Bevacizumab
Encyclopedia
Bevacizumab is a drug that blocks angiogenesis
, the growth of new blood vessels. It is commonly used to treat various cancers, including colorectal, lung, breast, kidney, and glioblastomas.
Bevacizumab is a humanized monoclonal antibody that inhibits vascular endothelial growth factor A
(VEGF-A). VEGF-A is a chemical signal that stimulates angiogenesis in a variety of diseases, especially in cancer
. Bevacizumab was the first clinically available angiogenesis inhibitor
in the United States.
Bevacizumab was approved by the U.S. Food and Drug Administration (FDA) for certain metastatic
cancers. It received its first approval in 2004 for combination use with standard chemotherapy
for metastatic colon cancer. While at one point approved for breast cancer
by the FDA, the approval was revoked on .
The approval for breast cancer was controversial, because although there was evidence that it slowed progression of metastatic breast cancer, there was no evidence that it extended life, or improved quality of life, and it caused adverse effects including severe high blood pressure and hemorrhaging. In 2008, the FDA gave bevacizumab provisional approval for metastatic breast cancer, subject to further studies. The FDA's advisory panel had recommended against approval. In July 2010, after new studies, the FDA's advisory panel again recommended against the indication for advanced breast cancer. Genentech requested a hearing, which was granted in June 2011. The FDA finally ruled to withdraw the breast cancer indication in November 2011. FDA approval is only required for Genentech to market a drug for that indication. Doctors can still prescribe it for that indication, although insurance companies are less likely to pay for it.
The drug is still approved for use in Australia.
In the curative setting (adjuvant therapy), clinical studies are still underway in breast cancer and lung cancer. A study released in April 2009 found that bevacizumab is not effective at preventing recurrences of non-metastatic colon cancer following surgery. In May 2009, it received FDA approval for treatment of recurring glioblastoma multiforme
, while treatment for initial growth is still in phase III clinical trial.
growth by preventing the formation of new blood vessels by targeting and inhibiting the function of a natural protein called vascular endothelial growth factor
(VEGF) that stimulates new blood vessel formation.
The drug was first developed as a genetically engineered version of a mouse antibody that contains both human and mouse components. Genentech is able to produce the antibody in production-scale quantities.
when used with standard chemotherapy treatment (as first-line treatment) and with 5-fluorouracil-based therapy for second-line metastatic colorectal cancer. This recommendation was based on E3200 trial - addition of bevacizumab to oxaliplatin/5-FU/leucovorin (FOLFOX4) therapy.
It was approved by the EMEA
in January 2005 for use in colorectal cancer
.
A subsequent European clinical trial, AVAiL, was first reported in 2009 and confirmed the significant improvement in progression-free survival shown in E4599 (Reck, et al. Ann. Oncol. 2010). An overall survival benefit was not demonstrated in patients treated with bevacizumab; however, this may be due to the more limited use of bevacizumab as maintenance treatment in AVAiL versus E4599 (this differential effect is also apparent in the European vs US trials of bevacizumab in colorectal cancer: Tyagi and Grothey, Clin Colorectal Cancer, 2006). As an anti-angiogenic agent, there is no mechanistic rationale for stopping bevacizumab before disease progression. Stated another way, the survival benefits achieved with bevacizumab can only be expected when used in accordance with the clinical evidence: continued until disease progression or treatment-limiting side effects.
Another large European-based clinical trial with bevacizumab in lung cancer, AVAPERL, was reported in October 2011 (Barlesi, et al. ECCM 2011). First-line patients were treated with bevacizumab plus cisplatin/pemetrexed for four cycles, and then randomized to receive maintenance treatment with either bevacizumab/pemetrexed or bevacizumab alone until disease progression. Maintenance treatment with bevacizumab/pemetrexed demonstrated a 50% reduction in risk of progression vs bevacizumab alone (median PFS: 10.2 vs 6.6 months, HR 0.50, p<0.001).
The National Comprehensive Cancer Network recommends bevacizumab as standard first-line treatment in combination with any platinum-based chemotherapy, followed by maintenance bevacizumab until disease progression. Bevacizumab is given as an intravenous infusion every three weeks at the dose of either 15mg/kg or 7.5mg/kg. The higher dose is usually given with carboplatin-based chemotherapy, whereas the lower dose is usually given with cisplatin-based chemotherapy.
Assuming the FDA follows through on the withdrawal, drugmaker Roche could lose up to $1 billion in revenue for its best-selling product, which generates over $6 billion per year. Avastin is FDA-approved for various types of colon, lung, kidney and brain cancer, which are not part of the debate. Doctors will still be allowed to prescribe Avastin for breast cancer, though insurers may not pay for it. When administration fees are included, a year's treatment of Avastin can cost over $90,000.
On October 11, 2011 the U.S. Food and Drug Administration
(FDA) announced that the agency is revoking the agency’s approval of the breast cancer indication for Avastin (bevacizumab) after concluding that the drug has not been shown to be safe and effective for that use.
