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Irinotecan and 5-FU/ Leucovorin in Metastatic Colorectal Cancer: Balancing Efficacy, Toxicity, and Logistics

Irinotecan and 5-FU/ Leucovorin in Metastatic Colorectal Cancer: Balancing Efficacy, Toxicity, and Logistics

ABSTRACT: Variations of fluorouracil (5-FU) therapy have formed the backbone of chemotherapy for advanced colorectal cancer for many years. With the advent of newer agents that often work best with or even require chemotherapy to optimize their activity, the issue of the optimal schedule and regimen of administration of 5-FU has taken on a renewed importance. The combination of irinotecan with 5-FU/leucovorin has consistently improved survival and response rates in comparison to 5-FU/leucovorin alone. However, the combination also increases the toxicity of the treatment, thus resulting in continuing attempts to improve on the toxicity profile of the combination, while retaining or improving upon the therapeutic outcomes. This article reviews the various combinations of irinotecan with 5-FU/leucovorin.

For more than 40 years, attempts
to improve upon therapy for
metastatic colorectal cancer revolved
around variations of administration
or modulation of fluorouracil
(5-FU), with no regimen or schedule
demonstrating clear superiority in terms
of survival. Moreover, three phase III
studies failed to demonstrate any significant
survival benefit with the use of
infusional 5-FU (Table 1).[1-7]

New Treatment Agents

With the advent of new cytotoxic
chemotherapeutic agents such as irinotecan
(Camptosar),[8-11] oxaliplatin
(Eloxatin),[7,12,13] and capecitabine
(Xeloda),[14,15] as well as more recently
and dramatically, targeted therapies
such as cetuximab (Erbitux)[16]
and bevacizumab (Avastin),[17] significant
advances have been made in
the treatment of advanced colorectal
cancer over the past decade (Table 2).
(Indeed, cetuximab has recently been
approved by the US Food and Drug
Administration [FDA] for the treatment
of patients with epidermal
growth factor receptor [EGFR]-positive
metastatic disease refractory to
irinotecan-based therapy.)

However, despite this proliferation
of new agents, the optimal combinations
and sequences of employing
these therapies remain uncertain. One
result of the numerous evaluations of
the permutations of 5-FU in metastatic
colorectal cancer is that there are
numerous ways that 5-FU/leucovorin
can be combined with these secondgeneration
chemotherapies and targeted
therapies.

For the foreseeable future, the initial
management of metastatic colorectal
cancer will continue to employ
some form of fluoropyrimidine, often
5-FU/leucovorin, as both oxaliplatin
and irinotecan in combination with
5-FU/leucovorin are significantly superior
to 5-FU/leucovorin alone.[7,10-
12] Furthermore, the registration study
of oxaliplatin as second-line chemo-
therapy has also clearly demonstrated
that oxaliplatin in combination with
infusional 5-FU/leucovorin possesses
greater antitumor activity than either
oxaliplatin or 5-FU/leucovorin
alone.[12] However, it remains unclear
whether irinotecan- or oxaliplatin-based
combination chemotherapy regimens
are superior. Studies that have controlled
for the fluoropyrimidine regimens
suggest that the antitumor efficacy
of oxaliplatin- or irinotecan-based regimens
are similar.[18]

Bevacizumab

The efforts to determine the optimal
initial chemotherapy combination
and schedule have taken on a renewed
importance in light of the phase III
study by Hurwitz et al.[17] A total of
813 patients with metastatic colorectal
cancer and no prior chemotherapy
for unresectable metastatic disease
were randomly assigned to the combination
of irinotecan and bolus
5-FU/leucovorin (IFL) administered
weekly for 4 weeks, followed by a
2-week break that was the standard
regimen in the United States at the
time of study design, with or without
the monoclonal antibody targeting
vascular endothelial growth factor
(VEGF) bevacizumab 5 mg/kg every
other week.

