known to increase risk of falling),
implementing an exercise program, supplying and repairing
aids (e.g., canes, walkers), and providing free hip protectors.
The team of researchers led by Jane Jensen, RPT, randomly
assigned 402 people over the age of 65 years to the 11-week
program or to a control group. The median age was 83 years;
and most were women. In Sweden, people who live in residential
care facilities are disabled from either cognitive or physical
impairment.
At the end of a 34-week follow-up period, Jensen and colleagues
found that the intervention program significantly reduced
the number of residents who fell, the total number of falls,
the time to first fall, and the number of hip fractures.
Hip fractures occurred in three residents in the intervention
program and 12 residents in the control group. The use of
hip protectors proved to be a major benefit because no hip
fractures occurred in residents wearing these undergarments
with padding on each side where the thigh bones meet the
hip. Three earlier studies, which also found positive results
for hip protectors, were cited by the Swedish researchers
at the end of this study.
At the end of a 34-week follow-up period, Jensen and colleagues
found that the intervention program significantly reduced
the number of residents who fell, the total number of falls,
the time to first fall, and the number of hip fractures.
Hip fractures occurred in three residents in the intervention
program and 12 residents in the control group. Use of hip
protectors proved to be a major benefit because no hip fractures
occurred in residents wearing these undergarments with padding
on each side where the thigh bones meet the hip. Three earlier
studies, which also found positive results for hip protectors,
were cited by the Swedish researchers at the end of this
study.
(August
2002)
Postmenopausal
Hormones: An Update
by Maryann Napoli
Postmenopausal hormones have been
promoted to women (and doctors) for nearly four decades
with promises of everything from youthful skin to increased
longevity. The currently popular indications-prevention
of heart attack and hip fracture-are not supported by good
research. Two large trials, which randomly assigned women
to take hormones or not, have failed to confirm estrogen's
heart protective effects. And while many randomized controlled
trials (RCTs) have proven estrogen's ability to stop the
loss of bone density, none lasted long enough to show that
this hormone actually prevents fractures.
Estrogen is still prescribed to women as a treatment for
osteoporosis (bone loss), though the Food and Drug Administration
removed this indication in 1999 because of lack of evidence.
Only one indication for taking hormones is backed up with
good research support-the relief of menopausal symptoms,
such as hot flashes.
The two large RCTs, which provided the heart-related results,
are the Women's Health Initiative (WHI) and the Heart and
Estrogen/Progestin Study (HERS). Together they included
about 30,000 participants. The HERS was designed to determine
whether hormones can prevent heart attacks in women, aged
44 to 79 years, who have heart disease. And the WHI, which
includes healthy women, aged 50-79 years, is exploring the
effects of hormone therapy on the prevention of heart disease
and osteoporosis-related fractures, and on the risk of breast
and uterine cancers. All participants had been randomly
assigned to take a placebo (inactive pill) or hormones (estrogen
alone for women who had a hysterectomy or estrogen plus
progestin for women with an intact uterus).
The data from these and other RCTs are being searched for
information about a range of health effects associated with
hormone therapy:
Cardiovascular Events: Both the HERS and the WHI
found a small increase in the number of heart attacks, strokes,
and blood clots in the lungs in the first one to two years
of hormone use. Researchers initially thought that this
small risk (fewer than 1% altogether) would disappear after
two years, but longer follow-up showed otherwise. Last year,
the WHI reported a continued increase in heart attacks,
strokes, and blood clots in women taking hormones.
Prevention of Another Stroke: Among 652 women (mean
age 71 years) who had suffered a non-disabling stroke or
a transient ischemic attack, those who had been randomly
assigned to take oral estradiol did not show a lower incidence
of death or stroke. Worse, the rate of fatal stroke was
significantly higher among those taking estradiol (a form
of estrogen).
Fractures: The WHI is designed to answer the question
of whether hormones prevent fractures, following its participants
for eight to 12 years.
Urinary Incontinence: 1,525 women with urinary incontinence
participated in the HERS. All were younger than 80 years
and had experienced at least one episode of urinary incontinence
per week. Incontinence improved in 26% who had been assigned
to take a placebo for four years, as compared with 21% assigned
to take hormones. Urinary incontinence worsened in 27% of
the placebo group, as compared with 39% of the hormone group.
Dry Eye Syndrome: 665 participants of Women's Health
Study, a RCT that began in 1992, found a slight increased
incidence of dry eye syndrome in hormone users (past and
current), especially among the women on estrogen alone.
According to questionnaires completed by the participants:
9% of those taking estrogen alone reported severe symptoms
diagnosed by physician, as compared with 7% among the estrogen
plus progesterone or progestin, and 6% among those who never
used hormones. Dry eye syndrome, a condition with no effective
treatment, can damage the surface of the eye.
Urinary Tract Infection: Women in the HERS who had
been randomly assigned to take hormones for four years did
not have a lower incidence of urinary tract infections.
Gallbladder Disease: The HERS showed gallbladder
disease to be 38% higher among those who had been assigned
to take estrogen/progestin therapy.
Annoying "Minor" Side Effects: Breast
tenderness with uterine bleeding caused 30% to stop taking
hormones by the end of one year.
What's Wrong With Observational Studies?
Many benefits attributed to hormones, such as prevention
of Alzheimer's disease, have yet to be validated in an RCT.
