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The Horizon of Antiangiogenic Therapy for Colorectal Cancer

The Horizon of Antiangiogenic Therapy for Colorectal Cancer

ABSTRACT: Vascular endothelial growth factor (VEGF) plays a crucial role in the growth and metastatic spread of cancer. Bevacizumab (Avastin) is the first commercially available VEGF inhibitor, earning US Food and Drug Administration (FDA) approval in February 2004. In combination with fluorouracil (5-FU)-based chemotherapy, this agent significantly prolongs overall and progression-free survival of patients with metastatic colorectal cancer. This review details the emerging role of the drug, its unique side effects, and other practical considerations related to bevacizumab therapy. Ongoing trials attempting to define additional indications for bevacizumab as well as the development of other promising angiogenesis inhibitors are also reviewed.

After more than 30 years of research,
antiangiogenesis therapy
has become a clinical reality,
representing one of the most
exciting therapeutic advances in oncology.
Of the numerous growth factor-
receptor complexes that promote
angiogenesis, the vascular endothelial
growth factor (VEGF) pathway is
of particular importance. Bevacizumab
(Avastin), a monoclonal antibody
that targets VEGF, is the first such agent
to gain US Food and Drug Administration
(FDA) approval after a landmark
placebo-controlled phase III trial confirmed
the efficacy of antiangiogenic
therapy in metastatic colon cancer.

The availability of bevacizumab
as first-line therapy for metastatic
colorectal cancer in combination with
irinotecan (Camptosar) and fluorouracil
(5-FU) has fostered a global effort
to further develop this and other
anti-VEGF therapies. Trials are either
planned or under way to define the
role of bevacizumab in the adjuvant
setting, to develop additional bevacizumab-
based combinations with
other chemotherapy agents or novel
targeted agents, and to optimize dosing.
This article surveys the ongoing
development of anti-VEGF-based
therapies for colorectal cancer as well
as the evaluation and management of
side effects unique to this drug class.

Role of VEGF in Regulation
of Angiogenesis

Angiogenesis is a complex process
leading to the formation and
maintenance of new blood vessels. It
involves processing of the extracellu
lar
matrix as well as cell proliferation
and organization, and is regulated by
a large number of activating and inhibitory
signals.[1] VEGF is a highly
specific and potent endothelial cell
mitogen, the expression of which is
induced primarily by hypoxia.[2,3]
VEGF binding sites are present exclusively
on vascular endothelium,
including quiescent cells, suggesting
a role in growth promotion and in
survival of established blood vessels.[
4] An additional and possibly
clinically important VEGF activity
consists of increasing vascular permeability.
The two main VEGF receptors
are designated fms-like
tyrosine kinase, VEGFR-1 (Flt-1), and
fetal liver kinase-1, kinase domain region,
VEGFR-2 (Flk-1/KDR).[5]

VEGF in Colorectal Cancer

Inadequate angiogenesis results in
tumor necrosis and impairs metastatic
potential.[6] Similar to other cancers,
colorectal adenocarcinomas exhibit
an abnormally high level of VEGF
mRNA and protein expression with
an increased level of both Flt-1 and
Flk-1/KDR receptors in adjacent vessels,
consistent with a paracrine mechanism.[
7] Serum levels of VEGF are
increased in colorectal cancer and correlate
with stage of disease. VEGF
overexpression has been validated as
a poor prognostic factor.[8-10] Tumor
VEGF overexpression predicts
for worse outcome in patients with
resected stage II disease and elevated
preoperative serum VEGF is a poor
prognostic factor in both stage II and
stage III disease.[11,12] Observational
studies indicate that VEGF has an
important role in hematogenous metastatic
spread of human colon adenocarcinoma
and establish a foundation
for therapeutic research targeting
VEGF and its receptors.

Different approaches toward inhibition
of VEGF-dependent angiogenesis
include the use of monoclonal
antibodies against VEGF or its receptors
(VEGFR), small-molecule inhibitors
of VEGFR-specific tyrosine
kinase activity, ribozymes specifically
cleaving VEGF/VEGFR mRNA,
soluble VEGF receptors acting as a
trap for the circulating factor, and antisense
oligonucleotides of VEGF
mRNA. The clinical development of
some of these agents is summarized
in Table 1. Existent inhibitors of the
VEGF pathway exhibit very limited
toxicity and can be combined safely
with conventional chemotherapy.

