Advanced Breast Cancer: Learn about treatment options.

Generic Name: Bevacizumab
Class: Antineoplastic Agents
VA Class: AN900
Chemical Name: Immunoglobulin G 1 (human-mouse monoclonal rhuMAb-VEGF γ-chain anti-human vascular endothelial growth factor), disulfide with human-mouse monoclonal rhuMAb-VEGF light chain, dimer
Molecular Formula: C6638H10160N1720O2108S44
CAS Number: 216974-75-3

Warning(s)

  • GI Perforations
  • GI perforation reported in 0.3–2.4% of patients receiving bevacizumab; may be severe or fatal.1 If GI perforation occurs, discontinue bevacizumab permanently.1 (See GI Perforation under Cautions.)

  • Surgery and Wound Healing Complications
  • Increased incidence of surgical and wound healing complications; may be serious and fatal.1 Discontinue bevacizumab permanently if wound dehiscence and wound healing complications requiring medical intervention occur.1 (See Surgery and Wound Healing Complications under Cautions.)

  • Appropriate interval between discontinuance of bevacizumab and subsequent elective surgery required to decrease risk of wound healing complications not established.1 However, manufacturer recommends discontinuing therapy ≥28 days prior to elective surgery.1

  • Do not initiate therapy until ≥28 days following major surgery and after surgical incision has fully healed.1

  • Hemorrhage
  • Severe, sometimes fatal, hemorrhagic events (e.g., hemoptysis, GI bleeding, hematemesis, CNS hemorrhage, epistaxis, vaginal bleeding) reported.1 Do not administer to patients with serious hemorrhage or recent hemoptysis.1 (See Hemorrhage under Cautions.)

Introduction

Antineoplastic agent; a recombinant humanized monoclonal antibody.1 2 3 4 5

Uses for Avastin

Colorectal Cancer

Used in combination with IV fluorouracil-based chemotherapy for the first-line treatment of metastatic cancer of the colon or rectum.1 2 3 4 9 Analysis of pooled data suggests that use of bevacizumab in combination with fluorouracil and leucovorin is associated with prolonged survival.20

Has also been used in combination with oxaliplatin-containing regimens as first-line therapy for metastatic colorectal cancer.38

Used in combination with IV fluorouracil-based chemotherapy for the second-line treatment of previously treated metastatic cancer of the colon or rectum.1 Interim analysis of data from one study indicated bevacizumab monotherapy was associated with decreased survival compared with combination regimen consisting of fluorouracil, leucovorin, and oxaliplatin.1

Investigated for use in combination with fluorouracil, leucovorin, and oxaliplatin (modified FOLFOX6) as adjuvant therapy following surgery for early-stage (i.e., stage II or III) colon cancer.28 Data from a randomized study demonstrated no improvement in disease-free survival; therefore, such use not recommended.53

Non-small Cell Lung Cancer

Used in combination with carboplatin and paclitaxel for first-line treatment of unresectable, locally advanced, recurrent or metastatic nonsquamous NSCLC.1 10 Data from a randomized study suggest that use of bevacizumab in combination with carboplatin and paclitaxel is associated with prolonged survival; benefit less certain in women, patients ≥65 years of age, and those with ≥5% weight loss.1 11

Slideshow: 2014 Update: First Time Brand-to-Generic Switches

Investigated for use in combination with cisplatin and gemcitabine for first-line treatment of locally advanced, metastatic, or recurrent nonsquamous NSCLC.1 Data from a randomized study suggest that such use is associated with prolonged progression-free survival but not prolonged overall survival.1

Glioblastoma

Used as a single agent for treatment of glioblastoma in patients whose disease has progressed following radiation therapy and chemotherapy (i.e., temozolomide).1 Efficacy is based on increased objective response rate; currently, no data available that demonstrate prolonged overall survival or amelioration of disease-related symptoms.1 47 48

