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Web Guide 1: John Marshall, MD
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Professor of Oncology and Medicine
Director, Developmental Therapeutics
Vincent T Lombardi Cancer Center
Georgetown University Medical Center |
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adjuvant therapy of colorectal cancer
All of us are quite anxious to incorporate agents such as
CPT-11 and capecitabine into the adjuvant setting; however,
currently, the standard of care is 5-FU/leucovorin. I discuss
incorporating CPT-11 with almost all stage III patients, but
I was more cavalier with CPT-11 before the recent toxicity
data was released.
toxicity associated with cpt-11
In clinical practice, I do not think we are seeing as much
toxicity with CPT-11 as reported in the clinical trials. The
recommendations are to watch the patients more closely and
to be a bit more generous with dose reductions. Another option
is changing the schedule.
capecitabine as front-line therapy
in metastatic disease
Capecitabine is approved for this use, and as doctors begin
to include capecitabine in their initial discussion of options,
they will see high patient acceptance. The patients experience
less diarrhea, do not lose their hair and do not need to visit
the clinic for two hours a week. They may get hand-foot syndrome,
but that can be managed with slight dosage reductions.
status of key clinical trials in metastatic
colorectal cancer
The toxicities associated with the Saltz regimen have forced
us to stop accrual to many trials, so we need to address those
issues quickly and re-open those studies. An important Intergroup
trial that has also been on hold is looking at reduced doses
of CPT-11 — it’s a three-arm study that compares
CPT-11/5-FU/leucovorin versus oxaliplatin/5-FU/leucovorin
versus oxaliplatin/CPT-11 to see if there’s a winner
among those. Some of the phase II metastatic trials are looking
at capecitabine in combination with CPT-11 or oxaliplatin
in attempts to take advantage of a better 5-FU drug.
creation of cea-based vaccines
Over the course of three different trials, we have shown
that cancer patients can make specific immune responses to
CEA peptides. The T-cells that they make are able to lyse
tumors. Occasionally, patients will have objective responses
to vaccines alone. It’s not clear whether patients with
high tumor burden or low tumor burden respond equally, and
we’re trying to answer that question. The vaccines are
safe, despite high T-cell counts against CEA.
Right now we’re also looking at vaccines that not only
carry the gene for CEA, but also carry three other genes for
what are called co-stimulatory molecules. These really turn
on the T-cell pathways much more aggressively, and certainly
the preclinical data for this four-gene construct suggests
that it’s much better.
The most exciting thing that we have done to date is that
we demontstrated a link between an individual patient’s
CEA-specific immune response and survival. It was in a small
study, but the differences were great. We are now trying to
replicate that in our current studies, and we have designed
a randomized trial for the high-risk adjuvant patient or for
the stage IV patient who’s been resected and has no evidence
of disease. We’re going to use the vaccine as an adjuvant
in that setting, but also try to correlate immune responses
to survival and validate that endpoint.
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