Avastin

Avastin is a brand name of a cancer medicine called bevacizumab, that is used to treat a certain type of brain tumor, and certain types of cancers of the kidney, lung, colon, rectum, cervix, ovary, or fallopian tube. Avastin is also used to treat cancer of the membrane lining the internal organs in your abdomen. It is usually given as part of a combination of cancer medicines.

Bevacizumab is a humanized monoclonal antibody to human vascular endothelial growth factor A (VEGF-A) and an anti-angiogenesis agent used in the therapy of colorectal, ovarian, renal and brain cancers ¹. Bevacizumab may be partially protective against the vascular hepatic damage caused by other chemotherapeutic agents. Bevacizumab injection (Avastin) is also sometimes used to treat wet age-related macular degeneration (an ongoing disease of the eye that causes loss of the ability to see straight ahead and may make it more difficult to read, drive, or perform other daily activities). Talk to your doctor about the risks of using bevacizumab to treat your condition.

Bevacizumab was approved in the United States in 2004 for use in metastatic colon cancer ¹. Indications were subsequently extended to selected forms of non-small cell lung cancer, breast and renal cancer and glioblastoma. However, the indication for use in breast cancer was withdrawn in 2011 because of lack of evidence that bevacizumab extended overall patient survival.

Bevacizumab is available vials of 100 or 400 mg (25 mg/mL) under the brand name Avastin. The typical dose is 5 to 10 mg/kg intravenously every 2 weeks or 7.5 to 15 mg every three weeks, usually in combination with other antineoplastic agents. Bevacizumab should be administered only by physicians with experience in using antineoplastic agents and managing their major complications.

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.

Bevacizumab has significant adverse side effects. Common adverse events include epistaxis, headache, dizziness, fatigue, hypertension, rhinitis, dry skin, back pain, excessive bleeding and skin rash. Rare complications include bowel, stomach or nasal septum perforation, poor wound healing, hemorrhage, thrombosis, renal dysfunction and ovarian failure. If you experience any of the following symptoms, tell your doctor immediately: difficulty breathing or shortness of breath, chills, shaking, sweating, headaches, chest pain, dizziness, feeling faint, flushing, itching, rash, or hives. Your doctor may need to slow down your infusion, or delay or stop your treatment if you experience these or other side effects.

Avastin treatment

Avastin or Bevacizumab is a humanized monoclonal antibody against vascular endothelial growth factor A (VEGF-A) and is used for the treatment of the below conditions. Avastin use is typically in combination with other chemotherapy agents ².

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 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 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 has approval 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

Avastin mechanism of action

Avastin or Bevacizumab is a recombinant humanized monoclonal IgG1 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. When used in combination with other antineoplastic agents, bevacizumab has been shown to extend both recurrence-free as well as overall patient survival in several forms of advanced cancer ¹.

Avastin special precautions

Before receiving a bevacizumab injection product:

• tell your doctor and pharmacist if you are allergic to bevacizumab, bevacizumab-awwb, any other medications, or any of the ingredients in bevacizumab injection products.
• tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention anticoagulants (blood thinners) such as warfarin (Coumadin, Jantoven); and sunitinib (Sutent). Also tell your doctor if you are taking or if you have ever taken an anthracycline (a type of chemotherapy used for breast cancer and some types of leukemia) such as daunorubicin (Cerubidine), doxorubicin, epirubicin (Ellence), or idarubicin (Idamycin). Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
• tell your doctor if you have ever been treated with radiation therapy to the left side of your chest or pelvis; and if you have or have ever had high blood pressure, or any condition that affects your heart or blood vessels (tubes that move blood between the heart and other parts of the body). Also, tell your doctor if you have recently coughed up blood.
• you should know that bevacizumab injection products may cause infertility in women (difficulty becoming pregnant); however, you should not assume that you cannot get pregnant. Tell your doctor if you are pregnant or plan to become pregnant. You should use birth control to prevent pregnancy during your treatment with a bevacizumab injection product and for at least 6 months after your final dose. If you become pregnant while using a bevacizumab injection product, call your doctor. Bevacizumab may harm the fetus and increase the risk of a pregnancy loss.
• tell your doctor if you are breastfeeding. You should not breastfeed during your treatment with a bevacizumab injection product and for at least 6 months after your final dose.
• tell your doctor if you have recently had surgery or if you plan to have surgery, including dental surgery. If you are scheduled to have surgery, your doctor will stop your treatment with an bevacizumab injection product at least 28 days before the surgery. If you have recently had surgery, you should not receive an bevacizumab injection product until at least 28 days have passed and until the area has completely healed.