Renal Cell Carcinoma

Used in combination with interferon alfa for first-line treatment of metastatic renal cell carcinoma1 (designated an orphan drug by FDA for this use).63

Breast Cancer

Previously labeled for use in combination with paclitaxel for first-line treatment of metastatic HER2-negative breast cancer.44 However, FDA concluded that such use has not been shown in postmarketing studies to prolong overall survival or provide sufficient clinical benefit (e.g., prolongation of progression-free survival, amelioration of disease-related symptoms, improvement in quality of life) to outweigh the risk of severe, potentially fatal, adverse effects (e.g., MI, CHF, severe hypertension, bleeding or hemorrhage, perforation and fistula/abscess formation,44 wound healing complications).65 66 68 Therefore, on November 18, 2011, FDA revoked approval of bevacizumab for this use;68 Health Canada, but not the European Medicines Agency (EMA), took similar action.65 69 The United Kingdom’s Institute for Health and Clinical Excellence (NICE) reached similar conclusions about the lack of evidence of clinical benefit and has not supported this use.65 70 The AHFS Oncology Expert Committee concluded that use of bevacizumab in combination with paclitaxel for first-line treatment of metastatic breast cancer currently is not fully established because of equivocal evidence.77

Patients currently receiving bevacizumab for breast cancer should consult their clinician about whether to continue bevacizumab therapy or consider other treatment options.67 Clinicians should use clinical judgment in deciding whether patients should continue receiving bevacizumab in combination with paclitaxel, receive paclitaxel monotherapy, or consider other treatment options.67

AHFS OncologyExpert Committee also concluded that use of bevacizumab in combination with chemotherapy (e.g., taxanes, capecitabine, gemcitabine, vinorelbine)14 75 for the treatment of metastatic breast cancer previously treated with cytotoxic chemotherapy currently is not fully established because of equivocal evidence.78

Ovarian Cancer

Investigated for use in treatment of ovarian cancer.26 Data from randomized studies suggest that use of bevacizumab in combination with carboplatin and paclitaxel is associated with prolonged progression-free survival, but not prolonged overall survival, and an increased risk of hypertension and GI perforation.71 72 Effects on overall survival not fully elucidated (i.e., no difference in overall survival reported in one study, final overall survival data not yet available for another study).71 72

Neovascular Age-related Macular Degeneration

Has been used by intravitreal injection in treatment of neovascular age-related macular degeneration.34 41 May be as effective as ranibizumab in improving visual acuity when administered according to the same schedule as ranibizumab; however, increased risk of serious systemic adverse effects (primarily hospitalizations) reported.41 (See Ocular Effects under Cautions.)

Avastin Dosage and Administration

General

  • Use alone or in combination with other chemotherapeutic agents.1 (See Dosage under Dosage and Administration.)

  • Do not initiate therapy until ≥28 days following major surgery and after surgical incision has fully healed.1 (See Surgery and Wound Healing Complications under Cautions.)

  • Discontinue therapy ≥28 days prior to elective surgery; do not resume until surgical incision has fully healed.1 (See Surgery and Wound Healing Complications under Cautions.)

Administration

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Administer by IV infusion.1 Do not administer by rapid IV injection (e.g., IV push or bolus.1

Dilution

Do not shake vial prior to dilution.1

Withdraw appropriate dose of bevacizumab and dilute in 100 mL of 0.9% sodium chloride.1 Do not administer or mix with dextrose solutions.1

Rate of Administration

Administer initial dose over 90 minutes.1 (See Infusion Reactions under Cautions.)