Avastin will still remain on the market as an approved treatment for certain types of colon, lung, kidney and brain cancer (glioblastoma multiforme).
In 2008, the FDA approved Bevacizumab for use in breast cancer
. A panel of outside advisers voted 5 to 4 against approval, but their recommendations were overruled. The panel expressed concern that data from the clinical trial did not show any increase in quality of life or prolonging of life for patients - two important benchmarks for late-stage cancer
treatments. The clinical trial
did show that bevacizumab reduced tumor volumes and showed an increase in progression free survival time
. It was based on this data that the FDA chose to overrule the recommendation of the panel of advisers. This decision was lauded by patient advocacy groups and some oncologists. Other oncologists felt that granting approval for late-stage cancer therapies that did not prolong or increase the quality of life for patients would give license to pharmaceutical companies to ignore these important benchmarks when developing new late-stage cancer therapies.
On March 28, 2007, the European Commission approved bevacizumab in combination with paclitaxel
for the first-line treatment of metastatic breast cancer.
In 2009, the FDA approved Bevacizumab for use in metastatic renal cell cancer
(a form of kidney cancer
)
, following earlier reports of activity and EU approval in 2007.
Also in 2009, an FDA advisory committee unanimously recommended Bevacizumab for treatment of glioblastoma multiforme
, a type of brain cancer.
In the September 2009 issue of the Journal of Clinical Oncology
, UCLA researchers reported that Avastin improves response and survival in patients with recurrent glioblastoma in comparison to historical controls. Avastin may also be useful in the treatment of radiation necrosis, since it reduces edema and mass effect and diminishes blood-brain-barrier leakage.
Bevacizumab did not meet its primary endpoint of extending overall survival (OS) in a recent phase III trial in unresectable gastric cancer (in combination with paclitaxel / Taxol), but it did demonstrate a positive result in treatment of ovarian cancer.
or irinotecan
.
, and glioblastoma multiforme
, a type of brain tumour, when used as a single agent. The FDA granted accelerated approval of Avastin for the treatment of recurrent glioblastoma multiforme in May 2009.
In 2010 two phase III trials showed a 27% and 54% increase in progression-free survival in ovarian cancer
.
Bevacizumab has been investigated as a possible treatment of pancreatic cancer
, as an addition to chemotherapy, but studies have shown no improvement in survival. It may also cause higher rates of high blood pressure, bleeding in the stomach and intestine, and intestinal perforations.
The drug is also undergoing initial trials as an addition to established chemotherapy protocols and surgery in the treatment of pediatric osteosarcoma.
, damage the retina
and cause blindness when blood vessels around the retina grow abnormally and leak fluid, causing the layers of the retina to separate. This abnormal growth is caused by VEGF, so bevacizumab has been successfully used to inhibit VEGF and slow this growth.
Bevacizumab has recently been used by ophthalmologists as an intravitreal agent
in the treatment of proliferative (neovascular) eye diseases, particularly for choroidal neovascular membrane
(CNV) in AMD. Although not currently approved by the FDA for such use, the injection of 1.25-2.5 mg of bevacizumab into the vitreous cavity has been performed without significant intraocular toxicity Many retina specialists have noted impressive results in the setting of CNV, proliferative diabetic retinopathy
, neovascular glaucoma, diabetic macular edema
, retinopathy of prematurity
and macular edema secondary to retinal vein occlusions.
Ranibizumab
, a Fab fragment
derived from the same parent molecule as bevacizumab, has been developed by Genentech (by the same scientist Napoleone Ferrara
) for intraocular use. This drug, under the trade name Lucentis, now has FDA approval. It has undergone extensive clinical trials. Reports indicate substantially better outcomes in patients treated with intravitreal Lucentis than conventional treatments in people with choroidal neovascularization
(wet age related macular degeneration). Most patients with choroidal neovascularization lose vision or at best maintain vision despite treatment with laser, photodynamic therapy or Macugen. A much larger proportion (up to 70%) gained vision with Lucentis.
When bevacizumab is used in the treatment of macular degeneration, only tiny and relatively inexpensive doses (compared to amounts used in colon and other cancers) are required. Some investigators believe that bevacizumab at a cost of around $42 a dose is as effective as ranibizumab at a cost of over $1,593 a dose.
The National Eye Institute
(NEI) of the National Institutes of Health
(NIH) announced in October 2006 that it would fund a comparative study trial of ranibizumab (Lucentis) and bevacizumab (Avastin) to assess the relative safety and effectiveness in treating AMD. This study, called the Comparison of Age-Related Macular Degeneration Treatment Trials (CATT Study), enrolled about 1,200 patients with newly diagnosed wet AMD, randomly assigning the patients to one of four treatment groups:
(Group1) Lucentis with four-week dosing, and after one year, re-randomization to Lucentis every four weeks or variable dosing as required based on diagnostic findings;
(Group 2) Bevacizumab with four-week dosing, and after one year, re-randomization to bevacizumab every four weeks or variable dosing as required based on diagnostic findings;
(Group 3) Lucentis on a variable dosing schedule for 2 years; after initial treatment, with monthly evaluation and re-treatment based on signs of lesion activity; and
(Group 4) Bevacizumab on a variable dosing schedule for 2 years; after initial treatment, with monthly evaluation and re-treatment based on signs of lesion activity.
