Continuing Education Activity
Bevacizumab is a humanized monoclonal antibody against vascular endothelial growth factor A (VEGF-A) and is used for the treatment of several different cancers. Its use is usually in combination with other chemotherapy agents. This activity will highlight the mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions) pertinent for members of the interprofessional team in the treatment of patients with bevacizumab.
- Identify the approved indications for bevacizumab.
- Summarize the mechanism of action of bevacizumab.
- Review the adverse events, contraindications, toxicities, and interactions of bevacizumab.
- Outline interprofessional team strategies for improving care coordination and communication to advance bevacizumab and improve outcomes in cancer treatment.
Mechanism of Action
Bevacizumab is a recombinant humanized monoclonal antibody that binds to all known vascular endothelial growth factor A (VEGF-A) isoforms. It blocks the interaction between VEGF-A and the VEGF receptors (VEGFR), primarily VEGFR-1 (fit-1) and VEGFR-2 (KDRflk-1), on the surface of endothelial cells. It is 93% human and 7% murine in the protein sequence. The binding of VEGF-A to VEGFR-1 and VEGFR-2 leads to endothelial cell proliferation and the activation of survival pathways as well as the formation of new blood vessels and angiogenesis. The administration of bevacizumab, therefore, inhibits microvascular growth and angiogenesis and is used for this purpose in the setting of cancer treatment to inhibit malignant cell growth and blood vessel formation.
Bevacizumab administration is via intravenous (IV) infusion. It should not be given as an IV bolus or mixed with dextrose. The first infusion should be over 90 minutes and subsequent infusions over 60 minutes if the first infusion is well tolerated. Additional infusions can be given over 30 minutes if the patient tolerates the 60-minute infusion well. Bevacizumab is also given off-label as an intravitreal injection for certain ophthalmic conditions. It has an elimination half-life of approximately 20 days in adults (range 11 to 50 days) and 12 days in pediatric patients (range 4 to 15 days) for IV infusions. It has an elimination half-life of 5 to 10 days when given as an intravitreal injection. Bevacizumab comes in 100 mg and 400 mg solutions in 4 mL and 16 mL, respectively.
The following adverse effects (AEs) were observed in greater than 10% of patients receiving bevacizumab, both as a single agent and in combination with other chemotherapy agents including paclitaxel, carboplatin, interferon alfa, fluorouracil, and others:
Hypertension (19% to 42%), venous thromboembolism (secondary: 21%; with oral anticoagulants), peripheral edema (15%), hypotension (7% to 15%), venous thromboembolism (8% to 14%)
Central nervous system-related AEs
Fatigue (33% to 82%), pain (8% to 62%), headache (22% to 49%), dizziness (13% to 26%), insomnia (21%), taste disorder (14% to 21%), peripheral sensory neuropathy (17% to 18%), anxiety (17%), myasthenia (13%)
Alopecia (6% to 32%), exfoliative dermatitis (23%), palmar-plantar erythrodysesthesia (11%)
Ovarian failure (34%), hyperglycemia (26% to 31%), hypomagnesemia (24% to 27%), weight loss (15% to 21%), hyponatremia (17% to 19%), hypoalbuminemia (11% to 16%), hypocalcemia (12%)
Nausea (72%), abdominal pain (33% to 61%), vomiting (33% to 52%), anorexia (35% to 43%), constipation (40%), diarrhea (21% to 39%), decreased appetite (34% to 35%), stomatitis (15% to 33%), gastrointestinal hemorrhage (19% to 24%), dyspepsia (17% to 24%), mucosal inflammation (13% to 15%)
Thrombocytopenia (5% to 58%), hemorrhage (40%), leukopenia (grades 3/4: 37%), pulmonary hemorrhage (4% to 31%), neutropenia (12%; grades ≥3: 8% to 27%, grade 4: 27%), bruise (17%), lymphocytopenia (12%)
Arthralgia (28% to 45%), myalgia (19% to 29%), limb pain (25%), back pain (12% to 21%), dysarthria (8% to 14%)
Increased serum creatinine (13% to 16%)
Epistaxis (17% to 55%), upper respiratory tract infection (40% to 47%), cough (26% to 30%), dyspnea (25% to 30%), allergic rhinitis (17%), oropharyngeal pain (16%), sinusitis (7% to 15%), nasal sign and symptoms (mucosal disorder: 14%)
Infection (55%), postoperative wound complication (1% to 15%), Proteinuria (4% to 36%), urinary tract infection (22%), pelvic pain (14%)
Additional serious adverse reactions
Gastrointestinal (GI) fistulae, non-GI fistulae, arterial thromboembolic events, venous thromboembolic events, severe hypertension, posterior reversible encephalopathy syndrome, proteinuria, infusion reactions, and ovarian failure.
