(Dad) Re: JNCI Article on low-dose CI

Liza this sounds good. Can I get it? Does anybody do this for colon mets? Which port is this? Up in the chest I think. I can live with that (maybe). dad

Liza May wrote:

(cont.)

And this one is a news article that just appeared in January in, as
you see, the Journal of the National Cancer Institute (here in
Bethesda), discussing the Browder paper and the work they're doing
up there.

Like I say, I've asked Michael Retsky some questions about this and
am waiting to hear back from him. I'm sure he, and probably Marshall
too, is at the conference until later this week.

I am composing an email for John Marshall too, (which I'll send only
to you, first, so you can change it however you want) asking his
opinions about this, Iressa, and the other things we're considering.

Anyway, here is this important article - that could possibly change
the way chemo is regarded, and administered. LOTS of politics
surrounding this, you can imagine.

Oh, and .... scroll all the way to the bottom of this email!!

Love Liza

~~~~~~~~~~~~~~~

Journal of the National Cancer Institute, Vol. 94, No. 2, 82-84,
January 16,
2002
© 2002 Oxford University Press

==================

NEWS

Could Less be More? Low-Dose Chemotherapy Goes on Trial
Ken Garber

Judah Folkman, M.D., is accustomed to skeptics. When he first
proposed, 30
years ago, the existence of a protein in the blood that blocked
tumor blood
vessel growth, the idea was almost universally ridiculed.
Antiangiogenesis,
of course, is now mainstream.

In April 2000, Folkman offered a new heresy: continuous, low-dose
chemotherapy that, by targeting the endothelial cells that form the
tumor’s
blood supply, might work against drug-resistant tumors.

"We said that, in some patients, you may be able to rescue them by
changing
the schedule and doing antiangiogenic chemotherapy," said Folkman.
The idea,
also dubbed "low-dose" or "metronomic" chemotherapy, challenged the
long-entrenched "more is better" orthodoxy, and many oncologists
openly
scoffed.

Now Folkman’s idea is being put to the test. Three North American
clinical
trials of metronomic chemotherapy are under way. Each uses low-dose,
continuous chemotherapy in combination with commercially available
antiangiogenesis drugs.

"The animal experiments are promising, the concept is plausible, and
well
designed clinical trials should be used to evaluate it," said Ian
Tannock,
M.D., Ph.D., professor of medical oncology at the University of
Toronto.
Tannock leads one of the trials, using low-dose cyclophosphamide and
Celebrex (celecoxib) to treat metastatic renal cancer. But, Tannock
cautioned, "There’s certainly no basis for using it outside the
setting of a
clinical trial."

In this trial, patients receive a daily 50mg/m2 oral dose of
cyclophosphamide indefinitely until the cancer progresses or
toxicities
emerge. By comparison, Tannock noted that a typical standard regimen
would
include cyclophosphamide doses of 500 to 1000 mg/m2 intravenously
every 3
weeks.

Low-dose/antiangiogenic/metronomic chemotherapy has precedents.
"Using
low-dose chemotherapy is not a new idea," said Robert Kerbel, Ph.D.,
of the
University of Toronto. "In fact, there are oncologists who will say
to you,
‘Hell, we’ve been using low-dose chemotherapy, or some kind of
continuous
regimen . . . for years.’ " Anecdotal reports of responses to
low-dose
palliative chemotherapy are common. In childhood leukemia,
continuous
"consolidation therapy" lasting 3 years is now standard.

"Eighty-two percent of the last 400 kids I’ve taken care of with
leukemia
are alive and well, and 89% are alive at 11 years, and it’s all
metronomic,"
said pediatric oncologist Barton Kamen, M.D., Ph.D., of the Cancer
Institute
of New Jersey, Princeton. "Did I win because I was killing the
vasculature
in the bone marrow? I can’t tell you that. But I can tell you that
the use
of chronic, repetitive low-dose medicine, regardless of the target,
works—absolutely works."

Others are skeptical. "Gee, it sounds wonderful, but there [are a
lot] of
good theories out there," said Roy Baynes, M.D., Ph.D., director of
the bone
marrow transplant program at Wayne State University in Detroit. "I
would
just make a plea, before everyone jumps overboard—let’s get the
data."

The antiangiogenic chemotherapy theory originated in the early 1990s
with
Tim Browder, M.D., an oncology fellow in Folkman’s laboratory.
Browder and
Folkman were puzzled that chemotherapy, which was known to have
antiangiogenic effects, always led to resistance. Tumor endothelial
cells,
in theory, should not become resistant to chemotherapy because they
lacked
the tumor’s genetic instability. Why, then, didn’t chemotherapy work
better?

"I had this discussion many times with Browder," Folkman recalled.
"Browder
came back and said, ‘I think the reason that chemotherapy doesn’t
act all
the time on endothelial cells is they keep stopping
[treatment]—taking
vacations, treatment vacations.’" Browder reasoned that giving
chemotherapy
continuously would prevent endothelial cell recovery and effectively
