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Cytotoxic Chemotherapy for Advanced Colorectal Cancer

Cytotoxic Chemotherapy for Advanced Colorectal Cancer

ABSTRACT: Several developments in the past few years have incrementally progressed the field and provided additional insights into the management of advanced colorectal cancer. This review discusses the components of current cytotoxic chemotherapy regimens for advanced colorectal cancer: fluorouracil (5-FU), capecitabine (Xeloda), irinotecan (Camptosar), and oxaliplatin (Eloxatin). The equivalence of several front-line regimens has provided opportunities for increased tailoring of therapies for individual patients. Preliminary data on pharmacogenomics provides hope that we will be able to better match patients with regimens and doses on the basis of individualized predictions of toxicity and response. The importance of second-line therapy in overall survival has again been highlighted; the best outcomes have occurred in patients treated with 5-FU, oxaliplatin, and irinotecan in combination with targeted therapies during the course of their disease. Elderly patients are no exception to this finding. Combination regimens and second-line therapy should be offered to elderly patients who have adequate performance status and no contraindicated comorbid conditions, without regard for their chronological age.

Colorectal cancer is the second
leading cause of cancer death
in the United States. Up to onethird
of patients have metastatic disease
at the time of initial presentation.
Although metastatic colorectal cancer
remains a terminal diagnosis for
the majority of patients, recent advances
have improved outcomes while
providing more treatment options for
clinicians. The median survival of patients
with metastatic disease has gone
from 12 to 24 months with increased
utilization of combination chemotherapeutic
regimens. These new developments
have provided opportunities
for increased tailoring of therapies to
match the characteristics of individual
cases and patients.

Research presented over the past
few years has changed our approach
to several important considerations in
the treatment of advanced colorectal
cancer. Although much attention has
been paid to the rapid developments
in targeted agents, significant advances
have been made in conventional
chemotherapy as well. This review
discusses these new developments in
cytotoxic chemotherapy regimens and
describes the changing approach to
these treatments, with a separate emphasis
on issues in the elderly patient.
The addition of targeted agents to
these regimens is discussed in an accompanying
article by Drs. Marshall
and Hwang.

Fluorouracil/Leucovorin

For many years fluorouracil (5-FU)
was the sole chemotherapeutic agent
for metastatic colon cancer. Fluorouracil
and its metabolites have at least
two mechanisms of action: binding
thymidylate synthetase, which depletes
uracil stores necessary for DNA
replication, and incorporation into
RNA, which subsequently disrupts
protein synthesis. Recent data from
the adjuvant setting suggest that below
normal levels of thymidylate synthetase,
as assessed by immunohistochemical
studies, may be associated
with prolonged survival.[1] The
addition of leucovorin to the regimen
improves efficacy by increasing the
amount of reduced folate cofactor
needed to bind thymidylate synthetase.
The addition of leucovorin increased
the rate of response to 5-FU from
11% to 21% in metastatic colorectal
cancer.[2]

Fluorouracil has traditionally been
given by bolus infusion in the United
States. However, several trials have
demonstrated that infusional regimens
offer greater benefit, possibly due to more prolonged inhibition of thymidylate
synthetase. A meta-analysis of
1,219 patients in six randomized trials
of 5-FU administered by bolus or
continuous infusion demonstrated a
higher response rate in patients who
received the drug by continuous infusion
(22% vs 14%).[3] The sideeffect
profile of continuous infusion
therapy included less neutropenia and
an increased incidence of hand-foot
syndrome.[4] The combination of leucovorin and infusional 5-FU has subsequently
been shown to produce better
outcomes than the infusional
regimen alone.[5] The most commonly
used infusional regimens are the
German AIO regimen of 5-FU (2,000
to 2,600 mg/m2) over 24 hours with
leucovorin (500 mg/ m2) weekly for
6 weeks, followed by 1 or 2 weeks rest,
and the de Gramont or LV5FU2 regimen
consisting of leucovorin (200
mg/m2 IV over 2 hours) and 5-FU
(bolus 400 mg/m2 and infusion 600
mg/m2) on days 1 and 2, repeated
every 2 weeks.