The CATT Study will be conducted at 47 clinical sites throughout the United States, and will follow the patients for two years and is expected to take four years to complete. Enrollment began on February 22, 2008, with fifteen sites beginning recruiting. One-year follow-up data will be reported in 2009.
The primary goals of the study are to better understand the safety and efficacy of intravitreal bevacizumab and to develop better dosing and re-treatment guidelines for both bevacizumab and Lucentis.
Results of the study were released on April 29, 2011. The benefits of both Avastin and Lucentis are essentially identical after one year. This has a significant impact because the price difference between the two medications means insurance providers and Medicare will fund treatment with Avastin in preference to the higher priced Lucentis.
As of July 2010, Avastin is being used successfully in a case study of Familial Exudative Vitreoretinopathy in Buffalo, New York.
, and as collateral circulation
around blocked or atherosclerotic
blood vessels. One concern is that bevacizumab will interfere with these normal processes, and worsen conditions like coronary artery disease or peripheral artery disease.
The main side effects are hypertension
and heightened risk of bleeding
. Bowel perforation has been reported. In advanced lung cancer, less than half of patients qualify for treatment.Nasal septum perforation, and renal thrombotic microangiopathy have been reported. In December 2010, the FDA warned of the risk of developing perforations in the body, including in the nose, stomach, and intestines.
These effects are largely avoided in ophthalmological
use since the drug is introduced directly into the eye thus minimizing any effects on the rest of the body.
has taken the public position that bevacizumab should not be funded by the NHS because it costs nearly £21,000 per patient but has only limited usage in cancer treatment because it merely extends life rather than providing a cure.In 2006 the Scottish Medicines Consortium recommended against the NHS funding Avastin, for first-line treatment of metastatic carcinoma of the colon or rectum, due to estimated costs of £24,000 to £93,000 per Quality-adjusted life year (QALY).
Though Genentech has adjusted the price for patients in certain situations, Genentech continues to insist that the benefit is worth the cost, and the medication's high cost helps cover the cost of the expensive and risky research needed to develop new drugs.
The addition of bevacizumab to standard treatment can prolong the lives of breast and lung cancer patients by several months, at a cost of $100,000 a year in the United States. For colorectal cancer
, Robert J. Mayer wrote in the New England Journal of Medicine
that bevacizumab extended life by 4.7 months (20.3 months vs. 15.6 months) in the initial study, at a cost of $42,800 to $55,000. Costs in other countries vary; in Canada it is reported to cost $40,000 CAD per year.
Angiogenesis
Angiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. Though there has been some debate over terminology, vasculogenesis is the term used for spontaneous blood-vessel formation, and intussusception is the term for the formation of new blood...
, the growth of new blood vessels. It is commonly used to treat various cancers, including colorectal, lung, breast, kidney, and glioblastomas.
Bevacizumab is a humanized monoclonal antibody that inhibits vascular endothelial growth factor A
Vascular endothelial growth factor A
Vascular endothelial growth factor A is a protein that in humans is encoded by the VEGFA gene.- Function :This gene is a member of the platelet-derived growth factor /vascular endothelial growth factor family and encodes a protein that is often found as a disulfide linked homodimer...
(VEGF-A). VEGF-A is a chemical signal that stimulates angiogenesis in a variety of diseases, especially in cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
. Bevacizumab was the first clinically available angiogenesis inhibitor
Angiogenesis inhibitor
An angiogenesis inhibitor is a substance that inhibits the growth of new blood vessels . Some angiogenesis inhibitors are a normal part of the body's control, some are administered as drugs, and some come from diet....
in the United States.
Bevacizumab was approved by the U.S. Food and Drug Administration (FDA) for certain metastatic
Metastasis
Metastasis, or metastatic disease , is the spread of a disease from one organ or part to another non-adjacent organ or part. It was previously thought that only malignant tumor cells and infections have the capacity to metastasize; however, this is being reconsidered due to new research...
cancers. It received its first approval in 2004 for combination use with standard chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
for metastatic colon cancer. While at one point approved for breast cancer
Breast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
by the FDA, the approval was revoked on .
The approval for breast cancer was controversial, because although there was evidence that it slowed progression of metastatic breast cancer, there was no evidence that it extended life, or improved quality of life, and it caused adverse effects including severe high blood pressure and hemorrhaging. In 2008, the FDA gave bevacizumab provisional approval for metastatic breast cancer, subject to further studies. The FDA's advisory panel had recommended against approval. In July 2010, after new studies, the FDA's advisory panel again recommended against the indication for advanced breast cancer. Genentech requested a hearing, which was granted in June 2011. The FDA finally ruled to withdraw the breast cancer indication in November 2011. FDA approval is only required for Genentech to market a drug for that indication. Doctors can still prescribe it for that indication, although insurance companies are less likely to pay for it.
