These findings do not surprise
J. Taylor Hays, M.D., professor of medicine at the Mayo Clinic and director
of its Nicotine Dependence Center in
Rochester, Minn. He said smoking cessation is just one of many unsubstantiated
claims about e-cigarettes with no clinical
proof to back them up.
“It’s the wild, wild West out there,”
Hays said. “How can you know if they
work, since there are all sorts of claims
and promises with no regulation and no
standardization of products which are
available even online?”
Hays said e-cigarettes don’t seem to
help people quit, because people are only
substituting them for regular cigarettes:
“This may in fact perpetuate their addiction and may in some ways conflict with
quitting attempts later on.”
Nor did the results surprise Dona
Upson, M.D., associate professor of
internal medicine at the University
of New Mexico School of Medicine in
Albuquerque.
“These results are consistent with
other studies that have looked at the efficacy of e-cigs for smoking cessation for
noncancer patients,” she said.
A recent study finding by the federal Tobacco-Related Disease Research
Program adds new concern for Upson:
Instead of quitting, more people are
moving toward dual use.
“They may cut down on their regular
cigarette use, but they’re not quitting,
and they’re adding e-cigs into the mix,”
Upson said.
“I think that the tobacco
industry—which now owns
one-third of the e-cigarette
market—is so smart and
has so much money and
resources that you have to
think they’ve done some of
this testing on their own,
and if the results were
good, they would be out
there trumpeting it in the
marketplace, but they’re not.”
Upson is also a member of the Tobacco
Action Committee at the American
Thoracic Society and vice chair of its
Health Policy Committee. She said one of
the important things about that study was
that more than 75% of the people they
wanted to enroll were either unreachable or refused to participate. She said
she wonders whether the clinicians and
patients are unaware of the benefits of
quitting smoking after cancer diagnosis.
“It might be
a sort of a fatalistic
attitude
that the damage has been
done, and they
might as well
let them enjoy
their cigarettes,
without realizing that it is a
Dona Upson, M.D.
quality-of-life
issue,” Upson
said. “This is a population that should have
been highly motivated.”
Upson said she is also alarmed at
the rapid increase of electronic cigarette
usage, especially among younger people.
“It is growing very fast, and we just
don’t have any good, solid data showing
harm reduction versus tobacco products.”
Upson said she’s concerned that the
product may undo much of the progress
over the last 50 years to reduce smoking
and nicotine dependence.
“I think that the tobacco industry—
which now owns one-third of the e-cigarette market—is so smart and has so
much money and resources that you have
to think they’ve done some of this testing
on their own, and if the results were good,
they would be out there trumpeting it in
the marketplace, but they’re not.”
© Oxford University Press 2015.
DOI:10.1093/jnci/dju496
First published online January 6, 2015
Expensive Cancer Therapies: Unintended Effects
By Cathryn M. Delude
During the past decade, rising costs of
new cancer drugs have coincided with
the approval of drugs that prolong life,
on average, by only months, if not weeks.
These linked trends are also tied to
the proliferation of redundant drugs
and stifled efforts to develop drugs with
greater clinical value, according to a July
2014 article by two cancer researchers
and an economist.1
First author Tito Fojo, M.D., Ph.D.,
a medical oncologist at the National
Cancer Institute, said that to address
marginal benefits:
• the U.S. Food and Drug Administration must raise the bar for approval of
new therapies;
• patients and oncologists must
demand drugs with more clinically
meaningful benefits; and
• academicians and associations must
stop exalting marginal results.
Also, he said, clinical trials should become
smaller, faster, and more targeted studies
that aim for meaningful clinical improvement, especially in overall survival (OS),
rather than statistical significance.
“It’s a timely article that highlights
many issues that the American Society of
Clinical Oncology has been increasingly
concerned about,” said ASCO president
Peter Yu, M.D. “We need to encourage
these discussions at the national policy
level and at the patient level, because
we know that patients and doctors may
assume that FDA approval signals a significant improvement over standard
therapies.”
To rein in escalating costs, the authors
argue that Medicare should be able to
negotiate drug prices—on the basis of
a therapy’s clinical value. Currently, no
relationship exists between drug efficacy
and price.
Marginal Clinical Benefits
ASCO recently summarized the work of
four committees tasked to consider what
would constitute a meaningful clinical
improvement over standard therapy in
four common cancers.2
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“The committees asked concrete
questions,” Yu said. “If someone is likely
to live 12 months with standard therapy, how much increased longevity is
required to consider a new therapy a significant breakthrough?”
The groups proposed a hazard ratio
of 0.8, which requires median OS to
improve by 2.5–6 months to be considered clinically meaningful. These findings were not intended to set standards
for regulations or insurance coverage,
but “to encourage patients and investigators to demand more from clinical
trials.”
