Bevacizumab (Avastin, Genentech, San Francisco, CA) is a recombinant humanized monoclonal IgG1 antibody that binds to and inhibits the biologic activity of human vascular endothelial growth factor (VEGF). This document addresses the indications and criteria for the use of bevacizumab in the treatment of oncologic conditions.

Note: Please see DRUG.00028 Intravitreal and Periocular Injection Treatment for Retinal Vascular Conditions for additional information.

Medically Necessary:

1. Bevacizumab is considered medically necessary for individuals with metastatic colon, rectal, colorectal, or small bowel adenocarcinoma as:
   1. first- line treatment in combination with 5-fluorouracil (5FU)-based chemotherapy; or
   2. second-line treatment when used in combination with 5FU-based chemotherapy or irinotecan in individuals who have not received prior bevacizumab; or
   3. second-line treatment in combination with 5FU-based chemotherapy or irinotecan, for individuals who have received prior bevacizumab when disease progression did not occur while on or within 3 months of cessation of bevacizumab.
      
      
2. Bevacizumab is considered medically necessary for individuals with unresectable, locally advanced, recurrent or metastatic non-squamous, non-small cell lung cancer (NSCLC) when used as first-line of therapy in individuals with performance status 0-1 and no history of hemoptysis when used in combination with both;
   1. platinum-based therapy and 
   2. taxane or pemetrexed.
      
      
3. Bevacizumab is considered medically necessary as maintenance therapy for individuals with unresectable, locally advanced, recurrent or metastatic non-squamous, non-small cell lung cancer (NSCLC) when all of the following criteria are met:
   1. Bevacizumab was previously administered as an agent in first-line combination regimen; and
   2. Used as a single agent; and
   3. May be used until disease progression.
      
      
4. Bevacizumab is considered medically necessary in the treatment of metastatic breast carcinoma when all of the following criteria are met:
   1. HER2-negative breast cancer; and
   2. Bevacizumab is used in first-line chemotherapy* for treatment of metastatic disease; and
   3. Bevacizumab is used in combination with paclitaxel or paclitaxel protein-bound.
      *NOTE: Hormonal therapy alone is not considered "chemotherapy"
      
      
5. Bevacizumab is considered medically necessary in the treatment of individuals with any of the following primary central nervous system tumors when used in only one line of therapy:
   1. Anaplastic astrocytoma; or
   2. Progressive or recurrent ependymoma that has failed radiation therapy; or
   3. Anaplastic glioma; or
   4. Recurrent, high-grade glioma; or
   5. Glioblastoma multiforme who have failed radiation therapy.
      
      
6. Bevacizumab is considered medically necessary in the treatment of recurrent, metastatic epithelial ovarian cancer; fallopian tube cancer or recurrent primary peritoneal cancer when the following criteria are met:
   1. Used as a single agent, and
   2. Used as 3^rd line of therapy or later (e.g., failure to respond or disease progression documented after, for example, two prior lines of chemotherapy).      
           
7. Bevacizumab is considered medically necessary as first-line treatment of metastatic clear cell renal carcinoma (RCC) in combination with interferon.
   
   
8. Bevacizumab is considered medically necessary when used as a single agent for treatment of angiosarcoma.
   
   
9. Bevacizumab is considered medically necessary when used in combination with temozolomide for the treatment of solitary fibrous tumor and hemangiopericytoma.
   

Investigational and Not Medically Necessary:

Bevacizumab is considered investigational and not medically necessary for treatment in all other indications not meeting the criteria above, including but not limited to the following:

• Adjuvant therapy following surgery for stage II or III adenocarcinoma of the colon;
• Prostate cancer;
• Carcinoid tumors;
• Metastatic melanoma;
• Metastatic adenocarcinoma of the pancreas;
• Metastatic breast cancer, second line therapy or greater, for example when progression noted following anthracycline and taxane chemotherapy;
• Neurofibromatosis type 2.

Concomitant use of bevacizumab with other targeted biologic agents (including, but not limited to erlotinib, cetuximab, panitumumab, trastuzumab, and lapatinib) is considered investigational and not medically necessary.

Bevacizumab is considered investigational and not medically necessary for the treatment of post-radiation necrosis.

A recombinant humanized monoclonal IgG1 antibody, bevacizumab binds to vascular endothelial growth factor (VEGF) and inhibits the interaction of VEGF to Flt1 and KDR receptors on the surface of endothelial cells. As a result of the binding process, the proliferation of endothelial cells and formation of new blood vessels is prevented (Product Information Label, 2009). 

Metastatic Colorectal and Small Bowel Adenocarcinoma
In 2004, bevacizumab received U.S. Food and Drug Administration (FDA) approval for use in combination with 5-fluorouracil (5-FU)-based chemotherapy as initial treatment of metastatic colorectal cancer. Bevacizumab was the first FDA approved angiogenesis inhibitor drug. The approval was based on results from 2 randomized controlled trials.

In June 2006, bevacizumab was approved by the FDA for the second-line treatment of individuals with metastatic colorectal cancer in combination with a 5-FU based regimen. The randomized controlled study involving 829 individuals in three study arms, compared 5-FU, leucovorin (LV) and oxaliplatin (FOLFOX4) alone, FOLFOX4 plus bevacizumab, and bevacizumab as monotherapy. After interim analysis provided evidence of decreased survival in the bevacizumab monotherapy arm compared to the FOLFOX4 arm, further accrual to the monotherapy cohort was closed. Overall survival was 13.0 months in the FOLFOX4 plus bevacizumab arm compared to the FOLFOX4 group of 10.8 months (Product Information Label, 2009). 

