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Not long ago, the defeat of cancer
seemed inevitable. Decades of research would soon pay off with a
completely fresh approach, an arsenal of clever new drugs to attack
the very forces that make tumors grow and spread and kill.
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No more chemotherapy, the
thinking went. No more horrid side effects. Just brilliantly
designed drugs that stop cancer while leaving everything
else untouched.
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Those elegant drugs
are now here. But so is cancer.
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The approach, which
appeared so straightforward, has proven disappointingly
difficult to turn into broadly useful treatments.
Some now wonder if malignancy will ever be reliably
and predictably cured.
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The dearth of
substantial impact so far suggests the fight against
cancer will continue to be a tedious slog, and
victories will be scored in weeks or months of extra
life, not years. The full potential of the new
approach may take decades to be realized.
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The drugs,
called targeted therapies, are intended to arrest cancer
by disrupting the internal signals that fuel its
unruly growth. Unlike chemo, which attacks all
dividing cells, these medicines are crafted with pinpoint
accuracy to go after the genetically controlled
irregularities that make cancer unique.
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Several have made it through
testing, but despite their apparent bull's-eye hits, lasting
results are rare. Instead, these new drugs turn out to
be about as effective -- or as powerful -- as old-line
chemotherapy. Aimed at the major forms of cancer, they
work spectacularly for a lucky few and modestly for
some.
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But for most? Not at all.
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Doctors have many theories
about what's gone wrong. But it is clear that cancer is
a surprisingly robust foe, packed with convoluted
backup systems that kick in when threatened by the
new drugs.
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At best,
experts now expect knocking down cancer will require an elaborate
mixture of targeted drugs, assembled to match the distinct
biology of each person's cancer.
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"It's a much more
complicated problem than anyone ever appreciated," says
Dr. Leonard Saltz, a colon cancer expert at Memorial
Sloan-Kettering Cancer Center. "It will, unfortunately,
be with us for a long time."
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The job is so
daunting, especially for advanced cancers propelled by
potentially dozens of nefarious genetic mutations,
that scientists are even rethinking the goal of cancer
research.
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"Society as a whole, and
most of the medical professional, have it wrong, understanding
we'll make up one morning and find out cancer is cured.
It won't happen. The public should give it up,"
says Dr. Craig Henderson, a breast cancer specialist
at the University of California, San Francisco,
and president of Access Oncology, a drug developer.
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"What we have
learned by these billions of dollars invested in
cancer biology is that cancer are us," he goes on.
True, cancer is different. But not different enough.
"Identify what makes cancer unique and wipe it out?
That won't happen. We cannot wipe out the cancer
without wiping out a lot of the rest of us."
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Henderson and many others
have shifted their sights to something less -- converting
cancer into a chronic disease, like diabetes or AIDS.
Treatments might slow or even stop its worst effects
so people survive for years reasonably free
of symptoms.
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Dr. Andrew
von Eschenbach, head of the National Cancer
Institute, argues that a cure is not even
necessary if this can be done, something he
optimistically hopes to see by 2015. But eliminate cancer?
"Not in the foreseeable future," he says.
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Still, experts
concede there is no firm evidence that targeted
treatments will tame cancer to a chronic condition,
either. Certainly, the ones tested so far do not often
come close to this for the common varieties, such as
lung, breast, colon and prostate cancer.
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Although targeted
therapies have their origins in basic cancer discoveries
of the 1980's, the story for many began at a meeting of
the American Society of Clinical Oncology in 1998.
Researchers were thrilled to hear of the first convincing
demonstration that a targeted drug could slow the course
of cancer even a little. It was proof that the principle
is sound.
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Usually wary
oncologists rhapsodized about a new era of treatment.
"A tidal wave," one of them called it. Even then,
no one predicted quick cures. But they clearly felt
they at least had the key to getting inside cancer
and fixing it.
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The drug that
caused the euphoria, Herceptin, became a standard
treatment for spreading breast cancer, typically
delaying progression by a few months in the quarter of
victims with a particular genetic profile.
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Since Herceptin,
targeted drugs have become the prevailing approach
in cancer research. Whenever any of these make
slight progress, the news is widely and sometimes
breathlessly reported. An estimated two-thirds of
the nearly 400 cancer medicines in human study take
this tack. Yet researchers do not envision successes
any more spectacular from this pipeline than the
modest effects of the handful already on the market.
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"Right now, in the
short run, we can bring an occasional miracle and have
an overall small benefit," says Dr. John Glaspy,
medical director of UCLA's surgical oncology center.
