Current Therapies for Advanced Colorectal Cancer
Current Therapies for Advanced Colorectal Cancer
Colorectal cancer is a worldwide
public health problem, with
nearly 800,000 new cases diagnosed
each year, resulting in approximately
500,000 deaths. In the
United States, it is the second leading
cause of cancer mortality; nearly
60,000 deaths will be attributed to
this disease in 2005. When diagnosed
as advanced, metastatic disease,
colorectal cancer is traditionally associated
with a poor prognosis, with
5-year survival rates in the range of
5% to 8%. This survival rate has remained
unchanged over the past 35 to
40 years. However, during the past 5
years, significant advances have been
made in treatment options so that improvements
in 2-year survival are now
being reported, with median survival
rates of 21 to 24 months in patients
with metastatic disease.
Chemotherapy has been the mainstay
approach for patients with advanced
colorectal cancer.[2,3] For
nearly 40 years, the main drug used for
this disease was the fluoropyrimidine
fluorouracil (5-FU). Since the late
1990s, there has been a marked increase
in the number of agents that
have been approved for colorectal cancer.
The anticancer agents that have
been approved by the US Food and
Drug Administration (FDA) include the
topoisomerase I inhibitor irinotecan
(Camptosar), the third-generation platinum
analog oxaliplatin (Eloxatin), and
the oral fluoropyrimidine capecitabine
(Xeloda). In February 2004, two novel
biologic agents were approved by the
FDA: the anti-epidermal growth factor
receptor (EGFR) antibody cetuximab
(Erbitux) and the anti-vascular endothelial
growth factor (VEGF) bevacizumab
The general approach to treating
patients with advanced colorectal cancer
has been to use either monotherapy
or combination therapy. In the
United States, up to 25% to 30% of
patients continue to be treated with
monotherapy, which refers to the use
of fluoropyrimidine chemotherapy-
either with intravenous 5-FU or with
the oral fluoropyrimidine capecitabine.
Response rates are in the 15% to
30% range, with a median survival of
11 to 14 months. The appropriate setting
for such an approach would include
elderly patients as well as those
with compromised performance status,
comorbid illnesses, and impaired
hepatic and/or renal function.
Combination therapy has become
the preferred approach for patients with
advanced disease; it is used in up to
75% of cases in the first-line setting.
Clinical efficacy is significantly improved
with combination therapy, with
response rates up to 35% to 50%, double
that of monotherapy, and median
overall survival approaching the 2-year
mark in the 15 to 21 month range.
For nearly 40 years, 5-FU was the
only active anticancer agent available
to treat advanced colorectal cancer in
the first-line setting. However, response
rates to 5-FU in patients with
advanced disease are low, at only 10%
to 15%. To improve the clinical efficacy
of 5-FU, the addition of certain
biomodulating agents such as the reduced
folate leucovorin and/or a
change in the schedule of administration
of 5-FU from bolus to continuous
infusion were investigated.[5,6]
The most commonly used bolus
schedules in the United States are the
monthly regimen developed by the
Mayo Clinic with 5-FU at a dose of
425 mg/m2 and leucovorin at 20 mg/m2
repeated every 4 weeks, and a weekly
regimen developed by the Roswell Park
Cancer Institute and the National Surgical
Adjuvant Breast and Bowel
Project (NSABP) using 5-FU at 600
mg/m2 and leucovorin at 500 mg/m2.
The three commonly used infusional
schedules include the Lokich regimen
of 5-FU at 300 mg/m2 for 28
days; the AIO German regimen of 5-
FU at 2,000 to 2,600 mg/m2 over 24
hours and leucovorin at 500 mg/m2
once weekly for 6 weeks with a 1-
week rest; and the LV5FU2 de Gramont
regimen, a combination of bolus
and infusional 5-FU/leucovorin administered
on days 1 and 2 on a biweekly
In general, while response rates are
improved by up to twofold with these
different strategies, overall survival
has not been substantively altered. A
recent meta-analysis incorporating
3,300 patients from 19 different clinical
trials revealed that treatment with
5-FU/leucovorin yielded a significantly
improved response rate of 21%
compared with an 11% response rate
for treatment with 5-FU alone (P < .0001). Of note, this analysis showed
a statistically significant survival benefit
for 5-FU/leucovorin compared
with 5-FU alone, albeit of only 1
month (11.7 vs 10.5 months; P < .004).