In a prospective, observational study, also known as the BRiTE trial, the safety and effectiveness of bevacizumab treatment for individuals with metastatic colorectal cancer (CRC) were reported by Grothey and colleagues (2008). Of the 1953 enrolled participants, 1445 individuals with mCRC disease progression (PD) were categorized into three groups which consisted of: no post-PD treatment (n=253); post-PD treatment without bevacizumab (n=531); and bevacizumab beyond first progression (BBP) (n=642). The median overall survival (OS) for the entire cohort was 25.1 months (95% confidence interval [CI], 23.4 to 27.5 months). After analyzing the data by classification, the BBP cohort had a statistically significant improved survival rate (HR 0.48; P< 0.001). The median OS rates also varied by group with 12.6 months for no post-PD treatment, 19.9 months for no-BBP group, and 31.8 months for the BBP group. Bevacizumab use varied within the 642 participants in the BBP group, with 312 individuals receiving continuous first-line to beyond first progressive disease. 132 participants had stopped bevacizumab prior to the first progressive disease, but restarted bevacizumab treatment within one month of PD.  198 participants discontinued the use of bevacizumab prior to PD or at first PD, and resumed bevacizumab more than one month after the first PD. 71 individuals resumed bevacizumab 4 or more months after the first progressive disease. The authors noted a higher incidence of new onset or worsening of hypertension in the BBP group, which was attributed to longer bevacizumab exposure. This study has significant methodological limitations which limit the applicability of the authors' conclusion. Further study in appropriately designed randomized trials is warranted. 

The National Comprehensive Cancer Network^® (NCCN) clinical practice guidelines (2011) for colon and rectal carcinoma state "there are no prospective data to support continuation of bevacizumab with a second-line regimen after progression on a bevacizumab-containing first-line regimen, and such continuation of bevacizumab beyond progression is not recommended. If bevacizumab is not used in initial therapy, it may be appropriate to consider if there is no contraindication to therapy." Additionally, the practice guideline lists the off-label use of bevacizumab in combination with FOLFOX; leucovorin with 5-FU and irinotecan (FOLFIRI); 5-FU plus leucovorin; or capecitabine plus oxaliplatin (CapeOx) regimens as initial therapy in individuals with unresectable, advanced or metastatic disease. In addition, for small bowel adenocarcinoma, the NCCN recommends "systemic chemotherapy according to the colon cancer guidelines." These recommendations were based on 2A category of evidence and uniform consensus. 

Non-small cell lung carcinoma (NSCLC)
Bevacizumab received FDA approval in October 2006, as first-line treatment in combination with carboplatin and paclitaxel for individuals with unresectable, locally advanced, recurrent or metastatic non-squamous, non-small cell lung cancer (NSCLC). In a large study, 878 participants were randomized to receive six cycles of paclitaxel and carboplatin (PC) or, PC plus bevacizumab at 15mg/kg. After completion of the six cycles, participants in the bevacizumab arm continued to receive bevacizumab alone every 21 days. Overall survival of 12.3 months in PC plus bevacizumab was statistically significant compared to 10.3 months in the PC alone cohort. The median progression free survival was 6.2 and 4.5 months respectively (Sandler, 2006). As a result of the Eastern Cooperative Oncology Group's (ECOG) phase II and III trials (ECOG4599), the use of bevacizumab in combination with paclitaxel and carboplatin has been recommended as the new standard of treatment (NCCN, 2011; Sandler, 2006).

Reck and colleagues (2009) reported results from a multi-center phase III trial that randomized participants to first-line treatment with cisplatin and gemcitabine plus low- or high-dose placebo versus low- or high-dose bevacizumab. Treatment allocation was blinded, and therefore no crossover was allowed, and the reported data from both placebo groups were combined. Treatment was planned for six cycles of combination chemotherapy, and thereafter maintained on single agent study drug until disease progression or unacceptable toxicity. In this trial, 1043 participants were randomized, but 57 participants were ineligible to receive treatment. Progression-free survival (PFS) was significantly longer in the treatment groups containing bevacizumab compared to placebo. In 2010, Reck and colleagues reported although the initial data demonstrated a trend for improved overall survival, the final analysis determined there was no significant overall survival benefit of bevacizumab when combined with cisplatin and gemcitabine compared to the cohort treated with cisplatin and gemcitabine.  

The NCCN practice guideline (2011) lists the off-label use of bevacizumab as first-line combination therapy with platinum-based regimens, and as a single-agent maintenance therapy for NSCLC if there was tumor response or stable disease following first-line chemotherapy that included bevacizumab. In addition, NCCN includes the off-label use of pemetrexed in combination with bevacizumab and platinum-based first-line therapy for NSCLC. These recommendations were based on 2A category of evidence and uniform consensus.

Breast Cancer
In February 2008, the FDA announced the accelerated approval for bevacizumab in conjunction with paclitaxel for the treatment of individuals who have not received chemotherapy for their metastatic HER-2 negative breast cancer. The approval was based on a phase III, Eastern Oncology Cooperative Group (E2100) trial analysis of 722 participants that demonstrated first line bevacizumab in combination with paclitaxel had a 52 percent reduction in disease progression (PFS) versus paclitaxel alone. A clinically significant median PFS (11.3 months compared with 5.8 months; p<0.001) was noted in the cohort receiving bevacizumab with paclitaxel versus paclitaxel alone. Although objective partial response rates were two fold higher in individuals treated with bevacizumab plus paclitaxel, there were no observed complete responses and no statistically significant improvement to overall survival. In addition, the product label notes bevacizumab is "not approved for use in combination with capecitabine or for use in second- or third-line treatment of metastatic breast cancer" (Miller, 2007; Product Information Label, 2009).

A retrospective, blinded reanalysis of radiologic and clinical data from all 722 participants in the open label E2100 trial was performed as a confirmatory study (Gray, 2009). Clinical data on 625 participants (86.6%) were obtained by an independent review facility (IRF) for analysis by radiologists who were blinded to the participants' clinical information. The IRF review confirmed a statistically significant (P < .0001) prolongation of PFS 11.3 months in the cohort treated with paclitaxel and bevacizumab versus 5.8 months in the group treated with paclitaxel alone.

