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'''Bevacizumab''' (trade name '''Avastin''', [[Genentech]]/[[Hoffmann–La Roche|Roche]]) is a treatment for cancer that starves tumors by blocking [[angiogenesis]], the growth of new blood vessels. It is widely used to treat various cancers, including colorectal, lung, breast, kidney, and glioblastoma.
'''Bevacizumab''' (trade name '''Avastin''', [[Genentech]]/[[Hoffmann–La Roche|Roche]]) is a drug that blocks [[angiogenesis]], the growth of new blood vessels. It is used to treat various cancers, including colorectal, lung, and kidney cancer, and eye disease.


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Bevacizumab is a humanized [[monoclonal antibody]] that inhibits [[vascular endothelial growth factor A]] (VEGF-A).<ref name=Los>{{cite journal |pages=443–50 |doi=10.1634/theoncologist.12-4-443 |title=Target Practice: Lessons from Phase III Trials with Bevacizumab and Vatalanib in the Treatment of Advanced Colorectal Cancer |year=2007 |last1=Los |first1=M. |last2=Roodhart |first2=J. M. L. |last3=Voest |first3=E. E. |journal=The Oncologist |volume=12 |issue=4 |pmid=17470687}}</ref> VEGF-A is a chemical signal that stimulates angiogenesis in a variety of diseases, especially in [[cancer]], [[retinal proliferation]] of diabetes in the eye. Bevacizumab was the first clinically available [[angiogenesis inhibitor]] in the United States.{{Citation needed|date=August 2010}}
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==Background==


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Bevacizumab is currently approved by the [[Food and Drug Administration (United States)|U.S. Food and Drug Administration]] (FDA) for cancers that are [[metastasis|metastatic]] (have spread to other parts of the body). It received its first approval in 2004 for combination use with standard [[chemotherapy]] for metastatic [[colon cancer]] and [[non-small cell lung cancer]].<ref>http://www.gene.com/gene/products/information/pdf/avastin-prescribing.pdf</ref>
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Bevacizumab is a humanized [[monoclonal antibody]] that inhibits [[vascular endothelial growth factor A]] (VEGF-A).<ref name=Los>{{cite journal |pages=443–50 |doi=10.1634/theoncologist.12-4-443 |title=Target Practice: Lessons from Phase III Trials with Bevacizumab and Vatalanib in the Treatment of Advanced Colorectal Cancer |year=2007 |last1=Los |first1=M. |last2=Roodhart |first2=J. M. L. |last3=Voest |first3=E. E. |journal=The Oncologist |volume=12 |issue=4 |pmid=17470687}}</ref> VEGF-A is a chemical signal that stimulates angiogenesis in a variety of diseases, especially in [[cancer]].

In 2008, the FDA approved bevacizumab for use in metastatic breast cancer. This was controversial, because the FDA's advisory panel recommended against approval, <ref name=nytimesref>{{cite news |url=http://www.nytimes.com/2008/02/22/business/apee-drug.html |title=F.D.A. Approves Drug's Use for Breast Cancer |work=[[The New York Times]] |date=February 22, 2008}}</ref> since it only slowed tumor growth but failed to extend survival. In July 2010, the FDA revoked the indication for advanced breast cancer,<ref name="YouTubeMed">{{cite news|url=http://www.youtube.com/watch?v=ykcjTO9W6vg|title=FDA Panel Nixes Bevacizumab for Breast Cancer|author=[http://www.medpagetoday.com MedPageToday]|date=2010-07-28|accessdate=2010-10-23}}</ref> although the drug is still approved for use in Australia.<ref>{{cite news |url=http://www.abc.net.au/news/stories/2010/07/22/2960728.htm|title=Breast cancer drug 'still safe' for Aussie women|word=[[Australian Broadcasting Corporation]]|date=July 22, 2010}}</ref> 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.

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It is prescribed off-label -on the basis of clinical studies- for treatment of [[macular degeneration]], an eye disease also characterized by proliferation of blood vessels in the retina.

Clinical studies are underway in non-metastatic [[breast cancer]], [[renal cell carcinoma]], [[glioblastoma multiforme]], [[ovarian cancer]], castrate-resistant (formally called hormone refractory) [[prostate cancer]], non-metastatic unresectable [[liver cancer]] and metastatic or unresectable locally advanced [[pancreatic cancer]]. A study released in April 2009 found that bevacizumab is not effective at preventing recurrences of non-metastatic [[colon cancer]] following surgery.<ref>[http://www.reuters.com/article/euRegulatoryNews/idUSLM27429520090422 Reed, Katie. "Roche drug Avastin fails cancer study, shares fall". ''Reuters'' 22 Apr 2009. Accessed 22 Apr 2009]</ref> 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.<ref>[http://www.marketwatch.com/story/fda-grants-accelerated-approval-of-avastin-for-brain-cancer-glioblastoma-that-has-progressed-following-prior-therapy Genentech, Inc. "FDA Grants Accelerated Approval of Avastin for Brain Cancer (Glioblastoma) That Has Progressed Following Prior Therapy". ''Market Watch'' 5 May 2009.]</ref>