Capecitabine is an oral fluoropyrimidine
carbamate prodrug of 5-FU
that was rationally designed to closely
simulate infusional administration
of 5-FU. In contrast to 5-FU,
capecitabine is readily absorbed by
the gastrointestinal tract. It is inactive
in its parent form and requires conversion
to 5-FU by three successive
enzymatic steps. The third and final
step is catalyzed by the enzyme
thymidylate phosphorylase. Of note,
the expression of thymidylate phosphorylase
appears to be higher in tumor
tissue when compared to
corresponding normal tissue. This differential
expression leads to enhanced
selective activation of capecitabine in
tumors, and in particular, in patients
with colorectal cancer.
Two randomized phase III trials
were performed comparing capecitabine
with bolus 5-FU/leucovorin
(Mayo Clinic regimen).[8,9] An integrated
analysis of the two studies
showed that the overall response rate
was significantly greater with capecitabine
than with 5-FU/leucovorin
(25.7% vs 16.7%; P < .0002), whereas
secondary measures of time to tumor
progression and survival were
equivalent. Moreover, patients
treated with capecitabine displayed an
improved safety profile and experienced
a significantly lower incidence
of effects in diarrhea, stomatitis, nausea,
alopecia, and grade 3/4 neutropenia.
The only side effect that was
observed with higher incidence on the
capecitabine arm was hand-foot syndrome.
Of note, the improved safety
profile associated with capecitabine
resulted in a marked reduction of hospitalizations
for adverse events when
compared to treatment with bolus 5-
FU/leucovorin. In the United Kingdom,
it was shown that capecitabine
treatment resulted in an improved use
of the medical health-care system.
Irinotecan is a semisynthetic derivative
of camptothecin, a natural alkaloid
first extracted from the
Camptotheca acuminata tree, and it
is a member of the topoisomerase I
inhibitor class of anticancer
agents. Irinotecan is essentially
inactive in its parent form and requires
conversion to its active metabolite,
SN-38, by a carboxylesterase
enzyme in the liver. This metabolite
forms a stable, covalent complex with
DNA and topoisomerase I that then
interrupts the breakage-reunion cycle
associated with topoisomerase I activity-
a process that eventually leads
to cell death.
Two randomized phase III studies
in patients with metastatic colorectal
cancer provided the initial evidence
that first-line combination therapy
with irinotecan plus 5-FU/leucovorin
(IFL) resulted in improved clinical
efficacy in terms of higher response
rate and greater overall and progression-
free survival when compared to
5-FU/leucovorin monotherapy. In
Europe, Douillard et al investigated
the clinical activity of infusional IFL,
and reported a response rate of 35%
in the IFL group and 22% in the
5-FU/leucovorin group for the intention-
to-treat analysis (P = .005); overall
survival was 17.4 and 14.2 months,
respectively (P = .031). Time to
treatment failure or progression was
6.7 months with IFL and 4.4 months
with 5-FU/leucovorin (P < .001). Saltz
et al reported similar results in their
North American trial, with response
rates of 39% vs 21% (P < .001), overall
survival times of 14.8 vs 12.6
months (P = .04), and median progression-
free survival times of 7.0 vs
4.3 months (P = .004) for the bolus,
weekly schedule of IFL and 5-FU/
These studies demonstrated the
clear superiority of IFL, whether it be
administered via an infusional or bolus
schedule, over 5-FU/leucovorin,
and established IFL as a new standard
in the first-line treatment of metastatic
Kohne et al reported the results of
a randomized phase III study comparing
the AIO weekly infusional
schedule of 5-FU/leucovorin vs the
same weekly infusional schedule of
5-FU/leucovorin combined with
weekly irinotecan. This regimen
was administered weekly for 6 weeks
and repeated every 7 weeks. In terms
of safety profile, the infusional IFL regimen
was relatively well-tolerated with
no significant increase in observed side
effects. Patients treated with the infusional
AIO IFL regimen experienced
significantly improved response rates
(54.2% vs 31.5%; P < .0001) and time
to tumor progression (8.5 vs 6.4 months;
P = .0001) when compared to patients
treated with 5-FU/leucovorin. While
patients on the IFL arm had improved
overall survival (20.1 vs 16.9 months)
when compared to 5-FU/leucovorin,
this difference did not reach statistical
significance (P = .2279 log-rank).