starve
tumors of their blood supply.

Proving the theory took years of exhaustive laboratory work,
culminating in
Browder and Folkman’s April 2000 paper in Cancer Research. Working
in mice,
Browder showed that continuous low-dose cyclophosphamide could cure
otherwise invariably fatal tumors. After creating a super-resistant
tumor
line, Browder then showed that low-dose cyclophosphamide could
greatly slow
tumor growth and improve survival.

The drug’s antiangiogenic effects, a variety of careful assays
demonstrated,
were responsible. "The tumor would be drug resistant ... but the
endothelial
cell would not," said Folkman. "And you could get [disease]
control."

Kerbel, at the same time, published results showing that a
combination of
low-dose vinblastine and an anti-VEGF (vascular endothelial growth
factor)
receptor antibody could completely eradicate tumors in mice. "The
tumors
completely regressed," Kerbel recalled. "They never came back during
7
months of continuous therapy." This and Browder and Folkman’s work
together
laid the theoretical groundwork for today’s clinical trials.

Besides Tannock’s renal cancer trial, two other human trials are
under way.
Rena Buckstein, M.D., of the Toronto Sunnybrook Regional Cancer
Center, is
leading a multicenter trial also using low-dose cyclophosphamide
with
celecoxib to treat non-Hodgkin’s lymphoma.

Meanwhile, oncologists at the Dana Farber Cancer Institute, Boston,
are
undertaking separate pediatric and adult trials using a combination
of two
chemotherapy agents—low-dose cyclophosphamide and etoposide—and two
antiangiogenic drugs, celecoxib and thalidomide.

"I think this has immense promise, and it deserves to be tested,"
said
principal investigator Mark Kieran, M.D., Ph.D. "If the philosophy
is right,
we will at least see a little bit of activity."

Kerbel said he is worried that, because celecoxib and thalidomide
are not
the optimal antiangiogenic agents, these trials will not demonstrate
metronomic therapy’s true potential. Experimental drugs targeting
VEGF or
the VEGF receptor would theoretically be more potent, but drug
companies
will only test such drugs against standard-dose chemotherapy, to
advance
their chances of Food and Drug Administration approval. "It’s a bit
frustrating," said Kerbel, who added that he hopes that the early
trials
will show enough effect to convince drug companies to test their new
agents
with low-dose chemotherapy.

Although results in mice and anecdotal reports in humans seem to
favor the
metronomic idea, there is at least one big worry: resistance. While
antiangiogenesis, in theory, bypasses the genetic instability that
leads to
tumor resistance, in some of Browder and Folkman’s experiments the
tumors
eventually returned.

"Even if you target the vasculature, there may be ways that you
still
nevertheless get resistance," said Kerbel. For example, tumors may
evolve to
survive in relatively hypoxic conditions. Or, in response to stress,
they
may secrete cytokines or growth factors that promote angiogenesis.

"A tumor could escape an angiogenesis inhibitor," admitted Folkman,
who,
nevertheless, is not worried. "We’ve actually seen that, but it
turns out
that now you just give more angiogenesis inhibitor, and you override
it."

Some think that metronomic chemotherapy not only blocks angiogenesis
but
also directly targets tumors. "I believe that metronomics is working
whether
the vasculature really turns out to be the target or not," said
Kamen. The
anti-inflammatory effects of low-dose chemotherapy may, Kamen
speculated,
allow natural killer cells better access to tumors. And since many
chemotherapy drugs only work against dividing cells in the process
of
synthesizing new DNA—the so-called "S phase"—continuous chemotherapy
is
necessary to kill all tumor cells present, in Kamen’s view. Higher
doses, if
given intermittently, will not help. "You can’t kill a cell twice,"
said
Kamen. "That’s what it comes down to."

Skeptics counter that high doses are absolutely necessary to
eradicate
tumors. "Systematic undertreatment compromises outcome," Wayne State
’s
Baynes said.

So the fate of metronomic chemotherapy rests on the clinical trials.
Even if
they succeed, it will not be easy to convince oncologists to abandon
the
"maximum tolerated dose" philosophy.

"There’s this view: If you’re not vomiting and you’re not having
your hair
fall out, then there’s probably nothing happening to your tumor,"
said
Kerbel. "That’s a very entrenched view among oncologists. Since that
’s been
a prevailing way of doing things for decades, it’s not easy, based
on a
couple of early clinical trials, to turn that around."

Folkman is more optimistic, since many doctors have already used
low-dose
chemotherapy successfully without knowing why it works. "Clinicians
come up
all the time and say, ‘I want to tell you a secret. I never stop
chemotherapy,’" Folkman said. "‘I keep giving it, but I was afraid
to
mention it, because everyone thought I was giving homeopathic doses.
’" Now,
Folkman said, "They have an explanation." All that’s missing is the
proof."