⚫
==Background==


Bevacizumab is a humanized [[monoclonal antibody]], and was the first commercially available [[angiogenesis inhibitor]]. It stops [[tumor]] 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.{{Citation needed|date=July 2011}}
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Bevacizumab is currently approved by the [[Food and Drug Administration (United States)|U.S. Food and Drug Administration]] (FDA) for cancers that are [[metastasis|metastatic]] (have spread to other parts of the body). It received its first approval in 2004 for combination use with standard [[chemotherapy]] for metastatic [[colon cancer]].<ref>http://www.gene.com/gene/products/information/pdf/avastin-prescribing.pdf</ref>


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.{{Citation needed|date=July 2011}}
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It is prescribed off-label for treatment of [[macular degeneration]], an eye disease also characterized by proliferation of blood vessels in the retina.


==Indications==
==Indications==
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=== Lung cancer ===
=== Lung cancer ===
The overall data shows that bevacizumab has no effect on survival but has been shown to improve [[Progression Free Survival|progression free survival time]] in some lung cancer types [Reck M, von PJ, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, Leighl N, Mezger J, Archer V, Moore N, et al. Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil. J Clin Oncol. 2009 Mar 10;27(8):1227-34.
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.
Reck M, von PJ, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, Leighl N, Mezger J, Archer V, Moore N, et al. Overall survival with cisplatin-gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer: results from a randomised phase III trial (AVAiL). Ann.Oncol. 2010 Sep;21(9):1804-9.}]


In 2006, the FDA approved bevacizumab for use in [[lung cancer]] in combination with standard first-line chemotherapy. A study conducted by the Eastern Cooperative Oncology Group (ECOG) demonstrated a 2-month improvement in overall survival in patients with Stage IIIb/IV non-small cell lung cancer (NSCLC). However, other studies have unfortunately not mirrored this finding and overall data shows that bevacizumab has no effect on survival. Due to the observance of severe pulmonary hemorrhage in patients with NSCLC with squamous histology in an earlier study, patients with such histology were excluded from the pivotal ECOG trial.{{Citation needed|date=July 2011}}
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.


=== Breast cancer ===
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).
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.<ref name="FDA breast1">{{cite press release
|title=FDA begins process to remove breast cancer indication from Avastin label
|publisher=FDA |date=2010-12-16
|url=http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm237172.htm |accessdate=2010-12-17}}
</ref><ref name="Breast Cancer">{{cite news | url=http://www.nytimes.com/2010/12/17/health/policy/17drug.html |title=F.D.A. Rejects Use of Drug in Cases of Breast Cancer|newspaper=NY Times
|date=December 16, 2010|accessdate=2010-12-16|author=Andrew Pollack}}</ref> 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.<ref name=scijul11>{{cite journal|author= Jennifer Couzin-Frankel and Yasmin Ogale |title= Once on 'Fast Track', Avastin Now Deralied |journal=Science|pages= 143 |volume= 333 |date= 8 July 2011}} </ref>


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.{{Citation needed|date=July 2011}} 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 $90,000.<ref name = scijul11/>
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.

==== 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.{{Citation needed|date=July 2011}}

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|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.<ref name=nytimesref />

On March 28, 2007, the European Commission approved bevacizumab in combination with [[paclitaxel]] for the first-line treatment of metastatic breast cancer.<ref name="Austria-Codex">{{cite book|title=Austria-Codex|editor=Jasek, W|publisher=Österreichischer Apothekerverlag|location=Vienna|year=2007|edition=2007/2008|isbn=3-85200-181-4|language=German}}{{Page needed|date=July 2011}}</ref>


=== Other cancers ===
=== Other cancers ===
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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.<ref>{{cite web| url=http://www.oncogenetics.org/web/avastin-dramatically-improves-response-survival-in-deadly-recurrrent-glioblastomas | title=Avastin dramatically improves response, survival in deadly recurrrent glioblastomas | author=OncoGenetics.Org| publisher=OncoGenetics.Org| accessdate=2009-09-02| month=September | year=2009}} {{Dead link|date=October 2010|bot=H3llBot}}</ref> Avastin may also be useful in the treatment of radiation necrosis, since it reduces edema and mass effect and diminishes blood-brain-barrier leakage.
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.<ref>{{cite web| url=http://www.oncogenetics.org/web/avastin-dramatically-improves-response-survival-in-deadly-recurrrent-glioblastomas | title=Avastin dramatically improves response, survival in deadly recurrrent glioblastomas | author=OncoGenetics.Org| publisher=OncoGenetics.Org| accessdate=2009-09-02| month=September | year=2009}} {{Dead link|date=October 2010|bot=H3llBot}}</ref> 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 <u>not</u> 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.{{Citation needed|date=July 2011}}

