Bevacizumab is a recombinant humanised monoclonal antibody that has been trialled for a variety of indications including colorectal, breast, ovarian, renal cell cancers, non-squamous non-small cell lung cancer and glioma. Bevacizumab inhibits angiogenesis which in turn inhibits tumour growth and the spread of cancer.

Angiogenesis, the complex formation of new blood vessels, is a normal physiological process that is essential in tissue growth, foetal development, and wound healing. Existing blood vessels are also remodelled and expanded. Angiogenesis is essential for the growth of tumours over 1-2mm in diameter. It also aids the spread of cancer to other parts of the body (metastasis).

Angiogenesis facilitates the delivery of essential components and is triggered by multiple stimuli including oxygen and glucose deprivation in cells. Anti-angiogenic factors are also released during normal physiological regulating processes. This balance is disrupted in cancer cells, which favour angiogenesis and the spread of the cancer.

Diseased or injured cells release multiple growth factors including proangiogenic Vascular Endothelial Growth Factor (VEGF). VEGF binds to receptors on the endothelial cells that line the interior surface of blood vessels and promotes permeability and cell growth, making more nutrients available to tumour cells. The VEGF receptor pathways also promote cell survival, cell migration and the production of tissue factors.

Bevacizumab binds to, and neutralises, the VEGF receptors to inhibit tumour growth and metastasis. VEGF is overexpressed in cancer cells, resulting in bevacizumab’s preferential action in tumour cells, making it a targeted therapy.

Multiple drug regimens are often more effective, and thus preferred, over monotherapy for cancer treatment, however the adverse effects may multiply. As the side effect profiles of targeted therapies like bevacizumab differ from traditional chemotherapies, they can be successfully added to many existing regimens without exacerbating adverse effects, making them an ideal choice.

Although different from chemotherapy, bevacizumab still has many potential adverse effects; increased risk of blood clots, bleeding, low blood cell counts, diarrhoea, impaired wound healing, anorexia, weakness, myalgia, dizziness, pain, headache, hypertension, proteinuria, fever and an increased risk of thromboembolic events including stroke, heart attack and angina. Serious side effects include osteonecrosis of the jaw, pulmonary hypertension, nasal septum perforation, gastro-intestinal perforation, hypertensive encephalopathy and reversible posterior leukoencephalopathy syndrome. Patients may experience hypersensitivity reactions including shortness of breath or anaphylaxis.

Infusion related reactions may include high or low blood pressure, flushing and chest pain. If any serious adverse effects occur, the infusion should be stopped immediately.

Elderly patients are more at risk of some adverse effects including thromboembolic events, neutropenia and diarrhoea. Extreme caution should be taken in patients with heart failure as there is some evidence that bevacizumab may increase the risk of heart failure.

It is not recommended in patients with recent pulmonary haemorrhage, active hypertension, a history of thromboembolic disease, or in combination with bisphosphonates. Patients should be monitored for signs of central nervous system (CNS) haemorrhage, and caution used in those with untreated CNS metastases.

As bevacizumab may reduce wound healing, discontinue it at least 6-8 weeks before, and until four weeks following major surgery, or until the wound has properly healed. Bevacizumab has not been studied in pregnancy, breastfeeding, or in paediatric patients. It may impair female fertility (possibly reversibly) and is embryotoxic and teratogenic in animals.

Pregnancy is not recommended during treatment because angiogenesis is a process of foetal development. Women should use contraception, and avoid breastfeeding for at least six months following treatment.

Bevacizumab can interact with other medications; it increases the incidence of severe and febrile neutropenia when combined with other myelosuppressive chemotherapy. Care should be exercised when bevacizumab is combined with platinum and taxane based chemotherapy regimens as fatalities have occurred.

It was investigated combined with sunitinib to treat metastatic renal cell carcinoma. However multiple patients developed potentially serious microangiopathic haemolytic anaemia which can be very serious, but all reversed on discontinuation of therapy.

If an initial intravenous infusion of bevacizumab is well tolerated over 90 minutes, it may be reduced to 60 minutes, and again to 30 minutes, for subsequent treatments. Specialist protocols should be referred to for administration and dosing recommendations.

