Continuing Education Activity

Bevacizumab is a humanized monoclonal antibody against vascular endothelial growth factor A (VEGF-A). It is used to treat several different cancers (cervical cancer, metastatic colorectal cancer, glioblastoma, non-squamous non-small cell lung cancer, ovarian, fallopian tube, primary peritoneal cancer, metastatic renal cell carcinoma, and hepatocellular carcinoma ). The administration of bevacizumab inhibits microvascular growth and angiogenesis and is used in cancer treatment to inhibit malignant cell growth and blood vessel formation. It is usually administered 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.

Objectives:

• Identify the approved indications for bevacizumab.
• Summarize the mechanism of action of bevacizumab.
• Review the potential adverse events of bevacizumab.
• Outline interprofessional team strategies for improving care coordination and communication to advance bevacizumab and improve outcomes in cancer treatment.

Indications

Bevacizumab is a humanized monoclonal antibody against vascular endothelial growth factor A (VEGF-A) and is used to treat the below conditions. Its use is typically in combination with other chemotherapy agents.[1][2][3]

FDA-approved Indications

1. Cervical cancer: Bevacizumab has approval for treating recurrent, persistent, or metastatic cervical cancer in combination with paclitaxel and either cisplatin or topotecan.
2. Metastatic colorectal cancer: Bevacizumab is a first-line or second-line therapy for metastatic colorectal cancer combined with fluorouracil (FU)-based chemotherapy regimens. 
3. Glioblastoma: Bevacizumab has approval as a single agent in patients with progressive glioblastoma following previous therapy.
4. Non-squamous non-small cell lung cancer (NSCLC): Bevacizumab is a first-line treatment combination with carboplatin and paclitaxel for recurrent, locally advanced, unresectable, or metastatic non-squamous non-small cell lung cancer.[4]
5. Ovarian, fallopian tube, or primary peritoneal cancer: Bevacizumab has approved the treatment of platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer in combination with a carboplatin chemotherapy regimen or the treatment of platinum-resistant disease in combination with paclitaxel, doxorubicin, or topotecan.[5]
6. Metastatic renal cell carcinoma: Bevacizumab has received approval to treat metastatic renal cell carcinoma in combination with interferon alfa.  
7. Hepatocellular carcinoma (HCC): Bevacizumab, in combination with atezolizumab, is indicated for treating unresectable metastatic hepatocellular carcinoma patients.[6]

Off-label Indications

1. Metastatic breast cancer[7]
2. Endometrial cancer
3. Angiosarcoma
4. Gliomas
5. Malignant pleural mesothelioma
6. Medulloblastoma (pediatric)
7. Diabetic macular edema
8. Age-related macular degeneration
9. Hemangiopericytoma and malignant solitary fibrous tumor
10. Hereditary hemorrhagic telangiectasia[8]

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, the activation of survival pathways, and the formation of new blood vessels and angiogenesis. Therefore, the administration of bevacizumab inhibits microvascular growth and angiogenesis and is used in cancer treatment to inhibit malignant cell growth and blood vessel formation.[9]

Pharmacokinetics

Absorption: A PK study concluded bevacizumab follows linear pharmacokinetics and is expected to reach 90% of steady-state concentration by 84 days.[10]

Distribution: The volume of distribution is 2.9 L. After correcting for body weight, males have a larger central volume of distribution (3.2 L vs. 2.7 L) than females.[11]

Metabolism: The metabolism of bevacizumab is likely identical to endogenous antibodies like IgG, i.e., by proteolytic catabolism, involving non-specific elimination pathways and target-mediated elimination by VEGF-expressing cells. Hence it doesn't affect the activity of drug-metabolizing enzymes in the liver.[12][13]

Elimination: The mean clearance is 0.23 L/day. After correcting for body weight, clearance is approximately 26% higher in men than in women. The estimated half-life is 20 days. The clearance of bevacizumab alters by body weight, sex, and tumor burden. Clearance is reduced with increased albumin and reduced alkaline phosphatase.[10][11]

Administration

Bevacizumab administration is via intravenous (IV) infusion. Bevacizumab comes in 100 mg and 400 mg solutions in 4 mL and 16 mL, respectively.[14] 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. There are many different dosing regimens based on the type of cancer treated; most fall between 5 mg to 15 mg/kg body weight on a cyclical treatment schedule (14 or 21 days), also depending on the type of cancer being treated.[15] Bevacizumab is also given off-label as an intravitreal injection for ophthalmic conditions such as macular edema and age-related macular degeneration.[16]