The drug is still approved for use in Australia.
In the curative setting (adjuvant therapy), clinical studies are still underway in breast cancer and lung cancer. A study released in April 2009 found that bevacizumab is not effective at preventing recurrences of non-metastatic colon cancer following surgery. In May 2009, it received FDA approval for treatment of recurring glioblastoma multiforme
Glioblastoma multiforme
Glioblastoma multiforme is the most common and most aggressive malignant primary brain tumor in humans, involving glial cells and accounting for 52% of all functional tissue brain tumor cases and 20% of all intracranial tumors. Despite being the most prevalent form of primary brain tumor, GBMs...
, while treatment for initial growth is still in phase III clinical trial.
Background
Bevacizumab is a humanized monoclonal antibody, and was the first commercially available angiogenesis inhibitor. It stops tumorTumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...
growth by preventing the formation of new blood vessels by targeting and inhibiting the function of a natural protein called vascular endothelial growth factor
Vascular endothelial growth factor
Vascular endothelial growth factor is a signal protein produced by cells that stimulates vasculogenesis and angiogenesis. It is part of the system that restores the oxygen supply to tissues when blood circulation is inadequate....
(VEGF) that stimulates new blood vessel formation.
The drug was first developed as a genetically engineered version of a mouse antibody that contains both human and mouse components. Genentech is able to produce the antibody in production-scale quantities.
Colorectal cancer
Bevacizumab was approved by the FDA in February 2004 for use in metastatic colorectal cancerColorectal cancer
Colorectal cancer, commonly known as bowel cancer, is a cancer caused by uncontrolled cell growth , in the colon, rectum, or vermiform appendix. Colorectal cancer is clinically distinct from anal cancer, which affects the anus....
when used with standard chemotherapy treatment (as first-line treatment) and with 5-fluorouracil-based therapy for second-line metastatic colorectal cancer. This recommendation was based on E3200 trial - addition of bevacizumab to oxaliplatin/5-FU/leucovorin (FOLFOX4) therapy.
It was approved by the EMEA
EMEA
EMEA may stand for:* the previous acronym of the European Medicines Agency, an EU regulatory agency for the evaluation of medicinal products* Europe, the Middle East and Africa...
in January 2005 for use in colorectal cancer
Colorectal cancer
Colorectal cancer, commonly known as bowel cancer, is a cancer caused by uncontrolled cell growth , in the colon, rectum, or vermiform appendix. Colorectal cancer is clinically distinct from anal cancer, which affects the anus....
.
Lung cancer
In 2006, the FDA approved bevacizumab for use in first-line advanced nonsquamous non-small cell lung cancer in combination with carboplatin/paclitaxel chemotherapy. The approval was based on the pivotal study E4599 (conducted by the Eastern Cooperative Oncology Group), which demonstrated a 2-month improvement in overall survival in patients treated with bevacizumab (Sandler, et al. NEJM 2004). A preplanned analysis of histology in E4599 demonstrated a 4-month median survival benefit with bevacizumab for patients with adenocarcinoma (Sandler, et al. JTO 2010); adenocarcinoma represents approximately 85% of all nonsquamous carcinomas of the lung.A subsequent European clinical trial, AVAiL, was first reported in 2009 and confirmed the significant improvement in progression-free survival shown in E4599 (Reck, et al. Ann. Oncol. 2010). An overall survival benefit was not demonstrated in patients treated with bevacizumab; however, this may be due to the more limited use of bevacizumab as maintenance treatment in AVAiL versus E4599 (this differential effect is also apparent in the European vs US trials of bevacizumab in colorectal cancer: Tyagi and Grothey, Clin Colorectal Cancer, 2006). As an anti-angiogenic agent, there is no mechanistic rationale for stopping bevacizumab before disease progression. Stated another way, the survival benefits achieved with bevacizumab can only be expected when used in accordance with the clinical evidence: continued until disease progression or treatment-limiting side effects.
Another large European-based clinical trial with bevacizumab in lung cancer, AVAPERL, was reported in October 2011 (Barlesi, et al. ECCM 2011). First-line patients were treated with bevacizumab plus cisplatin/pemetrexed for four cycles, and then randomized to receive maintenance treatment with either bevacizumab/pemetrexed or bevacizumab alone until disease progression. Maintenance treatment with bevacizumab/pemetrexed demonstrated a 50% reduction in risk of progression vs bevacizumab alone (median PFS: 10.2 vs 6.6 months, HR 0.50, p<0.001).
The National Comprehensive Cancer Network recommends bevacizumab as standard first-line treatment in combination with any platinum-based chemotherapy, followed by maintenance bevacizumab until disease progression. Bevacizumab is given as an intravenous infusion every three weeks at the dose of either 15mg/kg or 7.5mg/kg. The higher dose is usually given with carboplatin-based chemotherapy, whereas the lower dose is usually given with cisplatin-based chemotherapy.