"But there has not been a major improvement on what
happens to them ultimately."
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Furthermore, the dream of
abandoning chemotherapy has largely evaporated. Even the
targeted drugs' small benefits are typically seen only
when combined with standard chemo.
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Cancer doctors facing
waiting rooms full of dying cancer patients, with little
to offer but easing misery and perhaps a few extra months
of survival, clearly had wishes for more.
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"The hope was that these
targeted therapies would be the new magic bullet and
would cure cancer," says Dr. DAvid Decker, an oncologist
at William Beaumont Hospital outside Detroit. "It's fair
to say they haven't panned out the way we thought they
would."
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The targeted drugs
have been most impressive against cancers of the blood
and immune system, which are easier to control than the
most common organ tumors. For instance, about half of
patients getting Rituxan for non-Hodgkin's lymphoma have
at least a 50 percent reduction in their cancer, and
the improvement lasts an average of a year before the
disease progresses again.
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The one striking
success, Gleevec, unfortunately works only against two
rare blood and digestive cancers that involve unusually
simple signaling pathways, offering ideal targets.
Even so, Gleevec's stunning effects -- close to 90 percent
initially get better -- often wear off in time.
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In 2001, Dean
Gordanier, a Boston tax attorney with a cancer-swollen
belly, was "pretty much dying" when he started on Gleevec.
For 18 months, it was a miracle. He gained weight and
went back to work. Then, the day before Christmas,
he learned the tumor was growing again.
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For most who win
a cancer reprieve, that would be the end. But as it
turned out, another experimental targeted drug was
available at the Dana Farber Cancer Institute, and
Gordanier's cancer is in retreat again, although he
expects this medicine, too, will eventually fail.
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"I feel like
I'm riding the crest of a wave," he says. "It could
dump me at any time, but right now I'm cruising."
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Dr. Brian
Druker of Oregon Health and Sciences University, one of
Gleevec's developers, says, "What Gleevec tells us
is if we have the right target and the right drug,
we will have spectacular results. Until then, we will
be mired in incremental gains."
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Those gains seem
especially incremental against the far more complicated
common cancers. For instance, the drug Iressa was approved
in May on evidence that it temporarily shrinks advanced
lung cancer in just 10 percent of patients. Doctors often
assume drugs will work better if given earlier in the
disease. But when Iressa was combined with chemotherapy
in newly diagnosed lung cancer, the patients did not
respond to it at all.
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Others in the pipeline
seem hardly more potent.
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At this June's
clinical oncology meeting, doctors reported the results
with two targeted drugs for advanced colon cancer:
A growth signal blocker called Erbitux (the same medicine
that ensnarled Martha Stewart in a Wall Street scandal)
temporarily shrank tumors in a quarter of patients.
And Avastin, intended to stop cancers from building
blood vessels, improved average survival by four months.
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In theory, all of these
drugs should work better, because they block the communication
pathways hijacked by the genetic mutations that become
cancer.
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Cancer occurs when five to 10
ordinary genes develop mutations in a single cell over a person's
lifetime, the consequence of biological insults like smoking or
just bad luck. As a result, the genes may get stuck in hyperdrive,
churning out huge amounts of growth stimulating proteins,
or perhaps they get turned off inappropriately, robbing
cells of their brakes. Whatever the problem, the result is
cells that divide over and over; that take root in parts
of the body where they don't belong; that lose the normal
instinct to self-destruct when their wiring goes awry;
and that they never die.
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This mess is fueled
by hundreds, even thousands, of individual proteins.
The process of making new blood vessels alone may entail
30 or 40 of them lined up in several signaling pathways.
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With targeted drugs,
scientists envisioned bringing the entire process to a halt
by chemically knocking out a single protein link in one
chain of communication. Like a cut phone line, no signal gets
through. Therefore, no more growth and no new cancer.
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Although the process
has not worked out to be this simple, many in the field believe
that eventual progress is likely. Maybe the best-case
scenario is spun out bythe Dana Farber's Dr. William
Kaelin. He theorizes that a few key pathways will prove
important in many kinds of cancer, and drugs will be created
to effectively block them.
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Several dozen drugs
may offer enough choices to cover all the typical genetic
combinations at work in cancer. "This is the belief that is
driving all of us," says Kaelin. With the right mix of three
or four drugs for any individual, "we will make a major
inroad into the common adult tumors, such as lung, colon
and breast cancer."