Bevacizumab: First Anti-VEGF
Agent in Clinical Practice

Bevacizumab is a recombinant humanized
monoclonal antibody that is
able to neutralize all biologically active
isoforms of VEGF-A. In murine
xenograft models, the anti-VEGF antibody
was shown to inhibit the growth
of metastatic tumors while it was devoid
of cytotoxic activity on cell lines
in vitro.[13,14] In a phase I study, no
drug-specific grade 3 or 4 toxicities
were observed at bevacizumab doses
ranging from 0.1 to 10 mg/kg.[15]
More common adverse effects were
infusion-related asthenia, headache,
and fever. An elevation of systolic
and diastolic blood pressure of
10 mm Hg on average was noted at
higher dose levels. Two patients experienced
serious hemorrhages within
metastatic tumors. The 21-day
half-life of bevacizumab with linear
kinetics permits every-14-day dosing.
If the bevacizumab dose and schedule
is altered to 7.5 mg/kg every 3
weeks, pharmacokinetics and overall
dose exposure are similar to the currently
standard dosing of 5 mg/kg
once every 2 weeks.[16]

Major Clinical Trials

  • Phase II Study-Bevacizumab
    may be administered safely with
    either irinotecan-, oxaliplatin-, or
    5-FU-based chemotherapies with no
    additive toxicity.[17] As a treatment
    for metastatic colon cancer, bevacizumab
    has been combined with
    5-FU, leucovorin, 5-FU/irinotecan,
    and 5-FU/oxaliplatin (Eloxatin) in a
    variety of phase II protocols with encouraging
    response rates, time to tumor
    progression, and median overall
    survival durations. To date, bevacizumab
    at 5 mg/kg every other week has
    been associated with better clinical
    outcomes than the 10-mg/kg dose
    when combined with chemotherapy.

    A three-arm randomized phase II
    trial compared the Roswell Park regimen
    of 5-FU/leucovorin alone (bolus
    5-FU at 500 mg/m2 with 500 mg/m2 of
    leucovorin weekly for 6 weeks every
    8 weeks) with either 5 or 10 mg/kg of
    bevacizumab every other week.[18]
    The median time to disease progression
    was 5.2 months in the control arm,
    9 months in the 5-mg/kg bevacizumab
    arm (P = .005), and 7.2 months in the
    10-mg/kg arm. The decrease in the
    hazard of progression in the 10-mg/kg
    group was not statistically significant.
    An objective response was seen in 40%
    of patients who received 5 mg/kg of
    bevacizumab and 17% in the control
    group (P = .029 compared with the
    control arm), whereas the difference
    in response rates for the higher-dose
    bevacizumab arm did not reach statistical
    significance (24%, P = .434). Patients
    in the 5-mg/kg arm had an
    impressive although not statistically
    significant 21.5-month median survival
    compared with 13.8 months in the
    control arm, despite the fact that 61%
    of controls crossed over to single-agent
    bevacizumab therapy upon disease
    progression.

    Toxicities were more common in
    the experimental arms, including
    grade 3 and 4 events. These side effects
    are consistent with what is emerging
    as a bevacizumab-specific toxicity
    profile, summarized in Table 2. While
    bevacizumab did not worsen the usual
    5-FU/leucovorin-related adverse events
    (such as gastrointestinal toxicities or
    myelosuppression), hypertension,
    thrombotic, and hemorrhagic events
    were more frequent. The major hemorrhagic
    event was mild epistaxis lasting
    less than 5 minutes. Thromboembolic
    complications included a grade 5 pulmonary
    embolism in one patient receiving
    bevacizumab at the 10-mg/kg
    dose. Notably, the study was partly confounded
    by imbalances in randomization
    (more women and slightly worse
    performance profiles were assigned to
    the experimental arms). However, both
    efficacy and toxicity data favored the
    lower dose of bevacizumab.