The addition of the antibody resulted
in a significant improvement
in response rate (44.8% vs 34.8%;
P = .004), median progression-free
survival (10.6 vs 6.2 months; P < .001)
and median overall survival (20.3 vs
15.6 months; P < .001), in comparison
to the then-standard therapy IFL.
This benefit occurred with a relatively
modest increase in toxicity,
represented primarily by grade 3 (requiring
therapy) hypertension (11%
vs 2.3%) and intestinal perforation
(1.5% vs 0%).

The 60-day mortality rates in this
study were similar in the two arms
(4.5% with IFL and 3.0% with the
addition of bevacizumab).[17] An interesting
question that has arisen is
whether the benefits of bevacizumab
are specific to this combination of
IFL, or whether they can be extrapolated
to other fluoropyrimidine regimens
and schedules. Ongoing and
completed studies that will be reported
in the near future will help answer
this question. Therefore, the question
of the optimal schedule of IFL, thus
the method of administering 5-FU/
leucovorin, remains important.

5-FU/Leucovorin
With Irinotecan

The FDA approved the combination
of irinotecan with 5-FU/leucovorin
for use as initial chemotherapy
for patients with metastatic colorectal
cancer in 2000, based on two studies
that clearly demonstrated a survival
benefit from adding irinotecan to either
bolus or infusional 5-FU/leucovorin.[
10,11] Two different schedules
were approved: IFL and a biweekly
regimen of irinotecan on day 1, and
leucovorin with a combination of bolus
and infusional 5-FU and leucovorin.
The IFL regimen found initial
favor among US oncologists, apparently
because of the ease of administration
of bolus 5-FU/leucovorin.
Meanwhile, in Europe, the infusional
5-FU schedules had found greater
sway, in part because of somewhat
greater response rates, and an improved
toxicity profile in comparison
to bolus 5-FU/leucovorin schedules.

No phase III studies have yet compared
these two schedules. A randomized
phase II study from Morocco was
recently reported in which 154 patients
were randomly assigned to IFL,
infusional 5-FU/leucovorin (LV5FU2
or "de Gramont schedule") with irinotecan,
or alternating irinotecan with
bolus 5-FU/leucovorin ("Mayo schedule").
The arms were not intended to
be compared directly, but their antitumor
activity appeared similar. The toxicity
profiles were also similar to the
expected side effects, although the infusional
5-FU arm produced somewhat
less myelosuppression.[19]

IFL Toxicity

However, it has become evident
that IFL induces significant toxicity.
This was highlighted by Rothenberg
et al[20] in a 2001 review of toxic
deaths occurring within 60 days of
the initiation of treatment. The results
were obtained from the North Central
Cancer Treatment Group (NCCTG)
study 9741 (4.8% of 289 patients) in
metastatic disease, and the Cancer and
Leukemia Group B (CALGB) study
89803 (2.2% of 635 patients) evaluating
the potential role of IFL as adju-
vant therapy for patients with stage
III colorectal cancer. These results
could be compared to 0.8% 60-day
mortality with bolus 5-FU/leucovorin
as adjuvant therapy in patients with
stage III colorectal cancer, and 1.8%
with oxaliplatin with infusional 5-FU/
leucovorin (FOLFOX4) in metastatic
cancer.

This report divided the predominant
toxicities of IFL into several syndromes.
The first is a gastrointestinal
syndrome, comprising diarrhea, nausea,
vomiting, or abdominal cramping,
often in the setting of neutropenia,
dehydration, and electrolyte abnormalities.
The second is a vascular syndrome
that included myocardial
infarctions, pulmonary emboli, and
strokes. The former syndrome caused
deaths in about 2% of all patients treated,
and the latter about 1%.[20] As a
result of these findings, this regimen
started to fall somewhat from favor.