US FDA boxed warnings
Gastrointestinal perforations: Gastrointestinal (GI) perforations, some fatal, have been seen in patients treated with bevacizumab. It should be discontinued in patients with GI perforations. Most cases occurred within 50 days of treatment initiation. In particular, GI perforations were observed in platinum-resistant ovarian cancer patients.
Hemorrhage: Serious or fatal hemorrhage, including GI bleeding, central nervous system hemorrhage, vaginal bleeding, hemoptysis, and epistaxis, occur up to five times more frequently in patients receiving bevacizumab. These reports have primarily been in patients with non-small cell lung cancer with squamous cell histology. Intracranial hemorrhage has been observed in patients previously treated for glioblastoma.
Surgery and wound healing complications: The incidence of wound healing and surgical complications, including both serious and fatal complications, is increased in patients treated with bevacizumab. It should not be given for the 28 days before an elective surgical procedure or for at least 28 days following surgery or until complete healing of the surgical wounds.
Monitoring for signs of an infusion reaction is necessary during infusions with bevacizumab. Additional monitoring includes CBC with differential, blood pressure monitoring every 2 to 3 weeks, and tracking for proteinuria. Additionally, patients require monitoring for signs of GI perforation, fistula, bleeding, epistaxis, and both arterial and venous thromboembolism. When bevacizumab is used off-label for diabetic macular edema, clinicians should watch for intraocular pressure, visual acuity, and signs of cataracts and retinal detachment. US FDA boxed warnings include GI perforation, severe or fatal hemorrhage, and surgery and wound healing complications. Additional serious adverse reactions include GI fistulae, non-GI fistulae, arterial thromboembolic events, venous thromboembolic events, severe hypertension, posterior reversible encephalopathy syndrome, proteinuria, infusion reactions, and ovarian failure.
Researchers have not yet conducted extensive mutagenicity and carcinogenicity studies. Administration of bevacizumab in monkeys showed adverse effects on general growth and development, fertility, and wound healing. Teratogenicity is suspected based on studies in rabbits. There is no recommended treatment or antidote for an overdose of bevacizumab.
Enhancing Healthcare Team Outcomes
Bevacizumab is usually only prescribed by certain clinicians, including the oncologist, rheumatologist, ophthalmologist, and immunologist. However, the performance monitoring of patients treated with bevacizumab is by nurses. Monitoring for signs of an infusion reaction is necessary during infusions with bevacizumab; this will largely be the responsibility of the nursing staff. Additional monitoring includes CBC with differential, blood pressure monitoring every 2 to 3 weeks, and monitoring for proteinuria. Additionally, patients should be watched for signs of GI perforation, fistula, bleeding, epistaxis, and both arterial and venous thromboembolism.
US FDA boxed warnings include GI perforation, serious or fatal hemorrhage, and surgery, and wound healing complications. The pharmacist needs to educate the patient on the drug and its potential benefits and toxicity. Pharmacists must also examine bevacizumab in the context of the patient's overall drug regimen, and report any interactions or concerns to the treating physician. Challenging cases may require an oncology certified pharmacy practitioner. Communication between the clinicians who prescribe, dispense, and administer this agent is vital to prevent serious adverse effects. Bevacizumab requires all members of the interprofessional healthcare team to collaborate and communicate to optimize therapy and minimize adverse reactions. [Level V]