If well tolerated, administer second dose over 60 minutes.1

If second dose is well tolerated, administer subsequent doses over 30 minutes.1

Has been administered safely over shorter infusion times (0.5 mg/kg per minute).43

Dosage

Consult respective manufacturers or published protocols for dosage, method of administration, and administration sequence of drugs in combination regimens.3

Adults

Colorectal Cancer
First-line Treatment of Metastatic Colorectal Cancer
IV

5 mg/kg every 2 weeks; continue until disease progression or unacceptable toxicity occurs.1

Use in combination with IV fluorouracil-based chemotherapy.1 In clinical studies, bevacizumab was used in combination with the IFL regimen (irinotecan 125 mg/m2, fluorouracil 500 mg/m2, and leucovorin 20 mg/m2, administered by IV injection once weekly for 4 out of every 6 weeks)1 4 or the 5-FU/LV regimen (leucovorin 500 mg/m2 by IV infusion over 2 hours, then fluorouracil 500 mg/m2 by slow IV injection [1 hour after initiation of leucovorin] given once weekly for the first 6 weeks out of every 8-week cycle).1 2 3

Second-line Treatment of Metastatic Colorectal Cancer
IV

10 mg/kg every 2 weeks; continue until disease progression or unacceptable toxicity occurs.1

Use in combination with IV fluorouracil-based chemotherapy.1 In clinical studies, bevacizumab was administered on day 1 of the treatment cycle prior to the FOLFOX4 regimen (oxaliplatin 85 mg/m2 and leucovorin 200 mg/m2 concurrently IV, then fluorouracil 400 mg/m2 by direct IV injection, followed by fluorouracil 600 mg/m2 by continuous IV infusion on day 1; and leucovorin 200 mg/m2 IV, then fluorouracil 400 mg/m2 by direct IV injection, followed by fluorouracil 600 mg/m2 by continuous IV infusion on day 2; treatment cycles repeated every 2 weeks).1

Non-small Cell Lung Cancer
IV

15 mg/kg every 3 weeks; continue until disease progression or unacceptable toxicity occurs.1 e f

Use in combination with IV paclitaxel and carboplatin (PC regimen).1 f In clinical studies, bevacizumab was administered 1 hour after the PC regimen (paclitaxel 200 mg/m2 by IV infusion over 3 hours, then carboplatin [at dose required to obtain AUC of 6 mg/mL per minute] by IV infusion over 15–30 minutes beginning 60 minutes after completion of paclitaxel; treatment cycles repeated every 3 weeks).1 11 d e f In these studies, patients received up to 6 cycles of bevacizumab in combination with the PC regimen, after which bevacizumab monotherapy (15 mg/kg every 3 weeks) was continued until disease progression or unacceptable toxicity occurred.1 11 d e f A median of 7 treatment cycles (including cycles of bevacizumab monotherapy) was administered.11

Glioblastoma
IV

10 mg/kg every 2 weeks; continue until disease progression or unacceptable toxicity occurs.1

Renal Cell Carcinoma
IV

10 mg/kg every 2 weeks; continue until disease progression or unacceptable toxicity occurs.1

Use in combination with interferon alfa (9 million units sub-Q 3 times weekly).1

Breast Cancer
First-line Treatment of Metastatic Breast Cancer
IV

10 mg/kg every 2 weeks; has been used in combination with IV paclitaxel (90 mg/m2 IV once weekly for 3 out of 4 weeks).64 However, this regimen has not been shown to prolong overall survival or provide sufficient clinical benefit to outweigh the risk of severe, potentially fatal, adverse effects.65 (See Breast Cancer under Uses.)

Dosage Modification for Toxicity

Dosage reductions not recommended in any patient;1 instead, temporarily or permanently discontinue therapy based on causality.1

Discontinue therapy permanently if GI perforation (i.e., GI perforation, fistula formation in GI tract, intra-abdominal abscess), non-GI fistula formation involving an internal organ, wound dehiscence and wound healing complications requiring medical intervention, severe hemorrhage requiring medical intervention, severe arterial thromboembolic event, nephrotic syndrome, hypertensive crisis, or hypertensive encephalopathy occurs.1 7

Discontinue therapy if reversible posterior leukoencephalopathy syndrome (RPLS) occurs.1 31 32 (See Reversible Posterior Leukoencephalopathy Syndrome [RPLS] under Cautions.) Risk of reinitiating therapy in patients previously experiencing RPLS not known.1 32

Discontinue therapy temporarily in patients with evidence of moderate to severe proteinuria pending further evaluation, in patients with severe hypertension not controlled by medical management, or in patients with severe infusion reactions.1 (See Cautions.)