From the registration study and
NCCTG 9741, the toxicities of IFL
were similar. Severe neutropenia was
reported in 40% to 54% of patients,
diarrhea in 22% to 28%, and nausea/
vomiting in 9% to 16%.[10,13] Further
questions about the role of IFL
have been compounded by the findings
of NCCTG 9741 in which Goldberg
et al demonstrated that
FOLFOX4 was superior to IFL as initial
chemotherapy in metastatic colorectal
cancer.[13]

Irinotecan With LV5FU2
(DeGramont) Schedule

As a result of the difficulties with
the toxicities from the traditional IFL
schedule and the approval of oxaliplatin/
5-FU/leucovorin as second-line
chemotherapy, infusional schedules
have garnered greater attention and
acceptance in the United States. A
review of the studies evaluating infusional
5-FU/leucovorin with irinotecan
demonstrated that the mortality
rate with this schedule was less than
1%, compared to 2.2% to 4.8% with
IFL.[11] To date, the most thoroughly
studied regimen of infusional
5-FU/leucovorin with irinotecan in
phase III studies is in combination
with LV5FU2, or the de Gramont regimen.
Douillard et al treated 145 patients
with this combination as first-line
chemotherapy for metastatic disease.
Although neutropenia remained the
most commonly noted severe toxicity
(46% of patients), severe diarrhea
(13%) and vomiting (3%) were less
frequently reported than with IFL.[11]

Given the potential for pharmacogenetic
differences between Asians
and Europeans that comprised the
populations in most of the reported
studies with irinotecan and 5-FU/leucovorin,
a report on this regimen by
Tai et al is interesting. They reported
that in an Asian population, this regimen
was similarly well tolerated in
18 patients, with severe leukopenia or
diarrhea each in 8% of cycles, and
severe stomatitis in 3% of cycles. In
these patients who received the therapy
as second-line therapy after prior
oxaliplatin, four (22%) had partial responses,
with a median survival of
7.5 months.[21]

An interesting modification of this
regimen has been explored by a group
of Italian investigators. They administered
the dose of irinotecan as 90
mg/m2 on each day. When evaluated
in 54 patients in the initial therapy
setting, the regimen demonstrated similar
antitumor activity as other schedules
of IFL, as determined by objective
responses (41%, including 7% complete
responses) and a median time to
progression of 8.7 months, a median
survival of 18.8 months, and a 1-year
survival of 74%. Severe toxicities
were relatively uncommon: grade 3/4
neutropenia was reported in 17% of
patients, severe diarrhea, asthenia, and
thrombocytopenia were each seen in
6% of patients, and 4% of patients
experienced grade 3 or 4 nausea/vomiting
or anemia.[22]

FOLFIRI Regimen

However, administering LV5FU2
with irinotecan is logistically burdensome
to both the patient and physician,
and the development of
alternative schedules has been of great
interest. (Table 3 presents a listing of
combinations of irinotecan and 5-FU/
leucovorin.) The best-explored variant
of the LV5FU2 schedule with
irinotecan is FOLFIRI. This regimen
also involves a biweekly infusion of
irinotecan at 180 mg/m2 over 90 minutes
and leucovorin at 400 mg/m2,
followed by a 400-mg/m2 bolus of
5-FU, then a 46-hour infusion of 5-FU
at a dose of 2,400 to 2,800 mg/m2.

This regimen was first reported by
Andre et al,[23] and was initially evaluated
as a second-line regimen, after
the failure of oxaliplatin-based therapy.
While it induced an objective response
in only 6% of the 33 patients,
it resulted in a median survival of 43
weeks. Toxicity was modest, with severe
neutropenia in only 15% of patients
and grade 3/4 diarrhea and
nausea/vomiting in 12% and 15%, respectively.[
23] These efficacy and
toxicity results were confirmed by
British investigators using the regimen
in both the first- and second-line
setting. Leonard et al reported a response
rate of 30% in 43 patients receiving
FOLFIRI as initial chemotherapy,
and 23% in the 36 patients
who were treated with FOLFIRI after
prior fluoropyrimidine therapy.[24]

FOLFIRI vs FOLFOX

This schedule has also been the
focus of a French phase III study reported
by Tournigand et al,[18] as
first-line therapy, compared to
FOLFOX6. At the time of progression,
patients initially treated with
FOLFIRI subsequently received
FOLFOX6, and those who were given
FOLFOX6 as initial chemothera-
py then received FOLFIRI. In this
setting, FOLFIRI yielded responses
in 56% of 109 patients, and a median
time to progression of 8.6 months,
results that were similar to those with
FOLFOX6 (response rate of 54%,
median time to progression of 8.0
months).