  • Phase III Study-The results of
    AVF2107, a randomized, placebocontrolled
    phase III trial of bevacizumab
    in combination with irinotecan
    and bolus 5-FU/leucovorin (for details
    of this and other discussed regimens,
    refer to Figure 1) resulted in
    FDA approval of bevacizumab as first-
    line therapy for metastatic colorectal
    cancer in February 2004.[19] Nine
    hundred and twenty-three patients
    with previously untreated metastatic
    colorectal cancer were assigned to receive
    either IFL (irinotecan, 5-FU, leucovorin),
    IFL with bevacizumab, or
    5-FU/leucovorin (according to the
    Roswell Park schedule) with bevacizumab.
    The dose of bevacizumab was
    5 mg/kg every 2 weeks. Notable exclusion
    criteria included clinically
    significant cardiovascular disease (encompassing
    myocardial infarction,
    stroke, unstable angina, class II-IV
    congestive heart failure within 1 year,
    dysrhythmias requiring therapy, uncontrolled
    hypertension, grade 2 or
    higher peripheral vascular disease),
    full-intensity anticoagulation (except
    for cardiac doses of aspirin), ascites,
    or proteinuria exceeding 500 mg/d.

    Median survival, the primary end
    point, reached statistical significance
    with outcomes of 20.3 vs 15.6 months
    (P < .001), in favor of the IFL/bevacizumab
    combination. Similarly, the
    progression-free survival (10.6 vs 6.2
    months, P < .001) and response rate
    (44.8% vs 34.8%, P < .004) favored
    the experimental arm. The survival
    benefit of adding bevacizumab to IFL
    was evident in all study subgroups,
    including patients with advanced age
    and poor performance status.

    According to the trial design, once
    a planned preliminary safety analysis
    determined the feasibility of the IFL
    regimen with bevacizumab, accrual
    to the 5-FU/leucovorin-plus-bevacizumab
    arm ended. Nevertheless,
    among 110 evaluable patients, there
    was a provocative trend toward better
    survival in the 5-FU/leucovorin/bevacizumab
    arm (18.3 months) than in
    the IFL/placebo arm, and the difference
    in time to disease progression
    for these two groups reached statistical
    significance (8.8 vs 6.7 months,
    P = .03).

    In this large trial, further insight
    into the bevacizumab toxicity profile
    emerged. Side effects associated with
    the IFL-plus-bevacizumab arm are
    summarized in Table 2. A greater
    number of grade 3/4 adverse effects
    occurred in the IFL/bevacizumab arm
    (85% vs 74%), chiefly due to hypertension
    (11% vs 2.3%). Elevated blood
    pressure has been managed easily with
    single-agent antihypertensive therapy.
    The occurrence of gastrointestinal (GI)
    perforations in patients receiving bevacizumab
    (including one fatality) is
    very concerning and seems to represent
    a drug-specific toxicity. Ongoing
    efforts will attempt to identify
    subsets at risk for this side effect. Clinicians
    must consider GI perforation
    when patients deteriorate or develop
    abdominal symptomatology.

    Interestingly in this trial, no statistically
    significant increased incidence
    of severe hemorrhage, proteinuria, or
    venous thromboembolism was
    observed. However, a retrospective
    analysis of thromboembolic events revealed
    a higher rate of "any" arterial
    thrombotic event (3.3% vs 1.0%),
    myocardial infarction (1.5% vs 0.8%),
    and cerebrovascular accident (0.5%
    vs 0.0%) in the IFL-plus-bevacizumab
    arm compared with the IFL-plusplacebo
    arm.[20] Similarly, study
    AVF2192g (which included elderly
    or less fit patients with untreated metastatic
    colorectal cancer) corroborated
    this finding with an arterial
    thrombosis rate of 10% in the 5-FU/
    leucovorin-plus-bevacizumab arm vs
    4.8% in the 5-FU/leucovorin-plusplacebo
    arm.[20]

    Additional interest focused on trial
    participants who developed thromboembolism
    and required anticoagulation.[
    21] Fifty-three patients from
    the IFL/bevacizumab arm were treated
    concomitantly with full-dose warfarin
    for a median of 218 days. The
    incidence of grade 3/4 hemorrhage
    was actually slightly lower than that
    seen in anticoagulated patients from
    the placebo group (3.8% vs 6.7%, respectively).
    Therefore, full-intensity
    anticoagulation is not a contraindication
    to bevacizumab use. Consistent
    with other bevacizumab trials, the traditional
    toxicities of the IFL regimen
    (GI and myelosuppression) were not
    significantly augmented with the addition
    of bevacizumab.