Breast cancer
In December 2010, the FDA removed the breast cancer indication from bevacizumab, saying that it had not been shown to be safe and effective in breast cancer patients. The combined data from four different clinical trials showed that bevacizumab neither prolonged overall survival nor slowed disease progression sufficiently to outweigh the risk it presents to patients. This only prevented Genentech from marketing bevacizumab for breast cancer. Doctors are free to prescribe bevacizumab off label, although insurance companies are less likely to approve off-label treatments. In June 2011, an FDA panel unanimously rejected an appeal by Roche. A panel of cancer experts has ruled for a second time that Avastin, the best-selling cancer drug in the world, should no longer be used in breast cancer patients, clearing the way for the U.S. government to remove its endorsement from the drug. The June 2011 meeting of the FDA's oncologic drug advisory committee was the last step in an appeal by the drug's maker. The committee concluded that breast cancer clinical studies of patients taking Avastin have shown no advantage in survival rates, no improvement in quality of life, and significant side effects. Patient support groups were disappointed by the committee's decision.Assuming the FDA follows through on the withdrawal, drugmaker Roche could lose up to $1 billion in revenue for its best-selling product, which generates over $6 billion per year. Avastin is FDA-approved for various types of colon, lung, kidney and brain cancer, which are not part of the debate. Doctors will still be allowed to prescribe Avastin for breast cancer, though insurers may not pay for it. When administration fees are included, a year's treatment of Avastin can cost over $90,000.
On October 11, 2011 the U.S. Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
(FDA) announced that the agency is revoking the agency’s approval of the breast cancer indication for Avastin (bevacizumab) after concluding that the drug has not been shown to be safe and effective for that use.
Avastin will still remain on the market as an approved treatment for certain types of colon, lung, kidney and brain cancer (glioblastoma multiforme).
History relating to breast cancer
In 2010, before the FDA announcement, The National Comprehensive Cancer Network (NCCN) updated the NCCN Clinical Practice Guidelines for Oncology (NCCN Guidelines) for Breast Cancer to affirm the recommendation regarding the use of bevacizumab (Avastin, Genentech/Roche) in the treatment of metastatic breast cancer.In 2008, the FDA approved Bevacizumab for use in breast cancer
Breast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
. A panel of outside advisers voted 5 to 4 against approval, but their recommendations were overruled. The panel expressed concern that data from the clinical trial did not show any increase in quality of life or prolonging of life for patients - two important benchmarks for late-stage cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
treatments. The clinical trial
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
did show that bevacizumab reduced tumor volumes and showed an increase in progression free survival time
Progression Free Survival
Progression-free survival is the length of time during and after medication or treatment during which the disease being treated does not get worse...
. It was based on this data that the FDA chose to overrule the recommendation of the panel of advisers. This decision was lauded by patient advocacy groups and some oncologists. Other oncologists felt that granting approval for late-stage cancer therapies that did not prolong or increase the quality of life for patients would give license to pharmaceutical companies to ignore these important benchmarks when developing new late-stage cancer therapies.
On March 28, 2007, the European Commission approved bevacizumab in combination with paclitaxel
Paclitaxel
Paclitaxel is a mitotic inhibitor used in cancer chemotherapy. It was discovered in a U.S. National Cancer Institute program at the Research Triangle Institute in 1967 when Monroe E. Wall and Mansukh C. Wani isolated it from the bark of the Pacific yew tree, Taxus brevifolia and named it taxol...
for the first-line treatment of metastatic breast cancer.
Other cancers
In certain renal (kidney) cancers, Bevacizumab improves the progression free survival time but not survival time.In 2009, the FDA approved Bevacizumab for use in metastatic renal cell cancer
Renal cell carcinoma
Renal cell carcinoma is a kidney cancer that originates in the lining of the proximal convoluted tubule, the very small tubes in the kidney that filter the blood and remove waste products. RCC is the most common type of kidney cancer in adults, responsible for approximately 80% of cases...
(a form of kidney cancer
Kidney cancer
Kidney cancer is a type of cancer that starts in the cells in the kidney.The two most common types of kidney cancer are renal cell carcinoma and urothelial cell carcinoma of the renal pelvis...
)
, following earlier reports of activity and EU approval in 2007.
Also in 2009, an FDA advisory committee unanimously recommended Bevacizumab for treatment of glioblastoma multiforme
Glioblastoma multiforme
Glioblastoma multiforme is the most common and most aggressive malignant primary brain tumor in humans, involving glial cells and accounting for 52% of all functional tissue brain tumor cases and 20% of all intracranial tumors. Despite being the most prevalent form of primary brain tumor, GBMs...
, a type of brain cancer.
In the September 2009 issue of the Journal of Clinical Oncology
Journal of Clinical Oncology
The Journal of Clinical Oncology is a medical journal published 3 times a month by the American Society of Clinical Oncology , with a 2009 impact factor of 17.793...
, UCLA researchers reported that Avastin improves response and survival in patients with recurrent glioblastoma in comparison to historical controls. Avastin may also be useful in the treatment of radiation necrosis, since it reduces edema and mass effect and diminishes blood-brain-barrier leakage.
