B

7. Bendamustine therapy should be held or discontinued in the setting of

severe or progressive skin reactions.
8. Pregnancy category D. Breastfeeding should be avoided.

TOXICITY 1
Myelosuppression with neutropenia and thrombocytopenia is dose-limiting and
may warrant treatment delay or dose reduction.

TOXICITY 2
Mild nausea and vomiting.

TOXICITY 3
Hypersensitivity reactions presenting with fever, chills, pruritus, and rash.
Anaphylactoid and severe anaphylactic reactions have occurred rarely.

TOXICITY 4
Pyrexia, fatigue, and asthenia.

TOXICITY 5
Tumor lysis syndrome typically occurs within the first treatment cycle and in
high-risk patients.

TOXICITY 6
Skin rash, toxic skin reactions, and bullous exanthema occur in <10% of
patients.

Bevacizumab
TRADE NAME Avastin CLASSIFICATION Monoclonal
antibody, anti-
VEGF antibody

CATEGORY Biologic DRUG Genentech/

response MANUFACTURER Roche
modifier agent

MECHANISM OF ACTION
• Recombinant humanized monoclonal antibody directed against the
vascular endothelial growth factor (VEGF). Binds to all isoforms of
VEGF-A. VEGF is a pro-angiogenic growth factor that is overexpressed in
a wide range of solid human cancers, including colorectal cancer.
• Precise mechanism(s) of action remain(s) unknown.
• Binding of VEGF prevents its subsequent interaction with VEGF receptors
(VEGFR) on the surface of endothelial cells and tumors, and in so doing,
results in inhibition of VEGFR-mediated signaling.

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• Inhibits formation of new blood vessels in primary tumor and metastatic
tumors.
• Inhibits tumor blood vessel permeability and reduces interstitial tumoral
pressures, and in so doing, may enhance blood flow delivery within tumor.
• Restores antitumor response by enhancing dendritic cell function.
• Immunologic mechanisms may also be involved in antitumor activity, and
they include recruitment of ADCC and/or complement-mediated cell lysis.

MECHANISM OF RESISTANCE
• Increased expression of pro-angiogenic factor ligands, such as PlGF,
bFGF, and hepatocyte growth factor (HGF).
• Recruitment of bone marrow–derived cells, which circumvents the
requirement of VEGF signaling and restores neovascularization and
tumor angiogenesis.
• Increased pericyte coverage of the tumor vasculature, which serves to
support its integrity and reduces the need for VEGF-mediated survival
signaling.
• Activation and enhancement of invasion and metastasis to provide access
to normal tissue vasculature without obligate neovascularization.

DISTRIBUTION
Distribution in body is not well characterized. The predicted time to reach
steady-state levels is on the order of 100 days.

METABOLISM
Metabolism of bevacizumab has not been extensively characterized. Peripheral
half-life is on the order of 17–21 days with minimal clearance by the liver or
kidneys. Tissue half-life has not been well characterized.

INDICATIONS
1. Metastatic colorectal cancer—FDA-approved for use in combination with
any intravenous 5-fluorouracil (5-FU)–based chemotherapy in first-line
therapy.
2. Metastatic colorectal cancer—FDA-approved for use in the second-line
setting in combination with fluoropyrimidine-based chemotherapy after
progression on first-line treatment that includes bevacizumab.
3. NSCLC—FDA-approved for non-squamous NSCLC in combination with
carboplatin/paclitaxel.
4. Glioblastoma—FDA-approved as a single agent for glioblastoma with
progressive disease following prior therapy.
5. Renal cell cancer—FDA-approved in combination with interferon-α for
metastatic renal cell cancer.
6. Cervical cancer—FDA-approved in combination with cisplatin/paclitaxel or
paclitaxel/topotecan for metastatic or recurrent cervical cancer.
7. Ovarian, fallopian tube, or primary peritoneal cancer—FDA-approved
in combination with paclitaxel, pegylated liposomal doxorubicin, or
topotecan for platinum-resistant recurrent disease.