Special Populations

No dosage adjustment required in geriatric patients.1

Cautions for Avastin

Contraindications

  • None.1 3

Warnings/Precautions

Warnings

Consider the usual cautions, precautions, and contraindications of any other antineoplastic agents included in the therapeutic regimen.3

GI Perforation

Severe, sometimes fatal, GI perforation reported; generally manifested as abdominal pain, nausea, vomiting, constipation, and fever.1 Usually occurs within the first 50 days following initiation of bevacizumab.1

GI perforation sometimes associated with or complicated by fistula formation and/or intra-abdominal abscess.1 4

If GI perforation (GI perforation, fistula formation in GI tract, and/or intra-abdominal abscess) occurs, discontinue bevacizumab permanently.1

Surgery and Wound Healing Complications

Wound healing and bleeding complications (including wound dehiscence), sometimes fatal, reported.1

Do not initiate bevacizumab therapy until ≥28 days following major surgery and after surgical incision has fully healed.1

Discontinue bevacizumab ≥28 days prior to elective surgery.1 Appropriate interval between discontinuance of bevacizumab and subsequent elective surgery not established, but consider long half-life of bevacizumab.1 (See Half-life under Pharmacokinetics.) Manufacturer recommends resuming therapy only after surgical incision has fully healed.1

Discontinue bevacizumab permanently if wound dehiscence and wound healing complications requiring medical intervention occur.1 (See Boxed Warning.)

Hemorrhage

Severe, sometimes fatal, hemorrhagic events (e.g., hemoptysis, GI bleeding, hematemesis, CNS hemorrhage, epistaxis, vaginal bleeding) reported.1 (See Boxed Warning.)

Risk of severe or fatal pulmonary hemorrhage in patients with non-small cell lung cancer.1 Serious or fatal pulmonary hemorrhage reported in 31% of patients with squamous cell histology and in 4% of patients with nonsquamous cell histology.1

Risk of CNS hemorrhage in patients with NSCLC and CNS metastases.1 Intracranial hemorrhage reported in patients with glioblastoma.1

Mild hemorrhagic events, most commonly grade 1 epistaxis, also reported.1

Do not administer to patients with recent hemoptysis (≥½ teaspoon of red blood).1 If severe hemorrhage (i.e., requiring medical intervention) occurs, discontinue bevacizumab permanently.1

Sensitivity Reactions

Infusion Reactions

Infusion reactions (e.g., hypertension, hypertensive crisis associated with neurologic manifestations, wheezing, oxygen desaturation, grade 3 hypersensitivity, chest pain, headache, rigor, diaphoresis) reported.1

Infuse initial doses slowly, increasing rate of infusion as tolerated.1 (See Rate of Administration under Dosage and Administration.)

If severe infusion reactions occur, interrupt infusion and administer appropriate medical therapy.1 Adequate information on rechallenge not available.44

Other Warnings/Precautions

Non-GI Fistula Formation

Severe, sometimes fatal, non-GI fistula formation involving tracheo-esophageal, bronchopleural, biliary, vaginal, and bladder sites reported; usually occurs within first 6 months of treatment.1 If non-GI fistula formation involving an internal organ occurs, discontinue bevacizumab permanently.1

Thromboembolism

Serious, sometimes fatal, arterial thromboembolic events (e.g., cerebral infarction, TIA, MI, angina) reported.1 7 8 16 17 Increased risk in patients with a history of arterial thromboembolism or patients >65 years of age.1 7 Weigh risks against benefits of therapy.17 Discontinue therapy permanently if severe arterial thromboembolic event occurs;1 7 safety of resuming therapy after resolution of an arterial thromboembolic event not studied.1

