(Xeloda) research continues to bring to
light new combinations of agents in the
treatment of metastatic breast cancer, and
to test the combination of capecitabine/
radiation therapy in the treatment of other
solid tumors. A series of symposia sponsored
by Roche and held in conjunction
with the 39th Annual Meeting of the
American Society of Clinical Oncology explored
the use of capecitabine, a tumoractivated
oral fluoropyrimidine, in various
Essence of Radiosensitization
Edgar Ben-Josef, MD, of The Karmanos
Cancer Institute and Wayne State
University in Detroit, explained how
radiosensitization can be used to control
gastrointestinal (GI) malignancies without
increasing the complication rate. "This
is the essence of radiosensitization. We
want to achieve a therapeutic gain. And,
for effective radiosensitization, I can't
overemphasize the importance of not increasing
toxicity," Dr. Ben-Josef said.
Forty years ago, early work with
fluorouracil (5-FU) showed that combining
ineffective chemotherapeutic doses
and ineffective radiation doses could result
in cures in 30% of tumors in animal
models of cancer. Subsequent research
revealed the importance of correct timing.
For example, to be effective, 5-FU
must be in the tissues within 8 hours after
radiotherapy, Dr. Ben-Josef explained.
Dr. Ben-Josef reported his findings
comparing 5-FU and capecitabine and
testing a capecitabine/radiotherapy combination
in prostate cancer cell lines.
"5-FU adds nothing to radiation," he said,
"but capecitabine adds an important synergistic
To summarize the phase III data on
capecitabine vs 5-FU in metastatic colon
cancer, the response rate with capecitabine
was 25% compared to 16% with 5-FU.
The time to progression for both agents
was equivalent, as was survival. But according
to Dr. Ben-Josef, "there are clearly
fewer grade 3/4 toxicities with capecitabine."
Advantage in Lowering Doses
A study among 32 patients with a variety
of malignancies in the GI tract found
that the capecitabine/radiotherapy combination
had an advantage in older patients.
The median age of the patients in
the study was 67 years, but patients up to
84 years were included. Dr. Ben-Josef said,
"Because this combination of capecitabine
and radiotherapy is well tolerated, you
can treat patients you might not otherwise
consider for aggressive treatment,
either because they have comorbidities or
due to their advanced age."
The treatment regimen started with
capecitabine 1,250 mg/m2 bid, but it was
reduced to 625 mg/m2 bid. The median
dose, and the one most commonly used,
was 800 mg/m2 bid, 5 days a week with
radiotherapy. In a phase I study, there
were no dose-limiting toxicities at this
Results from the laboratory indicate
that with capecitabine there is effective
radiosensitization at much lower doses
than the maximum tolerated dose (MTD).
"This is the situation that we face with
most chemotherapeutic agents today," Dr.
Ben-Josef said. "For substantial tumor
responses, we have to accept fairly high
complication rates, and therefore the paradigm
has been to push the dose to the
MTD, to operate just below the MTD. It
doesn't make sense now to work in the
region of the MTD. The therapeutic gain
is much higher at lower doses. So I submit
that with newer, tumor-selective drugs
we need to start working with a new
paradigm: to identify the minimum effective
dose (MED), then operate a notch
above this minimum. Then we can explore
the full potential of the drug being
Metastatic Pancreatic Cancer
Current trials using capecitabine to
treat inoperable and metastatic pancreatic
cancer were reviewed by Robert Fine,
MD, Columbia University, New York.
Pancreatic cancer has a poor response
rate to chemotherapy (ASCO abstracts
1129 and 1517). "The mechanisms of drug
resistance are very important for understanding
why these tumors are so resistant,"
Dr. Fine said.
"First, to kill these cells, we have to
exploit biochemical synergisms, and lab
data show that if you achieve a biochemical
synergy between drugs being used,
you can overcome some mechanisms of
drug resistance. Second, with synergistic
chemotherapy you can significantly lower
the chemotherapy concentrations and
still kill the same number of cells-more
is not always better. So you add finesse to
what the oncologist wants to achieve:
shrink the tumor without hurting the
patient. Third, you want to target pathways
for p53 independent apoptosis because
75% to 80% of all pancreatic cancer
tumors have mutant p53-tumor cells in
pancreatic cancer patients are not going
to die through the classic p53-dependent
The Finesse of Oncology
Echoing Dr. Ben-Josef's description
of the importance of synergism in combination
therapies, Dr. Fine said, "You want
to reduce doses without sacrificing efficacy-
this is what I call the finesse of
Dr. Fine's goal in treating pancreatic
cancer is to induce p53-independent apoptosis.
"The gist of our work is that we
found in human pancreatic cancer cell
lines, gemcitabine (Gemzar), docetaxel,
and 5-FU produce synergistic cell-kill.
When we used this synergism, we were
able to reduce the doses by 50% and still
kill the same number of tumor cells."