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 B
DOSAGE RANGE
1. Recommended dose for the first-line treatment of advanced colorectal
cancer is 5 mg/kg IV in combination with intravenous 5-FU–based
chemotherapy on an every-2-week schedule.
2. Recommended dose for the second-line treatment of advanced colorectal
cancer in combination with FOLFOX-4 is 10 mg/kg IV on an every-2-week
schedule.
3. Can also be administered at 7.5 mg/kg IV every 3 weeks when used in
combination with capecitabine-based regimens for advanced colorectal cancer.
4. Recommended dose for advanced NSCLC is 15 mg/kg IV every 3 weeks
with carboplatin/paclitaxel.
5. Recommended dose for glioblastoma is 10 mg/kg IV every 2 weeks.
6. Recommended dose for renal cell cancer is 10 mg/kg IV every 2 weeks
with interferon-α.
7. Recommended dose for cervical cancer is 15 mg/kg every 3 weeks with
cisplatin/paclitaxel or paclitaxel/topotecan.
8. Recommended dose for ovarian, fallopian tube, or primary peritoneal
cancer is 10 mg/kg every 2 weeks with paclitaxel, pegylated liposomal
doxorubicin, or weekly topotecan or 15 mg/kg every 3 weeks with
topotecan given every 3 weeks.

DRUG INTERACTIONS
None well characterized to date.

SPECIAL CONSIDERATIONS
1. Patients should be warned of the increased risk of arterial
thromboembolic events, including myocardial infarction and stroke. Risk
factors are age ≥65 years and history of angina, stroke, and prior arterial
thromboembolic events. This represents a black-box warning.
2. Patients should be warned of the potential for serious and, in some cases,
fatal hemorrhage resulting from hemoptysis in patients with NSCLC. These
events have been mainly observed in patients with a central, cavitary, and/
or necrotic lesion involving the pulmonary vasculature and have occurred
suddenly. Patients with recent hemoptysis (≥1/2 tsp of red blood) should
not receive bevacizumab. This represents a black-box warning.
3. Bevacizumab treatment can result in the development of GI perforations,
which in some cases has resulted in death. This event represents a
black-box warning for the drug. Use with caution in patients who have
undergone recent surgical and/or invasive procedures. Bevacizumab
should be given at least 28 days after any surgical and/or invasive
intervention.
4. Bevacizumab treatment can result in the development of wound
dehiscence, which in some cases can be fatal. This represents a
black-box warning. Use with caution in patients who have undergone
recent surgical and/or invasive procedures. Bevacizumab should be given
at least 28 days after any surgical and/or invasive intervention.
5. Carefully monitor for infusion-related symptoms. May need to treat with
diphenhydramine (Benadryl) and acetaminophen.

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6. Use with caution in patients with uncontrolled hypertension as
bevacizumab can result in grade 3 hypertension in about 10% of
patients. Should be permanently discontinued in patients who develop
hypertensive crisis. In most cases, however, hypertension is well managed
by increasing the dose of the antihypertensive medication and/or with the
addition of another antihypertensive medication.
7. Bevacizumab should be terminated in patients who develop the nephrotic
syndrome. Therapy should be interrupted for proteinuria ≥2 grams/24 hours
and resumed when <2 grams/24 hours.
8. Bevacizumab treatment can result in RPLS, as manifested by headache,
seizure, lethargy, confusion, blindness and other visual side effects, as well
as other neurologic disturbances. This syndrome can occur from 16 hours to
1 year after initiation of therapy, and usually resolves or improves within days,
and magnetic resonance imaging is necessary to confirm the diagnosis.
9. There are no recommended dose reductions for bevacizumab. In the
setting of adverse events, bevacizumab should be discontinued or
temporarily interrupted.
10. Pregnancy category B.

TOXICITY 1
Gastrointestinal perforations and wound-healing complications.

TOXICITY 2
Bleeding complications with epistaxis being most commonly observed. Serious,
life-threatening pulmonary hemorrhage occurs in rare cases in patients with
NSCLC, as outlined previously in Special Considerations.

TOXICITY 3
Increased risk of arterial thromboembolic events, including myocardial
infarction, angina, and stroke. There is also an increased incidence of venous
thromboembolic events.

TOXICITY 4
Hypertension occurs in 5%–18%. Usually well controlled with oral antihypertensive
medication.

TOXICITY 5
Proteinuria with nephrotic syndrome <1%.

TOXICITY 6
Infusion-related symptoms with fever, chills, urticaria, flushing, fatigue,
headache, bronchospasm, dyspnea, angioedema, and hypotension. Infusion
reactions occur in <3% of patients and severe reactions occur in 0.2% of
patients.

TOXICITY 7
CNS events with dizziness and depression. RPLS occurs rarely (incidence of
<0.1%) and presents with headache, seizure, lethargy, confusion, blindness, and
other visual disturbances.

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