Grade 3 or 4 venous thromboembolic events (e.g., DVT, intra-abdominal venous thrombosis) reported.1 Increased risk of developing second thromboembolic event reported in patients with metastatic colorectal cancer receiving bevacizumab with chemotherapy despite use of full-dose warfarin therapy following an initial venous thromboembolic event.1

Hypertension

Severe hypertension (grade 3 or 4) reported.1

Monitor BP every 2–3 weeks during therapy.1 If hypertension occurs, initiate appropriate antihypertensive therapy and monitor BP regularly.1 Temporarily discontinue therapy in patients with severe hypertension not controlled with medical management.1 Discontinue therapy permanently if hypertensive crisis or hypertensive encephalopathy occurs.1 If therapy is discontinued because of hypertension, monitor BP at regular intervals thereafter.1

Reversible Posterior Leukoencephalopathy Syndrome (RPLS)

RPLS (a brain-capillary leak syndrome) reported.1 29 30 32 May manifest with headache, seizure, lethargy, confusion, blindness, and other visual and neurologic disturbances; mild to severe hypertension also may occur.1 32 Manifestations occurred from 16 hours to 1 year after initiation of bevacizumab.1 32 Magnetic resonance imaging (MRI) is necessary to confirm diagnosis of RPLS.1 32

Closely monitor and maintain strict control of BP during and following bevacizumab infusion.30 If RPLS develops, discontinue bevacizumab and initiate treatment of hypertension as clinically indicated.1 31 32 Symptoms usually lessen or resolve within days of drug discontinuance, but some patients have experienced ongoing neurologic sequelae.1 32 Risk of reinitiating bevacizumab in patients previously experiencing RPLS not known.1 32

Proteinuria

Increased incidence and severity of proteinuria reported.1 Severity ranges from clinically silent to nephrotic syndrome.6 Proteinuria with findings of thrombotic microangiopathy on renal biopsy reported in patients receiving bevacizumab alone or in combination with other antineoplastic agents for various cancers.1 37

Monitor patients for development or worsening of proteinuria with serial urinalysis.1 Further assessment (e.g., 24-hour urine collection) recommended if ≥2+ urine dipstick reading occurs.1 Interrupt bevacizumab therapy for moderate proteinuria (≥2 g per 24 hours); resume therapy when proteinuria is <2 g per 24 hours.1 Safety of continuing therapy in patients with moderate to severe proteinuria not known.1

Discontinue bevacizumab permanently in patients with nephrotic syndrome.1

Ovarian Failure

Ovarian failure reported in premenopausal women receiving bevacizumab in combination with chemotherapy (i.e., modified FOLFOX6) for adjuvant treatment of colorectal cancer.1 Recovery of ovarian function occurred in 22% of patients following discontinuance of bevacizumab.1 Long-term effects on fertility unknown.1

Inform women of childbearing potential of risk of ovarian failure prior to initiating bevacizumab.1

Neutropenia and Infection

Severe (grade 3 or 4) neutropenia, febrile neutropenia, infection with severe neutropenia (sometimes fatal), and serious infections (e.g., pneumonia, catheter infections, wound infections) reported.1

CHF

CHF reported; higher risk in patients also receiving or who had previously received anthracyclines.1

Safety of continuation or resumption of bevacizumab in patients who develop cardiac dysfunction not studied.1

Microangiopathic Hemolytic Anemia

Microangiopathic hemolytic anemia reported in patients with solid tumors receiving bevacizumab and sunitinib;35 36 cases were reversible within 3 weeks following discontinuance of both drugs without other interventions.35 36 Use of bevacizumab in combination with sunitinib is not recommended.35 36