  • ECOG Study-A phase II study
    conducted by the Eastern Cooperative
    Oncology Group (ECOG's
    E2200) assessed the combination of
    IFL with bevacizumab at 10 mg/kg
    every 2 weeks as first-line therapy,
    primarily evaluating progression-free
    survival and response rates.[22] Patients
    with a history of hemorrhage or
    thrombosis, or on chronic anticoagulant
    medication were excluded.
    Among 87 evaluable subjects, the
    major toxicities included grade 3 diarrhea
    (17%), grade 3/4 neutropenia
    (35%), any hemorrhages (54%; grade
    1 in > 90%), and grade 3/4 thrombosis
    (10%). Neither hypertension (2.3%
    grade 3) nor proteinuria posed clinically
    significant problems.

    The overall response rate was 49%
    with 6% complete remissions (as defined
    by Response Evaluation Criteria
    in Solid Tumors [RECIST]), while
    an additional 38% of patients had stable
    disease. The median progressionfree
    survival was 10 months. These
    efficacy data are concordant with the
    report of AVF2107 by Hurwitz et al.

FDA Approval
Based on the AVF2107 pivotal trial,
the FDA approved bevacizumab
for use in patients with previously
untreated colorectal cancer in conjunction
with 5-FU-based chemotherapy.
Neither cardiovascular disease nor
chronic anticoagulation are listed as
contraindications in the package insert.
Based on data derived from trials
of bevacizumab in non-small-cell
lung cancer (NSCLC), indicating a
9% risk of serious, even fatal pulmonary
hemorrhage, the drug is contraindicated
in patients with a recent history
of hemoptysis.[23] The safety and efficacy
of bevacizumab in patients with
central nervous system metastases have
not been evaluated. A warning concerning
congestive heart failure was
included in the approval, although this
adverse effect was observed mostly
in the context of prior or concomitant
anthracycline therapy in metastatic
breast cancer studies. Notably, biweekly
blood pressure evaluation and urine
analysis via dipstick, with 24-hour
urine collection in case of 2+ proteinuria,
are recommended.

Per the January 2005 amended
package insert, vigilance for signs and
symptoms of arterial thromboembolic
events including angina, myocardial
infarction, transient ischemic
attack, and cerebrovascular accidents
is warranted due to an estimated 4.4%
overall risk of such events associated
with bevacizumab use.

Which Chemotherapy
Regimen to Use?

The FDA approval of bevacizumab
is open-ended with regard to
choice of chemotherapy, advising
simply that bevacizumab be combined
with infusional 5-FU regimens.
The IFL regimen used in the pivotal
AVF2107 has been largely replaced
by programs utilizing infusional
forms of 5-FU in combination with
irinotecan (FOLFIRI) or oxaliplatin
(FOLFOX) due to their better efficacy
and safety profile.[24] These regimens
and their clinical outcomes are
summarized in Figure 1. The excellent
survival outcomes observed with
5-FU/bevacizumab in AVF2107 as
well as in the aforementioned phase II
experiences raise questions about the
relative contribution of irinotecan to
first-line 5-FU/bevacizumab and the
more general need to utilize chemotherapy
doublets in combination with
bevacizumab.

A placebo-controlled, randomized
study-AVF2192g-evaluated single-
agent 5-FU/leucovorin with or
without bevacizumab in 209 patients
deemed ineligible for combination
therapy using irinotecan or oxaliplatin
due to age or poor performance status.[
25] This approach proved useful,
again yielding a progression-free survival
of 9.2 months in the treatment
arm vs 5.5 months in the control arm,
although the overall survival difference
(16.6 vs 12.9 months) was not
statistically significant.

These survival outcomes are comparable
to those reported in studies of
FOLFOX or FOLFIRI regimens in
untreated general populations of patients
with metastatic colorectal cancer.[
26,27] The side-effect profile of
this trial again supports the observation
that bevacizumab does not worsen
typical 5-FU-associated side
effects but is associated with an increased
incidence of hypertension,
doubled rate of arterial thromboembolic
events (10%), and 2% incidence
of GI perforation. Bevacizumab with
5-FU, therefore, enables less fit patients
to enjoy survival benefits
similar to persons receiving other
highly active new chemotherapeutic
combinations such as FOLFIRI or
FOLFOX.

