HEADLINE:How Two Studies on Cancer Screening Led to Two Results
BYLINE: This essay is by H. Gilbert Welch, Steven Woloshin and Lisa M. Schwartz..
Dr.
Welch is the author of ''Should I Be Tested for Cancer? Maybe Not and
Here's Why'' (University of California Press). He, Dr. Schwartz and Dr.
Woloshin are senior research associates at the VA Outcomes Group in
White River Junction, Vt.
BODY:
Of
all the forms of cancer, lung cancer is by far the deadliest. So
doctors have long hoped to come up with a screening test that would
find it early, before it can grow and become untreatable.
Last fall, The New England Journal of Medicine published a study
concluding that spiral CT screening (a kind of three-dimensional chest
X-ray) would make most lung cancers curable. It sounded like wonderful
news. For proponents of screening, it was a call to action: the Lung
Cancer Alliance is starting an advertising campaign featuring sports
celebrities trying to persuade you to make the ''right call'' and get
screened.
But just last week The Journal
of the American Medical Association published a study concluding that
spiral CT screening is not only ineffective, but may actually be
harmful, prompting unnecessary surgery that carries risks of its own.
How could these two studies -- in the country's two most prestigious
medical journals -- arrive at diametrically opposite conclusions? An
answer requires a clear understanding of the goal of cancer screening.
That goal is to save lives -- or, in scientific terms, reduce mortality. Simply finding cancer early is not enough.
Finding cancer early saves lives only if two conditions are met: the
cancers detected are the ones that kill people; and early treatment
prevents these deaths.
It is not enough
to increase survival. While that may seem to be the mirror image of
mortality, it can be a terribly misleading measure of the value of
screening.
In the 1970s and '80s, there
was great interest in screening smokers for lung cancer using
conventional chest X-rays. The question was seen as so important that
it was examined using the gold standard of medical studies, a
randomized trial. Half the participants were randomly selected to
receive regular chest X-rays; half did not and served as the control
group.
Three such randomized trials
were conducted, and all three showed that screening did not reduce
mortality. In fact, two reported slightly higher death rates in the
group receiving chest X-rays.
The most
famous of these trials, at the Mayo Clinic, showed how misleading
survival can be. Although the 10-year survival rate doubled with
screening, mortality was not reduced; indeed, screening may have
increased it. The Mayo trial also showed that more than a decade after
screening was stopped, there were still more cancers in the screened
group. This shouldn't happen: in two large randomly selected groups,
there should be the same number of cancers in both. The chest X-rays
must have detected some lung cancers that were never destined to cause
symptoms or death -- a phenomenon known as overdiagnosis.
This phenomenon challenges our conventional view of cancer as an
inexorably progressive disease. Research in screening has demonstrated
that what pathologists call cancer encompasses a broad spectrum of
disorders: some cancers rapidly progress to death, some do so more
slowly, and some don't progress at all (or may even regress).
Overdiagnosis is even more of a concern for spiral CT, because it can
detect far more abnormalities than chest X-rays. In fact, a screening
program in Japan found about 10 times as many lung cancers with spiral
CT as had been found in the same population using chest X-rays. More
remarkably, the chance of having lung cancer detected by spiral CT was
almost the same in nonsmokers and smokers.
This flies in the face of everything we know about lung cancer and
smoking -- 50 years of research showing that smokers are 10 to 20 times
as likely as nonsmokers to die from lung cancer. This is powerful
evidence that spiral CT detects some lung cancers that will never
affect patients.
Because all lung
cancer patients get treated, overdiagnosis means some people receive
treatment that can't help them (because they do not need it) and can
only cause harm. Most patients given diagnoses of early lung cancer
undergo surgery to remove part of a lung, a major operation from which
about 5 percent die within a month.
With this background, let's look at the two recent studies on screening.
The New England Journal study reported screening about 31,000 people
with spiral CTs and finding 484 with lung cancer. These patients had a
10-year survival of 80 percent -- compared with 10 percent for current
lung cancer patients in the United States. The JAMA study reported
screening about 3,200 people and finding 144 with lung cancer. (The
detection rate was higher because this study had older patients and
longer follow-up.) Of 3,200 people, 38 died from lung cancer -- the
same mortality rate expected for people of similar age and smoking
history in the absence of screening.
In short, The New England Journal reported increased survival; JAMA reported no difference in mortality.
Most of us interpret ''increased survival'' to mean fewer deaths. But
it does not, because survival is subject to two powerful distortions.
The first is called lead-time bias. Simply advancing the time of
diagnosis (as with CT screening) will always increase survival.
Imagine two patients with lung cancer. Even if both die at age 70, a
patient with cancer diagnosed by spiral CT screening at age 59 has a
longer survival than one with cancer diagnosed because of symptoms
(cough, weight loss and so on) at age 67. The first patient survives 11
years; the second 3 years. But both died at the same age. Survival is
increased, but mortality is the same.
A
second source of distortion results from overdiagnosis, when screening
finds cancers that were never destined to progress and cause death.
Overdiagnosis bias can also drastically inflate survival statistics,
even if mortality is unchanged.
To
understand why, you need to understand the definition of the two
statistics. Both are fractions. Survival is calculated over a fixed
period, for example 5 or 10 years.
Overdiagnosis inflates both the numerator of the survival statistic
(number alive at a specified time) and the denominator (number of
diagnoses). For the mortality statistic, overdiagnosis has no effect on
the numerator (number of deaths) or the denominator (number studied).
Perhaps the easiest way to understand this is to imagine if we told all
the people in the country that they had lung cancer today: lung cancer
mortality would be unchanged, but lung cancer survival would skyrocket.
The goal of lung cancer screening is to reduce mortality -- to save
lives. Because the New England Journal study examines only survival, it
cannot tell us whether any lives are saved. Because the JAMA study
examines mortality, it is the more valid study. It also corroborates
the Mayo trial finding that a significantly increased survival rate can
coexist with no difference in mortality.
The JAMA study also highlights the tradeoffs involved in lung cancer
screening. The findings show that compared with no screening, if 1,000
people are screened over five years there would be 48 more lung cancer
diagnoses, 46 more lung cancer operations (which would be expected to
cause 2 deaths) and no lung cancer deaths prevented. The study data are
consistent with as many as eight deaths prevented by screening, or
eight extra deaths caused by it.
But
neither study is definitive, because neither was a randomized trial.
And both required assumptions. Given the potential benefit (so many
people die from lung cancer) and the potential harms (some die from
treatments), no one should have to assume anything.
Luckily, two randomized trials are under way -- one a Dutch-Belgian
collaboration, the other sponsored by the National Cancer Institute.
Recent experience, notably with hormone replacement in postmenopausal
women, has demonstrated how presuming benefits in the absence of
randomized trials can cause real harm. To avoid repeating these
mistakes, we should not screen for lung cancer unless the trials
demonstrate a reduction in mortality.
URL: http://www.nytimes.com
GRAPHIC:
Drawing (Drawing by Frank Stockton)Chart: ''Sources of Bias''Focusing
on 10-year survival rates can exaggerate the effectiveness of cancer
screening, some experts argue. Here are two sources of potential
bias:Chart tracks the survival rate, with and without screenings, for
cancer. (Source by H. Gilbert Welch, ''Should I Be Tested for
Cancer?'')
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