In a phase III, randomized, double-blinded multicenter trial, Miles (2010) reported results from the AVADO trial which studied bevacizumab in either 7.5 mg/kg or 15 mg/kg in combination with docetaxel versus placebo plus docetaxel. The primary endpoint of the study was PFS from randomization to disease progression or death. Best overall response, duration of response, time to treatment failure (TTF), safety and overall survival (OS) were secondary endpoints. A total of 736 individuals were randomly assigned in a 1:1:1 manner. Median follow-up was 25 months. Median PFS in the placebo arm was 8.2 months, and 9.0 months in the bevacizumab 7.5mg arm (HR, 0.86; P=.12) and 10.1 months in the bevacizumab 15mg arms (HR, 0.77; P=.006). Adverse events occurred more frequently in the bevacizumab cohorts compared to the placebo group. Grade 3 or greater adverse events were 78% in the bevacizumab 7.5mg group, 75% in the bevacizumab 15mg group, and 67% in the placebo group. The minimal difference in PFS between groups does not support the use of docetaxel in combination with bevacizumab in metastatic breast cancer.

In 2005, Miller and colleagues reported on a multi-center trial of 462 individuals with metastatic breast cancer previously treated with anthracycline and a taxane. Participants were randomized to monotherapy with capecitabine or capecitabine in combination with bevacizumab. The phase III trial resulted in significantly increased objective response rates of 19.8% in the cohort receiving capecitabine and bevacizumab compared to 9.1% response rate in the group receiving capecitabine monotherapy. However, there was no significant difference in the PFS and OS rates. This lack of difference in PFS and OS does not support the use of capecitabine with bevacizumab in metastatic breast cancer.

There remain significant questions regarding the combinations of chemotherapy with bevacizumab which produce improvements in net health outcome. It is notable that the NCCN practice guideline (2011) lists the off-label use of bevacizumab in combination with paclitaxel, as a treatment for metastatic breast cancer, but NCCN does not currently recommend the combination of bevacizumab with docetaxel or bevacizumab with capecitabine.

Central Nervous System- Primary Tumors)
In May 2009, the FDA announced the accelerated approval of bevacizumab as a single agent, for the treatment of glioblastoma with progressive disease following prior therapy. This approval was based on an improved objective response rate. There are no data demonstrating an improvement in disease-related symptoms or increased survival with bevacizumab (Product Information Label, 2009). 

Some of the highest concentrations of VEGF are found in malignant gliomas. The overall prognosis for grade III (anaplastic astrocytoma, anaplastic oligoastrocytoma and anaplastic oligodendroglioma) – grade IV glioma (glioblastoma multiforme [GBM]) is grim and treatment options are limited. In 2007, Vredenburgh reported results of a phase II prospective trial investigating the efficacy of irinotecan combined with bevacizumab for recurrent gliomas in adults. Individuals requiring therapeutic anticoagulation were excluded from the study as a safety precaution. Of 32 participants, 23 individuals had grade IV GBM and 9 individuals had grade III gliomas (7[22%] with anaplastic astrocytoma, and 2[6%] with anaplastic oligoastrocytoma). Twenty (63%) had radiographic responses noted on magnetic resonance imaging (MRI). The overall 6 month PFS was 38%. A difference in PFS was noted by severity of disease between participants with grade III versus grade IV PFS of 56% compared with 30%, respectively. Median PFS of 23 weeks (95% confidence interval [CI], 15-30 weeks) with an overall 6 month survival is 72% (95% CI, 58-89%). Eight participants (25%) continued therapy with bevacizumab and irinotecan for more than 48 weeks after initiating therapy. The response data did not stratify responses by types of grade III gliomas. There were two treatment related events, arterial ischemic stroke and thromboembolic complications resulting in death. Vredenburgh and colleagues (2007b) contrasted results to data from another trial utilizing other chemotherapy regimens with a 6 month PFS of 15% and median PFS of 9 weeks. Another multicenter phase II trial is currently in progress to validate the results. Despite the natural disease progression of high grade glioma, the early trial results demonstrated improved PFS with the use of bevacizumab in combination with irinotecan.

There are multiple clinical trials studying the effectiveness of off-label bevacizumab used as first-line therapy for newly diagnosed GBM, but the data have not been published.

Metastatic renal cell carcinoma (RCC)
In July 2009, bevacizumab was approved by the FDA in combination with interferon alfa as a treatment for metastatic renal cell carcinoma. Data from a phase III randomized, multi-center, double-blind clinical trial compared bevacizumab plus interferon alfa-2a (IFN-α2a) versus placebo plus interferon alfa-2a as first-line treatment for metastatic clear cell renal cell carcinoma. Progression free survival was prolonged and statistically significant for participants receiving bevacizumab and IFN-α2a compared to controls (10.2 months vs. 5.4 months; p<0.0001). Although there were objective response rates (ORR) noted in participants, there was no improvement in overall survival between the cohorts (median OS of 23 months for bevacizumab plus IFN-α2a compared to 21 months for the control arm).

Ovarian carcinoma
A phase II consortium trial studied the use of bevacizumab and erlotinib to treat individuals with recurrent or refractory epithelial ovarian, primary peritoneal or fallopian tube cancer (Nimeiri, 2008). Thirteen participants were enrolled and there were two major objective responses for a 15% response rate (RR). However, there were two fatal gastrointestinal perforations and the trial was suspended. The authors concluded early identification of individuals at high-risk for perforation should be determined prior to further studies of bevacizumab for treatment of ovarian cancer.

This high frequency of often fatal bowel perforation and gastrointestinal hemorrhage related to bevacizumab therapy documented in this population must be considered in the context of the availability of alternative disease controlling treatments for which similar harm has not been observed. In a recent study using single agent bevacizumab, Simpkins and colleagues (2007) found no bowel perforations in the cohort of 25 participants with epithelial ovarian cancer selected with stringent criteria. Clinical exclusions included individuals with evidence of bowel obstruction, rectosigmoid involvement or evidence of bowel involvement on CT scan. There does appear to be a treatment benefit for recurrent disease and a low toxicity profile if individuals are carefully chosen for treatment, avoiding individuals with significant bowel involvement.

The American Hospital Formulary Service^® (AHFS^®, 2010) notes bevacizumab is being investigated in the treatment of metastatic epithelial ovarian and primary peritoneal cancer.

The NCCN Practice Guideline (2011) lists the off-label use of bevacizumab as a single agent treatment for recurrent epithelial ovarian cancer. These recommendations were based on 2A category of evidence and uniform consensus. Also, specialty consensus opinion suggests that single-agent bevacizumab be used for treatment of recurrent, metastatic epithelial ovarian carcinoma. There are ongoing phase three trials to study the use of bevacizumab in combination with other agents as first-line therapy, but the data from these trials have not yet been published.

