CHICAGO-The pharmacology of capecitabine(Drug information on capecitabine) (Xeloda) exhibits similarities
to fluorouracil(Drug information on fluorouracil) (5-FU) that make it a
suitable substitute to 5-FU infusion, but
capecitabine also has unique qualities that
make it a distinct drug. These attributes
include several pharmacologic effects,
such as a selective effect that results in a
higher concentration of 5-FU at the tumor,
a potential for more effective interaction
with several chemotherapy agents
and radiation, and advantageous effects
on genes involved in apoptosis and DNA
repair. Furthermore, when capecitabine
and radiation are combined, a relatively
dramatic synergistic effect is achieved
compared with the use of either alone. No
such effect is observed with a combination
of radiation and 5-FU.
These conclusions were reported by
Robert Diasio, MD, of the University of
Alabama, Birmingham, at a symposium
sponsored by Roche on integrating
capecitabine in the management of colorectal
cancer. Dr. Diasio listed several
properties of capecitabine that distinguish
it from 5-FU. "The compound has excellent
bioavailability: it crosses the intestinal
membrane and then is converted
through a three-step activation process
(see Figure 1). The third step involves
thymidine phosphorylase (TP), which is
present more in tumor than in normal
tissue, and accounts for much of the selectivity
of this drug," Dr. Diasio said.
The goal in developing capecitabine
was to create an agent that would work
specifically at the tumor site, and thereby
maximize antitumor activity and improve
tolerability. "The oral drug capecitabine
has many potential advantages. These benefits
include generating 5-FU in both plasma
and cells for a longer duration than IV
bolus. Many of the complications associated with IV administration can be avoided
when an oral drug is used; and oral
drug administration is more convenient."
When the mean ratio of 5-FU concentrations
following capecitabine administration
are assessed, results indicate a significant
localization of 5-FU within the
tumor compared with concentrations in
healthy colon or rectal tissues or in plasma.
"This indicates that capecitabine really
gets to the point where you want it to
be maximally present-within the tumor
itself," Dr. Diasio said.
"It is worth noting that the very important
processes of apoptosis and DNA
repair are affected by capecitabine," Dr.
Diasio added.
"One of capecitabine's most important
attributes is that the activation of the
drug can be upregulated by some of the
other therapies that we use. A number of
drugs have the ability to induce TP, and
when they are used in combination with
capecitabine, we achieve a selective effect
in terms of upregulation."
Rationale for XELOX
Dr. Diasio also outlined the rationale
for developing the XELOX regimen
(capecitabine plus oxaliplatin(Drug information on oxaliplatin) [Eloxatin])
and some aspects that make this a desirable
combination:
-
These two drugs have different
molecular mechanisms of action.
-
A superior response rate and time
to progression are observed with the addition
of oxaliplatin to 5-FU/leucovorin
- There are no overlaps in key toxicities.
- There is evidence of synergistic activity
beyond additive effects.
"Looking at xenograft studies, capecitabine
alone or oxaliplatin alone has a
similar effect, but both taken together (at
two-thirds of the maximum tolerated
dose) actually results in an effect that is
beyond an additive effect alone-it is a
super-additive effect," Dr. Diasio said.
Combined With Radiation
Radiation can also upregulate TP in
tumor tissue and not in adjacent normal
tissue, and it works specifically at the last
selective enzymatic step in the activation
process. "If we look at the effect of radiation
on TP levels in the tumor, there is a
dose-related effect even from a single dose
of radiation therapy,"Dr. Diasio said.
"This presents the possibility of minimizing
radiation damage while increasing the
chemotherapy effect. When we combine
capecitabine and radiation therapy, we
get a relatively dramatic effect compared
with either one used alone. After 35 days,
this achieves a level of change that is beyond
super-additive; it is synergistic. There
is not such an effect seen with radiation
therapy and 5-FU."
Dr. Diasio also notes that unlike 5-FU,
capecitabine has a selective effect in terms
of apoptosis. It inhibits Bcl2, a gene that
blocks tumor cell death induced by the
radiation and chemotherapy agents. Also,
capecitabine has a greater effect than
5-FU in terms of inhibiting ERCC1, an
important DNA repair gene that also
blocks the effect of radiation and
oxaliplatin.