=== 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 [[oxaliplatin]] or [[irinotecan]].{{Citation needed|date=July 2011}}


===Investigational===
===Investigational===
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In 2010 two phase III trials showed a 27% and 54% increase in [[progression-free survival]] in [[ovarian cancer]].<ref>{{cite news |url=http://www.genengnews.com/gen-news-highlights/roche-claims-phase-iii-data-supports-use-of-avastin-in-ovarian-cancer/81244051/ |title=Roche Claims Phase III Data Supports Use of Avastin in Ovarian Cancer |date=12 Oct 2010 }}</ref>
In 2010 two phase III trials showed a 27% and 54% increase in [[progression-free survival]] in [[ovarian cancer]].<ref>{{cite news |url=http://www.genengnews.com/gen-news-highlights/roche-claims-phase-iii-data-supports-use-of-avastin-in-ovarian-cancer/81244051/ |title=Roche Claims Phase III Data Supports Use of Avastin in Ovarian Cancer |date=12 Oct 2010 }}</ref>

Bevacizumab has been investigated as a possible treatment of [[pancreatic cancer]], as an addition to chemotherapy, but studies have shown no improvement in survival.<ref>{{cite journal |author=Saif MW |title=New developments in the treatment of pancreatic cancer. Highlights from the "44th ASCO Annual Meeting". Chicago, IL, USA. May 30 - June 3, 2008 |journal=JOP |volume=9 |issue=4 |pages=391–7 |year=2008 |pmid=18648128 |url=http://www.joplink.net/prev/200807/27.html}}</ref><ref>{{cite journal |pages=435–46 |doi=10.1097/CAD.0b013e3282fc9d11 |url= |title=New directions in the management of advanced pancreatic cancer: a review |year=2008 |last1=Rocha-Lima |first1=Caio M. |journal=Anti-Cancer Drugs |volume=19 |issue=5 |pmid=18418211}}</ref><ref>{{cite journal |pages=123–9 |doi=10.1007/978-3-540-71279-4_14 |chapter=Antiangiogenic Strategies in Pancreatic Cancer |title=Pancreatic Cancer |series=Recent Results in Cancer Research |year=2008 |last1=Riess |first1=Hanno |isbn=978-3-540-71266-4 |volume=177}}</ref> 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.<ref>{{cite web|title=Md. Girl,11, First To Try New Cancer Treatment|url=http://www.wbaltv.com/health/23686741/detail.html}}</ref>
The drug is also undergoing initial trials as an addition to established chemotherapy protocols and surgery in the treatment of pediatric osteosarcoma.<ref>{{cite web|title=Md. Girl,11, First To Try New Cancer Treatment|url=http://www.wbaltv.com/health/23686741/detail.html}}</ref>
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Many diseases of the eye, such as age-related [[macular degeneration]] (AMD) and [[diabetic retinopathy]], 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.
Many diseases of the eye, such as age-related [[macular degeneration]] (AMD) and [[diabetic retinopathy]], 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 [[vitreous humour|intravitreal agent]] in the treatment of proliferative (neovascular) eye diseases, particularly for [[choroidal neovascularization|choroidal neovascular membrane]] (CNV) in AMD. Although not currently approved by the FDA for such use, the injection of 1.25-2.5&nbsp;mg of bevacizumab into the vitreous cavity has been performed without significant intraocular toxicity{{Citation needed|date=June 2010}} Many retina specialists have noted impressive results in the setting of CNV, proliferative [[diabetic retinopathy]], [[neovascular glaucoma]], diabetic [[macular edema]], [[retinopathy of prematurity]]<ref>{{cite journal |doi=10.4103/0301-4738.33057 |title=Intravitreal bevacizumab in aggressive posterior retinopathy of prematurity |year=2007 |last1=Azad |first1=Rajvardhan |last2=Chandra |first2=Parijat |journal=Indian Journal of Ophthalmology |volume=55 |issue=4 |pages=319 |pmid=17595491}}</ref> and macular edema secondary to retinal vein occlusions.