Sex cord-stromal tumors include the most common granulosa cell tumor which is typically associated with good prognosis (NCCN, 2011). The NCCN practice guideline recommendations for individuals with these rare stage II-IV tumors who have a subsequent clinical relapse include recurrence therapy or treatment with bevacizumab. Tao and colleagues (2009) reported on a series of eight individuals with recurrent granulose tumors. At a median follow-up of 23.6 months, the median progression-free survival was 7.2 months, and the overall survival was not reached. Clinical trials continue to investigate bevacizumab and other chemotherapies to treat this rare ovarian sex cord tumor.

Soft Tissue Sarcoma
Hemangiopericytoma (HPC) is a vascular soft tissue tumor of fibroblastic cell origin that is characterized by Zimmerman's pericytes. Soft fibrous tumors (SFT) and HPC have over-lapping clinical and morphologic features.  HPC and SFT are viewed as a spectrum of a single entity and can be referred to as HPC/SFT (Park, 2009). In a review by Park (2009), 10-year overall survival of 54 – 89% after primary surgical resection has bee reported. Incidence of recurrence with aggressive disease has been reported an estimated 15 – 20% of the time (Park, 2009). A retrospective study of 14 individuals with HPC/SFT treated with combined temozolomide and bevacizumab resulted in median PFS of 8.6 months with a median followup of 20 months (Park, 2009).

The NCCN practice guideline (2011) lists the off-label use of bevacizumab as a single-agent therapy for angiosarcoma. Combination bevacizumab with temozolomide was recommended for the treatment of solitary fibrous tumor and hemangiopericytoma. These recommendations were based on 2A category of evidence and uniform consensus. In addition, specialty consensus opinion suggests Bevacizumab to treat these specific soft tissue sarcomas. 

Other Proposed Uses:

Carcinoid tumors
In a phase II study of 44 individuals with carcinoid tumors on stable doses of octreotide, participants were randomly assigned to 18 weeks of treatment with either bevacizumab or PEG interferon alfa-2b. At the end of 18 weeks, or upon disease progression, whichever occurred earlier, participants received the combined bevacizumab and PEG interferon alfa-2b until progression of disease. Twenty four individuals consented to functional computerized tomography (CT) scans. A statistically significant decrease in tumor blood flow was noted in participants treated with bevacizumab versus PEG interferon alfa-2b. However, a clinical correlation between decreased blood flow and treatment could not be made. The PFS rate at week 18 in participants treated with bevacizumab was 95% and 68% for the individuals treated with PEG interferon. The overall median PFS for all 44 participants was 63 weeks. The authors noted a larger randomized trial is ongoing to confirm the safety and efficacy from the phase II trial (Yao, 2008). However, at this time, there are no additional published randomized control trials to support the use of bevacizumab for carcinoid tumors.

Metastatic Melanoma
A phase 2 trial consisted of 53 participants with unresectable metastatic melanoma treated with bevacizumab, paclitaxel and carboplatin. The primary endpoint of the trial was an 8-week event free survival (EFS) rate. A median of 5 cycles were administered. Treatment was discontinued in 39 participants due to tumor progression, 5 participant refusals, and 9 with adverse events. One death was attributed to hemorrhaging related to a brain metastasis. The 8-week EFS rate was 74% (90% CI, 62%-83%). A minimum follow-up of 8.5 months or until death resulted in an estimated median progression free survival of 6 months and a median overall survival of 12 months. The investigators noted further study was needed to determine the optimal drug regimens and schedule for treatment of stage IV melanoma (Perez, 2009). There are multiple ongoing trials investigating various drug combinations plus bevacizumab as a treatment for this disease. Although early reports from phase 3 trials appear encouraging, the publication of outcomes and long term results are still pending. Currently, the off-label use of bevacizumab to treat metastatic melanoma is not included in treatment recommended by the National Cancer Institute and the NCCN.

Neurofibromatosis type 2
An inherited genetic condition with a prevalence of 1 in 25,000 births, neurofibromatosis type 2 involves benign tumors that develop from the Schwann cells in the eighth cranial nerve. Progressive tumor growth results in progressive loss of hearing. Surgery or radiation is standard therapy for unilateral schwannomas. However, the procedures may impair hearing in the affected ear. Therefore, medical interventions are being studied in a variety of clinical trials. 

In a retrospective series of ten consecutive participants with neurofibromatosis type 2 and growing vestibular schwannomas, Plotkin and colleagues (2009) reported results from bevacizumab treatment. The participants were not candidates for surgery and radiation or had refused the therapies. Median duration of treatment was 12 months and follow-up at a minimum of 1 year occurred for six participants. There was one case of progressive disease despite eight months of therapy, and one death after meningioma resection. Seven out of ten participants were eligible for a hearing response. Four participants had improved word-recognition scores that were durable for 11 to 16 months. Although there was evidence of tumor-volume reduction and some improvement in hearing, the follow-up is short term. The authors noted additional long-term research is needed to determine the optimal dosing and duration along with adverse events (Plotkin, 2009).

Pancreatic carcinoma
Fifty-two individuals with untreated advanced pancreatic carcinoma were enrolled in a phase II multi-center trial investigating the efficacy of bevacizumab in combination with gemcitabine. Partial responses were noted in eleven individuals (21%) and 24 individuals (46%) had stable disease. The median duration of response was ten months with a median follow-up of 8 months. The median PFS was 5.4 months. Survival rates at 6 month and 1-year were 77% (95% CI, 63% to 86%) and 29% (95% CI, 17% to 42%) respectively. Side effects attributed to bevacizumab were hypertension, proteinuria and visceral perforations (Kindler, 2005).

Based on the encouraging results of the phase II trial, a phase III randomized controlled trial was performed. Kindler (2010) reported no statistically significant difference in median overall survival (OS) was noted in a study of 602 randomly assigned individuals. The cohort treated with gemcitabine and bevacizumab had a median OS of 5.8 months compared to 5.9 months for the control group treated with gemcitabine and placebo (P=.95).  