Current data only supports bevacizumab being cost effective, and subsidised by the Pharmaceutical Benefits Scheme (PBS), for use in patients with previously untreated metastatic colorectal cancer, who must also receive first-line chemotherapy.

In over half of colorectal cancers, VEGF is overexpressed. Higher amounts of VEGF expression correlates to a worse prognosis. Adding bevacizumab to first-line chemotherapy improves progression-free survival and overall survival. It has been trialled in combination with several first-line treatments including fluorouracil plus oxaliplatin, irinotecan, or capecitabine.

Trials of bevacizumab, in combination with paclitaxel for first-line treatment of locally recurrent or metastatic breast cancer, showed improved progression-free survival (and also overall survival, but this was not statistically significant). It is only indicated as a first-line treatment of metastatic breast cancer, combined with paclitaxel, for patients where anthracycline medications are contraindicated.

Bevacizumab combined with paclitaxel has not been compared with anthracycline protocols, or investigated as second or third-line treatment at this stage. Further research for bevacizumab use in breast cancer is required.

Patients with advanced, metastatic or recurrent non-small cell lung cancer (excluding those with predominantly squamous cell histology) were trialled with bevacizumab in combination with carboplatin and paclitaxel. The bevacizumab treatment group had a statistically significant increase in overall survival compared with patients using chemotherapy alone. Though promising, further research is required to confirm the benefit of bevacizumab in these patients.

Trials combining bevacizumab with interferon alfa-2a monotherapy for advanced and/or metastatic renal cell cancer, achieved statistically significant secondary endpoints of improved progression-free survival and objective tumour response rates.

However, the overall improvement in survival (the primary endpoint) of two months in the bevacizumab group was not statistically significant.

Bevacizumab was studied, in patients with grade four glioma, in combination with irinotecan or with radiotherapy and temozolomide. It improved the six month progression-free survival and objective response rate, and is approved for use in patients with grade four glioma who have relapsed or have disease progression after chemotherapy and other standard therapies.

Investigation into the treatment of epithelial ovarian, fallopian tube, and primary peritoneal cancers showed bevacizumab, in combination with carboplatin plus paclitaxel or gemcitabine, increases progression-free survival.

However, statistically there wasn’t a significant increase in overall survival. Bevacizumab’s place in therapy for the treatment of these cancers requires more investigation. It has also been trialled for adjuvant colon cancer, but more relapses and deaths due to disease progression were observed. This is not an indication for bevacizumab.

Bevacizumab is a targeted therapy which shows encouraging results in the treatment of many solid tumours. The introduction of new anticancer therapies with new mechanisms of action allows cancer treatment to be more dynamic. The combination of chemotherapy and targeted therapies can improve treatment outcomes.

Bevacizumab is currently only PBS subsidised for metastatic colorectal cancer. Further research is required to demonstrate the benefits of this medication for other indications.

References:

  1. Avastin (bevacizumab) Australian approved product information. Sydney: Roche. Approved 24 February 2005.
  2. eMims [internet]. New South Wales: UBM Medica Australia Pty Ltd; 2013. Accessed 15 February 2013.
  3. Gray R, Bhattacharya S, Bowden C, Miller K, Comis RL. Independent review of e2100: a phase iii trial of bevacizumab plus paclitaxel versus paclitaxel in women with metastatic breast cancer. J Clin Oncol 2009; 27(30): 4966-72.
  4. Rossi S, editor. Australian Medicines Handbook 2013. Adelaide: Australian Medicines Handbook Pty Ltd; 2013.
  5. Shih T. Bevacizumab: An angiogenesis inhibitor for the treatment of solid malignancies. Clin Ther 2006; 28(11): 1779-1802.
  6. Wagner ADADW, Arnold D, Grothey AAG, Haerting J, Unverzagt S. Anti-angiogenic therapies for metastatic colorectal cancer. Cochrane Db Syst Rev 2009, Issue 3. Art. No.: CD005392.
  7. Welch S, Spithoff K, Rumble RB, Maroun J, Gastrointestinal Cancer Disease Site Group. Bevacizumab combined with chemotherapy for patients with advanced colorectal cancer: a systematic review. Ann Oncol 2010; 21(6): 1152-62.

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