For their article, Fojo and colleagues
used the ASCO standard to evaluate 71
drugs approved for solid tumors between
2002 and 2014. Only 30 (42%) met this
“very modest” standard. Overall, median
gains in progression-free survival and
OS were 2.5 and 2.1 months, respectively. Median patient enrollment in the
trials was 582, a large number that the
authors assert they needed to ensure
statistical benefit. Some approvals not
meeting the ASCO standard for clinical
benefit stemmed from large clinical trials seeking additional indications for a
newly approved drug to replace a standard therapy. The authors contend that
a pharmaceutical company’s desire to
increase the market for its drug—rather
than improve cancer therapy—drove
those trials. They ask: How could we
have invested so much time, effort, and
money and still find ourselves with so
little progress? Patients expect more, and
the oncology community and the FDA
should too.
Yu attributes some of the oncology
field’s acceptance of marginal benefits
to decades of developing combination
chemotherapy regimens in which no
single component drug had substantial
effect and yet combinations working
together could produce cures. But with
current knowledge of molecular drivers
and molecular biomarkers to target therapies to patients most likely to benefit,
researchers should expect more robust
results.
“It’s not that we’re aiming for
incremental improvements in cancer therapy,” said Derek Lowe, Ph.D., a
medicinal chemist who writes the blog
“In the Pipeline.” “We’re trying for major
breakthroughs but failing because cancer is so complicated.”
Keith Flaherty, M.D., a melanoma
researcher at Massachusetts General
Hospital in Boston, said that targeted
therapies will also probably prove more
effective in combination but are currently
tested as single therapies, although he
expects that to change.
“These marginal results are not the
endgame,” he said. “We’re trying to build
regimens, analogous to the three-drug
AIDS cocktail, that match the complexity
of cancer. But we’re still in the early days
of developing the components.”
“It’s not that we’re
aiming for incremental
improvements in cancer
therapy. We’re trying for
major breakthroughs but
failing because cancer is so
complicated.”
He said he thinks the article is taking
a short view, while the field is now on a
trajectory toward improved efficacy.
Escalating Costs
Discourage Progress
The authors, however, argue that the
high prices these new drugs can command slow that trajectory. Some typically enter the market costing $10,000
per month. Rather than stimulate innovation and progress toward transformational therapies, drug prices encourage
a proliferation of “me too” drugs that
focus too much effort on the same target
in some cancers while neglecting more
common cancers. According to their
analysis, 74% of the drugs in the pipeline of nine large companies are similar
to drugs being developed by other companies. One example: the ALK mutation
that occurs in less than 5% of non–smallcell lung cancers. FDA recently approved
two ALK inhibitors, crizotinib and ceritinib, and at least six more are in development. Crizotinib did meet the ASCO
standard for achieving true clinical benefit over the previous standard of care,
and ceritinib may again achieve benefit
over crizotinib. Nevertheless, at $14,282
per month, crizotinib was the highestpriced drug when introduced, and just a
few months later ceritinib came on the
market at a monthly cost of $16,197—
almost 13% more. Fojo predicted that if
another ALK inhibitor gains approval,
it will probably cost even more. The
likelihood of high profits, rather than a
desire to fulfill an unmet need in cancer
therapy, motivates this research on additional ALK inhibitors, Fojo said.
“Do we really need all this investment of our limited research resources
in more ALK inhibitors that will benefit
maybe 3% of non-small cell lung cancer
patients when we still need to move the
field
forward
for the majority
of lung cancer
patients?”
“I agree with
Fojo that the
me-too
mentality is a problem, but I think
he is liberal in
how he defined
me-too
drugs
and overlapping
Derek Lowe, Ph.D.
pipelines,”
Yu
said. “It’s valid to have overlap to improve
efficacy or to overcome resistance or toxicity.” Regarding the resources devoted to
therapies that could benefit only a small
subset of cancer patients: “It’s the future
of oncology to slice and dice anatomically defined cancers into multiple subgroups and to develop therapies for the
smaller populations of patients. We have
to follow where the science takes us.”
Yu said he agrees that financial incentives for drug companies encourage them
to develop relatively risk-free drugs that target proven mechanisms of actions and discourage the more financially risky search
for breakthrough therapies. Companies
make an enormous financial investment
to develop one drug, he said, and they are
beholden to shareholders and investors
who prefer lower risk for guaranteed profit.
Value Pricing
The problem, the researchers said, is
ultimately the Medicare reimbursement system, in which a drug’s price
bears no relation to its clinical value.
Medicare, the largest insurer for cancer patients, must pay the manufacturer’s set price for an FDA-approved
drug, regardless of its benefit to
patients. Moreover, the 2003 Medicare
Prescription Drug, Improvement, and
Modernization Act prevents Medicare
from negotiating drug prices, as is done
in Canada, Europe, and elsewhere. (The
U.S. Department of Veterans Affairs can
negotiate drug prices and saves millions of dollars per year.) Private insurers generally follow Medicare’s lead in
coverage. Because of this guaranteed
market, “market forces don’t apply
and drug companies charge what they
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compensate by offering more benefits
in survival.
“It requires all of us to agree on
benchmarks,” Fojo said. “For example,
a smaller gain could be valued more in
pancreatic or rare cancers that currently
have no effective therapy.”