The NCCN (2011) noted "although phase II trials utilizing bevacizumab for pancreatic carcinoma had been promising, phase III results have indicated only the combination of gemcitabine plus erlotinib is associated with statistically significant increase in survival when compared to gemcitabine alone."

Koh and colleagues (2010) reported results of a phase 2 trial with 36 enrolled individuals who were treated with bevacizumab and erlotinib for metastatic pancreatic cancer that had progressed on first-line chemotherapy. The primary endpoint of 6-month survival was not met with 8 out of 36 (22.2%) individuals alive at the threshold. Median time to progression was 40 days (95% CI, 35-41 days) and more than 80% of the participants had progressive disease and discontinued the study treatment.

Prostate cancer
The American Hospital Formulary System^® (AHFS, 2011) noted bevacizumab "in combination with chemotherapy are being investigated for use in the treatment of prostate cancer."

Clinical trials continue to investigate the effectiveness and safety of bevacizumab in the treatment of additional off-label indications such as carcinoid, melanoma, pancreatic and prostate cancers. In addition, there are studies combining bevacizumab with other targeted biologic agents. However there is insufficient data to support the safety and efficacy in the investigational indications.

Radiation necrosis
Gonzalez (2007) reported a retrospective, uncontrolled case series of eight individuals diagnosed with radiation necrosis from a group of 15 individuals treated with bevacizumab for malignant brain tumors. The novel application of bevacizumab to decrease the symptoms of radiation necrosis needs to be studied in a randomized controlled trial to determine the efficacy and safety for this indication. An updated literature search through August 2009 did not result in any published clinical trial results on the use of bevacizumab for radiation necrosis.

Combination with other targeted biologic agents
In a phase 3, open-label trial, 755 individuals with metastatic, unresectable colon or rectal carcinoma were randomized to receive treatment with capecitabine-bevacizumab (CB) and oxaliplatin, or capecitabine-bevacizumab-cetuximab (CBC) with oxaliplatin. A total of 732 individuals initiated treatment, with an equal distribution of 366 individuals in each group. The CBC cohort had a significantly decreased median progression-free survival (PFS) of 9.4 months compared to the CB group of 10.7 months, P=0.01. Overall quality of life and global health status in 532 individuals (276 in the CB group, 256 in the CBC group) improved significantly more in the CB group (P=0.007) compared to the CBC cohort (P=0.03). The investigators concluded the addition of cetuximab to capecitabine, oxaliplatin and bevacizumab "resulted in a significant decrease in progression-free survival and a poorer quality of life" (Tol, 2009). Tol and colleagues noted the results from the combination of anti-VEGF and anti-EGFR antibodies in the phase 3 trial were unexpected and differed from results in earlier phase II studies such as the BOND-2 (Saltz, 2007) trial.

The Panitumumab Advanced Colorectal Cancer Evaluation (PACCE) study (Hecht, 2009) is a phase IIIb randomized, open label clinical trial evaluating cohorts of a chemotherapy regimen including bevacizumab, with and without panitumumab, an anti- epidermal growth factor receptor (EGFR), as first-line treatment of individuals with previously untreated metastatic colorectal carcinoma (mCRC). Investigators chose a 5-FU, leucovorin and oxaliplatin-based regimen (Ox-CT; n= 823) or a 5-FU, leucovorin and irinotecan-based regimen (Iri-CT; n= 230), each with bevacizumab. Individuals were randomized to receive the selected regimen, or chemotherapy with the addition of panitumumab. A statistically significant difference in PFS in favor of the control arm (without panitumumab) was unveiled at the first planned interim analysis (Zhu, 2007) which resulted in a discontinuation of panitumumab. In the final analysis (Hecht, 2009) median PFS was 10.1 months for panitumumab and 11.7 months for the control group (HR, 1.19; 95% CI, 0.79 to 1.79). In a safety analysis of 804 individuals in the Ox-CT cohort and 224 individuals in the Iri-CT cohort, both groups had more adverse events (AEs) of grade 3 or higher in the panitumumab cohorts compared to the control groups (Ox-CT 367 (90%) versus 305 (77%), respectively; Iri-CT 100 (90%) versus 71 (63%) respectively). Serious AEs included diarrhea, infections and pulmonary embolism. Seven (1%) deaths were attributed to be panitumumab-related. The authors concluded the decreased PFS and increased serious AEs do not support panitumumab in combination with bevacizumab and oxaliplatin- or irinotecan-based chemotherapy as a treatment for mCRC. "Administration of chemotherapy and dual EGFR/VEGF inhibition should be conducted only in a research setting (Hecht, 2009)."

Citing lack of improved outcomes and increased toxicities from combination therapies used in two phase III randomized trials, the NCCN colon and rectal Clinical Practice Guidelines (2011) "strongly recommend against the use of therapy involving the combination of an anti-EGFR agent" and bevacizumab.

Angiogenesis is the growth of new blood vessels. Vascular endothelial growth factor (VEGF), a cytokine, appears to have a key role in angiogenesis and vascular permeability. Overexpression of VEGF has been found in most human tumors (Crane, 2006).

A monoclonal antibody is a protein developed in the laboratory that can locate and bind to specific substances in the body and on the surface of cancer cells (National Cancer Institute [NCI], 2010). Bevacizumab is a recombinant humanized monoclonal IgG1 antibody genetically engineered from both mouse and human antibody components. Bevacizumab binds to and inhibits the biologic activity of human vascular endothelial growth factor (VEGF). As a result, bevacizumab may interrupt the signals necessary for the growth of blood vessels necessary for the proliferation and survival of cancer cells.

Standard of care treatment for high-grade glioma includes surgical resection, radiation and chemotherapy. Recently, the addition of temozolomide to radiation regimen has increased the median survival by 2.5 months and increased the 2-year survival rate (Sathornsumetee, 2006).

According to the National Cancer Institute, glioblastoma (World Health Organization grade IV) is also known as glioblastoma multiforme (GBM). The peak incidence for GBM occurs between the ages of 45 and 70 years. GBM is histologically anaplastic and may develop from a diffuse astrocytoma or an anaplastic astrocytoma but more commonly presents de novo without evidence of a less malignant precursor. Glioblastoma is the most frequently occurring brain tumor accounting for approximately 12% to 15% of all brain tumors and 50% to 60% of all astrocytic tumors. Giant cell glioblastoma and gliosarcoma are two histologic variants of glioblastoma multiforme.