Capecitabine

The oral fluoropyrimidine capecitabine
(Xeloda) is a prodrug of 5-FU
that has activity similar to that of infusional
5-FU. Two large randomized
phase III studies demonstrated that
capecitabine had a higher response
rate (26% vs 17%) and a better safety
profile than bolus 5-FU.[6] Side effects
are similar to those of infusional
5-FU, although the incidence of handfoot
syndrome is higher in patients
who receive capecitabine. Thymidine
phosphorylase, one of the enzymes
responsible for conversion of capecitabine
to the active metabolite, is increased
in tumor cells, suggesting that
the oral prodrug has increased selectivity
over infusional 5-FU.

Capecitabine is being investigated
as a substitute for 5-FU in most frontline
regimens. Several recent studies
have demonstrated the safety and tolerability
of these combinations. Most
studies have focused on combinations
with oxaliplatin (Eloxatin), five of
which were reported at the 2005
American Society of Clinical Oncology
Annual Meeting (Table 1). These
trials are briefly reviewed here.

The CAPOX regimen was compared
to FUFOX, a weekly infusional
5-FU plus oxaliplatin regimen.[7] The
toxicity profiles were similar, aside
from a higher incidence of hand-foot
syndrome with CAPOX. The response
rates for CAPOX and FUFOX were
similar (47% vs 49%, P = .70). Although
the difference in progressionfree
survival did not reach statistical
significance (7.0 vs 8.0 months, P =
.11), the trend favored the intravenous arm; the difference suggests caution
when analyzing this study.

The TREE-1 study randomized
patients to receive modified FOLFOX6,
bFOL, or CapeOx.[8] With
the approval of bevacizumab (Avastin),
enrollment in TREE-1 was discontinued
in favor of a similar design
with bevacizumab added to each arm
(TREE-2). The high rate of diarrhea
and dehydration seen with the TREE-1
capecitabine dose of 1,000 mg/m2
twice daily led to a dose reduction in
the TREE-2 trial. Bevacizumab added
to the efficacy of all regimens,
with a clear increase in response rates.
The bFOL had the lowest response
rate, and it was statistically inferior to
the response rate seen with the FOLFOX6
regimen.

Preliminary results from a third
phase III trial of capecitabine/oxaliplatin
and infusional 5-FU/oxaliplatin
in a slightly different schedule produced
comparable toxicity profiles
and response rates in the two arms
(47% vs 54%, respectively).[9] Interim
results were recently presented of
another study comparing XELOX to
the popular FOLFOX6 regimen after
enrollment of 177 of 304 planned patients.
This initial safety analysis demonstrated
much lower rates of
neutropenia in patients who received
the XELOX regimen than in those
who received FOLFOX6 at an oxaliplatin
dose of 100 mg/m2.[10]

A strategy of prolonged continuous
infusion 5-FU with oxaliplatin was
compared to XELOX in a randomized
phase II study.[11] Survival data
are still maturing, but preliminary results
demonstrate similar response
rates. Surgical resection of liver metastases
was attempted more frequently
in the XELOX arm (9.6% vs 4.1%).

A report has been recently published
of a more dose-intense capecitabine
regimen in 89 patients.[12] In
this study, capecitabine doses of 3,500
mg/m2 were given on days 1-7 and
14-21, with oxaliplatin at 85 mg/m2
days 1 and 14, repeated every 4 weeks.
Response rates were higher than those
of the standard XELOX regimen (55%
vs 42%), and toxicity profiles were similar.
Median progression-free survival
also favored the dose-intense regimen
(10.5 vs 6.0 months, P < .01).

Although capecitabine's potential
as a substitute for infusional 5-FU
was confirmed in these studies, larger
phase III studies are needed to demonstrate
equivalence to FOLFOX. A
trial comparing FOLFOX plus bevacizumab
to XELOX plus bevacizumab
is ongoing and will address the
interchangeability of capecitabine for
5-FU. Until these data are presented,
combination capecitabine regimens
should be reserved for patients understanding
and willing to accept that
there is a small potential risk of a
difference in efficacy, for the convenience
of an oral fluoropyrimidine.