Investigating Properties
Trials designed to further investigate
the properties of capecitabine, particularly
in combination regimens in the treatment
of colorectal cancer were described
by Leonard Saltz, MD, of Memorial Sloan-
Kettering Cancer Center. He pointed out
that phase I and II studies of capecitabinebased
combinations in colorectal cancer show encouraging activity and a tolerable
safety profile. However, at present there is
no randomized phase III data regarding
the use of capecitabine in combination
with
irinotecan(Drug information on irinotecan) (CPT-11, Camptosar),
oxaliplatin (Eloxatin), or radiation therapy,
and no phase III comparisons of
capecitabine vs an infusional 5-FU regimen
have been reported.
CapOx vs FOLFOX
Dr. Saltz discussed two studies comparing
capecitabine/oxaliplatin (CapOx)
to one of the FOLFOX regimens (fluorouracil/
leucovorin/oxaliplatin) as firstline
therapy for colorectal cancer. A study
supported by Roche is evaluating CapOx
vs FOLFOX-4 among 1,000 patients. The
primary objective is time to progression,
and the secondary end points are overall
survival, response rate, time to treatment
failure, duration of response, tolerability,
medical care use, and convenience. "This
study will be looking at biomarkers and
pharmacokinetics, and, to the degree that
it can be obtained, pharmacogenetic
analysis as well," Dr. Saltz said.
A study from the Southwest Oncology
Group (SWOG) will assess CapOx vs
modified FOLFOX-6 (with 85 mg/m
2 oxaliplatin).
The study will involve a larger
patient population (with an accrual goal
of 1,730). The primary end point of the
SWOG trial is overall survival.
In addition, the two studies together
will indirectly provide a comparison
between FOLFOX-4 and the modified
FOLFOX-6. The studies will be conducted
in the United States, Europe, and elsewhere.
FOLFIRI vs IFL vs CapIri
A three-arm study is comparing FOLFIRI
(fluorouracil, oxaliplatin, irinotecan)
vs IFL on a 2-weeks on, 1-week off schedule
vs CapIri (capecitabine, irinotecan).
This study will look at whether giving IFL
on a 2-week on, 1-week off basis will improve
the tolerability of the regimen, and
provide adequate efficacy. "The rationale
is that if there is lower toxicity, patients
may stay on the drug longer and then
perhaps they will do better," Dr. Saltz
said. "The 2-week on, 1-week off regimen
will probably be easier on the patient.
Whether it will also be easier on the tumor
is something this trial will address."
The X-ACT Study
Other studies are investigating whether
capecitabine should replace 5-FU/leucovorin
in the adjuvant treatment of colon
cancer. The X-ACT study is an
open-label, multicenter, phase III trial
evaluating capecitabine vs the Mayo Clinic
bolus 5-FU/leucovorin schedule. Disease-
free survival is the primary end point,
and a primary objective is to demonstrate
at least equivalence. Secondary end points
include overall survival, safety, quality of
life, health economics, and biochemical
markers.
This study opened in 1998 and reached
its targeted recruitment goal with 1,987
patients in 164 centers in 25 countries.
Safety data were presented at this year's
American Society of Clinical Oncology
annual meeting and efficacy data will be
presented at next year's meeting.
Capecitabine + Radiation for
Treating Rectal Cancer
Another study, the National Surgical
Adjuvant Breast and Bowel Project
(NSABP) R-04 schema, is addressing the
question of whether capecitabine should
replace 5-FU/leucovorin in conjunction
with radiation for rectal cancer. Patients
with T3-4 operable rectal cancers will be
stratified for various risk factors and will
receive radiation therapy either with
capecitabine or infusional protracted
5-FU.
"What is a little disquieting," Dr. Saltz
noted, "is that the dose limiting toxicity
when the capecitabine was combined with
radiation was hand-foot syndrome. This
'must give us pause.' The wrong thing to
do is to adopt it routinely. The right thing
to do is to conduct the trial."
In summarizing, Dr. Saltz said, "There
is extensive ongoing phase III testing of
capecitabine-based combinations in
colorectal cancer. Trials are going to be
widely available. There won't be many
people without access to the trials. And
entrance to the trials should be strongly
encouraged."
