Avastin (Bevacizumab)

Avastin (Bevacizumab) is a recombinant humanized monoclonal IgG1 antibody that binds to and inhibits the biologic activity of human vascular endothelial growth factor (VEGF) in vitro and in vivo assay systems.

Bevacizumab contains human framework regions and the complementarily determining regions of a murine antibody that binds to VEGF.

Mechanism of action:

Bevacizumab binds VEGF and prevents the interaction of VEGF to its receptors (Flt-1 and KDR) on the surface of endothelial cells. The interaction of VEGF with its receptors leads to endothelial cell proliferation and new blood vessel formation in vitro models of angiogenesis. Administration of Bevacizumab to xenotransplant models of colon cancer in nude (athymic) mice caused reduction of microvascular growth and inhibition of metastatic disease progression.

Uses:

Metastatic carcinoma of the colon or rectum.

Unresectable, locally advanced, recurrent or metastatic non-squamous, non-small cell lung cancer

Indication and usage:

Avastin, in combination with intravenous (infusion) 5-fluorouracil–based chemotherapy, is indicated for first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum. Avastin, in combination with carboplatin and paclitaxel, is indicated for first line treatment of patients with unresectable, locally advanced, recurrent or metastatic non-squamous, non-small cell lung cancer.

Initiation of therapy:

Avastin should be started at least 28 days following major surgery when the surgical incision is completely healed.

Dose and administration:

Avastin is supplied in 100 mg and 400 mg preservative-free, single use vials to deliver 4 mL or 16 mL of Avastin (25 mg/mL).

The first dose is given slowly, usually over about 90 minutes. If tolerated the second dose is given over 60 minutes and 30 minutes thereafter with special precautions to possible infusion reactions.

It is important to keep in mind that Bevacizumab is proved to give statistically significant superior results (mainly in term of progression free survival PFS) when added to active regimens. This means that there are no data support the addition of Bevacizumab Avastin to a regimen that already showed no activity and gave no response. Bevacizumab augment the activity and does not transform inactive regiments into active ones.

Metastatic Carcinoma of the Colon or Rectum

Avastin, used in combination with intravenous 5-FU-based chemotherapy (infusion 5FU), is administered as an intravenous infusion (5 mg/kg or 10 mg/kg) every 14 days.

Avastin that was used in combination with bolus-IFL, was given at a dose of 5 mg/kg. It is important to note that the IFL is removed from the recent 2007 colorectal treatment guidelines due to its toxicity profile and lower efficacy (NCCN).

The recommended dose of Avastin, when used in combination with Oxaliplatin (XELOX and FOLFOX) or Irinotecan (FOLFIRI)based regimens, is 10 mg/kg every two weeks.

Non-Squamous, Non-Small Cell Lung Cancer

Avastin is given at a dose of 15 mg/kg, as an IV infusion every 3 weeks.

Toxicity:

The most serious toxicities of Bevacizumab are:

Gastrointestinal Perforations:

The typical presentation was reported as abdominal pain associated with symptoms such as constipation and vomiting and most events were reported within the first 50 days. The incidence of gastrointestinal perforation (gastrointestinal perforation, fistula formation, and/or intra-abdominal abscess) was 2.4% and 0.9% in patients with colorectal cancer and non-small cell lung cancer (NSCLC), respectively. Therapy should be permanently discontinued. A large review of clinical trials suggested that the overall risk for GI perforation is 1.5% and that GI perforation risk was higher in in patients who have the primary tumor intact, a recent history of sigmoidoscopy or colonoscopy, or previous adjuvant radiotherapy.

Arterial thrombotic events:

There is a small although a statically significant increase in transient ischemic attacks, angina or stokes. Patients with high risk should be well evaluated before they receive Bevacizumab and is considered a relative contraindication.

Wound Healing Complications

Some cases with fetal wound dehiscence occurred following Avastin administration thus the interval between subsequent elective surgery and termination of Avastin to avoid the risks of impaired wound healing/wound is (approximately) 20 days, although not definitely determined.

Hemorrhage

The reason behind excluding the squamous cell type of lung cancer from Bevacizumab indications was the high incidence of severe or fatal hemoptysis, which was 31%. Patients with recent hemoptysis (≥1/2 tsp of red blood) are not given Avastin. Other bleeding forms were reported in different studies and some were fatal.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS)

A post marketing reported complication is RPLS (with an incidence of <0.1%), which present with headache, seizure, lethargy, confusion, blindness and other visual and neurological disturbances. The onset of symptoms seems to occur from 16 hours to 1 year after initiation of Avastin. The safety to reinitiate Avastin after recovery is still equivocal.

Hypertension is common side effect that is usually mild and may be a sign for diagnosis of RPLS. Most antihypertensive agents are effective. Safety of reinitiating AVASTIN therapy in patients previously experiencing RPLS is not known.

When to discontinue therapy:

Permanent Avastin discontinuation in patients who develop gastrointestinal perforation, wound dehiscence requiring medical intervention, serious bleeding, a severe arterial thromboembolic event, nephrotic syndrome, hypertensive crisis or hypertensive encephalopathy. In patients developing RPLS, discontinue treatment, evaluate patients, confirm diagnosis and manage hypertension.

On the other hand temporary suspension of Avastin is recommended in patients with evidence of moderate to severe proteinuria till complete evaluation and in patients.

Refrences:

The information contained in this page is based on factsheet which is prodived by relaible sources which you can visit for more information like:

- FDA website.
- National Comprehensive Cancer Network NCCN.