"And for simplicity of administration,
we used capecitabine. We gave 42 metastatic
patients 750 mg/m2 of capecitabine
twice daily. The result was a complete
response rate of 9.5% and a partial response
rate of 47%. Also, 74% had a clinical
benefit response," Dr. Fine reported.
GTX Regimen and Variation
"We used an apoptotic assay with a
human pancreatic cancer cell line. We
found that 5-FU and gemcitabine killed a
small number of tumor cells, and docetaxel
kills a few more. But if you put them
together, you get this powerful synergism.
That experiment led to the regimen that
we refer to as GTX."
The GT-X regimen consists of capecitabine
500 to 750 mg/m2 twice daily for 14
days. After 4 days, patients receive gemcitibine
750 mg/m2 over 75 minutes and
low-dose docetaxel (Taxotere) 30 mg/m2
over 30 minutes. It is a 2-week regimen
with the third week off, and responses are
evaluated after three cycles.
In the case of GTX failure, Dr. Fine
then separated the administration of the
drugs. This was based on lab experiments
showing resistance to GTX was due to
cytokinetic cell cycle resistance. The same
three drugs that had just failed were used
again, but this time in a sequential manner.
This modified regimen is referred to
as sequential GT-X. Dr. Fine comments,
"This is a very easy treatment for the patient.
The dose is about 60% to 75% of the
GTX doses. In a preliminary study of 10
patients who failed GTX, there was one
complete response and two partial responses
of their metastatic disease. Four
other patients achieved stable disease.
Median duration of stable disease was 5.5
months. Three patients did not respond.
There were no grade 2 or higher toxicities,"
"The GTX regimen is based on in vitro synergisms and equal activity in mutant
and wild type p53
PC cells," Dr. Fine said.
"The toxicity profile is favorable. Lower
doses still kill tumor cells. Response rates
are promising in the advanced state, and
further studies are warranted to ascertain
the true clinical benefit," Dr. Fine concluded.
Metastatic Breast Cancer
A phase III study of capecitabine plus
bevacizumab (Avastin) in metastatic
breast cancer was discussed by Kathy Miller,
MD, of Indiana University Medical
Center, Indianapolis (ASCO abstract 766).
"For the past 2 to 3 decades, it has been
known that tumor growth is dependent of
angiogenesis. This discovery generated an
investigation as to what factors stimulate
or inhibit blood vessel growth. Vascular
endothelial growth factor (VEGF) is one
of the most potent stimulators of angiogenesis,
and this finding led to explosive
growth in the development of agents that
inhibit VEGF signaling. One of the earliest
agents was bevacizumab, a humanized
monoclonal antibody directed against VEGF itself. It recognizes all of the VEGF
isoforms, and it has activity in monotherapy,"
Dr. Miller explained.
In heavily pretreated breast cancer
patients, about 9% of patients have an
objective response to bevacizumab monotherapy,
Dr. Miller reported, and an additional
10% are without progression at 22
weeks. This finding led to a phase III trial
for patients with prior anthracycline or
taxane therapy for metastatic breast cancer,
or who had a relapse within 12 months
of completing anthracycline and taxanecontaining
The study had 462 patients who were
well balanced for demographics and all of
the prognostic factors that might influence
progression-free survival and overall
survival. Three-quarters of the patients had visceral disease, so it was a difficult
patient population. Both capecitabine and
bevacizumab toxicity mirrored what was
seen in earlier trials.
Response Was Increased
But Not the Duration
Response rates, as evaluated by investigators
or by a blinded review facility,
nearly doubled, but there was no difference
in duration of response. Therefore
the progression-free survival data are not
much different between the two treatment
arms (4.17% for capecitabine, 4.86%
for capecitabine plus bevacizumab). There
was no improvement in median progression-
"When we measure median progression
free survival, we measure the median,"
Dr. Miller stressed. "Response rates
of 10% to 20% do not drive median progression-
free survival. That is driven by
the 80% to 90% of patients who did not
respond to therapy. Time to response
shows the time the patient is in response
to therapy. If the patient never responded,
the patient has a time of 0. In this
study, at each time point, the patients who
are given the combination therapy are
doing slightly better, but most of that
benefit is early in the treatment. By the
third time point, most of the excess responses
gained by the combination arm
are lost. So, there are excesses, but they are
short-lived. And without that, you will
never see an improvement in the time to
progression," Dr. Miller explained.
VEGF Expression Matters
"VEGF expression does matter, but
probably not in the way that most people
would have predicted, " Dr. Miller said.
"Basically, this was a negative study
because it was powered to look at differences
in median progression-free survival,
and there were no differences, but in
my mind it is a critical proof of concept
study, and it really validates the importance
of antiangiogenic therapy. That conclusion
is because of the clear increase in
objective response rate while taking into
account that this was a very difficult patient
population," she continued.
"Our challenge now is to take advantage
of that activity so we can get even
greater benefit for our patients," Dr. Miller