Drugs to cure cancer have had little success. We
need new ones that prevent it.
Pills against cancer
By Philip E. Ross
Forbes Magazine May 31, 1999
Oncologists like to joke about cardiology envy:
While heart specialists now routinely prescribe
drugs that stop disease before it starts, cancer
specialists must resort to last-ditch heroics.
Numbers tell the story. The death rate for coronary
heart disease has declined 24% since 1986, but
cancer casualties have fallen just 3% from a peak
in 1990. Most of that gain comes not from high-tech
cures but from a simple preventative: quitting
smoking.
Sure, everyone should do that—and eat fruits and
vegetables, and get screened for cancer, and stay
out of the noonday sun. But what we really need is
a new generation of preventative drugs—newfangled
chemicals that will be taken, daily and over many
years, by people who are genetically predisposed
to cancer risk.
That isn't all that far-fetched. The world's first
cancer-preventing drug recently won approval:
Zeneca Pharmaceuticals' tamoxifen. Several other
promising drugs now are in human testing. As more
move down the pipeline, inevitable questions will
arise: Will the new drugs be worth the risk of side
effects in decades-long use? And will insurers
willingly pay now for pills to prevent disease, buying
the argument that they can save money on cancer
care in the long run?
"A daily pill for all? It could happen in 15 or 20
years," says the National Cancer Institute's chief of
prevention, Peter Greenwald. "This will be the
standard approach," says Harmon Eyre, head of
research at the American Cancer Society. "We'll be
addressing cancer before it becomes cancer."
This strategy grows out of the emerging view of
cancer not as a state but as a process—a
decades-long trek to accumulate the six to ten
genetic mutations required to turn normal cells into
an invasive tumor. At any point the right chemical
intervention could derail this process, and the
sooner, the better. The first preventatives will aim at
patients whose risks are so high that they can
easily justify any threat of side effects from
long-term therapy. Those patients will then serve as
guinea pigs for the rest of us.
That's the story behind Zeneca's tamoxifen. It
began life in the 1970s as an oral contraceptive,
reached the market in 1977 as a treatment for
advanced breast cancer and won approval for earlier
stages of that disease. In November it got the nod
for preemptive use in women who don't have breast
cancer but are at high risk of getting it.
"We weren't looking for a preventative effect," says
Paul V. Plourde, the endocrinologist who runs
Zeneca's breast cancer program. But doctors
discovered that women taking tamoxifen to treat a
tumor in one breast also got fewer cancers in the
contralateral or healthy breast. And the drug had
remarkably mild side effects, making it a promising
prospect for prevention.
While other cancer chemotherapy kills all
cells—healthy and lethal—to try to rid the body of
cancer, tamoxifen works through hormonal trickery.
In breast cancer a woman's estrogen continuously
shouts a redundant message to certain cells:
"Grow!" Tamoxifen snaps onto breast-cell receptors
tailored to read signals from estrogen, thereby
blocking them from hearing the directive.
In a $60 million clinical trial, paid for by the U.S.
government, 13,000 healthy women took tamoxifen
or a sugar pill for five years. In the tamoxifen group
breast cancer appeared only half as frequently as in
the control group, a savings of about 280 cases.
It's too early to know how many years of life the
drug adds or whether it saves money. But just
putting off cancer by five years could offer a
significant financial payoff. The last year of cancer
care can easily cost $20,000; the $6,000 bill for five
years of tamoxifen begins to look cheap.
Yet insurers would have to pay for treating many
thousands of healthy women, all to avoid only a few
hundred cases of cancer. Keeping 6,500 women
(half the trial) on tamoxifen over five years would
cost almost $40 million; the 280 cases would cost
only $5.6 million for a final year of cancer care. How
much is a saved life worth?
Now researchers are studying whether a second
estrogen inhibitor, Eli Lilly & Co.'s raloxifene, might
work even better. Next month a five-year trial
begins, comparing the preventative effects of
tamoxifen and raloxifene in 22,000 women over age
35.It has already been approved for use against
osteoporosis, and some doctors already prescribe
it to at-risk women. Zeneca has sued Lilly for
allegedly encouraging such "off-label" uses.
Celebrex, the new arthritis drug, also shows
surprising promise as a cancer-stopper. Marketed
by Pfizer Inc. and G.D. Searle & Co., Celebrex is a
so-called cox-2 inhibitor that quells arthritis pain
without upsetting the stomach. Now the companies
are testing whether the drug can reduce the number
of precancerous polyps in people with familial
polyposis, a rare disease that often leads to colon
cancer. They refuse to discuss the project, but
landing quick approval for that narrow use could
pave the way for using the drug in lower-risk
groups.
A second arthritis drug, sulindac, already has been
found to fight polyposis, but it can cause serious
gastric problems in some patients. Cell Pathways,
a biotech boutique in Horsham, Pa., has found a
metabolic breakdown product of sulindac that has
no effect in blunting arthritis but does seem to
prevent cancer growth, both in animals and in
human cell cultures.
A year or so ago it looked as if it would do the
same in patients. In preliminary trials, a few
early-stage polyps left in a patient's colon shrank
over time, with no noticeable side effects. But in the
second of three major phases of clinical trials the
chemical was unable to demonstrate statistically
significant results.
Rifat Pamukcu, chief scientist for Cell Pathways,
blames the ambiguous results on the fact that the
company was able to sign up only 74 patients. He
says he still believes in the product. "We appear to
be hitting cells in the early as well as the late stage
of progression to cancer."
Indeed, in interim results just released from an
ongoing trial, Cell Pathways' drug showed
significant reductions of PSA, a marker for the
recurrence of prostate cancer.
None of these drugs is yet ready for those of us
who can't be pigeonholed into a high-risk
category—but the push for prevention has to start
somewhere. "Prevention offers an enhanced quality
of life, as well as an extension of it," insists
Michael Sporn of Dartmouth Medical School, a
pioneer in the field. "One day there'll be very large
numbers of people on chemopreventive therapy;
we'll begin with those at very high risk, then work
our way down."
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