Bevacizumab


Article Author:
Valerie Gerriets


Article Editor:
Anup Kasi


Editors In Chief:
Sebastiano Cassaro
Joseph Lee
Tanya Egodage


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Frank Smeeks
Kristina Soman-Faulkner
Trevor Nezwek
Radia Jamil
Patrick Le
Sobhan Daneshfar
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Pritesh Sheth
Hassam Zulfiqar
Navid Mahabadi
Steve Bhimji
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Nazia Sadiq
Hajira Basit
Phillip Hynes
Tehmina Warsi


Updated:
3/5/2019 5:06:59 PM

Indications

Bevacizumab is a humanized monoclonal antibody against vascular endothelial growth factor A (VEGF-A) and is used for the treatment of the below conditions.  It is typically used in combination with other chemotherapy agents.[1][2][3][4][5]

FDA-approved indications

  1. Cervical cancer: Bevacizumab is approved for use for the treatment of recurrent, persistent or metastatic cervical cancer in combination with paclitaxel and either cisplatin or topotecan.
  2. Metastatic colorectal cancer: Bevacizumab is used as a first-line or second-line therapy for metastatic colorectal cancer when used in combination with fluorouracil (FU)-based chemotherapy regimens. 
  3. Glioblastoma: Bevacizumab is approved as a single agent in patients with progressive glioblastoma following previous therapy.
  4. Non-squamous non-small cell lung cancer (NSCLC): Bevacizumab is used as a first-line treatment in combination with carboplatin and paclitaxel for recurrent, locally advanced, unresectable or metastatic nonsquamous non-small cell lung cancer. 
  5. Ovarian, fallopian tube or primary peritoneal cancer: Bevacizumab is approved for 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. 
  6. Metastatic renal cell carcinoma: Bevacizumab is approved for the treatment of metastatic renal cell carcinoma in combination with interferon alfa.  

Off-label indications

  1. Metastatic breast cancer
  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

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.

Administration

Bevacizumab is administered as an intravenous (IV) infusion.  It should not be given as an IV bolus or mixed with dextrose. The first infusion should be administered over a 90-minute period and subsequent infusions over 60 minutes if the first infusion is well tolerated.  Additional infusions can be given over a 30-minute period if the 60-minute infusion is well tolerated. 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.

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:

Cardiovascular-related AEs

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%)

Dermatology-related AEs

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

Endocrine-related AEs

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%)

Gastrointestinal-related AEs

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-related AEs

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%)

Musculoskeletal-related AEs

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

Renal-related AEs

Increased serum creatinine (13% to 16%)

Respiratory-related AEs

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%)

Miscellaneous AEs

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.[6][7][8][9]

US 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, occurs 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 prior to an elective surgical procedure or for at least 28 days following surgery or until the surgical wounds are completely healed.

Contraindications

There are currently no contraindications listed for bevacizumab.

Monitoring

Monitoring for signs of an infusion reaction is needed during infusions with bevacizumab. Additional monitoring includes CBC with differential, blood pressure monitoring every 2 to 3 weeks and monitoring for proteinuria. Additionally, patients should be monitored for signs of GI perforation, fistula, bleeding, epistaxis and both arterial and venous thromboembolism.  When bevacizumab is used off-label for diabetic macular edema, intraocular pressure, visual acuity, and signs of cataracts and retinal detachment should be monitored. US boxed warnings include GI perforation, serious 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.

Toxicity

Mutagenicity and carcinogenicity studies have not been extensively conducted. 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 healthcare workers including the oncologist, rheumatlogist, ophthalmologist and immunologist. However, the monitoring of patients treated with bevacizumab is by nurses.Monitoring for signs of an infusion reaction is needed during infusions with bevacizumab. Additional monitoring includes CBC with differential, blood pressure monitoring every 2 to 3 weeks and monitoring for proteinuria. Additionally, patients should be monitored for signs of GI perforation, fistula, bleeding, epistaxis and both arterial and venous thromboembolism. 

US boxed warnings include GI perforation, serious or fatal hemorrhage, and surgery and wound healing complications. It is important for the pharmacist to educate the patient on the drug and its potential benefits and toxicity.


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Bevacizumab - Questions

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Which of the following drugs has been indicated for the treatment of metastatic colon cancer?