Immunogenicity

Potential for immunogenicity.1 Incidence of antibody formation not established.1

Ocular Effects

Permanent loss of vision, endophthalmitis (infectious and sterile), intraocular inflammation, retinal detachment, increased IOP, hemorrhage (including conjunctival, vitreous, or retinal hemorrhage), vitreous floaters, ocular hyperemia, and ocular pain or discomfort reported in patients receiving intravitreal injection of bevacizumab for treatment of various ocular disorders.1

Specific Populations

Pregnancy

Category C.1

Lactation

Not known whether distributed into milk.1 Discontinue nursing or the drug, taking into account the long half-life (approximately 20 days) and the importance of the drug to the woman.1

Pediatric Use

Safety and efficacy not established in children <18 years of age.1 3

Geriatric Use

No difference in overall survival relative to younger adults observed in patients receiving bevacizumab and chemotherapy for metastatic colorectal cancer.1 However, possible increased risk of asthenia, sepsis, deep thrombophlebitis, hypertension, hypotension, MI, CHF, diarrhea, constipation, anorexia, leukopenia, anemia, dehydration, hypokalemia, hyponatremia, nausea, vomiting, ileus, and fatigue.1

Increased incidence of arterial thromboembolic events in patients >66 years of age receiving bevacizumab with chemotherapy compared with younger adults.1 (See Thromboembolism under Cautions.)

Increased risk of proteinuria in patients ≥65 years of age receiving bevacizumab in combination with paclitaxel and carboplatin, compared with younger adults.1 (See Proteinuria under Cautions.)

Possible increased incidence of dyspepsia, GI hemorrhage, edema, epistaxis, increased cough, and voice alteration compared with younger adults.1

Common Adverse Effects

Epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain, exfoliative dermatitis.1

Interactions for Avastin

Specific Drugs

Drug

Interaction

Comments

Carboplatin

No effect on carboplatin exposure1

Interferon alfa

No effect on interferon alfa exposure1

Irinotecan

No effect on pharmacokinetics of irinotecan or the active metabolite of irinotecan1 5

Paclitaxel

Possible decreased paclitaxel exposure after 4 treatment cycles of bevacizumab in combination with paclitaxel and carboplatin1

Sunitinib

Possible microangiopathic hemolytic anemia35 36 (see Microangiopathic Hemolytic Anemia under Cautions)

Use of bevacizumab in combination with sunitinib not recommended35 36

Avastin Pharmacokinetics

Absorption

Plasma Concentrations

Relationship between bevacizumab exposure and clinical outcome not studied.1

Elimination

Metabolism

Metabolized by reticuloendothelial system.3

Elimination Route

Eliminated via reticuloendothelial system.3

Half-life

Approximately 20 days (range: 11–50 days).1

Special Populations

Clearance varies by body weight, gender, and tumor burden.1 Increased clearance observed in men and in patients with higher tumor burden; however, no evidence of reduced efficacy.1

Stability

Storage

Parenteral

Injection Concentrate

2–8°C.1 Do not freeze; protect from light.1

Store diluted solution at 2–8°C for up to 8 hours.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

No incompatibilities with PVC or polyolefin bags.1

Solution Compatibility

Compatible

Sodium chloride 0.9%

Incompatible

Dextrose solutions

Actions

  • Antineoplastic agent;1 3 5 a recombinant humanized monoclonal IgG1 antibody containing human framework regions and murine complementarity-determining regions.1 6

  • Binds to human vascular endothelial growth factor (VEGF) and prevents interaction of VEGF with its receptors (Flt-1, KDR) on the surface of endothelial cells.1 This may result in inhibition of angiogenesis, thus reducing microvascular growth of tumors and inhibiting metastatic disease progression.1 2 3 5

Advice to Patients

  • Importance of understanding potential risks associated with therapy, including severe hypertension, wound healing complications, arterial thromboembolic events, and ovarian failure.1

  • Importance of routine monitoring of BP; advise patients to inform clinician if BP is elevated.1