Many clinical trials continue to investigate the effectiveness and safety of bevacizumab in the treatment of additional off-label indications such as pancreatic and prostate cancers. However, at this time, there is insufficient data to support the safety and efficacy in the investigational indications.

A systematic review and meta-analysis of fifteen randomized controlled trials (RCTs) consisting of 7956 individuals, was published by Nalluri and colleagues (2008). The goal of the study was to evaluate the occurrence of venous thromboembolism resulting from treatment with bevacizumab for oncologic indications. The studies enrolled individuals with various solid tumor types such as colorectal, breast, lung, and renal cell carcinomas. An all-grade venous thromboembolism incidence of 11.9% (95% CI, 6.8% to 19.9%) was noted in an analysis of 6 studies with 2279 individuals. In an analysis of 3795 individuals in 13 studies, high-grade venous thromboembolism (grades 3-5) had an incidence of 6.3% (95% CI, 4.8%-8.3%). The authors noted significant morbidity and mortality is associated with high-grade venous thromboembolism. The overall relative risk (RR) of all-grade and high-grade venous thromboembolism in all tumor types was 1.33 (95% CI, 1.13-1.56; P< .001) compared to controls. Individuals treated with low dose (2.5mg/kg/week) and high dose (5mg/kg/week) bevacizumab had a significantly increased risk of venous thromboembolism with a RR of 1.31 for both dosing schedules. The authors concluded venous thromboembolism continues to be an emerging adverse complication of anti-angiogenic agents and additional trials are needed to study the prevention and management of venous thromboembolism.

A meta-analysis by Ranpura and colleagues (2011) included sixteen randomized controlled trials. The overall incidence of fatal adverse events (FAEs) with bevacizumab was increased with the addition of bevacizumab versus chemotherapy alone with an RR of 1.46 (95% CI, 1.09-1.94); P=.01). The overall incidence of FAEs with bevacizumab was 2.5% (95% CI, 1.7%-3.9%) which varied with chemotherapy regimen combinations, but did not have a significant variation by tumor type. Overall, hemorrhage (23.5%) was the most common cause of FAEs, followed by neutropenia (12.2%) and gastrointestinal tract perforation (7.1%). The authors noted "risk reduction includes selecting appropriate patients for therapy, prophylactic granulocyte colony-stimulating factor, early assessment of toxic effects, and adequate management of serious adverse events" (Ranpura, 2011).

Warnings from the 2009 FDA Product Information label include the following:

• Bevacizumab administration can result in serious and sometimes fatal gastrointestinal perforation. The incidence of perforation ranged from 0.3 to 2.4% across clinical studies. Typical presentation may include abdominal pain, nausea, emesis, constipation and fever. Perforation can be complicated by intra-abdominal abscess and fistula formation. The majority of cases occurred within the first 50 days of initiation of bevacizumab. Bevacizumab therapy should be permanently discontinued in patients with gastrointestinal perforation.
  
  
• Bevacizumab impairs wound healing in animal models. In clinical trials, administration of bevacizumab was not allowed until at least 28 days after surgery. In a controlled clinical trial, the incidence of wound healing complications, including serious and fatal complications, in patients with mCRC who underwent surgery during the course of bevacizumab treatment was 15% and in patients who did not receive bevacizumab was 4%. Bevacizumab should not be initiated for at least 28 days following surgery and until the surgical wound is fully healed. Discontinue bevacizumab in patients with wound healing complications requiring medical intervention. The appropriate interval between the last dose of bevacizumab and elective surgery is unknown.
  
  
• Bevacizumab can result in two distinct patterns of bleeding: minor hemorrhage, most commonly Grade 1 epistaxis and serious, and in some cases fatal, hemorrhagic events. Severe or fatal hemorrhage including hemoptysis, gastrointestinal bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal bleeding occurred up to five-fold more frequently in patients receiving bevacizumab compared to patients receiving only chemotherapy. The incidence of severe or fatal hemoptysis was 31% in patients with squamous histology and 4% in patients with NSCLC excluding predominant squamous histology. Patients with hemoptysis (greater than or equal to ½ tsp of red blood) should not receive bevacizumab. Intracranial hemorrhage occurred in 8 of 163 patients with previously treated glioblastoma; two patients had Grade 3-4 hemorrhage.
  
  
• Serious and sometimes fatal non-gastrointestinal fistula formation involving tracheo-esophageal, bronchopleural, biliary, vaginal and bladder sites occurs at a higher incidence in bevacizumab-treated patients compared to controls. The incidence of non-gastrointestinal perforation was less than 0.3% in clinical studies. Most events occurred within 6 months of treatment with bevacizumab. Discontinue bevacizumab in patients with fistula formation involving an internal organ.
  
  
• Two distinct patterns of bleeding have occurred in patients receiving bevacizumab. The first is minor hemorrhage, most commonly epistaxis. The second is serious and in some cases fatal hemorrhagic events. Do not administer bevacizumab to patients with recent history of hemoptysis of greater than or equal to ½ tsp of red blood. Other serious bleeding events occurring in patients receiving bevacizumab include gastrointestinal and subarachnoid hemorrhage and hemorrhagic stroke.
  
  
• Serious and sometimes fatal, arterial thromboembolic events (ATE) including cerebral infarction, transient ischemic attacks, myocardial infarction, angina, and a variety of other ATE occurred at a higher incidence in patients receiving bevacizumab compared to those in the control arm. Across indications, the incidence of Grade 3 or greater ATE in the bevacizumab containing arms was 2.6% compared to 0.8% in the control arms.  
  
  
• The incidence of severe hypertension is increased in patients receiving bevacizumab compared to controls. Across clinical studies, the incidence of Grade 3 or 4 hypertension ranged from 5-18%. Temporarily suspend bevacizumab in patients with severe hypertension not controlled with medical management. Discontinue bevacizumab in patients with hypertensive crisis or hypertensive encephalopathy.
  