[[Ranibizumab]], a [[Fragment antigen binding|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.{{Citation needed|date=July 2011}}
[[Ranibizumab]], a [[Fragment antigen binding|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.{{Citation needed|date=July 2011}}

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.<ref>[http://online.wsj.com/article/SB20001424052748703513604575311070894017154.html Medicare Eye Study Finds Untapped Savings], Wall Street Journal, June 17, 2010</ref><ref>{{cite journal |doi=10.1136/bmj.c2459 |title=Bevacizumab for neovascular age related macular degeneration (ABC Trial): multicentre randomised double masked study |year=2010 |last1=Tufail |first1=A. |last2=Patel |first2=P. J. |last3=Egan |first3=C. |last4=Hykin |first4=P. |last5=Da Cruz |first5=L. |last6=Gregor |first6=Z. |last7=Dowler |first7=J. |last8=Majid |first8=M. A. |last9=Bailey |first9=C. |journal=BMJ |volume=340 |pages=c2459–c2459}}</ref>

As Genentech has developed both drugs it has little interest in seeing Bevacizumab use in the eye and it is likely to remain off label. Off-label use of this medication has created significant controversy in medical retina and vitreo-retinal surgery. On October 11, 2007, Genentech issued a letter to Physicians that they would no longer sell bevacizumab to compounding pharmacies.<ref>http://www.gene.com/gene/features/avastin/letter-to-physicians.html</ref> This would have effectively stopped its use for macular degeneration patients who had no insurance coverage for Ranibizumab (Lucentis) and for any patient who had other vision threatening conditions where Bevacizumab has been shown to work.{{Citation needed|date=July 2011}}

However, the ophthalmic community, led by the American Academy of Ophthalmology (AAO) and the American Society of Retinal Specialists (ASRS), fought back and managed to get Genentech to agree to continue providing bevacizumab to retinal surgeons, who in turn could get compounding pharmacies to "cut" the dosage to the appropriate ophthalmic dosage for continued use.<ref>http://patentdocs.typepad.com/patent_docs/2007/10/genentech-acts-.html{{Unreliable medical source|date=July 2011}}</ref>

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.<ref>http://clinicalstudies.info.nih.gov/cgi/wais/bold032001.pl?A_08-EI-0061.html</ref> 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:<ref>http://irvaronsjournal.blogspot.com/2007/09/catt-study-update-3-avastin-vs-lucentis.html{{Unreliable medical source|date=July 2011}}</ref>

(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.<ref>http://www.clinicaltrials.gov/ct2/show/NCT00593450</ref> Enrollment began on February 22, 2008, with fifteen sites beginning recruiting.<ref>http://www.clinicaltrials.gov/ct2/show/locn/NCT00593450</ref> 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.{{Citation needed|date=July 2011}}

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.{{Citation needed|date=July 2011}}

As of July 2010, Avastin is being used successfully in a case study of Familial Exudative Vitreoretinopathy in Buffalo, New York.{{Citation needed|date=July 2010}}


==Concerns==
==Concerns==
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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 healing]], and as [[collateral circulation]] around blocked or [[atherosclerosis|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]].<ref>New England Journal of Medicine, 8 May 2008, 358(19):2066, Clinical Implications of Basic Research: A New Weapon for Attacking Tumor Blood Vessels, Gregg L. Semenza.</ref>
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 healing]], and as [[collateral circulation]] around blocked or [[atherosclerosis|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]].<ref>New England Journal of Medicine, 8 May 2008, 358(19):2066, Clinical Implications of Basic Research: A New Weapon for Attacking Tumor Blood Vessels, Gregg L. Semenza.</ref>


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.<ref>{{cite journal |doi=10.1097/01243894-200606000-00023 |title=The Proportion of Patients with Metastatic Non-small Cell Lung Cancer Potentially Eligible for Treatment with Bevacizumab: A Single Institutional Survey |year=2006 |last1=Velcheti |first1=Vamsidhar |last2=Viswanathan |first2=Avinash |last3=Govindan |first3=Ramaswamy |journal=Journal of Thoracic Oncology |volume=1 |issue=5 |pages=501 |pmid=17409907}}</ref><ref>{{cite journal |pages=86–91 |doi=10.1007/s11912-008-0013-z |title=Reversible posterior leukoencephalopathy syndrome in cancer |year=2008 |last1=Vaughn |first1=Christopher |last2=Zhang |first2=Louann |last3=Schiff |first3=David |journal=Current Oncology Reports |volume=10 |pmid=18366965 |issue=1}}</ref>[[nasal septum perforation]], and renal thrombotic microangiopathy have been reported.<ref>{{cite journal |doi=10.1056/NEJMoa0707330 |title=VEGF Inhibition and Renal Thrombotic Microangiopathy |year=2008 |last1=Eremina |first1=Vera |last2=Jefferson |first2=J. Ashley |last3=Kowalewska |first3=Jolanta |last4=Hochster |first4=Howard |last5=Haas |first5=Mark |last6=Weisstuch |first6=Joseph |last7=Richardson |first7=Catherine |last8=Kopp |first8=Jeffrey B. |last9=Kabir |first9=M. Golam |journal=New England Journal of Medicine |volume=358 |issue=11 |pages=1129–1136 |pmid=18337603 |pmc=3030578}}</ref> In December 2010, the FDA warned of the risk of developing perforations in the body, including in the nose, stomach, and intestines.
⚫
The main side effects are [[hypertension]] and heightened risk of [[bleeding]]. [[Bowel perforation]] has been reported. These effects are largely avoided in [[Ophthalmology|ophthalmological]] use since the drug is introduced directly into the eye thus minimizing any effects on the rest of the body.{{Citation needed|date=July 2011}}