  • Importance of immediately informing clinician if unusual bleeding, high fever, rigors, sudden worsening of neurologic function, persistent or severe abdominal pain, severe constipation, or vomiting occurs.1

  • Risk of fetal toxicity.1 Necessity of advising women to use an effective method of contraception during and for ≥6 months after last dose of bevacizumab.1 3

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Bevacizumab (Recombinant)

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection, concentrate, for IV infusion

25 mg/mL (100 and 400 mg)

Avastin

Genentech

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Avastin 100MG/4ML Solution (GENENTECH): 4/$645.96 or 12/$1,850.05

Avastin 400MG/16ML Solution (GENENTECH): 16/$2,525.85 or 48/$7,374.16

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions August 23, 2012. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Genentech, Inc. Avastin (bevacizumab) prescribing information. South San Francisco, CA; 2011 Dec.

2. Kabbinavar F, Hurwitz HI, Fehrenbacher L et al. Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol. 2003; 21:60-5. [IDIS 495428] [PubMed 12506171]

3. Genentech, South San Francisco, CA: Personal communication.

4. Hurwitz H, Fehrenbacher L, Novotny W et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004; 350:2335-42. [IDIS 516117] [PubMed 15175435]

5. Presta LG, Chen H, O’Connor SJ et al. Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders. Cancer Res. 1997; 57:4593-9. [PubMed 9377574]

6. Zondor SD, Medina PJ. Bevacizumab: An angiogenesis Inhibitor with efficacy in colorectal and other malignancies. Ann Pharmacother. 2004; 38:1258-64. [IDIS 528874] [PubMed 15187215]

7. Barron H. Dear healthcare provider regarding adverse arterial thromboembolic events associated with Avastin. South San Francisco, CA: Genentech; 2004 Jul.

8. Food and Drug Administration. Avastin (bevacizumab) injection [August 13, 2004: Genentech]. MedWatch drug labeling changes. Rockville, MD; August 2004. From FDA website.

9. Colon cancer. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2007 Aug 9.

10. Non-small cell lung cancer. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2007 May 1.

11. Sandler A, Gray R, Perry MC et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small lung cancer. N Engl J Med 2006; 355:2542-50. [PubMed 17167137]

12. Yang JC, Haworth L, Sherry RM et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med. 2003; 349:427-34. [IDIS 502305] [PubMed 12890841]

13. Rini BI, Halabi S, Rosenberg JE et al. CALGB 90206: A phase III trial of bevacizumab plus interferon-alpha versus interferon-alpha monotherapy in metastatic renal cell carcinoma. Proc ASCO 2008 Genitourinary Cancers Symposium. 2008; Abstract 350.

14. 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; 23:792-9. [IDIS 532659] [PubMed 15681523]

15. Miller K, Wang M, Gralow J et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007; 357:2666-76. [PubMed 18160686]

16. Food and Drug Administration. MedWatch—Safety-related drug labeling changes: Avastin (bevacizumab) [January 2005]. From FDA website.

17. Barron H. Dear healthcare provider letter regarding increased risk of arterial thromboembolic events associated with the use of Avastin in combination with chemotherapy. South San Francisco, CA: Genentech; 2005 Jan 5.

18. Hurwitz HI, Fehrenbacher L, Hainsworth JD et al. Bevacizumab in combination with fluorouracil and leucovorin: an active regimen for first-line metastatic colorectal cancer. J Clin Oncol. 2005; 23:3502-8. [IDIS 536385] [PubMed 15908660]

19. Kabbinavar FF, Schulz J, McCleod M et al. Addition of bevacizumab to bolus fluorouracil and leucovorin in first-line metastatic colorectal cancer: results of a randomized phase II trial. J Clin Oncol. 2005; 23:3697-705. [IDIS 540182] [PubMed 15738537]

