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(Drug information on irinotecan)-, oxaliplatin(Drug information on 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(Drug information on 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(Drug information on 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.
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(Drug information on 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(Drug information on 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.
A 52-year-old man presented with an erythematous lesion in the axilla of unknown duration. Surgical excision was performed. What is your diagnosis?