The principle of combining
capecitabine with irinotecan (Camptosar)
was proven by the combination's
effectiveness in phase II studies.
However, recent larger series combining
capecitabine and irinotecan
have been less successful. A large
European Organisation for Research
and Treatment of Cancer trial compared
CAPE/IRI (capecitabine at
1,000 mg/m2 twice a day for days
1-14 and irinotecan at 250 mg/m2 day
1, on a 3-week cycle) to FOLFIRI
(leucovorin at 200 mg/m2 day 1,
5-FU at 400 mg/m2 bolus, days 1 and
2, 600-mg infusion over 22 hours,
days 1 and 2; irinotecan at 180 mg/m2
on day 1, on a 2-week cycle).[13]

The trial was stopped early owing
to increased mortality in the CAPE/
IRI arm (6 deaths in 44 patients). The
deaths were the result of severe diarrhea
or thromboembolic events. Dose
reduction was required in 61% of patients
on the CAPE/IRI arm. Patients
also were randomized to receive celecoxib
(Celebrex) or placebo, although
this did not have an apparent impact
on the toxicity. These poor results
were similar to those of a smaller
phase II trial of the same regimen.[14]
In that small study, dose reductions
were required in 80% of the patients
owing to diarrhea and neutropenia.
Further studies of this combination
are planned with a reduced dose of
irinotecan.

An alternate regimen employs a
2-week cycle of irinotecan at 175
mg/m2 on day 1 and capecitabine at
1,000 mg/m2 bid days 2-8, with upfront
dose reductions to 140 mg/m2
and 750 mg/m2 bid, respectively, for patients older than 65.[15] The overall
response rate was 50%. Grade 3 or
4 diarrhea or neutropenia occurred in
less than 2% of cycles. This approach
may be an alternative to the earlier,
more toxic, regimens.

Irinotecan

Irinotecan has been used successfully
as a single agent and in combination
regimens. Irinotecan is a
prodrug that is metabolized in the liver
by uridine diphosphate glucuronosyl
transferases (UGT) into SN-38,
an active topoisomerase inhibitor. The
toxicity profile is notable for significant
diarrhea, which can be fatal in
severe cases. Combination of irinotecan
with bolus 5-FU and leucovorin
in the IFL regimen resulted in high
rates of toxicity. In the initial trial of
IFL, grade 3 or 4 diarrhea occurred in
23% of patients.[16] Efficacy was increased;
the combination yielded a response
rate of 39% and a median
progression-free survival of 7.0 months.

Several alternative combinations
have been investigated in attempts to
improve response rates and decrease
toxicity. The AIO infusional 5-FU regimen
was combined with irinotecan,
yielding a response rate of 62% and
time to progression of 8.5 months.[17]
However, the rate of grade 3 or 4
diarrhea remained high, at 36%. The
FOLFIRI regimen had a similar response
rate (56%) and median progression-
free survival (11 months) but
an improved toxicity profile; the rate
of grade 3 or 4 diarrhea was only
14%.[18] Given its high response rate
and tolerability, this regimen is a reasonable
first-line therapy for metastatic
colorectal cancer.

Several recent studies have investigated
the importance of UGT promoter
polymorphisms in predicting
irinotecan-induced toxicity and response
to therapy. In one study of a
group of 81 patients receiving frontline
irinotecan-containing regimens,
dose-limiting toxic effects occurred
in 18% of patients with mutations in
UGT1A1.[19] In contrast, none of
those without the mutation discontinued
the treatment because of toxicity.
Response rates were lower in patients
with the mutation (57% vs 43%).

A similar study of 67 patients receiving
irinotecan with capecitabine
demonstrated that those with mutations
in UGT1A7 had a higher response
rate and lower toxicity rate
than patients with a wild-type genotype.[
20] The response rate was 85%
(11 of 13 patients) in patients with
mutations associated with lower
UGT1A7 activity and 44% (19 of 43)
in patients with other genotypes. Similarly,
none of the patients with these
mutations had grade 3 or 4 diarrhea or
neutropenia, whereas 23% of patients
with other genotypes experienced at
least one of these toxic effects.