Use in Specific Patient Populations

Patients with Hepatic Impairment: No information about dose adjustment is provided in the manufacturer's labeling. Based on the literature review, no dose adjustment is likely needed in hepatic impairment.[17]

Patients with Renal Impairment: No dose adjustment is suggested for renal impairment. However, nephrotoxicity manifested by proteinuria and nephrotic syndrome has been reported in the literature. Bevacizumab administration should be temporarily withheld if 24-hour urine protein levels are >2 g, and it should be resumed when levels are <2 g. Treatment discontinuation is recommended in nephrotic syndrome.[18]

Pregnancy Considerations: Dysregulation of VEGF due to bevacizumab therapy is associated with preeclampsia. Case reports suggest that preeclampsia resolved on discontinuation of bevacizumab.[19] In addition, VEGF plays a role in maintaining the corpus luteum and amniotic fluid regulation. Hence clinicians should perform a risk-benefit evaluation, and pregnant mothers should be informed regarding the risk of bevacizumab therapy during pregnancy.[20] 

Women of childbearing age should be informed regarding the potential adverse effects of intravitreal bevacizumab on fetal health and should be encouraged to use proper contraceptive methods during treatment. Intravitreal bevacizumab should be avoided, particularly during the first trimester, as susceptibility to teratogens is maximum during organogenesis (3 to 8 weeks postconception).[21]

Breastfeeding Considerations: Bevacizumab has a high molecular weight, and the concentration in milk is likely to be low. However, VEGF is believed to assist in the maturation of the infant's gastrointestinal tract; hence use of VEGF inhibitors during breastfeeding is not advised. In addition, there is a lack of clinical data; hence it is recommended that breastfeeding should be stopped during intravenous bevacizumab treatment and for six months after the last dose due to the possibility of serious drug adverse reactions in breastfed infants. Similarly, intravitreal bevacizumab has the longest half-life of the VEGF inhibitors used in eye disorders, and an alternate intravitreal agent(Aflibercept, ranibizumab) may be preferred.[22]

Adverse Effects

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[23][24]:

Cardiovascular

• Hypertension (19% to 42%), venous thromboembolism (secondary: 21%; with oral anticoagulants), peripheral edema (15%), hypotension (7% to 15%)

Central Nervous System

• 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%)

Dermatology

• Alopecia (6% to 32%), exfoliative dermatitis (23%), palmar-plantar erythrodysesthesia (11%)

Endocrine

• Hyperglycemia (26% to 31%), hypomagnesemia (24% to 27%), weight loss (15% to 21%), hyponatremia (17% to 19%), hypoalbuminemia (11% to 16%), hypocalcemia (12%)

Gastrointestinal

• 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%)

Hematology

• Thrombocytopenia (5% to 58%),  leukopenia (grades 3/4: 37%), neutropenia (12%; grades ≥3: 8% to 27%, grade 4: 27%), bruise (17%), lymphocytopenia (12%)

Musculoskeletal

• Arthralgia (28% to 45%), myalgia (19% to 29%), limb pain (25%), back pain (12% to 21%), dysarthria (8% to 14%)

Renal

• Increased serum creatinine (13% to 16%)

Respiratory

• 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%)

Miscellaneous

• Infection (55%), urinary tract infection (22%), pelvic pain (14%)

Warnings and Precautions

• 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 ovarian cancer patients.[25] The incidence of GI complications is highest in patients with cervical cancer.[26][27] Discontinue bevacizumab in patients who develop gastrointestinal perforation and tracheoesophageal fistula.[28][29]

• 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 non-small cell lung cancer patients with squamous cell histology and a history of hemoptysis (grade ≥2).[30] Intracranial hemorrhage has been observed in patients previously treated for glioblastoma. The possible mechanism of bevacizumab included disruption of endothelial cell integrity in the tumor microvasculature. Concerns of life-threatening hemorrhage are high, but a retrospective review of 10,598 cancer patients in 57 clinical trials of anti-VEGF treatment, including bevacizumab, indicated that the rate of intracranial hemorrhage in high-grade glioma, and brain metastases, is nominal.[31]