⚫
These effects are largely avoided in [[Ophthalmology|ophthalmological]] use since the drug is introduced directly into the eye thus minimizing any effects on the rest of the body.{{Citation needed|date=July 2011}}

===Costs===
Bevacizumab is one of the most expensive drugs widely marketed. In 2008, [[Annual pharmaceutical drug sales|sales of Avastin]] generated nearly $2.7 billion for Genentech.<ref>[http://www.sec.gov/Archives/edgar/data/318771/000031877109000003/form10-k_2008.htm Genentech 2008 10-K Report,]</ref> Both physicians and the media have criticized the high cost of a drug that doesn't cure cancer{{Citation needed|date=June 2011}} but only prolongs life{{Citation needed|date=June 2011}}. 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 its use because of its extraordinarily lop-sided cost-benefit ratio; in the U.K., for example, the [[National Institute for Health and Clinical Excellence]] 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.<ref name="BBCReport">{{cite news|url=http://www.bbc.co.uk/news/health-11060968 |title=Critics condemn bowel cancer drug rejection| author=Briggs, Helen (BBC News Health Reporter)| accessdate=2010-08-24|date=August 24, 2010}}</ref>

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).<ref>http://www.scottishmedicines.org.uk/files/bevacizumab__Avastin__Resubmissionn_May_06_FINAL_for_website.pdf</ref>

Though Genentech has adjusted the price for patients in certain situations,{{Citation needed|date=July 2011}} 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.<ref>[http://www.nytimes.com/2006/02/15/business/15drug.html A Cancer Drug Shows Promise, at a Price That Many Can't Pay], By ALEX BERENSON, New York Times, February 15, 2006.</ref> 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.<ref>{{cite journal |doi=10.1056/NEJMe048098 |title=Two Steps Forward in the Treatment of Colorectal Cancer |year=2004 |last1=Mayer |first1=Robert J. |journal=New England Journal of Medicine |volume=350 |issue=23 |pages=2406–2408 |pmid=15175443}}</ref> Costs in other countries vary; in Canada it is reported to cost $40,000 CAD per year.<ref>[http://www.cbc.ca/canada/prince-edward-island/story/2009/11/26/pei-avastin-stein-currie-584.html P.E.I. sole holdout on cancer drug] CBC News, November 26, 2009</ref>


==See also==
==See also==

Revision as of 20:35, 7 October 2011

Bevacizumab
Monoclonal antibody
TypeWhole antibody
SourceHumanized (from mouse)
TargetVEGF-A
Clinical data
Trade namesAvastin
AHFS/Drugs.comMonograph
License data
Routes of
administration		Intravenous
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability100% (IV only)
Elimination half-life20 days (range: 11–50 days)
Identifiers
CAS Number
DrugBank
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC6638H10160N1720O2108S44
Molar massapprox. 149 kDa g·mol−1

Bevacizumab (trade name Avastin, Genentech/Roche) is a drug that blocks angiogenesis, the growth of new blood vessels. It is used to treat various cancers, including colorectal, lung, and kidney cancer, and eye disease.

Bevacizumab is a humanized monoclonal antibody that inhibits vascular endothelial growth factor A (VEGF-A).[1] VEGF-A is a chemical signal that stimulates angiogenesis in a variety of diseases, especially in cancer, retinal proliferation of diabetes in the eye. Bevacizumab was the first clinically available angiogenesis inhibitor in the United States.[citation needed]

Bevacizumab is currently approved by the U.S. Food and Drug Administration (FDA) for cancers that are metastatic (have spread to other parts of the body). It received its first approval in 2004 for combination use with standard chemotherapy for metastatic colon cancer and non-small cell lung cancer.[2]

In 2008, the FDA approved bevacizumab for use in metastatic breast cancer. This was controversial, because the FDA's advisory panel recommended against approval, [3] since it only slowed tumor growth but failed to extend survival. In July 2010, the FDA revoked the indication for advanced breast cancer,[4] although the drug is still approved for use in Australia.[5] 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.

It is prescribed off-label -on the basis of clinical studies- for treatment of macular degeneration, an eye disease also characterized by proliferation of blood vessels in the retina.

