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Chemoradiation With Capecitabine Appears To Be Well-Tolerated and May Replace Infusional 5-FU in Locally Advanced Rectal Cancer

Aug 1, 2003
Volume: 
12
Issue: 
8

HOUSTON-Preoperative radiotherapy
with continuous infusion fluorouracil
(5-FU) is known to improve
sphincter preservation and produce
pathologically complete remissions in
10% to 30% of patients with locally advanced
rectal cancer. A preliminary safety
analysis from a phase II study suggests
that chemoradiation with capecitabine
appears to be very well tolerated and may
replace preoperative radiotherapy with
5-FU in this setting.

This interim analysis was reported by
Edward H. Lin, MD, assistant professor
gastrointestinal medical oncology, and
Nora Janjan, MD, professor of radiation
oncology, at the M. D. Anderson Cancer
Center, Houston (ASCO abstract 1152).

Dr. Lin described how "randomized
studies comparing preoperative vs postoperative
5-FU-based chemoradiation in
locally advanced rectal cancer appeared
to favor preoperative chemoradiation for
local control because the intact tumor is
better vascularized and oxygenated, allowing
for better drug delivery. The preoperative
approach offers the potential
for sphincter-sparing resection and it is
better tolerated because of reduced radiation
exposure to the small bowel. Furthermore,
it produces evidence of 5-FU chemosensitivity in contrast to the postoperative
approach."

Additive Effect

Capecitabine is preferentially converted
to 5-FU in tumor tissue by three enzymatic
conversions. Thymidine phosphorylase
is responsible for the last step of
conversion and can be 70-fold higher in
tumor tissue than in normal tissue. TP
activation of capecitabine increases 5-FU
concentrations in the tumor.

Radiotherapy also upregulates TP in
tumor tissue. The effect of capecitabine is
at least additive when combined with radiotherapy
in xenograft models. "Capecitabine
is preferentially converted by thymidine
phosphorylase, which is then
activated up to 17-fold by radiation in the
tumor," Dr. Lin explained. "This relation
ship may allow greater delivery of 5-FU to
the tumor tissue."

Dr. Lin pointed out that capecitabine
mimics continuous infusion 5-FU in its
superior response rate and safety profiles
compared to bolus 5-FU. Continuous infusion
5-FU, however, "is cumbersome,
expensive, and is associated with catheter
and pump-related complications.
Capecitabine simplifies chemoradiation
by its oral administration and is highly
appealing to patients," Dr. Lin said.

Phase II Study

Based on phase I data that capecitabine
is safe and appears to be effective, "we
initiated a phase II study of oral capecitabine
825 mg/m2 twice daily with radiotherapy
45 Gy/25 fractions to the pelvis
and 52.5 Gy/30 fractions to the primary
and perirectal nodes in 54 patients with
locally advanced rectal cancer," Dr. Lin
said. "All patients will have surgery, and
an interim efficacy analysis for the first 19
patients is planned. Eligible patients will
also receive 4 months of adjuvant capecitabine
postoperatively."

The primary objective of the study is
to determine the rate of pathologic response,
and the secondary objectives are
safety, tolerability, overall survival, quality
of life, and biomarkers. Patients with
T3 or T4, N0 or N1 disease on endoscopic
ultrasound are eligible.

Preliminary Results

"Preliminary results suggested that
capecitabine provided many advantages
without compromising efficacy, compared
with the less convenient infusional
5-FU plus radiation regimen," Dr. Lin
said.

"As of May 2003, 19 patients have been
enrolled in the study and completed
chemoradiation, and all are evaluable for
toxicities. Fifteen of these patients underwent
surgery and are evaluable for pathologic
response. Two patients have completed
the fourth 21-day cycle of adjuvant
treatment with capecitabine, and five additional
patients are completing their third
cycle," he reported.

No reduction in capecitabine dose was
necessary for 12 patients, and 4 patients
required only minor dose modification
due to diarrhea or hand-foot syndrome.

Clinical Downstaging

Effective downstaging with capecitabine
and radiation was observed (see Table
1). The overall pathological response was
87% (n = 15). Pathologic response rates
included complete response (20%), microscopic
residual tumor (27%), greater
than 70% reduction in tumor volume
(40%), and stable/progressive disease
(13%). Overall pathologic downstaging
was seen in 73%: primary tumor (47%)
and node (57%).

Of the six patients with locally advanced
rectal cancer who received capecitabine
chemoradiation off protocol, all had
clinical downstaging, with three patients
achieving pathologic complete response.

"The results in terms of pathologic
downstaging (87%) with pathologic complete
response (20%) and microscopic
residue (27%) suggest that this treatment
regimen is better or at least equivalent to
the historical M. D. Anderson experience
with continuous infusion-5-FU plus radiation
in this regard," Dr. Lin said.

The most common toxicities are of
grade 1 in nature and include fatigue,
radiation dermatitis, diarrhea, nausea and
anorexia. Grade 2 toxicities are less common,
about 10% to 15%, and included
three cases of nausea/vomiting, two cases
each of radiation dermatitis, diarrhea, and
hand-foot syndrome, and one case of fatigue.

Serious grade 3 and 4 toxicities are rare
at 5% to 6% and included two patients
with diarrhea and one patient each with
nausea/vomiting, deep venous thrombosis,
radiation enteritis, dehydration, and
renal failure. "Although grade 3/4 toxicities
are rare, they do seem to cluster in
elderly patients," Dr. Lin said. "Therefore,
caution should be exercised for those
patients who are 65 years or older and
receiving chemoradiation with capecitabine."

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