Oxaliplatin

As a single agent, oxaliplatin has
minimal efficacy in metastatic colorectal
cancer. In combination with
5-FU/leucovorin, however, oxaliplatin
has significant synergy and yields high
response rates. The most common
oxaliplatin-containing combination
regimen, FOLFOX, has undergone
several iterations. The FOLFOX4 regimen
uses bolus and continuous infusion
5-FU on days 1 and 2 with
oxaliplatin at 85 mg/m2. This regimen
has been shown to be superior to irinotecan
with bolus 5-FU/leucovorin
(IFL) in a large trial of 795 patients,
which included a comparison of IFL
to FOLFOX4 and found a higher response
rate and overall survival duration
with FOLFOX4 (45% vs 31%,
19.5 vs 15.0 months, respectively).[
21] Although FOLFOX4 was better
tolerated than IFL, 20% of the
patients who received FOLFOX4 developed
grade 3 neuropathy.

FOLFOX6 increased the dose of
oxaliplatin to 100 mg/m2 and attempted
to improve patient convenience
by removing the 5-FU bolus on the
second day. This resulted in an increased
rate of neuropathy, however,
and the oxaliplatin dose was reduced
back to 85 mg/m2 in the popular modified
FOLFOX6 regimen. In frontline
therapy, this regimen produced a
response rate of 54% and a median
progression-free survival duration of
8.0 months[18]; it is now the most
widely used regimen in the United
States.

The neuropathy associated with
oxaliplatin is usually dose-dependent;
most patients experience dose-limiting
neuropathy after a cumulative dose of
700 to 800 mg/m2 (8 to 10 cycles).
There is a subset of patients who develop
early-onset neuropathy. Recent data
suggest that a glutathione S-transferase
polymorphism may predict this early
toxicity.[22] The 13% of patients with
the GSTP1 I105V polymorphism were
more likely to stop treatment because
of neuropathy (23% vs 10%) and had
a higher rate of early-onset neuropathy.
These results await further validation
before this approach can move
into the clinic.

The combination of irinotecan and
oxaliplatin (IROX) has been investigated
in the front-line setting in several
studies, with disappointing results.
When compared to FOLFOX4, IROX
had a trend for lower response rate and
shorter overall survival interval.[21] A
similar combination was recently compared
to FOLFIRI, revealing a trend
toward worse progression-free survival
for IROX (8.7 vs 7.3 months,
P = .15).[23] Toxicity rates also were
higher in the IROX arm. This combination
does not appear to improve the
results seen with FOLFOX or FOLFIRI
and should not be used routinely
in front-line therapy.

Selecting a Combination

Modified FOLFOX6 and FOLFIRI
have shown similar efficacy and tolerability.
The different side-effect profiles
allow tailoring of front-line
regimens to individual patients. Patients
with preexisting neuropathies
or underlying conditions that put them
at risk for early neuropathy from oxaliplatin,
such as poorly controlled diabetes,
could receive FOLFIRI.
Similarly, patients with symptoms of
irritable bowel syndrome or poor tolerance
of diarrhea may better tolerate
modified FOLFOX6. It is our hope
that pharmacogenomic studies, once validated, may help guide the selection
and dosing of an appropriate regimen
for each individual.

The question of which combination
regimen to use in the front-line
setting was addressed by a trial that
randomized patients to receive frontline
FOLFOX6 or FOLFIRI, followed
by planned treatment with the alternate
regimen on disease progression.[
18] Front-line response rates,
progression-free survival, and overall
survival were similar between the two
arms. Several limitations of this study
complicate interpretation, including
lower rates of second-line therapy per
protocol in the front-line FOLFIRI
arm and a mismatch in the rates of
subsequent metastasectomy in the two
groups. Nevertheless, this long overall
survival duration demonstrates the
importance of treatment with an active
second-line agent in combination
with 5-FU/leucovorin.

The most important determinant of
overall survival duration appears to be
the number of active agents that a patient
receives. A retrospective study of
seven phase III trials demonstrated that
overall survival duration was greatest
in patients who had received 5-FU/leucovorin,
irinotecan, and oxaliplatin during
the course of their treatment[24]
(Figure 1).

A large study from the United Kingdom,
MRC-FOCUS, evaluated the
appropriate sequence of chemotherapy.[
25] The trial has only been presented
in preliminary form and full results
are not available.Up-front combination
therapy, when compared to infusional
5-FU followed by the addition of irinotecan
or oxaliplatin on disease progression,
did not show a significant
difference in overall survival, despite a
higher response rate in patients who
initially received combination regimens.
However, the median survivals
for all arms were shorter than expected,
and the relatively small number of
patients receiving all three active agents
may have played a significant role in
these results.

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