Irinotecan in Combination With Capecitabine
The combination of irinotecan/
capecitabine (XELIRI) is being actively
investigated in an attempt to replace
the more complicated and potentially
more toxic 5-FU/leucovorin regimens
with the oral fluoropyrimidine.
Patt et al conducted a phase II study
in the United States in which patients
under age 65 received capecitabine at
1,000 mg/m2 twice daily (days 1-14)
plus irinotecan at 250 mg/m2 (day 1)
in a 21-day cycle, while those over
age 65 received capecitabine at 750
mg/m2 twice daily plus irinotecan at
200 mg/m2. Treatment with XELIRI
yielded a 42% overall response
rate and a median time to tumor progression
of 7.1 months. Of interest,
no apparent differences in clinical activity
were observed between patients
> 65 and < 65 years of age. Disease
control (ie, complete response/partial
response plus stable disease) was
achieved in 71% of evaluable patients.
The XELIRI regimen was relatively
well tolerated, with the most common
grade 3/4 toxicities being
diarrhea (20%) and neutropenia
(18%). However, patients older than
65 experienced a nearly twofold higher
incidence of neutropenia and dehydration
when compared to those < 65
years. In contrast, no significant differences
were observed with respect
to gastrointestinal toxicity.
Bajetta et al conducted a multicenter,
phase II trial of two different
schedules of irinotecan combined with
capecitabine in the first-line treatment
of metastatic colorectal cancer. A
total of 140 patients received capecitabine
at a dose of 1,250 mg/m2 twice
daily on days 2 through 15 and irinotecan
at a dose of either 300 mg/m2 on
day 1 (arm A) or 150 mg/m2 on days
1 and 8 (arm B), and cycles were
given on an every-3-week schedule.
The doses of capecitabine and irinotecan
were subsequently reduced during
the course of the trial to improve
the safety profile of the combination.
The dose of capecitabine was reduced
to 1,000 mg/m2, while the irinotecan
dose was reduced to 240 mg/m2 on
arm A and 120 mg/m2 on arm B.
Overall response rates and median
progression-free survival were similar
in the treatment groups: 47% and
8.3 months for arm A and 44% and
7.6 months for arm B. In patients treated
on arm A, the incidence of grade 3/
4 gastrointestinal toxicity in the form
of diarrhea was nearly 36%; however,
upon dose reduction, the incidence
of grade 3/4 diarrhea dropped to 25%,
which was much lower than the nearly
38% incidence of grade 3/4 diarrhea
observed in patients treated on
arm B (days 1 and 8 schedule).
Oxaliplatin is a third-generation
platinum compound that exerts its cytotoxic
effects through the formation
of intrastrand and interstrand DNA
crosslinks. It is the only platinum analog
with activity against colorectal
cancer, and it exhibits a different spectrum
of toxicity when compared with
other platinum compounds. In contrast
to cisplatin, it does not cause nephrotoxicity,
nor does it give rise to the
same degree of myelosuppression and
alopecia commonly observed with carboplatin
(Paraplatin).[3,17] The main
dose-limiting toxicity is neurotoxicity,
and this specific adverse event presents
as both an acute and chronic
sensory neuropathy. The acute form,
exhibited by nearly all patients, typically
presents as transient paresthesias
that are exacerbated upon
exposure to cold. In addition, about
3% to 4% of patients experience laryngopharyngeal
spasms. In contrast, the
chronic form is a cumulative sensory
neuropathy that develops in up to 12%
to 15% of patients.