Avastin dose

Bevacizumab injection products come as a solution (liquid) to administer slowly into a vein. Bevacizumab injection products are administered by a doctor or nurse in a medical office, infusion center, or hospital. Bevacizumab injection products are usually given once every 2 or 3 weeks. Your dosing schedule will depend on the condition that you have, the other medications you are using, and how well your body responds to treatment.

It should take 90 minutes for you to receive your first dose of a bevacizumab injection product. A doctor or nurse will watch you closely to see how your body reacts to bevacizumab. If you do not have any serious problems when you receive your first dose of a bevacizumab injection product, it will usually take 30 to 60 minutes for you to receive each of your remaining doses of the medication.

Important administration information

• Do not administer Avastin until at least 28 days following surgery and the wound is fully healed.

Monitoring

Monitoring for signs of an infusion reaction is necessary during infusions with bevacizumab. Additional monitoring includes complet blood count (CBC) with differential, blood pressure monitoring every 2 to 3 weeks and monitoring for proteinuria. Additionally, patients require monitoring for signs of gastrointestinal 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 boxed warnings include gastrointestinal perforation, severe or fatal hemorrhage, and surgery and wound healing complications. Additional serious adverse reactions include gastrointestinal fistulae, non-gastrointestinal fistulae, arterial thromboembolic events, venous thromboembolic events, severe hypertension, posterior reversible encephalopathy syndrome, proteinuria, infusion reactions, and ovarian failure.

Metastatic colorectal cancer

The recommended dosage when Avastin is administered in combination with intravenous fluorouracil-based chemotherapy is:

• 5 mg/kg intravenously every 2 weeks in combination with bolus-IFL.
• 10 mg/kg intravenously every 2 weeks in combination with FOLFOX4.
• 5 mg/kg intravenously every 2 weeks or 7.5 mg/kg intravenously every 3 weeks in combination with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy in patients who have progressed on a first-line Avastin-containing regimen.

First-line non-squamous non-small cell lung cancer

• The recommended dosage is 15 mg/kg intravenously every 3 weeks in combination with carboplatin and paclitaxel.

Recurrent glioblastoma

• The recommended dosage is 10 mg/kg intravenously every 2 weeks.

Metastatic renal cell carcinoma

• The recommended dosage is 10 mg/kg intravenously every 2 weeks in combination with interferon alfa.

Persistent, recurrent, or metastatic cervical cancer

• The recommended dosage is 15 mg/kg intravenously every 3 weeks in combination with paclitaxel and cisplatin or in combination with paclitaxel and topotecan.

Epithelial ovarian, fallopian tube or primary peritoneal cancer

• ​Stage III or IV Disease Following Initial Surgical Resection: ​The recommended dosage is 15 mg/kg intravenously every 3 weeks in combination with carboplatin and paclitaxel for up to 6 cycles, followed by Avastin 15 mg/kg every 3 weeks as a single agent for a total of up to 22 cycles or until disease progression, whichever occurs earlier.
• Recurrent Disease:
  • Platinum Resistant:
    • The recommended dosage is 10 mg/kg intravenously every 2 weeks in combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan (every week).
    • The recommended dosage is 15 mg/kg intravenously every 3 weeks in combination with topotecan (every 3 weeks).
  • Platinum Sensitive:
    • The recommended dosage is 15 mg/kg intravenously every 3 weeks, in combination with carboplatin and paclitaxel for 6 to 8 cycles, followed by Avastin 15 mg/kg every 3 weeks as a single agent until disease progression.
    • The recommended dosage is 15 mg/kg intravenously every 3 weeks, in combination with carboplatin and gemcitabine for 6 to 10 cycles, followed by Avastin 15 mg/kg every 3 weeks as a single agent until disease progression.

Avastin side effects

The following side effects were observed in greater than 10% of patients receiving Avastin or bevacizumab, both as a single agent and in combination with other chemotherapy agents including paclitaxel, carboplatin, interferon alfa, fluorouracil, and others:

Cardiovascular-related side effects

• 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 side effects

• 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 side effects

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

Endocrine-related side effects

• 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 side effects

• 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 side effects

• 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 side effects

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

Renal-related side effects

• Increased serum creatinine (13% to 16%)

Respiratory-related side effects

• 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 side effects

• 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 ³.

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, 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.

References

1. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. Bevacizumab (Antineoplastic) [Updated 2017 Sep 26]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK548877
2. 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. Br J Ophthalmol. 2019 Dec;103(12):1753-1758.
3. 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. Endocr. Pathol. 2019 Jun;30(2):118-127.