Bevacizumab did not meet its primary endpoint of extending overall survival (OS) in a recent phase III trial in unresectable gastric cancer (in combination with paclitaxel / Taxol), but it did demonstrate a positive result in treatment of ovarian cancer.
Drug administration
Bevacizumab is usually given intravenously every 14 days. In colon cancer, it is given in combination with the chemotherapy drug 5-FU (5-fluorouracil), leucovorin, and oxaliplatinOxaliplatin
Oxaliplatin is a coordination complex that is used in cancer chemotherapy. These platinum-based drugs are usually classified as alkylating agents, although they are not actually alkylating groups ....
or irinotecan
Irinotecan
Irinotecan is a drug used for the treatment of cancer.Irinotecan prevents DNA from unwinding by inhibition of topoisomerase 1. In chemical terms, it is a semisynthetic analogue of the natural alkaloid camptothecin....
.
Investigational
Bevacizumab has also demonstrated activity in ovarian cancerOvarian cancer
Ovarian cancer is a cancerous growth arising from the ovary. Symptoms are frequently very subtle early on and may include: bloating, pelvic pain, difficulty eating and frequent urination, and are easily confused with other illnesses....
, and glioblastoma multiforme
Glioblastoma multiforme
Glioblastoma multiforme is the most common and most aggressive malignant primary brain tumor in humans, involving glial cells and accounting for 52% of all functional tissue brain tumor cases and 20% of all intracranial tumors. Despite being the most prevalent form of primary brain tumor, GBMs...
, a type of brain tumour, when used as a single agent. The FDA granted accelerated approval of Avastin for the treatment of recurrent glioblastoma multiforme in May 2009.
In 2010 two phase III trials showed a 27% and 54% increase in progression-free survival in ovarian cancer
Ovarian cancer
Ovarian cancer is a cancerous growth arising from the ovary. Symptoms are frequently very subtle early on and may include: bloating, pelvic pain, difficulty eating and frequent urination, and are easily confused with other illnesses....
.
Bevacizumab has been investigated as a possible treatment of pancreatic cancer
Pancreatic cancer
Pancreatic cancer refers to a malignant neoplasm of the pancreas. The most common type of pancreatic cancer, accounting for 95% of these tumors is adenocarcinoma, which arises within the exocrine component of the pancreas. A minority arises from the islet cells and is classified as a...
, as an addition to chemotherapy, but studies have shown no improvement in survival. It may also cause higher rates of high blood pressure, bleeding in the stomach and intestine, and intestinal perforations.
The drug is also undergoing initial trials as an addition to established chemotherapy protocols and surgery in the treatment of pediatric osteosarcoma.
Uses in eye disease
Many diseases of the eye, such as age-related macular degeneration (AMD) and diabetic retinopathyDiabetic retinopathy
Diabetic retinopathy is retinopathy caused by complications of diabetes mellitus, which can eventually lead to blindness....
, damage the retina
Retina
The vertebrate retina is a light-sensitive tissue lining the inner surface of the eye. The optics of the eye create an image of the visual world on the retina, which serves much the same function as the film in a camera. Light striking the retina initiates a cascade of chemical and electrical...
and cause blindness when blood vessels around the retina grow abnormally and leak fluid, causing the layers of the retina to separate. This abnormal growth is caused by VEGF, so bevacizumab has been successfully used to inhibit VEGF and slow this growth.
Bevacizumab has recently been used by ophthalmologists as an intravitreal agent
Vitreous humour
The vitreous humour or vitreous humor is the clear gel that fills the space between the lens and the retina of the eyeball of humans and other vertebrates...
in the treatment of proliferative (neovascular) eye diseases, particularly for choroidal neovascular membrane
Choroidal neovascularization
Choroidal neovascularization is the creation of new blood vessels in the choroid layer of the eye. This is a common symptom of the degenerative maculopathy wet AMD .-Causes:...
(CNV) in AMD. Although not currently approved by the FDA for such use, the injection of 1.25-2.5 mg of bevacizumab into the vitreous cavity has been performed without significant intraocular toxicity Many retina specialists have noted impressive results in the setting of CNV, proliferative diabetic retinopathy
Diabetic retinopathy
Diabetic retinopathy is retinopathy caused by complications of diabetes mellitus, which can eventually lead to blindness....
, neovascular glaucoma, diabetic macular edema
Macular edema
Macular edema occurs when fluid and protein deposits collect on or under the macula of the eye and causes it to thicken and swell. The swelling may distort a person's central vision, as the macula is near the center of the retina at the back of the eyeball...
, retinopathy of prematurity
Retinopathy of prematurity
Retinopathy of prematurity , previously known as retrolental fibroplasia , is an eye disease that affects prematurely-born babies. It is thought to be caused by disorganized growth of retinal blood vessels which may result in scarring and retinal detachment. ROP can be mild and may resolve...
and macular edema secondary to retinal vein occlusions.
Ranibizumab
Ranibizumab
Ranibizumab is a monoclonal antibody fragment derived from the same parent mouse antibody as bevacizumab . It is much smaller than the parent molecule and has been affinity matured to provide stronger binding to VEGF-A...