FOLFOX4 is now firmly established
as an effective first-line treatment
for patients with metastatic
colorectal cancer. In a phase III study,
de Gramont et al compared the FOLFOX4 regimen (oxaliplatin at a dose
of 85 mg/m2 as a 2-hour infusion on
day 1, every 2 weeks, plus LV5FU2)
with the de Gramont regimen of
5-FU/leucovorin (LV5FU2) alone in
420 patients with previously untreated
advanced colorectal cancer.
FOLFOX4 was associated with significantly
longer median progressionfree
survival times (9 vs 6.2 months;
P = .0003) and better response rates
(50.7% vs 22.3%; P = .0001), although
the two treatment groups did not differ
significantly in regard to overall
survival (16.2 vs 14.7 months; P = .12).
Grade 3/4 neutropenia, diarrhea, and
neurosensory toxicity were more
frequent with FOLFOX4 than with
5-FU/leucovorin alone, although measures
of quality of life did not differ
between the groups.
Intergroup trial N9741 was a randomized
phase III trial in which the
first-line therapy for metastatic colorectal
cancer with the bolus, weekly
IFL regimen as the control
arm. The two experimental arms
of this trial included FOLFOX4 and
arm of irinotecan and oxaliplatin
(IROX). This pivotal study showed
that FOLFOX4 had significantly
greater clinical efficacy than IFL in
terms of response rate (45% vs 31%;
P = .002), time to tumor progression
(8.7 vs. 6.9 months; P = .0014),
and median overall survival (19.5
vs 15 months; P = .0001).
In addition, when compared to IFL
or IROX, FOLFOX4 was associated
with markedly lower incidence of febrile
neutropenia and fewer gastrointestinal
side effects in terms of
nausea/vomiting, diarrhea, and dehydration.
However, peripheral sensory
neuropathy and myelosuppression
were more common with both FOLFOX4
and IROX when compared to
IFL. Based on the results from this
large phase III clinical trial, FOLFOX4
was approved for use in the United
States as first-line treatment of patients
with advanced colorectal cancer
in January 2004.
The FOLFOX6 regimen incorporated
a higher dose of oxaliplatin
(100 mg/m2) on day 1 with a simplified
schedule in which a single dose
of leucovorin and bolus 5-FU was
given on day 1 followed by a single
continuous 46-hour infusion of 5-
FU every 2 weeks. Treatment with
FOLFOX6 yielded overall response
rates of 54% and 27%, respectively,
in the first- and second-line settings,
and yielded similar overall
and progression-free survival when
compared with previous FOLFOX
de Gramont and colleagues in France
then developed the FOLFOX7 regimen
in an effort to maximize the dose intensity
of oxaliplatin. This regimen incorporated
the same simplified infusion
schedule of 5-FU as was delivered with
FOLFOX6, but used a higher dose of
oxaliplatin (130 mg/m2). In a phase II
study in previously treated patients,
FOLFOX7 resulted in a 42% response
rate and a median overall survival of
The FOLFOX7 regimen was subsequently
selected for further testing
in the first-line setting in the OPTIMOX
trial, where it was compared
directly to the FOLFOX4 regimen.[
23] To reduce the incidence of
patients enrolled in the FOLFOX7 arm
of the OPTIMOX trial received intermittent
exposure to oxaliplatin:
6 cycles of FOLFOX7, followed by
12 cycles of 5-FU/leucovorin, and
then reintroduction of oxaliplatin for
an additional 6 cycles of FOLFOX7.
The safety profile appeared to be
improved with FOLFOX7 as the incidence
of grade 3/4 neutropenia was
reduced significantly in patients treated
with the FOLFOX7 regimen
(21.9%) compared to FOLFOX4
(33.2%) (P = .013). There was, however,
a higher incidence of grade 3/4
thrombocytopenia with the FOLFOX7
regimen (10.6%) than with FOLFOX4
(3.1%) (P = .0006). With respect to
clinical efficacy, median overall survival,
at the time of the original analysis,
was not significantly different
between the two treatment arms: 20.7
months for patients in the FOLFOX4
arm and 21.4 months for the patients
in the FOLFOX7 arm. In addition,
both the FOLFOX7 and FOLFOX4
regimens achieved comparable response
and resection rates as well as
similar total disease control rates.
