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are here: Home: CCU 2 | 2003: James
N Atkins, MD
Edited comments by Dr Atkins
Phase II trial of pemetrexed and oxaliplatin
as first-line therapy
The NSABP developed a foundation to conduct Phase II clinical
trials to ensure that novel agents will be available for
evaluation in Phase III trials. The first trial evaluated
pemetrexed 500 mg/m2 and oxaliplatin 120 mg/m2 in patients
previously untreated for metastatic colorectal cancer.
Pemetrexed is a multitargeted antifolate that inhibits
at least three enzymes — thymidylate synthase, dihydrofolate
reductase and glycinamide ribonucleotide formyltransferase — involved
in folate metabolism. Since it's multitargeted, it may have
more activity than 5-FU. It is synergistic with a number
of other agents, including oxaliplatin, and has activity
in a number of cancers, including breast, colon, pancreatic
and lung cancer.
Pemetrexed is generally well-tolerated. The major toxicities
in our study were neutropenia and thrombocytopenia, but most
of this was abrogated by B12 and folate supplementation.
The incidence of Grade III-IV neutropenia was 23 percent,
which compares favorably with what has been observed with
5-FU/irinotecan and 5-FU/oxaliplatin. No Grade III-IV diarrhea
was observed, and there was minimal Grade III-IV neurotoxicity.
The incidence of neurotoxicity was three percent, whereas
in studies of oxaliplatin/5-FU it is approximately 18 percent.
Pemetrexed may actually reduce oxaliplatin-associated neurotoxicity.
The overall response rate in our trial was 23 percent,
and another 50 percent of patients had stable disease. Some
received up to 18 cycles of therapy, which was given every
21 days. Some patients did extremely well with very minimal
toxicity. The response rate may not be quite as high as seen
with other 5-FU regimens, and it's possible the dose should
be escalated. Another group is conducting a Phase II trial
with this combination using much higher doses of the pemetrexed.
We chose the 500 mg/m2 because of the lack of available Phase
I data for higher doses. The other issue that needs to be
evaluated is using a 14-day schedule.
Importance of clinical trial participation
There are a number of reasons I support clinical trials.
First, I believe patients on clinical trials do better than
those who are not, and we are starting to see data to support
this. The reason may be the regimented follow-up and high
likelihood that patients will receive appropriate cancer
therapy.
In addition, data from Sloan-Kettering shows that the cost
of care for patients on clinical trials is decreased. We
drive costs up by ordering unnecessary and expensive tests.
Sometimes we do this because we are in a pattern — on “auto
pilot.” Five or ten years can go by, and we may not
change our practice. It's easy to be lulled into complacency
and do the things you’ve always done. But, in the context
of a clinical trial, you follow a protocol or a “recipe”,
which has been developed by the best cancer minds in the
world.
I also believe clinical trials are important because physicians
are very biased. We don’t always know the best treatment
for a particular patient. The bone marrow transplant trials
in breast cancer are a good example. One thousand women,
at a cost of roughly $100,000 each, participated. This works
out to a cost of approximately one hundred million dollars.
At the same time, 36,000 women had bone marrow transplants
outside of clinical trials at a cost of $3.5 billion dollars — for
no benefit. Physicians thought it would be better but were
obviously wrong.
I practice in a small town, but each year we enter about
150 patients into clinical trials. Many physicians in the
community are committed to research. In private practice
I have the best of all worlds. I can be as involved as I
want in clinical research without the headaches of academic
medicine. I work very closely with CALGB and NSABP, and my
colleagues work with SWOG and RTOG. Overall, I am very comfortable
with the clinical trials process.
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