Of the 111 patients who received
first-line FOLFOX6, 68 then received
FOLFIRI as second-line therapy upon
the diagnosis of progressive disease.
As second-line therapy in this study,
FOLFIRI was somewhat disappointing,
producing an objective response in
4% of patients and a median progression-
free survival of 2.5 months. Overall,
the median survival for patients in
the two arms was similar: 21.5 months
with initial FOLFIRI and 20.6 months
with second-line FOLFIRI.

As expected, FOLFIRI was well
tolerated as both first- and secondline
therapy. Severe neutropenia was
reported in 24% of patients treated
with FOLFIRI as initial therapy and
21% treated with second-line FOLFIRI.
Grade 3/4 nonhematologic toxicity
was also relatively infrequent:
diarrhea (14%/8%), nausea/vomiting
(13%/3%), and mucositis (10%/3%
of patients who received FOLFIRI as
first- and second-line therapy, respectively).
A major concern with IFL is
the toxicity of the regimen, as reflected
by the 60-day mortality rates. As
first- and second-line therapy, FOLFIRI
yielded 60-day mortality rates
of 4% and 3%, respectively, which
were comparable to those for FOLFOX6
(3% as first-line therapy and
4% as second-line therapy) in this
study.[18]

Modifications to FOLFIRI

Although FOLFIRI is a promising
regimen, French investigators have
undertaken several modifications to
attempt to improve further the combination.
The FOLFIRI2 regimen sought
to evaluate the value of changing the
timing of the interaction between
5-FU and irinotecan by delivering
the latter after the completion of the
5-FU infusion. Further modulation of
5-FU was attempted with the addition
of 1,500 mg of hydroxyurea daily
during therapy. Not surprisingly,
increases in severe neutropenia (52%
of 29 patients), diarrhea (31%), nausea
(17%), and mucositis (14%) were
reported. Responses were reported in
17% of patients, and the median survival
of patients was 42 weeks.[25]
Since the antitumor efficacy did not
appear superior to FOLFIRI despite
greater toxicity, further investigation
of this regimen has not been
undertaken.

More recently, the same investigators
created the FOLFIRI3 regimen,
in which patients receive 100 mg/m2
of irinotecan both prior to and after the
46-hour 5-FU infusion that has been
reduced to a dose of 2,000 mg/m2. The
bolus 5-FU and the leucovorin were
eliminated. A pair of reports (initially
from a single institution and more recently
a multi-institutional study) have
consistently reported a 20% response
rate in second-line therapy after oxaliplatin
and infusional 5-FU. This
regimen was fairly well-tolerated: severe
neutropenia (30% to 35% of patients),
diarrhea (15% to 19%), and
mucositis in (5% to 7.5%).[26,27]

A potential concern with this schedule
is based on data from Falcone et
al, who conducted a study evaluating
the impact of sequencing irinotecan
and a 48-hour infusion of 5-FU. Their
results suggested that administration
of irinotecan prior to 5-FU is better
tolerated, with less diarrhea, nausea/
vomiting, myelosuppression, and stomatitis
than the sequence of 5-FU followed
by irinotecan.[28] However, the
FOLFIRI3 regimen suggests that there
is no significant difference in toxicity
compared to a schedule where irinotecan
is administered only before 5-FU.