The different FOLFOX regimens
typically require infusional therapy
over 2 days every 2 weeks, whereas
oxaliplatin regimens in combination
with capecitabine involve one 2-hour
infusion every 3 weeks. There is growing
evidence that the oral fluoropyrimidine
capecitabine can effectively
substitute for bolus or infusional
schedules of 5-FU/leucovorin in combination
with oxaliplatin in the metastatic
Scheithauer et al conducted a study
in 89 patients with advanced colorectal
cancer using a dose-intensified bimonthly
schedule for capecitabine
(3,500 mg/m2 days 1-7 and 14-21)
plus oxaliplatin (85 mg/m2 days 1 and
14) every 4 weeks vs a conventional
dose regimen. Patients receiving
high-dose therapy experienced a higher
response rate (54.5% vs 42.2%)
and a significantly longer median progression-
free survival time than those
receiving the conventional dose (10.5
vs 6.0 months; P = .0013). Quite surprisingly,
the safety profile was similar
to that observed with the
lower-intensity regimen. While diarrhea
was the most frequent side effect,
in general it was well controlled.
Cassidy et al performed a phase II
multicenter international study investigating
the XELOX regimen. The
dosing regimen of capecitabine 1,000
mg/m2 twice daily (days 1-14) plus
oxaliplatin at 130 mg/m2 IV (day 1)
every 3 weeks yielded an overall response
rate of 55%, similar to that
observed with infusional 5-FU/leucovorin
plus oxaliplatin, and a median
overall survival of 19.5 months. The
most common grade 3/4 adverse
events observed in the study were gastrointestinal
side effects, myelosuppression,
and neurotoxicity. The
incidence of grade 3/4 myelosuppression
was less than 10%, which was
significantly lower than the 40% to
45% incidence typically observed with
the FOLFOX4 regimen. These findings
suggest that the XELOX combination
is an effective and welltolerated
regimen in the first-line treatment
of patients with metastatic colorectal
Novel Targeted Agents
The significant advances in molecular
oncology have provided an
enhanced understanding of the critical
signaling pathways involved in
tumor growth and proliferation. These
insights have served as the rational
basis for the development of novel
targeted therapies for solid tumors.
Such agents are designed to modulate,
inhibit, and interfere with the
function of specific molecular targets
that are essential to the malignancy of
tumors. The biologic agents that are
currently approved for colorectal cancer
are the monoclonal antibodies
cetuximab and bevacizumab.
Cetuximab is a chimeric monoclonal antibody directed against the external cell surface of the EGFR. The EGFR is overexpressed in up to 85% of colorectal tumors, and its expression has been correlated with metastatic disease and poor prognosis. The EGFR signaling pathway leads to activation of several key cellular events involved in cellular growth and proliferation, invasion and metastasis, and angiogenesis. In addition, this pathway inhibits the cytotoxic activity of various anticancer agents and radiation therapy, presumably through suppression of key apoptotic mechanisms, thereby leading to the development of cellular drug resistance. Saltz et al initially reported a 17% response rate in patients with irinotecan- refractory metastatic colorectal cancer who were treated with the combination of cetuximab and irinotecan.[ 27] A follow-up study evaluated the clinical activity of weekly cetuximab monotherapy in patients with refractory colorectal cancer whose tumors expressed EGFR. In this trial, 57 patients were evaluated; the overall response rate was 9% with a median survival of 6.4 months. This therapy was generally well-tolerated. The most common side effects were acne-like skin rash presenting mainly on the face and upper torso as well as asthenia, fatigue, malaise, and/or lethargy. The BOND (Bowel Oncology With Cetuximab Antibody) trial was a randomized phase II study in heavily pretreated patients with advanced colorectal cancer. This study enrolled 329 patients with EGFR-positive metastatic colorectal cancer who had failed to respond to irinotecan (progressing on or within 30 days). Patients were randomized in a 2:1 ratio to receive cetuximab as a 400-mg/m2 infusion, followed by weekly cetuximab at 250 mg/m2, plus irinotecan at the same dose and schedule on which they had been progressing, or cetuximab monotherapy. The objective response rate (22.9% vs 10.8; P = .0074), time to tumor progression (4.1 vs 1.5 months; P < .0001), and disease control rate (55.5% vs 32.4%; P = .0001) were significantly higher in the combination therapy group. Of note, cetuximab treatment did not worsen the toxicities normally associated with irinotecan chemotherapy. The most