• Surgery and wound healing complications: Incidents of wound healing and surgical complications (including serious and fatal complications) increase in patients treated with bevacizumab. It should not be given for the 28 days before an elective surgical procedure, at least 28 days following surgery, or until complete healing of the surgical wounds. Necrotizing fasciitis has been documented in patients receiving bevacizumab. Discontinue bevacizumab in patients who develop necrotizing fasciitis.[32][33]

• Arterial thromboembolic events (ATE): The risk of cerebral infarction, transient ischemic attacks, myocardial infarction, and angina is higher in patients receiving bevacizumab. In a postmarketing retrospective cohort study involving 2012 patients, acute coronary syndrome and stroke rates were higher two years after intravitreal bevacizumab.[34]

• Severe hypertension: Hypertension occurs as anti-VEGF therapy causes enhanced expression of the pre-pro ET-1 gene, increasing endothelin-1 and decreasing NO bioavailability. Angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, beta-blockers, and calcium channel blockers are all commonly used to treat bevacizumab-induced hypertension. As NO availability is decreased in patients with VEGF inhibitors-induced hypertension, long-acting oral nitrates have been used for refractory hypertension.[35]

• Renal injury and proteinuria: As discussed above, nephrotic syndrome and proteinuria are potential complications of bevacizumab therapy. Nephrotic syndrome requires cessation of bevacizumab treatment, while proteinuria needs temporary discontinuation and monitoring.[18]

• Posterior reversible encephalopathy syndrome (PRES): PRES is a neurological complication characterized by headaches, seizures, visual disturbances, nausea & vomiting associated with hypertension. Discontinuing bevacizumab and blood pressure control is recommended.[36]

• Ovarian failure:   VEGFA is assumed to play an essential role in regulating angiogenesis in the ovary. The incidence of ovarian failure increases in premenopausal women given bevacizumab. Bevacizumab induces ovarian damage; it is likely that this damage is temporary and disappears within the expected drug clearance in most cases. However, frequent and prolonged drug therapy may complicate the toxicity, and fertility may be temporarily or permanently compromised following bevacizumab administration.[37]

• Congestive heart failure: Bevacizumab treatment significantly increases cancer patients' risk of developing CHF. In a meta-analysis, increased risks of developing CHF were observed in patients with breast cancer, renal cell cancer, and glioblastoma. Asymptomatic LVEF dysfunction during bevacizumab therapy should be treated with ACE inhibitors. Discontinuation of bevacizumab is recommended in CHF.[38][39]

Contraindications

There are currently no contraindications listed for bevacizumab. Bevacizumab should not be administered in a dextrose solution due to the formation of insoluble aggregates.[40]

Monitoring

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. Patients also require monitoring for signs of GI perforation, epistaxis, and 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. Monitor for severe hemorrhage, wound healing complications, GI fistulae, non-GI fistulae, hypertension, and ovarian failure.[41] The healthcare team should monitor for signs of fluid overload and heart failure.[39]

Toxicity

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.[42] Infusion reactions can be severe, requiring discontinuation and early therapy for hypersensitivity reactions requires prompt treatment.[43]

Enhancing Healthcare Team Outcomes

Bevacizumab is usually only prescribed by specific clinicians, including oncologists, rheumatologists, ophthalmologists, immunologists, and ophthalmologists. However, the routine monitoring of patients treated with bevacizumab is done 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, patient education by healthcare providers should include risk-benefit evaluation and consideration of severe hypertension, gastrointestinal complications, bleeding tendencies, and arterial and venous thromboembolism.

Warnings and precautions include GI perforation, bleeding, surgery, and wound healing complications. The pharmacist must educate the patient on the drug's 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, pharmacists, and nurses who prescribe, dispense and administer this agent is vital to prevent serious adverse effects. Bevacizumab requires all interprofessional healthcare team members to collaborate and communicate to optimize therapy and minimize adverse reactions. [Level 5]

In addition, a study examined the outcomes of ovarian cancer by patient-centered care through a multidisciplinary, interprofessional approach involving gynecological surgeons, pathologists, oncologists and collaboration with other healthcare professionals, including nurses, radiologists, nuclear medicine physicians, nutritionists, vascular surgeons, urologists, gynecologists, and psychologists can provide valuable input in all the decision-making steps of ovarian cancer management which translates to better patient outcomes.[44] [Level 5]