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Which medication is used to treat metastatic colon cancer?



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What agent has been proven partially effective as an adjuvant treatment for colorectal cancer in a patient with unresectable metastases?



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A patient is being treated for small cell lung cancer with chemotherapy and radiation. She develops a tracheoesophageal fistula. Which drug likely was combined with the chemotherapy and radiation?



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Bevacizumab is used in the treatment of which of the following?



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A 34-year old man with colon cancer was treated with a chemotherapy regimen consisting of leucovorin, fluorouracil, oxaliplatin, and bevacizumab. Soon after, the patient reported that he has been experiencing excessive bleeding and wounds were not healing as expected. Which drug was likely to be responsible for these side effects?



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A 42-year-old patient with cervical cancer is taking a combination of four chemotherapy agents for her recurrent disease. One of these agents is a drug that inhibits the interaction of VEGF-A with the VEGF receptor. Which of the following answer choices best describes this drug?



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A 45-year-old patient with cervical cancer is taking a combination of four chemotherapy agents for her recurrent disease. One of these agents is a humanized monoclonal antibody. Which of the following answer choices best describes this drug?



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A 36-year-old man with colon cancer was treated with a chemotherapy regimen consisting of leucovorin, fluorouracil, oxaliplatin and a monoclonal antibody against VEGF-A. Which of the following drugs best fits this description?



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A 36-year-old man with colon cancer was treated with a chemotherapy regimen consisting of leucovorin, fluorouracil, oxaliplatin and a drug with side effects of impaired wound healing, hemorrhage, and gastrointestinal perforation. Which of the following drugs best fits this description?



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Bevacizumab - References

References

Kandasamy R,Constantinou M,Rogers SL,Sandhu SS,Wickremasinghe S,Al-Qureshi S,Lim LL, Prospective randomised clinical trial of intravitreal bevacizumab versus triamcinolone in eyes with diabetic macular oedema undergoing cataract surgery: 6-month results. The British journal of ophthalmology. 2019 Feb 28;     [PubMed]
Marchetti C,Muzii L,Romito A,Benedetti Panici P, First-line treatment of women with advanced ovarian cancer: focus on bevacizumab. OncoTargets and therapy. 2019;     [PubMed]
Perdrizet K,Leighl NB, The Role of Angiogenesis Inhibitors in the Era of Immune Checkpoint Inhibitors and Targeted Therapy in Metastatic Non-Small Cell Lung Cancer. Current treatment options in oncology. 2019 Feb 18;     [PubMed]
Belin PJ,Lee AC,Greaves G,Kosoy J,Lieberman RM, The use of bevacizumab in pediatric retinal and choroidal disease: A review. European journal of ophthalmology. 2019 Feb 13;     [PubMed]
Zhuang H,Shi S,Yuan Z,Chang JY, Bevacizumab treatment for radiation brain necrosis: mechanism, efficacy and issues. Molecular cancer. 2019 Feb 7;     [PubMed]
Alshaikh OM,Asa SL,Mete O,Ezzat S, An Institutional Experience of Tumor Progression to Pituitary Carcinoma in a 15-Year Cohort of 1055 Consecutive Pituitary Neuroendocrine Tumors. Endocrine pathology. 2019 Jan 31;     [PubMed]
Kini SD,Yiu DW,Weisberg RA,Davila JF,Chelius DC, Bevacizumab as Treatment for Epistaxis in Hereditary Hemorrhagic Telangiectasia: A Literature Review. The Annals of otology, rhinology, and laryngology. 2019 Jan 29;     [PubMed]
Belgioia L,Desideri I,Errico A,Franzese C,Daidone A,Marino L,Fiore M,Borghetti P,Greto D,Fiorentino A, Safety and efficacy of combined radiotherapy, immunotherapy and targeted agents in elderly patients: A literature review. Critical reviews in oncology/hematology. 2019 Jan;     [PubMed]
Kaveh S,Ebrahimi P,Rezapour A,Mozafari M,Sayehmiri K, Bevacizumab and erlotinib versus bevacizumab for colorectal cancer treatment: systematic review and meta-analysis. International journal of clinical pharmacy. 2019 Feb;     [PubMed]

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