  
• Reversible posterior leukoencephalopathy syndrome (RPLS) has been reported with and incidence of less than 0.1% in clinical studies. RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging (MRI) is necessary to confirm the diagnosis of RPLS. Onset of symptoms occurred from 16 hours to 1 year after initiation of bevacizumab.
  
  
• Increased rates of severe neutropenia, febrile neutropenia, and infection with severe neutropenia (including some fatalities) have been observed in patients treated with myelosuppressive chemotherapy plus bevacizumab.
  
  
• The incidence and severity of proteinuria is increased in patients receiving bevacizumab compared to control. Nephrotic syndrome occurred in less than 1% of patients receiving bevacizumab in clinical trials, in some instances with fatal outcome. Suspend bevacizumab administration for 2 or more grams of proteinuria/24 hours and resume when proteinuria is less than 2 gm/24 hours. Discontinue bevacizumab in patients with nephrotic syndrome.  
  
  
• Bevacizumab should not be given as an IV Push or IV bolus.
  
  
• The safety and effectiveness of bevacizumab in pediatric patients has not been studied.
  
  

Further studies on angiogenic biomarkers are needed to identify patients that may best benefit from this therapy.

Adjuvant therapy: Treatment given after the primary treatment to increase the chances of a cure. May include chemotherapy, radiation, hormone, or biological therapy.

Anaplastic astrocytoma (WHO grade III): A tumor which may arise from a diffuse astrocytoma or may arise de novo without indication of a less malignant precursor. Also known as malignant astrocytoma and high-grade astrocytoma.

Angiogenesis: Blood vessel formation; in tumors, angiogenesis is the growth of blood vessels from surrounding tissue to a solid tumor. This is caused by the release of chemicals by the tumor.

Capecitabine (Xeloda^®, Roche Laboratories, Inc., Nutley, NJ): A pro-drug that is enzymatically converted into 5-fluorouracil (5-FU) in vivo.                                                                                                                                                 

Complete response: The disappearance of all signs of cancer as a result of treatment. May also be called complete remission. This does not indicate the cancer has been cured.

Ependymoma: A slow-growing tumor of children and young adults that originates from the wall of the cerebral ventricles or from the spinal canal and is composed of neoplastic ependymal cells.

Glioblastoma multiforme: Stage IV glioblastoma, which includes World Health Organization [WHO] recognized variants, giant cell glioblastoma and gliosarcoma.

Hormonal therapy: Treatment that adds, blocks, or removes hormones. Agents that slow or stop the growth of certain cancers, synthetic hormones or other drugs may be given to block the body's natural hormones.

Line of therapy:

• First-line therapy: The first or primary treatment for the diagnosis. This may include surgery, chemotherapy, radiation therapy or a combination of these therapies. Also called primary therapy and primary treatment.
• Second-line therapy: Treatment given when initial treatment (first-line therapy) is not effective or there is disease progression.
• Third-line therapy: Treatment given when both initial (first-line therapy) and subsequent treatment (second-line therapy) are not effective or there is disease progression.

Metastasis: The spread of cancer from one part of the body to another. A metastatic tumor contains cells that are like those in the original (primary) tumor and have spread.

Monoclonal antibody: A protein developed in the laboratory that can locate and bind to specific substances in the body and on the surface of cancer cells.

Partial response: A decrease in the size of a tumor, or in the amount of cancer in the body, resulting from treatment. May also be called partial remission.

Targeted biologic agent: A newer type of drug developed specifically to target genetic changes in cells that cause cancer. It works differently than standard chemotherapy drugs, often with different side effects. 

Vascular Endothelial Growth Factor (VEGF): A substance made by cells that stimulates new blood vessel formation.

The following codes for treatments and procedures applicable to this document are included below for informational purposes.  Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy.  Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member. 

When services may be Medically Necessary when criteria are met:

When services are Investigational and Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met, and for all other malignant neoplasm diagnoses not listed.

Future ICD-10 coding (effective 10/01/2013)
A draft of ICD-10 Coding related to this document, as it might look today, is available for reference and comments at: Appendix 1: Future ICD-10 coding

Peer Reviewed Publications:

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9. Giantonio BJ, Levy DE, O'dwyer PJ, et al. A phase II study of high-dose bevacizumab in combination with irinotecan, 5-fluorouracil, leucovorin, as initial therapy for advanced colorectal cancer: results from the Eastern Cooperative Oncology Group study E2200. Ann Oncol. 2006; 17(9):1399-1403.
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13. Hainsworth JD, Sosman JA, Spigel DR, et al. Treatment of metastatic renal cell carcinoma with a combination of bevacizumab and erlotinib. J Clin Oncol. 2005; 23(31):7889-7896.
14. Hecht JR, Mitchell E, Chidiac T, et al. A randomized phase IIIB trial of chemotherapy, bevacizumab, and panitumumab compared with chemotherapy and bevacizumab compared alone for metastatic colorectal cancer. J Clin Oncol. 2009; 27(5): 672-680.
15. Johnson DH, Fehrenbacher L, Novotny WF, et al. Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol. 2004; 22(11):2184-2191.
16. Kindler HL, Friberg G, Singh DA, et al. Phase II trial of bevacizumab plus gemcitabine in patients with advanced pancreatic cancer. J Clin Oncol. 2005; 23(31):8033-8040.
17. Kindler HL, Niedzwiecki D, Hollis D, et al. Gemcitabine plus bevacizumab compared with gemcitabine plus placebo in patients with advanced pancreatic cancer: phase III trial of the Cancer and Leukemia Group B (CALGB 80303). J Clin Oncol. 2010; 28(22):3617-3622.
18. Ko AH, Venook AP, Bergsland EK, et al. A phase II study of bevacizumab plus erlotinib for gemcitabine-refractory metastatic pancreatic cancer. Cancer Chemother Pharmacol. 2010; 66(6):1051-1057.
19. Miles DW, Chan A, Dirix LY, et al. Phase IIII study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2010; 28(20):3239-3247.
20. Miller KD, Chap LI, Holmes FA, et al. Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol. 2005; 23(4):792-799.
21. Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007; 357(26):2666-2676.
22. Monk B, Han E, Josephs-Cowan C, et al. Salvage bevacizumab (rhumba VEGF)-based therapy after multiple prior cytotoxic regimens in advanced refractory epithelial ovarian cancer. Gynecol Oncol. 2006; 102(2):140-144.
23. Nalluri SR, Chu D, Keresztes R, et al. Risk of venous thromboembolism with the angiogenesis inhibitor bevacizumab in cancer patients. JAMA. 2008; 300(19):2277-2285.
24. Nimeiri HS, Oza AM, Morgan RJ, et al.; Chicago Phase II Consortium; PMH Phase II Consortium; California Phase II Consortium. Efficacy and safety of bevacizumab plus erlotinib for patients with recurrent ovarian, primary peritoneal and fallopian tube cancer: a trial of the Chicago, PMH, and California Phase II Consortia. Gynecol Oncol. 2008; 110(1):49-55.
25. Perez DG, Suman VJ, Fitch TR, et al. Phase 2 trial of carboplatin, weekly paclitaxel, and biweekly bevacizumab in patients with unresectable stage IV melanoma. Cancer. 2009; 115(1):119-127.
26. Plotkin SR, Stemmer-Rachamimov AO, Barker FG II, et al. Hearing improvement after bevacizumab in patients with neurofibromatosis type 2. N Engl J Med. 2009: 361(4):358-367.
27. Ramaswamy B, Elias AD, Kelbick NT, et al. Phase II trial of bevacizumab in combination with weekly docetaxel in metastatic breast cancer patients. Clin Cancer Res. 2006; 12(10):3124-3129.
28. Ranpura V, Hapani S, Wu S. Treatment-related mortality with bevacizumab in cancer patients. A meta-analysis. JAMA. 2011; 305(5):487-494.
29. Reck M, von Pawel J, Zatloukal P, 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; 27(8):1227-1234.
30. Reck M, von Pawal J, Zatloukal P, 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 randomized phase III trial (AVAiL). Ann Oncol. 2010; 21(9):1804-1809.
31. Rini BI, Halabi S, Taylor J, et al. Cancer and Leukemia Group B 90206: A randomized phase III trial of interferon-alpha or interferon-alpha plus anti-vascular endothelial growth factor antibody (bevacizumab) in metastatic renal cell carcinoma. Clin Cancer Res. 2004; 10(8):2584-2586.
32. Rini BI, Weinberg V, Fong L, et al. Combination immunotherapy with prostatic acid phosphatase pulsed antigen-presenting cells (provenge) plus bevacizumab in patients with serologic progression of prostate cancer after definitive local therapy. Cancer. 2006; 107(1):67-74.
33. Robert NJ, Dieras V, Glaspy J, et al. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2 – negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011; 29(10):1252-1260.
34. Saltz LB, Lenz HJ, Kindler L, et al. Randomized phase II trial of cetuximab, bevacizumab, and irinotecan compared with cetuximab and bevacizumab alone in irinotecan-refractory colorectal cancer: the BOND-2 study. J Clin Oncol. 2007; 25(29):4557-4561.
35. Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006; 355(24):2542-2550.
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37. Shah MA, Ramanathan RK, Ilson DH, et al. Multicenter phase II study of irinotecan, cisplatin, and bevacizumab in patients with metastatic gastric or gastroesophageal junction adenocarcinoma. J Clin Oncol. 2006; 24(33):5201-5206.
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Government Agency, Medical Society, and Other Authoritative Publications:

1. American Hospital Formulary Service^® (AHFS). AHFS Drug Information 2009^®. Bethesda, MD: American Society of Health-System Pharmacists^®, 2010.
2. Avastin [Product Information]. South San Francisco, CA. Genentech, Inc.; July 31, 2009. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/125085s0168lbl.pdf. Accessed on May 19, 2011.
3. Bevacizumab (systemic). In: DrugPoints^® System [Internet. database]. Greenwood Village, CO: Thomson Healthcare. Updated periodically. Available at: http://www.thomsonhc.com. Accessed on May 16, 2011.
4. Blue Cross Blue Shield Association. Off-Label Uses of Bevacizumab: Breast and Lung Cancer Indications. TEC Assessment, 2007; 21(8).
5. Blue Cross Blue Shield Association. Off-Label Uses of Bevacizumab: Renal Cell Carcinoma and Other Miscellaneous Non-Colorectal Cancer Indications. TEC Assessment, 2007; 21(9).
6. NCCN Clinical Practice Guidelines in Oncology™. © 2011 National Comprehensive Cancer Network, Inc. For additional information: http://www.nccn.org/index.asp. Accessed on May 19, 2011.
   • Breast Cancer (V.2.2011). Revised March 25, 2011.
   • Central Nervous System Cancer (V.2.2011). Revised January 31, 2011.
   • Colon Cancer (V.3.2011). Revised February 25, 2011.
   • Kidney Cancer (V.2.2011). Revised February 23, 2011.
   • Non-Small Cell Lung Cancer (V.3.2011). Revised January 7, 2011.
   • Ovarian Cancer (V.2.2011). Revised November 15, 2010.
   • Pancreatic Adenocarcinoma (V.2.2011). Revised March 28, 2011.
   • Prostate Cancer (V.2.2011). Revised April 26, 2011.
   • Rectal Cancer (V.4.2011). Revised February 25, 2011.
7. Socinski MA, Crowell R, Hensing TE, et al.; American College of Chest Physicians.Treatment of non-small cell lung cancer, stage IV: ACCP evidence-based clinical practice guidelines (2nd edition). Chest. 2007; 132(3 Suppl):277S-289S.
8. U.S. Food and Drug Administration MedWatch. April 21, 2007. Available at: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm150835.htm. Accessed on May 19, 2011.
9. U.S. Food and Drug Administration MedWatch. July 14, 2008. Available at: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm075132.htm.  Accessed on May 19, 2011.

1. American Cancer Society (ACS). Available at: http://www.orgsites.com/ga/acs/. Accessed on May 19, 2011.
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3. National Cancer Institute. Dictionary of Cancer Terms. Available at: http://www.cancer.gov/dictionary/. Accessed on May 19, 2011.

Avastin
Bevacizumab
Monoclonal Antibody
VEGF

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.