BRADFORD, United Kingdom-
Oral capecitabine (Xeloda) has an improved
safety profile as adjuvant therapy
for Duke's C colon cancer compared with
IV fluorouracil (5-FU)/leucovorin, the
Mayo Clinic regimen, according to a study
reported by Chris Twelves, MD, University
of Leeds and Bradford, United Kingdom
(ASCO abstract 1182). This improved
safety profile of capecitabine in
the adjuvant setting mirrors that reported
in the metastatic setting, he added.
"These results are part of a planned
safety analysis that was conducted 18
months after enrollment of the last patient
on a phase III trial of capecitabine vs
bolus 5-FU/leucovorin as adjuvant therapy
for colon cancer (the X-ACT study),"
Dr. Twelves said.
"The results of the safety analysis demonstrated
that oral capecitabine, as adjuvant
treatment for Duke's C colon cancer,
was associated with significantly less diarrhea,
nausea and vomiting, stomatitis,
alopecia, and grade 3/4 neutropenia," he
Adjuvant IV 5-FU/leucovorin improves
outcomes in colon cancer. Capecitabine
does too, but it is a tumor-activated
oral fluoropyrimidine. "Two large phase
III studies demonstrated that capecitabine
achieves superior activity and improved
safety compared with IV 5-FU/
leucovorin as first-line therapy for metastatic
colorectal cancer," Dr. Twelves reported.
Oral Therapy Preferred
The oral administration of capecitabine
enables twice-daily dosing that mimics
continuous infusion 5-FU. "Of particular
importance is the fact that 9 out of 10
patients prefer oral chemotherapy to IV
administration," Dr. Twelves noted.
"Outpatient oral chemotherapy allows patients
to live a more normal life while
receiving adjuvant treatment. This activity and patient preference for oral chemotherapy
justifies comparing capecitabine
with 5-FU/leucovrin as adjuvant treatment
of Dukes'C colon carcinoma."
Phase III X-ACT Trial
The X-ACT trial was an open-label,
multinational, randomized, parallelgroup,
phase III trial of adjuvant therapy
for Duke's C colon cancer. Between November
1998 and November 2001, 1,987
patients were enrolled at 164 centers
worldwide. The primary end point of the
trial was noninferiority in disease-free
survival, and secondary end points were
3-year survival, safety profile, and quality
of life. To determine the safety profile,
safety was continuously monitored during
treatment plus 28 days afterwards in
all patients who received at least one dose
of study medication (n = 1,970).
The baseline characteristics were well
balanced in the two treatment arms. For
example, the median age in the capecitabine
group was 62, and in the 5-FU/leucovorin
group, it was 63.
Both groups experienced a similar low
incidence of treatment-related withdrawals.
Eighty-two percent of patients receiving
capecitabine completed all eight cycles
and 88% of patients on 5-FU/
leucovorin received all six cycles.
In both groups, the median delivered
dose per cycle was greater than 95% of the
planned dose throughout the treatment.
Fewer patients in the capecitabine arm
required dose reductions due to adverse
events (41% with capecitabine vs 44%
Fewer Dose Reductions
Overall, fewer adverse events occurred
in the capecitabine arm than in the 5-FU/
leucovorin arm (4,158 vs 4,665, respectively).
There were fewer treatment-related
grade 3/4 adverse events in the capecitabine
arm than in the 5-FU/leucovorin
arm (533 vs 560). There was significantly
less stomatitis and neutropenia in the
capecitabine arm, a low incidence of nausea
and vomiting (3%) in both arms, and
less neutropenia in the capecitabine arm.
Dr. Twelves did note that "hand-foot
syndrome was significantly more common
with capecitabine, but it can be easily
managed with dose interruption and when
necessary, with dose modification." He
said that hyperbilirubinemia was more
common with capecitabine, but that this
is a known side effect of fluoropyrimidines
and is rarely associated with clinical
or enzymatic abnormalities.
Three treatment-related deaths occurred
in the capecitabine arm vs four in
the 5-FU/leucovorin. There was a low incidence
of all-cause, 60-day mortality: five
(0.5%) deaths in the capecitabine arm
and four (0.4%) in the 5-FU/leucovorin
Dr. Twelves concluded a description
of the safety analysis by stating, "There
were fewer adverse events with capecitabine
than with 5-FU/leucovorin, and
capecitabine was associated with fewer
life-threatening adverse events. The improved
safety profile of capecitabine in
the adjuvant setting mirrors that in the
metastatic setting. A notable difference in
the capecitabine safety profile in the adjuvant
and metastatic settings is less nausea/
vomiting in the adjuvant setting, suggesting
that increased nausea/vomiting in the
metastatic setting is disease-related."