frequent grade 3/4 events in patients receiving combination therapy were diarrhea (21.2%), asthenia (13.7%), neutropenia (9.5%), acne-like rash (9.4%), and vomiting (6.1%). The results of this randomized study, along with supporting clinical data from the US phase II clinical studies, led to the approval of cetuximab for use in combination with irinotecan for the treatment of EGFRexpressing, metastatic colorectal cancer in patients who are refractory to irinotecan-based chemotherapy. This agent was also granted approval for use as a single agent for the treatment of EGFR-expressing, recurrent metastatic colorectal cancer in patients who are intolerant to irinotecan-based chemotherapy. At the American Society of Clinical Oncology (ASCO) 2004 annual meeting, Lenz and colleagues reported the results of a large (N = 346) phase II study of single-agent cetuximab in heavily pretreated patients who had previously failed both irinotecan and oxaliplatin. The response rate in this trial was 12% and the median overall survival was 6.7 months. These results exactly paralleled those previously reported in irinotecan-refractory patients. Of note, nine patients with EGFR-negative disease were treated with cetuximab monotherapy, of which two showed a partial response. The fact that patients with EGFR-negative tumors were able to respond to cetuximab treatment suggests that EGFR testing may not be necessary for patient selection for cetuximab therapy. An important issue that is being actively investigated is whether cetuximab in combination with standard chemotherapy can be used in the firstline setting. Phase II studies have been performed with cetuximab in combination with either bolus or infusional IFL, and both combinations have demonstrated relatively promising clinical activity with response rates being 50% and 70%, respectively. In follow- up to these studies, Rougier and colleagues performed a phase II study where FOLFIRI was combined with cetuximab. The addition of cetuximab did not worsen the safety profile normally observed with FOLFIRI chemotherapy. With respect to clinical efficacy, the overall response rate was 43% with an overall tumor control rate approaching 80%. Tabernero and colleagues have studied the combination of cetuximab and FOLFOX4 in the first-line setting.[ 31] At the ASCO 2004 annual meeting, they reported that this combination was well tolerated with a manageable safety profile. The addition of cetuximab did not worsen the toxicities normally associated with oxaliplatin-based chemotherapy. Moreover, this combination showed significant clinical activity with an overall response rate of 81% and a total disease control rate of 98%. Bevacizumab
Vascular endothelial growth factor is considered to be one of the most important angiogenic growth factors known to regulate angiogenesis. The growth of both primary and metastatic tumors requires an intact vasculature; for this reason, VEGF and the VEGF-signaling pathway represents an attractive target for chemotherapy. Several approaches have been taken to inhibit VEGF signaling, and they include inhibition of VEGF/VEGF receptor interactions by targeting either the VEGF ligand with antibodies or soluble chimeric receptors or by direct inhibition of the VEGF receptor- associated tyrosine kinase activity by small molecule inhibitors. Bevacizumab is a recombinant humanized monoclonal antibody that targets all forms of VEGF-A. This antibody binds to and prevents VEGFA from interacting with the target VEGF receptors. In a pivotal randomized phase III study, previously untreated patients with metastatic colorectal cancer who received bevacizumab plus standard chemotherapy with the bolus weekly IFL regimen had longer progression-free survival (10.6 vs 6.2 months, P < .00001) and improved median overall survival (20.3 vs 15.6 months; P = .00003) compared to those receiving IFL chemotherapy plus placebo. The only adverse event that occurred with greater frequency in patients treated with bevacizumab was grade 3 hypertension, which was managed effectively with oral medications. Six patients treated on the bevacizumab arm experienced a gastrointestinal perforation, although this number did not reach statistical significance. No increases in thromboembolic events, bleeding complications, and proteinuria were observed in patients treated with bevacizumab. Based on the strikingly positive clinical results of this phase III pivotal trial, bevacizumab was granted FDA approval in February 2004 as a firstline treatment for metastatic colorectal cancer in combination with any intravenous fluoropyrimidine-containing regimen. Trial AVF2192g was a randomized, double-blind, placebo-controlled, multicenter study of patients in the first-line setting who were deemed to be not optimal candidates for irinotecan-based chemotherapy.