Clinical studies are underway in non-metastatic breast cancer, renal cell carcinoma, glioblastoma multiforme, ovarian cancer, castrate-resistant (formally called hormone refractory) prostate cancer, non-metastatic unresectable liver cancer and metastatic or unresectable locally advanced pancreatic cancer. A study released in April 2009 found that bevacizumab is not effective at preventing recurrences of non-metastatic colon cancer following surgery.[6] 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.[7]

Background

Bevacizumab is a humanized monoclonal antibody, and was the first commercially available angiogenesis inhibitor. It stops tumor 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.[citation needed]

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.[citation needed]

Indications

Colorectal cancer

Bevacizumab was approved by the FDA in February 2004 for use in metastatic colorectal cancer 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.[citation needed]

Lung cancer

The overall data shows that bevacizumab has no effect on survival but has been shown to improve progression free survival time in some lung cancer types [Reck M, von PJ, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, Leighl N, Mezger J, Archer V, Moore N, et al. Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil. J Clin Oncol. 2009 Mar 10;27(8):1227-34. Reck M, von PJ, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, Leighl N, Mezger J, Archer V, Moore N, et al. Overall survival with cisplatin-gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer: results from a randomised phase III trial (AVAiL). Ann.Oncol. 2010 Sep;21(9):1804-9.}]

In 2006, the FDA approved bevacizumab for use in lung cancer in combination with standard first-line chemotherapy. A study conducted by the Eastern Cooperative Oncology Group (ECOG) demonstrated a 2-month improvement in overall survival in patients with Stage IIIb/IV non-small cell lung cancer (NSCLC). However, other studies have unfortunately not mirrored this finding and overall data shows that bevacizumab has no effect on survival. Due to the observance of severe pulmonary hemorrhage in patients with NSCLC with squamous histology in an earlier study, patients with such histology were excluded from the pivotal ECOG trial.[citation needed]

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.[8][9] 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.[10]

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.[citation needed] 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 $90,000.[10]

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.[citation needed]

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.[3]

On March 28, 2007, the European Commission approved bevacizumab in combination with paclitaxel for the first-line treatment of metastatic breast cancer.[11]

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 (a form of kidney cancer) [12] ,[13] following earlier reports of activity[14] 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.[15]

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.[16] 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.[citation needed]

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 oxaliplatin or irinotecan.[citation needed]

Investigational

Bevacizumab has also demonstrated activity in ovarian cancer,[17][18] and glioblastoma multiforme,[19] 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.[20]

In 2010 two phase III trials showed a 27% and 54% increase in progression-free survival in ovarian cancer.[21]

Bevacizumab has been investigated as a possible treatment of pancreatic cancer, as an addition to chemotherapy, but studies have shown no improvement in survival.[22][23][24] 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.[25]

Uses in eye disease

Many diseases of the eye, such as age-related macular degeneration (AMD) and diabetic retinopathy, 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[citation needed] Many retina specialists have noted impressive results in the setting of CNV, proliferative diabetic retinopathy, neovascular glaucoma, diabetic macular edema, retinopathy of prematurity[26] 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.[citation needed]

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.[27][28]

As Genentech has developed both drugs it has little interest in seeing Bevacizumab use in the eye and it is likely to remain off label. Off-label use of this medication has created significant controversy in medical retina and vitreo-retinal surgery. On October 11, 2007, Genentech issued a letter to Physicians that they would no longer sell bevacizumab to compounding pharmacies.[29] This would have effectively stopped its use for macular degeneration patients who had no insurance coverage for Ranibizumab (Lucentis) and for any patient who had other vision threatening conditions where Bevacizumab has been shown to work.[citation needed]

However, the ophthalmic community, led by the American Academy of Ophthalmology (AAO) and the American Society of Retinal Specialists (ASRS), fought back and managed to get Genentech to agree to continue providing bevacizumab to retinal surgeons, who in turn could get compounding pharmacies to "cut" the dosage to the appropriate ophthalmic dosage for continued use.[30]

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.[31] 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:[32]

(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.[33] Enrollment began on February 22, 2008, with fifteen sites beginning recruiting.[34] 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.[citation needed]

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.[citation needed]

As of July 2010, Avastin is being used successfully in a case study of Familial Exudative Vitreoretinopathy in Buffalo, New York.[citation needed]

Concerns

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 healing, 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.[35]

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.[36][37]nasal septum perforation, and renal thrombotic microangiopathy have been reported.[38] 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.[citation needed]

Costs

Bevacizumab is one of the most expensive drugs widely marketed. In 2008, sales of Avastin generated nearly $2.7 billion for Genentech.[39] Both physicians and the media have criticized the high cost of a drug that doesn't cure cancer[citation needed] but only prolongs life[citation needed]. 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 its use because of its extraordinarily lop-sided cost-benefit ratio; in the U.K., for example, the National Institute for Health and Clinical Excellence 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.[40]

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).[41]

Though Genentech has adjusted the price for patients in certain situations,[citation needed] 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.[42] 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.[43] Costs in other countries vary; in Canada it is reported to cost $40,000 CAD per year.[44]