, a Fab fragment
Fragment antigen binding
The fragment antigen-binding is a region on an antibody that binds to antigens. It is composed of one constant and one variable domain of each of the heavy and the light chain. These domains shape the paratope — the antigen-binding site — at the amino terminal end of the monomer...
derived from the same parent molecule as bevacizumab, has been developed by Genentech (by the same scientist Napoleone Ferrara
Napoleone Ferrara
Napoleone Ferrara, M.D., Ph.D. is an Italian-American molecular biologist and is currently a Genentech Fellow in tumor biology and angiogenesis. He is credited with identifying the human VEGF gene and describing its proangiogenic properties, which formed the basis for the development of Genentech's...
) for intraocular use. This drug, under the trade name Lucentis, now has FDA approval. It has undergone extensive clinical trials. Reports indicate substantially better outcomes in patients treated with intravitreal Lucentis than conventional treatments in people with choroidal neovascularization
Choroidal neovascularization
Choroidal neovascularization is the creation of new blood vessels in the choroid layer of the eye. This is a common symptom of the degenerative maculopathy wet AMD .-Causes:...
(wet age related macular degeneration). Most patients with choroidal neovascularization lose vision or at best maintain vision despite treatment with laser, photodynamic therapy or Macugen. A much larger proportion (up to 70%) gained vision with Lucentis.
When bevacizumab is used in the treatment of macular degeneration, only tiny and relatively inexpensive doses (compared to amounts used in colon and other cancers) are required. Some investigators believe that bevacizumab at a cost of around $42 a dose is as effective as ranibizumab at a cost of over $1,593 a dose.
The National Eye Institute
National Eye Institute
The National Eye Institute is one of the US National Institutes of Health that was established in 1968. The mission of NEI is to prolong and protect the vision of the American people. The NEI conducts and performs research into treating and preventing diseases affecting the eye or vision....
(NEI) of the National Institutes of Health
National Institutes of Health
The National Institutes of Health are an agency of the United States Department of Health and Human Services and are the primary agency of the United States government responsible for biomedical and health-related research. Its science and engineering counterpart is the National Science Foundation...
(NIH) announced in October 2006 that it would fund a comparative study trial of ranibizumab (Lucentis) and bevacizumab (Avastin) to assess the relative safety and effectiveness in treating AMD. This study, called the Comparison of Age-Related Macular Degeneration Treatment Trials (CATT Study), enrolled about 1,200 patients with newly diagnosed wet AMD, randomly assigning the patients to one of four treatment groups:
(Group1) Lucentis with four-week dosing, and after one year, re-randomization to Lucentis every four weeks or variable dosing as required based on diagnostic findings;
(Group 2) Bevacizumab with four-week dosing, and after one year, re-randomization to bevacizumab every four weeks or variable dosing as required based on diagnostic findings;
(Group 3) Lucentis on a variable dosing schedule for 2 years; after initial treatment, with monthly evaluation and re-treatment based on signs of lesion activity; and
(Group 4) Bevacizumab on a variable dosing schedule for 2 years; after initial treatment, with monthly evaluation and re-treatment based on signs of lesion activity.
The CATT Study will be conducted at 47 clinical sites throughout the United States, and will follow the patients for two years and is expected to take four years to complete. Enrollment began on February 22, 2008, with fifteen sites beginning recruiting. One-year follow-up data will be reported in 2009.
The primary goals of the study are to better understand the safety and efficacy of intravitreal bevacizumab and to develop better dosing and re-treatment guidelines for both bevacizumab and Lucentis.
Results of the study were released on April 29, 2011. The benefits of both Avastin and Lucentis are essentially identical after one year. This has a significant impact because the price difference between the two medications means insurance providers and Medicare will fund treatment with Avastin in preference to the higher priced Lucentis.
As of July 2010, Avastin is being used successfully in a case study of Familial Exudative Vitreoretinopathy in Buffalo, New York.
Adverse effects
Bevacizumab inhibits the growth of blood vessels, which is part of the body's normal healing and maintenance. The body grows new blood vessels in wound healingWound healing
Wound healing, or cicatrisation, is an intricate process in which the skin repairs itself after injury. In normal skin, the epidermis and dermis exists in a steady-state equilibrium, forming a protective barrier against the external environment...
, and as collateral circulation
Collateral circulation
Collateral circulation is when an area of tissue or an organ has a number of different pathways for blood to reach it. This is often as a result of anastamoses - branches formed between adjacent blood vessels....
around blocked or atherosclerotic
Atherosclerosis
Atherosclerosis is a condition in which an artery wall thickens as a result of the accumulation of fatty materials such as cholesterol...
blood vessels. One concern is that bevacizumab will interfere with these normal processes, and worsen conditions like coronary artery disease or peripheral artery disease.
The main side effects are hypertension
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
and heightened risk of bleeding
Bleeding
Bleeding, technically known as hemorrhaging or haemorrhaging is the loss of blood or blood escape from the circulatory system...
