sciencemag.org SCIENCE
tering Cancer Center in New York City, the
clinician who led the trial.
The initial trial did have one unexpected
benefit: It halted the growth of tumors
that had metastasized to the brain, mostly
likely because the high doses helped the
drug cross the blood-brain barrier. Michor
hopes to launch another pulse trial with
a newer, more potent EGFR inhibitor.
With some drugs, pulse dosing can also kill tumor cells
more effectively than the same
dose spread out over time,
says cancer biologist William
Sellers, who recently left Novartis for the Broad Institute
in Cambridge, Massachusetts.
“The biology by which the
tumor responds can be completely different,” he says.
McMahon and others propose another twist on intermittent dosing: Whenever a
targeted therapy is paused,
administer a second drug that
targets a different growth protein in the remaining cancer
cells. That could pack an even
more powerful punch, perhaps
leading to long remissions,
McMahon says.
Nor does variable dosing
need to be limited to targeted
therapies, says Gatenby, who
believes it can boost the effectiveness even of traditional
chemotherapies and hormonal treatments. He prefers
to call his approach “adaptive
therapy,” because rather than
sticking to a set dose schedule
based on modeling, he adjusts
the dose to how a patient’s tumor evolves—sometimes even
fully withdrawing the drug
when tumors become small
enough. His goal is to preserve
a population of drug-sensitive
cells, which will be fitter than
resistant cells and will suppress their growth.
In work published last year
in Science Translational Medicine, Gatenby’s team gave high-dose chemotherapy to mice implanted with
human breast tumor cells, then lowered the
drug dose after tumors began to shrink. This
kept the size of tumors stable for 6 months,
much longer than on continuous dosing,
and in nine of 12 mice they were able to stop
treatment altogether for a time. Gatenby has
had similar preclinical success in ovarian
cancer, and is preparing a trial in people with
that disease.
He’s also pushing ahead with an adaptive dosing strategy for the hormonal
treatments traditionally used in prostate
cancer. Oncologists generally prescribe a
continuous maximum dose of a drug that
suppresses the body’s androgens, which
promote tumor growth. But patients often
develop resistance to the blocker, when
their tumor evolves the ability to grow without androgens. Gatenby’s group is now running a clinical trial in which patients whose
cancers initially respond to the androgen
blocker abiraterone go off the drug until
imaging tests reveal that their tumor has
grown or they have had a significant rise
in their level of prostate-specific antigen, a
cancer blood biomarker.
Next month at the American Associa-
tion for Cancer Research annual meeting
in Washington, D.C., the team will report
that nine of 11 patients have remained re-
sponsive to abiraterone for a median of
21 months, roughly twice as long as usual,
while getting less than 40% of the usual to-
tal amount of drug. “Our goal is to maintain
people with their tumor under control for
as long as possible and extend their lives
with a better quality of life,” Gatenby says.
RESEARCHERS WHO STUDY variable dosing schedules caution
that they are not ready to be
used routinely. For one thing, if
cancer patients suddenly stop
taking a drug, their tumor can
sometimes grow explosively.
“You have be extremely careful
that you don’t lose control of
it,” Gatenby says.
What the field needs most
are more basic lab studies,
proponents say. But variable
dosing is not exactly a booming area of research. “There
are very few of us thinking
about these issues,” says Neal
Rosen, a cancer biologist at
Sloan Kettering.
Sellers notes other hurdles.
Most academic labs doing preclinical cancer studies aren’t
set up to measure the drug metabolism parameters needed
to hone dosing schedules, he
says. And companies, he adds,
are initially focused on gaining
regulatory approval for their
drugs. “Not enough attention
is being paid to alternative
dosing regimens” before drugs
reach the clinic, he says.
Grant reviewers tend to
be wary, too, says Sloan Kettering’s Paul Chapman, who
is starting an intermittent
dosing trial of a targeted
therapy for a form of melanoma in the eye. He and
his collaborator, Richard
Given the increasing evidence that many
cancers can overcome a steady stream of
even the best drug, the field should be more
open-minded about new dosing strategies,
Chapman argues. “We’re not saying we
know this will work, but it makes sense and
we ought to test it.” j
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Timetables for treatment
Hoping to slow tumors, several research groups are experimenting with new treatment
strategies in which the maximum safe dose of a cancer drug is not given continuously.
Continuous dosing
Nonstop use of a cancer
drug often selects for deadly
resistant cells.
Intermittent dosing
Because drug-resistant cells may depend on the drug for optimal growth,
interrupting treatment can slow tumors and extend survival.
Adaptive dosing
Adjusting a drug’s dose to tumor size may also let sensitive
and resistant cells compete, delaying tumor growth.