See also

References

  1. ^ Los, M.; Roodhart, J. M. L.; Voest, E. E. (2007). "Target Practice: Lessons from Phase III Trials with Bevacizumab and Vatalanib in the Treatment of Advanced Colorectal Cancer". The Oncologist. 12 (4): 443–50. doi:10.1634/theoncologist.12-4-443. PMID 17470687.
  2. ^ http://www.gene.com/gene/products/information/pdf/avastin-prescribing.pdf
  3. ^ a b "F.D.A. Approves Drug's Use for Breast Cancer". The New York Times. February 22, 2008.
  4. ^ MedPageToday (2010-07-28). "FDA Panel Nixes Bevacizumab for Breast Cancer". Retrieved 2010-10-23. {{cite news}}: External link in |author= (help)
  5. ^ "Breast cancer drug 'still safe' for Aussie women". July 22, 2010. {{cite news}}: Unknown parameter |word= ignored (help)
  6. ^ Reed, Katie. "Roche drug Avastin fails cancer study, shares fall". Reuters 22 Apr 2009. Accessed 22 Apr 2009
  7. ^ Genentech, Inc. "FDA Grants Accelerated Approval of Avastin for Brain Cancer (Glioblastoma) That Has Progressed Following Prior Therapy". Market Watch 5 May 2009.
  8. ^ "FDA begins process to remove breast cancer indication from Avastin label" (Press release). FDA. 2010-12-16. Retrieved 2010-12-17.
  9. ^ Andrew Pollack (December 16, 2010). "F.D.A. Rejects Use of Drug in Cases of Breast Cancer". NY Times. Retrieved 2010-12-16.
  10. ^ a b Jennifer Couzin-Frankel and Yasmin Ogale (8 July 2011). "Once on 'Fast Track', Avastin Now Deralied". Science. 333: 143.
  11. ^ Jasek, W, ed. (2007). Austria-Codex (in German) (2007/2008 ed.). Vienna: Österreichischer Apothekerverlag. ISBN 3-85200-181-4. {{cite book}}: Check |isbn= value: checksum (help)[page needed]
  12. ^ FDA clears Genentech drug for kidney cancer San Francisco Chronicle, August 2, 2009
  13. ^ http://www.genengnews.com/news/bnitem.aspx?name=59562374 "FDA Gives Roche's Avastin the Go-Ahead for Metastatic Renal Carcinoma "
  14. ^ Rini, B. I. (2007). "Vascular Endothelial Growth Factor-Targeted Therapy in Renal Cell Carcinoma: Current Status and Future Directions". Clinical Cancer Research. 13 (4): 1098–106. doi:10.1158/1078-0432.CCR-06-1989. PMID 17317817.
  15. ^ Pollack, Andrew (2009-03-31). "F.D.A. Panel Supports Avastin to Treat Brain Tumor". New York Times. Retrieved 2009-08-13.
  16. ^ OncoGenetics.Org (2009). "Avastin dramatically improves response, survival in deadly recurrrent glioblastomas". OncoGenetics.Org. Retrieved 2009-09-02. {{cite web}}: Unknown parameter |month= ignored (help) [dead link]
  17. ^ Konner JA et al. Proc ASCO 2007 (2008). "A phase II study of intravenous (IV) and intraperitoneal (IP) paclitaxel (Tax), IP cisplatin (Cis), and IV bevacizumab (Bev) as first-line chemotherapy for optimal stage II or III ovarian, primary peritoneal, and fallopian tube cancer". http://www.asco.org/ASCO/Abstracts+&+Virtual+Meeting/Abstracts?&vmview=abst_detail_view&confID=47&abstractID=31096. {{cite journal}}: Cite journal requires |journal= (help); External link in |location= (help); Unknown parameter |month= ignored (help)CS1 maint: location (link) CS1 maint: numeric names: authors list (link)
  18. ^ Burger RA et al. J Clin Oncol 28:7s, 2010 (2010). "Phase III trial of bevacizumab (BEV) in the primary treatment of advanced epithelial ovarian cancer (EOC), primary peritoneal cancer (PPC), or fallopian tube cancer (FTC): A Gynecologic Oncology Group study". http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=74&abstractID=52788. {{cite journal}}: Cite journal requires |journal= (help); External link in |location= (help); Unknown parameter |month= ignored (help)CS1 maint: location (link) CS1 maint: numeric names: authors list (link)
  19. ^ Cloughesy, T. F.; Prados, M. D.; Wen, P. Y.; Mikkelsen, T.; Abrey, L. E.; Schiff, D.; Yung, W. K.; Maoxia, Z.; Dimery, I. (2008). "A phase II, randomized, non-comparative clinical trial of the effect of bevacizumab (BV) alone or in combination with irinotecan (CPT) on 6-month progression free survival (PFS6) in recurrent, treatment-refractory glioblastoma (GBM)". Journal of Clinical Oncology. 26 (15S): 2010b.