Such information comes from less reliable research, known
as observational studies. Such research takes a backward
look at women who chose to take hormones to determine whether
their health status differs from that of women who did not
take hormones.
The problem with observational studies is this: Women who
take hormones tend to be upper income and well educated.
Both characteristics are associated with better heart health
and longevity. Susan Love, MD, author of Dr. Susan Love's
Hormone Book, identified the problem: "We don't know
whether hormones made the women healthy, or whether healthy
women take hormones." It is the observational studies
that misled so many gynecologists to believe that estrogen
prevents heart disease.
An RCT provides more trustworthy results because participants
of similar age, health status, etc, are randomly assigned
to take the drug or not. Then they are followed for years.
Most RCTs are double-blind, which means that neither the
participants nor the health professionals monitoring them
know who is on the placebo and who is taking the active
drug.
Benefits and Risks Yet to Be Confirmed:
Colorectal Cancer: Observational studies have produced
inconsistent findings regarding the possibility that hormones
lower the risk of colorectal cancer. The results range from
no reduction to a 33% reduction in colorectal cancer.
Cognition: Observational studies suggest that hormone
therapy may reduce the risk of cognitive decline. A systematic
review of all studies, including some RCTs, that explored
this topic was published last year in the Journal of the
American Medical Association. The participants, who had
been taking hormones for the symptoms of menopause, showed
improvements in "verbal memory, vigilance, reasoning,
and motor speed, but no enhancement in other cognitive functions."
The authors went on to explain that most of these studies
had significant limitations.
Alzheimer's Disease: No RCT has been conducted regarding
the risk of dementia. Earlier observational studies suggest
that women taking hormones were less likely to develop Alzheimer's
disease, but more recent observational studies did not find
this benefit.
Breast Cancer: Does estrogen use increase the risk
of developing breast cancer? More than 30 observational
studies have been conducted to answer this question. But,
here too, the results have been inconsistent. Some found
estrogen use to be associated with a reduced risk of developing
breast cancer; others found an increased risk of breast
cancer beginning after five years of use. And some studies
found no risk. The WHI has been designed to provide a reliable
answer to the question of whether there is an association
between estrogen and breast cancer.
Endometrial (uterine) Cancer: Ever since it became
known that estrogen increases a woman's odds of developing
uterine cancer, the drug is now prescribed with another
hormone, progestin, to women with an intact uterus. Not
all doses of progestin protect the uterus, however. For
the results of a review of all trials that determined appropriate
doses, see "Protecting the endometrium" by Gibbons
and Thorneycroft in the Journal of Reproductive Medicine
(2/99).
For More Information About the WHI:
The Women's Health Initiative is sponsored by the U.S.
National Heart, Lung and Blood Institute. Visit its Web
site at www.nhlbi.nih.gov/whi/hrt/htm
for more information about the progress of this trial.
(March
2002)
Inappropriate
Drug Prescribed For Prostate Cancer
by Maryann Napoli
Doctors frequently prescribe an inappropriate drug to men
with early prostate cancer. Though the consequences of this
treatment are severe, most men reported a high degree of
satisfaction with their care. These paradoxical findings
come from the first major study to look at the quality of
life for men who were not treated surgically or with radiation
therapy.
This study is an important contribution to the debate about
whether the prostate-specific antigen (PSA) screening test
for prostate cancer causes more harm than good. As its use
increased dramatically over the last decade, so too has
the diagnosis of early prostate cancer. The blood test is
now routinely given to men with no symptoms, though studies
show that most prostate cancers remain dormant an entire
lifetime. Consequently, many men are treated unnecessarily.
Previous studies of men with early disease who remained
untreated showed that their prostate cancer death rate was
similar to that of men given a prostatectomy. Neither the
PSA test, nor any other, can accurately identify the minority
of prostate cancers destined to be fatal. And there is no
proof that treating the potentially fatal version at an
early-stage saves lives.
There is a consensus among researchers, though not among
urologists, that the decision to remain untreated is a valid
choice. This used to mean-no treatment until symptoms occur
("watchful waiting"). But now it appears that
many men who forego a radical prostatectomy or radiation
therapy are being treated with a drug that stops their production
of the male hormone, androgen. Known as androgen deprivation
therapy (ADT), the treatment amounts to a medical castration,
usually with the injectable drug, Lupron.
Lupron has been tested and proven useful only as a palliative
treatment for men with advanced prostate cancer. A palliative
treatment means that the drug can only alleviate symptoms.
And now the drug is being prescribed for early-stage cancer
in men without symptoms-at a great physical cost, according
to the new study published recently in the Journal of the
National Cancer Institute (3/20/02). "There is no definitive
evidence that early ADT alone improves length or quality
of life in men with clinically localized prostate cancer,"
according to the study's authors, Arnold L. Potosky, PhD,
and colleagues.
All of the men who agreed to take part in this study had
been newly diagnosed in 1994-5 with cancer that had not
spread beyond the prostate gland. They are participants
in a much larger project called the Prostate Cancer Outcomes
Study (PCOS), initiated by the National Cancer Institute
to investigate variations in the treatment of prostate cancer
and to determine how the men fared afterward. Significantly,
the PCOS is primarily following men who were treated at
community medical practices, as opposed to a research-based
cancer center. The participants include men under 60, as
well as African-Americans and Hispanics,