The AIO Schedule

A weekly 24-hour infusion of
5-FU, with leucovorin, has been extensively
evaluated by the German
Cancer Society Arbeitsgemeinschaft
Internistische Onkologie (AIO). Vanhoefer
et al performed a dose-escalation
study adding weekly irinotecan.
They recommended for further investigation
a dose of irinotecan at
80 mg/m2 and 5-FU at 2,600 mg/m2
over 24 hours and leucovorin at
500 mg/m2 weekly for 6 weeks, followed
by a 1-week break. The prima-
ry toxicity encountered on this schedule
was diarrhea, with little myelosuppression.[
29]

Based on the European patterns of
5-FU/leucovorin use, as well as the results
from this phase I study, this combination
has undergone further
evaluation. In their phase III study evaluating
infusional 5-FU/leucovorin with
or without irinotecan, Douillard et al
also treated a group of patients with the
German AIO schedule. The 54 patients
treated with this regimen also experienced
frequent severe neutropenia
(29%), diarrhea (44%), vomiting
(11%), and asthenia (7%).[11]

To clarify the benefits of the addition
of irinotecan to the weekly infusional
AIO schedule of 5-FU/
leucovorin, Kohne et al[30] and the
European Organisation for Research
and Treatment of Cancer conducted
an additional phase III study (EORTC
40986). A total of 430 patients with
metastatic colorectal cancer without
prior chemotherapy for metastatic
disease were randomly assigned to
the AIO 5-FU (2,600 mg/m2 over
24 hours)/leucovorin (500 mg/m2 over
2 hours) weekly for 6 weeks, with
cycles every 7 weeks, or 5-FU/leucovorin
(500 mg/m2 over 2 hours) on
the AIO schedule, with a dose reduction
in 5-FU/leucovorin, in combination
with irinotecan (80 mg/m2 over
30 minutes).

In the experimental arm, the initial
dose of infusional 5-FU was
2,300 mg/m2 over 24 hours. The incidence
of severe diarrhea in these patients
was concerning, occurring in 36%
of patients, and the dose was subsequently
reduced to 2,000 mg/m2. As a
result of this protocol change, the occurrence
of severe diarrhea decreased
to 24%, which was comparable to that
with 5-FU/leucovorin in the control
arm (21%). Aside from a slight increase
in the frequency of grade 3/4
neutropenia (7% with irinotecan, vs
3%), other severe toxicities were similar
in the two arms, including severe
nausea/vomiting in 9% of patients,
and stomatitis in 3% in those receiving
irinotecan. The toxic death rate
(1.9% in each arm) and deaths within
60 days of therapy (2.3% with irinotecan,
compared to 3.2% in the control
arm) were similar, supporting the
hypothesis of an acceptable tolerability
of the combination. Moreover, the
median relative dose intensity of 5-FU
was 81% with irinotecan and 83% without
irinotecan; the median relative dose
intensity of irinotecan was 79%

Not surprisingly, this study also
demonstrated that the addition of
irinotecan to 5-FU/leucovorin produced
a significantly greater objective
response rate (54.2% vs 31.8%;
P = .0001), and met its primary objective
of a significant improvement
in progression-free survival (8.5
months compared to 6.4 months; P =
.0001). However, the improvement in
median survival with the addition of
irinotecan (20.1 vs 16.9 months; P =
.2779 and .0509) was not statistically
significant, perhaps because 62% of
the patients who received 5-FU/leucovorin
alone as initial therapy subsequently
received irinotecan.[30] As
a result of the findings from this study,
the regimen of irinotecan at 80 mg/m2
with at 5-FU 2,000 mg/m2 over 24
hours and leucovorin at 500 mg/m2
weekly for 6 weeks, with cycles repeated
every 7 weeks, is now the reference
standard for the EORTC.