. Bowel perforation has been reported. In advanced lung cancer, less than half of patients qualify for treatment.Nasal septum perforation, and renal thrombotic microangiopathy have been reported. In December 2010, the FDA warned of the risk of developing perforations in the body, including in the nose, stomach, and intestines.
These effects are largely avoided in ophthalmological
Ophthalmology
Ophthalmology is the branch of medicine that deals with the anatomy, physiology and diseases of the eye. An ophthalmologist is a specialist in medical and surgical eye problems...
use since the drug is introduced directly into the eye thus minimizing any effects on the rest of the body.
Costs
The media have criticized the high cost of a drug that doesn't cure cancer but only prolongs life. In the U.S., many insurance companies have refused to pay for all or part of the costs of bevacizumab. In countries with national health care systems (such as the UK and Canada), many of those national health services have restricted on the basis of cost-benefit calculations; in the U.K., for example, the National Institute for Health and Clinical ExcellenceNational Institute for Health and Clinical Excellence
The National Institute for Health and Clinical Excellence is a special health authority of the English National Health Service , serving both English NHS and the Welsh NHS...
has taken the public position that bevacizumab should not be funded by the NHS because it costs nearly £21,000 per patient but has only limited usage in cancer treatment because it merely extends life rather than providing a cure.In 2006 the Scottish Medicines Consortium recommended against the NHS funding Avastin, for first-line treatment of metastatic carcinoma of the colon or rectum, due to estimated costs of £24,000 to £93,000 per Quality-adjusted life year (QALY).
Though Genentech has adjusted the price for patients in certain situations, Genentech continues to insist that the benefit is worth the cost, and the medication's high cost helps cover the cost of the expensive and risky research needed to develop new drugs.
The addition of bevacizumab to standard treatment can prolong the lives of breast and lung cancer patients by several months, at a cost of $100,000 a year in the United States. For colorectal cancer
Colorectal cancer
Colorectal cancer, commonly known as bowel cancer, is a cancer caused by uncontrolled cell growth , in the colon, rectum, or vermiform appendix. Colorectal cancer is clinically distinct from anal cancer, which affects the anus....
, Robert J. Mayer wrote in the New England Journal of Medicine
New England Journal of Medicine
The New England Journal of Medicine is an English-language peer-reviewed medical journal published by the Massachusetts Medical Society. It describes itself as the oldest continuously published medical journal in the world.-History:...
that bevacizumab extended life by 4.7 months (20.3 months vs. 15.6 months) in the initial study, at a cost of $42,800 to $55,000. Costs in other countries vary; in Canada it is reported to cost $40,000 CAD per year.
See also
- glioblastoma multiformeGlioblastoma multiformeGlioblastoma multiforme is the most common and most aggressive malignant primary brain tumor in humans, involving glial cells and accounting for 52% of all functional tissue brain tumor cases and 20% of all intracranial tumors. Despite being the most prevalent form of primary brain tumor, GBMs...
- metastatic breast cancer
- angiogenesisAngiogenesisAngiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. Though there has been some debate over terminology, vasculogenesis is the term used for spontaneous blood-vessel formation, and intussusception is the term for the formation of new blood...
- colorectal cancerColorectal cancerColorectal cancer, commonly known as bowel cancer, is a cancer caused by uncontrolled cell growth , in the colon, rectum, or vermiform appendix. Colorectal cancer is clinically distinct from anal cancer, which affects the anus....
- Vascular endothelial growth factorVascular endothelial growth factorVascular endothelial growth factor is a signal protein produced by cells that stimulates vasculogenesis and angiogenesis. It is part of the system that restores the oxygen supply to tissues when blood circulation is inadequate....
(VEGF) - renal cell carcinomaRenal cell carcinomaRenal cell carcinoma is a kidney cancer that originates in the lining of the proximal convoluted tubule, the very small tubes in the kidney that filter the blood and remove waste products. RCC is the most common type of kidney cancer in adults, responsible for approximately 80% of cases...
External links
- Avastin.com
- Off Label Uses of Avastin for AMD
- Avastin-info.com Information for healthcare professionals outside of the US
- Avastin News provided by insciences organisation
- A Cancer Drug Shows Promise, at a Price That Many Can't Pay New York Times, February 15, 2006, Alex Berenson
- NCI Drug Information Summary on Bevacizumab for Patients
- NCI Drug Dictionary Definition for Bevacizumab
- Phase II Clinical Trial of Bevacizumab for Adenocarcinoma of the Pancreas
- CATT Study Update 3: Avastin vs. Lucentis -- To Get Underway by Year's End!
- Comparison of Age-Related Macular Degeneration Treatments Trials: Lucentis-Avastin Trial
- Evolution of Bevacizumab-Based Therapy in the Management of Breast Cancer
- U.S. National Library of Medicine: Drug Information Portal - Bevacizumab
- NCCN Guidelines For Breast Cancer Updated; Bevacizumab Recommendation Affirmed
- Avastin Adverse Events Reported to the FDA Adverse Event Reporting System (AERS)