Trials evaluating bevacizumab in
combination with either FOLFOX or
capecitabine (Xeloda)-oxaliplatin
doublets (XELOX, CAPEOX) in patients
with previously untreated metastatic
colorectal cancer are either
ongoing or planned. Until mature outcome
data are available from these
trials, the general concept of selecting
a regimen based on toxicity profile,
patient comorbidity, and patient
preference should govern the choice
of chemotherapy to combine with
bevacizumab.

Treatment Duration: Maintenance
vs Intermittent Therapy

The intriguing concept of continuing
bevacizumab therapy with sequential
non-cross-resistant chemotherapy
regimens is being explored. Patients
in the experimental arms of the pivotal
AVF2107 trial were allowed to continue
bevacizumab after disease
progression in combination with other
chemotherapy regimens (25% of
patients received oxaliplatin). Some
patients have received bevacizumab
for up to 3 years. No late toxic events
have been observed in association with
chronic bevacizumab therapy of 1 or
more years. The subset of patients
who continued to receive bevacizumab
in conjunction with second-line
oxaliplatin attained a median survival
of 25 months.[28]

The results of ECOG trial E3200
were announced at the American Society
of Clinical Oncology (ASCO)
gastrointestinal symposium in January
2005.[29] This phase III study
randomized 829 patients with metastatic
colorectal carcinoma progressing
on first-line, irinotecan-based
therapy into treatment with FOLFOX4
alone or with the addition of bevacizumab
at 10 mg/kg. A third arm of
single-agent bevacizumab (10 mg/kg)
was discontinued after planned
interim analysis due to inferior efficacy.
Participants were monitored
for proteinuria, and if it exceeded
500 mg/24 hours, the dose of bevacizumab
was adjusted to 5 mg/kg. A
survival benefit (12.5 vs 10.7 months,
P = .0024) favored the experimental
arm in this patient population.

The toxicity analysis in the E3200
trial is consistent with results of the
other bevacizumab trials in metastatic
colorectal cancer (Table 2). There
was no significant increase in hematologic
toxicity but somewhat higher
rates of nausea and vomiting (20% vs
9%) and neuropathy (15% vs 9%).
The incidence of grade 3 hemorrhage
was 2% in the FOLFOX4/bevacizumab
arm, compared to 0% in the control
arm; rates of thrombosis were
identical. The incidence of bowel perforation
was approximately 1% with
one fatal event. Three other deaths
possibly associated with bevacizumab
included pneumonitis, a possible pulmonary
embolism, and a brain hemorrhage
complicating deep-vein
thrombosis-related anticoagulation.

Preliminary data regarding the ac-
tivity of bevacizumab plus cetuximab
(Erbitux) with or without irinotecan
as second- or third-line therapy for
patients with irinotecan-refractory disease-
the so-called BOND-2 trial-
were also presented at the January 2005
ASCO gastrointestinal malignancy
symposium. A response rate of 38%
with a median time to disease progression
of 8.5 months was attained in the
irinotecan-containing arm. An encouraging
23% response rate and 6.9-month
median time to disease progression
was attained in the bevacizumabcetuximab-
alone arm.

Since the median time to disease
progression with first-line bevacizumab
therapy is consistently approaching
10 to 11 months, a practical issue
of whether to continue therapy until
disease progression or hold therapy
after disease control has been attained
(usually with 4-6 months of treatment),
and retreat upon disease progression
needs to be addressed. Such
intermittent therapy has been demonstrated
to be effective with regard to
survival outcomes in the treatment of
metastatic breast and non-small-cell
lung cancer (NSCLC), and this strategy
is already applied by oncologists
treating those diseases. Comparable
survival outcomes with intermittent
5-FU-based therapy vs uninterrupted
therapy until disease progression also
have been demonstrated in patients
with metastatic colorectal cancer.[30]
Whether intermittent therapy can be
applied to bevacizumab-based regimens
without sacrificing survival outcomes
is an important yet unstudied
issue.

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