Irinotecan With Longer
Infusions of 5-FU

Several investigators have also
studied irinotecan in combination with
longer infusions of 5-FU. In a dose-
escalation study, Kakolyris et al administered
a 4-day infusion of 5-FU
followed by irinotecan on day 4. The
recommended dose of 5-FU was 600
mg/m2/d, with 350 mg/m2 of irinotecan,
with cycles repeated every 21
days. As first-line therapy, an overall
response rate of 22% in 42 patients
was noted, with 62% of patients alive
with a median follow-up of 13 months.
The predominant toxicities reported
were diarrhea and neutropenia, with
few patients experiencing nausea/
vomiting and mucositis.[31]

Also focusing on an extended infusion
of 5-FU, Ohtsu et al performed
a phase II study of irinotecan at 150
mg/m2 on days 1 and 15, and a 5-day
infusion of 5-FU at 600 mg/m2/d from
days 3 through 7, with cycles repeated
every 28 days. When employed as
initial chemotherapy for metastatic
disease, the investigators reported a
response rate of 45% in 40 patients,
with a median survival of 15.9 months,
1-year survival rate of 62.5%, and
median progression-free survival of
7.0 months.

Again, the main severe toxicities
of this regimen were diarrhea (17.5%
of patients) and neutropenia (40%).
Similarly, grade 3/4 nausea/vomiting
(7.5% of patients) and anemia (12.5%
of patients) were less commonly experienced.
However, three patients
discontinued therapy because of toxicity.[
32] Taken together, these studies
do not suggest that the prolonged
5-FU infusion was superior to other
infusional 5-FU/leucovorin schedules,
and it is not the major focus of further
development in combination with
irinotecan.

Bolus 5-FU/Leucovorin
With Irinotecan

Attempting to explore further the
potential value of bolus 5-FU/leucovorin
in combination with irinotecan,
and build upon their standard method
of administering 5-FU, Glimelius et
al[33] and the Nordic group reported
a novel regimen, both as IV boluses.
Expanding on prior experience, they
administered 5-FU at 500 mg/m2, followed
by leucovorin at 60 mg/m2 on
days 1 and 2, with irinotecan at 210
mg/m2 on day 1 of a fortnightly schedule.
Using this regimen as initial therapy
in metastatic colorectal cancer,
they reported responses in 39% of 74
patients in this phase II study, with a
median survival of 15.6 months. The
toxicity of this regimen was similar to
that seen for IFL. Severe neutropenia
occurred in 66% of patients, diarrhea
in 16%, vomiting in 11%, and stomatitis
in 3%. Only one patient died from
toxicity of therapy, from intestinal
bleeding.[33]

In a similar approach, the Southern
Italian Cooperative Oncology
Group (SICOG) has also studied a
biweekly irinotecan and bolus 5-FU/
leucovorin combination, dubbed
IRAFAFU. Irinotecan at 200 mg/m2
was administered on day 1, and on
the following day, leucovorin at 250
mg/m2 was infused over two hours,
followed immediately by an IV bolus
of 5-FU at 850 mg/m2. A total of 118
patients received this combination in
a phase II/III study of patients who
had not previously received chemotherapy
for unresectable metastatic
colorectal cancer.

The antitumor efficacy of
IRAFAFU was similar to that reported
with other irinotecan and 5-FU/
leucovorin combinations, with objective
responses documented in 36% of
patients, including 8% with complete
responses, and stabilization of disease
or minor response in an additional
21% of patients. The median time to
tumor progression was 7.2 months,
with a median survival of 14.7 months.
The 1-, 2-, and 3-year overall survivals
were 60%, 23%, and 11%, respectively.

This regimen was fairly well-tolerated,
with severe neutropenia report
ed in 40% of patients and two cases of
neutropenic fever. Severe diarrhea
occurred in 13% of patients and severe
nausea/vomiting and stomatitis
were noted in 3% each.[34] Overall,
the antitumor activity and toxicity profile
was promising enough for the investigators
to name IRAFAFU the
new reference standard for the group.

Recently, Comella et al reviewed
the outcomes with this regimen from
this study, focusing on the tolerability
and efficacy of the regimen in the
elderly population (17 patients who
were 70 years of age or older). In the
resulting somewhat limited report,
they reported no evidence of more
severe toxicity or poorer outcomes
that occurred in this subgroup of older
patients when compared to the others.
This led the authors to conclude
that IRAFAFU may be a regimen that
is suitable for use in otherwise healthy
elderly patients.[35]

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