According to Yu, ASCO is developing
a framework to compare value of treatments on the basis of clinical benefit,
toxic effects, and cost.
How much is society pressing to move
in this direction?
“My patients aren’t complaining.
They don’t actually know what these
drugs cost because insurance pays for
them,” Flaherty said. “The groundswell
of protest over pricing is among insurance companies, and I can see why,”
said Lowe, also agreeing with the other
researchers that having Medicare
negotiate drug prices would be one
straightforward way to better align
them with clinical value. How likely
is that?
“I’m an optimist,” Yu said. “All oncologists are.”
Notes
1. JAMA Otolaryngol. Head Neck Surg.
doi:10.1001/jamaoto.2014.1570.
2. J. Clin. Oncol. 2014;32:1277–80.
3. Blood 2013;121:4439–42.
4. J. Clin. Oncol. 2013;31:3600–4.
5. J. Oncol. Pract. 2014;10:e208–11.
6. J. Natl. Cancer Inst. 2009;101:1044–8.
© Oxford University Press 2015.
DOI:10.1093/jnci/dju497
First published online January 6, 2015
Renewed Focus on Preventing Gastric Cancer
By Susan Jenks
With the heavy burden of gastric cancer in the developing world, researchers
have begun to target its principal cause,
Helicobacter pylori, in hope of preventing it.
This ancient microbe has resided in
the human gut for at least 100,000 years.
Eradicating it still raises concerns about
swapping one deadly cancer for another.
Even so, data from several recent randomized trials have shown enough benefit, researchers say, to warrant a more
aggressive prevention approach. The
World Health Organization declared
H. pylori a class I human carcinogen
in 1994.
“Ignoring gastric cancer in the hope
that it will soon disappear is not a tenable health policy,” three scientists wrote
in an editorial (JAMA 2014;312:1197–8).
Their recommendation: Countries with
high rates of gastric cancers should
begin large population-based evaluation
programs to screen for and treat H. pylori
while awaiting results of four long-term
clinical trials. One prevention trial in
China involves more than 200,000 people.
An International Agency for Research
on Cancer working group made similar recommendations in a 2013 report
amid “an acute need to commit more
public health resources to gastric cancer
control.”
Often diagnosed at advanced stages,
gastric (or stomach) cancers kill more
people globally than any other cancer,
except lung and liver, according to the
World Health Organization. More than
700,000 men and women are expected
to die of this disease in 2014, most in
East Asia and South America, where
poor socioeconomic conditions favor
H. pylori’s easy transmission, usually during childhood.
H. pylori is responsible for an estimated 75%–80% of gastric cancers. These
spiral-shaped bacteria burrow into the
stomach’s protective mucosal lining,
where they cause inflammation and
extensive cellular damage over time.
Although about half the world’s population harbors H. pylori, individual risk for
developing stomach cancer is less than
2%. Nevertheless, chronic H. pylori infection carries the blame for many clinical
conditions, including peptic ulcers, pernicious anemia, and dyspepsia.
U.S. gastric cancer rates have fallen
precipitously since the 1950s, partly
because of dietary changes and a dramatic decline in smoking, according to
Philip Taylor, M.D., senior investigator in
the National Cancer Institute’s genetic
epidemiology branch. The “so-called
hygiene theory” also comes into play, he
said, as the U.S. and other industrialized
nations have improved food storage and
sanitation measures, thwarting H. pylori’s
ability to spread.
Even globally, gastric cancer rates
have been decreasing, Taylor said. But
as the world’s population increases and
ages, epidemiologists expect to see a rise
in these cancers.
Still Divisive
How best to screen and treat H. pylori
remains a divisive issue within the gastrointestinal community, however. Two
prominent scientists still sit on opposite
sides of the controversy—one calling for
eradication of the bacterium whenever
possible, the other suggesting that doing
so indiscriminately could cause more
harm than good. Others take a middle
ground.
“From a cancer prevention point of
view, the theory is wonderful,” an infection story whose cure lies in a vaccine,
Taylor said. But no promising vaccine yet
exists for H. pylori, and eradicating it may
be “a good idea only if you don’t look at
the downside.”
One possible downside: losing protection against esophageal cancers. Several
observational studies have shown that
H. pylori infection decreases stomach
acid secretion. So eliminating the infection would lead to more acid secretion
as the stomach recovers, possibly worsening gastroesophageal reflux disease, a
major risk factor for esophageal cancer.
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can get away with—because they can,”
said Hagop Kantarjian, M.D., a leukemia researcher at the University of
Texas M. D. Anderson Cancer Center
in Houston, who also writes about this
topic. “Drug companies are increasing
drug prices to the extent it is harming
our patients. Advocating for lower drug
prices is a necessity to save the lives of
patients who can’t afford them.”
Elsewhere, Kantarjian, Fojo, and
colleagues have endorsed value pricing. In this alternative model, a drug’s
price reflects the proportional benefit
to patients, such as prolonging OS and
improving quality of life—concepts
that guide price negotiations in Europe
and elsewhere.3–6 Drugs with greater
benefit may cost more, and those that
adversely affect quality of life should