NEW YORK - Weekly bolus IFL
acid]) "should not be used" in the
management of stage III colon cancer,
according to Leonard Saltz, MD, an
associate attending physician at
Memorial-Sloan Kettering Cancer
Compared with the Roswell Park
schedule of bolus 5-FU/leucovorin
(FL), weekly bolus IFL had no additional
clinical benefit, and it was associated
with greater toxicity and more
deaths on treatment, Dr. Saltz report-
ed (abstract 3500) (Table 1).
"These are not preliminary findings,"
Dr. Saltz said. "The futility
boundaries have been crossed and this
will not be a positive study."
Route of Administration
May Play Role
Positive results using IFL to treat
metastatic colorectal cancer have led
investigators to hypothesize that IFL
also may be beneficial in the adjuvant
setting. It is unclear why such a benefit
was not shown, although there is some
speculation that the route of 5-FU
administration (bolus vs infusional)
may play a role.
"Why didn't it work? Was it the
drug or the regimen? I don't think we
know the answer yet," Dr. Saltz said.
"There is certainly some evidence that
adding other efficacious agents, such
as oxaliplatin [Eloxatin], to 5-FU/leu-
covorin can lead to favorable outcomes
in stage III colorectal cancer."
Dr. Saltz reported the results of the
Cancer and Leukemia Group B
(CALGB) study C89803, an intergroup
trial designed to evaluate the usefulness
of irinotecan when added to bolus
FL after curative resection for patients
with stage III colon cancer (TanyN1-2M0)
who have had no prior chemotherapy.
Patients were randomized to receive:
the Roswell Park FL schedule of
leucovorin 500 mg/m2 IV over 2 hours,
plus 5-FU 500 mg/m2 1 hour after start
of leucovorin, 6 weeks on, 2 weeks off
for four cycles; or
an IFL schedule of irinotecan
125 mg/m2 over 90 minutes followed
by leucovorin 20 mg/m2 IV bolus, then
5-FU 500 mg/m2 IV bolus 4 weeks on,
2 weeks off for five cycles.
'No Meaningful Differences'
Approximately 55% of patients
were male and about 25% were age 70
years or older. Zubrod performance
status was 0 in more than 70% of
patients; the rest had a performance
status of 1. Seventy-five percent had
T3 disease and the majority of patients
(61%) had N1 disease.
With a median follow-up of 3 years,
there were "no meaningful differences"
in overall survival between IFL and
FL (P = .81), Dr. Saltz reported. The
investigational arm actually tracked
"slightly below" the control arm,
although not to a significant degree
(see Figure 1).
Similarly, failure-free survival and
disease-free survival data provided no
indication of improving when irinotecan
was added (P values of .89 and
There was an excess of potentially
treatment-related deaths accruing to
the IFL arm, 2.8% vs 1% for FL (P =
.008). While diarrhea and nausea rates
were similar for IFL and FL, rates of
neutropenia and febrile neutropenia
were higher for IFL; the rate of febrile
neutropenia was 4% for IFL vs 1% for
FL (P = .0005, see Table 1).
These results were somewhat unexpected.
Irinotecan has proven ben-
efit in second-line treatment of metastatic
colorectal cancer, and as firstline
therapy, irinotecan improves survival
when added to bolus or infusional
"It seemed like a reasonable and
almost slam-dunk idea," Dr. Saltz said,
"that if we put irinotecan into the
adjuvant setting, we would improve
outcomes for our patients."
There is certainly evidence that other
active agents, namely oxaliplatin,
can lead to favorable outcomes when
added to standard therapy for stage III
colorectal cancer. Last year at ASCO,
De Gramont et al showed that oxaliplatin
plus infusional FL (FOLFOX-4)
significantly improved 3-year diseasefree
survival rates vs infusional FL
"The question is whether this would
be seen with irinotecan and infusional
FL," Dr. Saltz.
Other Studies Underway
There are studies underway that
will address the question of irinotecan
plus infusional FL in the adjuvant setting.
One is PETACC III, a large,
randomized trial comparing a 5-FU/
folinic acid/irinotecan (FOLFIRI) regimen
with infusional FL in 800 stage II
and 2,330 stage III patients. The study
closed to accrual in 2002 and results
are expected later this year.
The phase III randomized Accord02/
FFCD9802 trial is also evaluating
the FOLFIRI regimen vs infusional
FL. That trial has enrolled 400
patients. Interim safety results were
described at ASCO 2003 (abstract
1183) and more results are anticipated
in late 2004.
"We need to keep an open mind on
the question of whether or not irinotecan
with infusional 5-FU will be efficacious
or not in stage III patients,"
Dr. Saltz said. "Right now, we simply
don't have data."