20. Kabbinavar FF, Hambleton J, Mass RD et al. Combined analysis of efficacy: the addition of bevacizumab to fluorouracil/leucovorin improves survival for patients with metastatic colorectal cancer. J Clin Oncol. 2005; 23:3706-12. [IDIS 540183] [PubMed 15867200]

21. Giantonio BJ, Catalano PJ, Meropol NJ et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol. 2007; 25:1539-44. [PubMed 17442997]

22. Chen HX, Mooney M, Boron M et al. Phase II multicenter trial of bevacizumab plus fluorouracil and leucovorin in patients with advanced refractory colorectal cancer: an NCI treatment referral center trial TRC-0301. J Clin Oncol. 2006; 24:3354-60. [PubMed 16849749]

23. Picus J, Halabi S, Rini B et al. The use of bevacizumab (B) with docetaxel (D) and estramustine (E) in hormone refractory prostate cancer (HRPC): initial results of CALGB 90006. Proc ASCO. 2003; Abstract No. 1578.

24. Kelly W, protocol chair. Phase III randomized study of docetaxel and prednisone with versus without bevacizumab in patients with hormone-refractory metastatic adenocarcinoma of the prostate. Protocol ID: CALGB-90401. Last modified: 7/22/2006. National Cancer Institute: Clinical Trials (database).

25. Kindler H, protocol chair. Phase III randomized study of gemcitabine with versus without bevacizumab in patients with locally advanced or metastatic adenocarcinoma of the pancreas. Protocol ID: CALGB-80303. Last modified: 4/19/2006. National Cancer Institute: Clinical Trials (database).

26. Burger R, Fleming G, protocol chairs. Phase III randomized study of carboplatin and paclitaxel versus carboplatin, paclitaxel, and concurrent bevacizumab with versus without extended bevacizumab in patients with stage III or IV ovarian epithelial or primary peritoneal cancer. Protocol ID: GOG-0218. Last modified: 10/10/2008. National Cancer Institute: Clinical Trials (database).

27. National Comprehensive Cancer Network (NCCN). Clinical practice guidelines in oncology: non-small cell lung cancer. Version 2.2006.

28. Allegra C, protocol chair. Phase III randomized study of adjuvant chemotherapy comprising fluorouracil, leucovorin calcium, and oxaliplatin with versus without bevacizumab in patients with resected stage II or III adenocarcinoma of the colon. Protocol ID: NSABP-C-08. Last modified: 6/20/2008. National Cancer Institute: Clinical Trials (database).

29. Glusker P, Recht L, Lane B. Reversible posterior leukoencephalopathy syndrome and bevacizumab. N Engl J Med. 2006; 354:980-1. [PubMed 16510760]

30. Ozcan C, Wong SJ, Hari P. Reversible posterior leukoencephalopathy syndrome and bevacizumab. N Engl J Med. 2006; 354:981-2.

31. Barron H. Reversible posterior leukoencephalopathy syndrome and bevacizumab. Manufacturer reply. N Engl J Med. 2006; 354:982.

32. Barron H. Dear healthcare provider letter regarding reversible posterior leukoencephalopathy syndrome in patients receiving bevacizumab (Avastin). South San Francisco, CA: Genentech; 2006 Sep.

33. Cruzan S (US Food and Drug Administration). FDA approves new combination therapy for lung cancer. Rockville, MD; 2006 Oct 12. Press release P06-166.

34. Steinbrook R. The price of sight—ranibizumab, bevacizumab, and the treatment of macular degeneration. N Engl J Med. 2006; 355:1409-12. [PubMed 17021315]

35. Food and Drug Administration. Safety Alert: Avastin (bevacizumab) [July 14 2008]. From FDA web site .

36. Barron H. Dear healthcare provider letter: Important drug warning: microangiopathic hemolytic anemia (MAHA) in patients treated with Avastin (bevacizumab) and sunitinib malate. South San Francisco, CA: Genentech; 2008 Jul.

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