[ 33] The primary objective of the trial was survival. Secondary end points included response rate, progression free survival, response duration, quality-of-life assessment, and safety. Patients were randomized to one of two treatment arms. In arm 1, patients received the Roswell Park regimen of 5-FU/leucovorin and bevacizumab at 5 mg/kg, while in arm 2 patients received the Roswell Park regimen of 5-FU/leucovorin plus placebo. The overall median survival was 12.9 months on the placebo arm compared to 16.6 months on the bevacizumab arm (P = .159). Progressionfree survival in the placebo arm was 5.5 months compared to 9.2 months in the bevacizumab arm (P = .0002). The overall response rate was 15% in the placebo arm and 26% in the bevacizumab arm (P = .0552), with all responses being partial responses in both arms. Hypertension (4.8% vs 32%) and proteinuria (19.2% vs 38%) were observed more frequently in patients treated with bevacizumab, and as was observed in the pivotal registation trial, two patients in the bevacizumab arm experienced gastrointestinal perforations. In addition to being used in combination with either 5-FU/leucovorin or the bolus, weekly IFL schedule, bevacizumab has been studied with oxaliplatin-based chemotherapy in the second-line setting. A total of 829 patients with advanced colorectal cancer, previously treated with 5-FU- based therapy and irinotecan for advanced disease or relapsed disease following adjuvant chemotherapy, were randomized to one of three treatment arms, including FOLFOX4, FOLFOX4 and bevacizumab, and bevacizumab alone. With respect to toxicity, the addition of bevacizumab to FOLFOX4 did not appear to increase the side effects normally associated with oxaliplatin. With respect to clinical efficacy, patients receiving bevacizumab in combination with FOLFOX4 had a 26% relative reduction in risk of death when compared to FOLFOX4 alone. Median overall survival was 12.5 months for FOLFOX4 plus bevacizumab vs 10.7 months for FOLFOX4 alone, which resulted in a significant 17% absolute improvement in median overall survival.[ 35] Summary Significant advances have been made in the treatment of advanced colorectal cancer over the past 5 years. This progress has been made possible with the introduction of three novel cytotoxic agents-capecitabine, irinotecan, and oxaliplatin-and with the recent approval of two biologic agents-bevacizumab and cetuximab. During this time period, the median survival of patients with advanced, metastatic disease has gone from 10 to 12 months to nearly 24 months. Intense efforts have focused on identifying novel targeted therapies which target specific growth factor receptors, critical signal transduction pathways, and/or key pathways that mediate the process of angiogenesis. The recent clinical results with the anti-VEGF antibody bevacizumab, in combination with the IFL bolus weekly regimen, the weekly Roswell Park schedule of 5-FU/leucovorin, and the FOLFOX4 regimen, validate the process of angiogenesis as being an important chemotherapeutic target for colorectal cancer and suggest that this antibody can be safely and effectively used in combination with each of the active anticancer agents used in colorectal cancer. Similarly, the randomized phase II BOND study validated the role of the EGFR-signaling pathway as a key target for chemotherapy, and recent studies now suggest that this agent can be safely and effectively developed in the front-line setting as well as in the salvage setting. Despite the development of active combination regimens, significant improvements in the actual cure rate have not yet been achieved. Combination regimens with activity in advanced disease are being evaluated in the adjuvant and neoadjuvant setting. Investigators continue to focus efforts on identifying novel therapies that target specific growth factor receptors, critical signal transduction pathways, and/or key pathways that mediate the process of angiogenesis. The goal is to integrate these targeted strategies into standard chemotherapy regimens so as to advance the therapeutic options for the treatment of advanced colorectal cancer. Finally, intense efforts are attempting to identify the critical molecular biomarkers that can be used to predict for either clinical response to chemotherapy and/or targeted therapies and/ or the drug-specific side effects. The goal of such studies is to facilitate the evolution of empiric chemotherapy to individually tailored treatments for patients with colorectal cancer.
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