  20. ^ Richard Pazdur, M.D. (2009). "FDA Approval for Bevacizumab". National Cancer Insitute. Retrieved 2010-05-11. {{cite web}}: Unknown parameter |month= ignored (help)
  21. ^ "Roche Claims Phase III Data Supports Use of Avastin in Ovarian Cancer". 12 Oct 2010.
  22. ^ Saif MW (2008). "New developments in the treatment of pancreatic cancer. Highlights from the "44th ASCO Annual Meeting". Chicago, IL, USA. May 30 - June 3, 2008". JOP. 9 (4): 391–7. PMID 18648128.
  23. ^ Rocha-Lima, Caio M. (2008). "New directions in the management of advanced pancreatic cancer: a review". Anti-Cancer Drugs. 19 (5): 435–46. doi:10.1097/CAD.0b013e3282fc9d11. PMID 18418211.
  24. ^ Riess, Hanno (2008). "Pancreatic Cancer". Recent Results in Cancer Research. 177: 123–9. doi:10.1007/978-3-540-71279-4_14. ISBN 978-3-540-71266-4. {{cite journal}}: |chapter= ignored (help); Cite journal requires |journal= (help)
  25. ^ "Md. Girl,11, First To Try New Cancer Treatment".
  26. ^ Azad, Rajvardhan; Chandra, Parijat (2007). "Intravitreal bevacizumab in aggressive posterior retinopathy of prematurity". Indian Journal of Ophthalmology. 55 (4): 319. doi:10.4103/0301-4738.33057. PMID 17595491.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  27. ^ Medicare Eye Study Finds Untapped Savings, Wall Street Journal, June 17, 2010
  28. ^ Tufail, A.; Patel, P. J.; Egan, C.; Hykin, P.; Da Cruz, L.; Gregor, Z.; Dowler, J.; Majid, M. A.; Bailey, C. (2010). "Bevacizumab for neovascular age related macular degeneration (ABC Trial): multicentre randomised double masked study". BMJ. 340: c2459–c2459. doi:10.1136/bmj.c2459.
  29. ^ http://www.gene.com/gene/features/avastin/letter-to-physicians.html
  30. ^ http://patentdocs.typepad.com/patent_docs/2007/10/genentech-acts-.html[unreliable medical source?]
  31. ^ http://clinicalstudies.info.nih.gov/cgi/wais/bold032001.pl?A_08-EI-0061.html
  32. ^ http://irvaronsjournal.blogspot.com/2007/09/catt-study-update-3-avastin-vs-lucentis.html[unreliable medical source?]
  33. ^ http://www.clinicaltrials.gov/ct2/show/NCT00593450
  34. ^ http://www.clinicaltrials.gov/ct2/show/locn/NCT00593450
  35. ^ New England Journal of Medicine, 8 May 2008, 358(19):2066, Clinical Implications of Basic Research: A New Weapon for Attacking Tumor Blood Vessels, Gregg L. Semenza.
  36. ^ Velcheti, Vamsidhar; Viswanathan, Avinash; Govindan, Ramaswamy (2006). "The Proportion of Patients with Metastatic Non-small Cell Lung Cancer Potentially Eligible for Treatment with Bevacizumab: A Single Institutional Survey". Journal of Thoracic Oncology. 1 (5): 501. doi:10.1097/01243894-200606000-00023. PMID 17409907.
  37. ^ Vaughn, Christopher; Zhang, Louann; Schiff, David (2008). "Reversible posterior leukoencephalopathy syndrome in cancer". Current Oncology Reports. 10 (1): 86–91. doi:10.1007/s11912-008-0013-z. PMID 18366965.
  38. ^ Eremina, Vera; Jefferson, J. Ashley; Kowalewska, Jolanta; Hochster, Howard; Haas, Mark; Weisstuch, Joseph; Richardson, Catherine; Kopp, Jeffrey B.; Kabir, M. Golam (2008). "VEGF Inhibition and Renal Thrombotic Microangiopathy". New England Journal of Medicine. 358 (11): 1129–1136. doi:10.1056/NEJMoa0707330. PMC 3030578. PMID 18337603.
  39. ^ Genentech 2008 10-K Report,
  40. ^ Briggs, Helen (BBC News Health Reporter) (August 24, 2010). "Critics condemn bowel cancer drug rejection". Retrieved 2010-08-24.
  41. ^ http://www.scottishmedicines.org.uk/files/bevacizumab__Avastin__Resubmissionn_May_06_FINAL_for_website.pdf
  42. ^ A Cancer Drug Shows Promise, at a Price That Many Can't Pay, By ALEX BERENSON, New York Times, February 15, 2006.
  43. ^ Mayer, Robert J. (2004). "Two Steps Forward in the Treatment of Colorectal Cancer". New England Journal of Medicine. 350 (23): 2406–2408. doi:10.1056/NEJMe048098. PMID 15175443.
  44. ^ P.E.I. sole holdout on cancer drug CBC News, November 26, 2009
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