Coverage Policies

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Effective Date: 06/01/2011 Title: Bevacizumab (biosimilar products and Avastin)
Revision Date: 04/01/2020 Document: BI299:00
CPT Code(s): C9257, J9035,Q5107, Q5118
Public Statement

Effective Date:

a)    This policy will apply to all services performed on or after the above revision date which will become the new effective date.

b)    For all services referred to in this policy that were performed before the revision date, contact customer service for the rules that would apply.


1)    High-dose bevacizumab (both Avastin and biosimilar products) is an intravenous medication used to treat certain advanced cancers.  It is also used in a low-dose form to treat age related macular degeneration.

2)    High-dose bevacizumab (both Avastin and biosimilar products) requires pre-authorization when used to treat cancer. For patients starting therapy, a biosimilar product must be tried first before brand name Avastin would be approved.

a)    Bevacizumab is not covered for more than one line of therapy for any cancer (except colorectal cancer).

b)    Bevacizumab may be added later to approved combinations if the patient is recovering from a surgical procedure. Coverage is allowed if the drug is added within 90 days of the start of therapy.

3)    On November 18, 2011, the FDA revoked the agency’s approval of the breast cancer indication for Avastin (bevacizumab) after concluding that the drug has not been shown to be safe and effective for that use.

4)    High-dose bevacizumab may be used on an emergency basis to stop severe, intractable bleeding that has not responded to other measures—only for patients with an inherited syndrome called Hereditary Hemorrhagic Telangiectasia (HHT). 

a)    High-dose bevacizumab requires pre-authorization when used to prevent severe, recurrent bleeding for patients with HHT.

Medical Statement

1)    Low-dose Avastin (bevacizumab, 0.25 mg) is eligible for coverage through the specialty pharmacy program for neovascular (“wet”) age related macular degeneration.  See BI169.

2)    High-dose bevacizumab (both Avastin and biosimilar products), 10 mg  is considered medically necessary for treatment of cancers under the following criteria. For new patients starting therapy on bevacizumab, a biosimilar product must be tried first before brand name Avastin would be approved.

a)    Adult intracranial or spinal ependymoma:  as treatment for disease progression after radiation therapy or recurrence

b)    Anaplastic glioma or glioblastoma: as treatment for recurrent disease or salvage therapy

c)    Cervical cancer:

i)     persistent, recurrent, or metastatic cervical cancer AND

ii)    Being used in combination with paclitaxel and cisplatin or topotecan

d)    Colon/rectal cancer:

i)     First or second line treatment for advanced or metastatic disease

ii)    Neoadjuvant or adjuvant therapy for patients with resectable or unresectable liver and/or lung metastases

e)    Renal cancer:

f)     Nonsquamous non-small cell lung cancer: 

i)     First-line therapy for unresectable, locally advanced, recurrent, or metastatic disease in patients with performance status 0-1 with no history of hemoptysis

ii)    Continuation maintenance therapy in patients who achieve tumor response or stable disease after first-line treatment that included Avastin

iii)   Second line therapy for progression in patients with multiple symptomatic systemic lesions in combination with platinum doublet therapy

g)     Ovarian cancer:

i)     For clinical relapse in patients with stage II-IV granulosa cell tumors

ii)    For progressive or persistent disease on primary chemotherapy or relapse after complete remission in patients with stage II-IV epithelial/fallopian tube/primary peritoneal disease

iii)   For primary treatment for patients with suspected unresectable residual disease

iv)   for primary adjuvant treatment for stage II-IV disease

h)    Soft tissue sarcoma:

i)     Angiosarcoma as a single agent

ii)    Solitary fibrous tumor or hemangiopericytoma in combination with temozolomide

i)     Endometrial carcinoma: 

i)     Single agent therapy for disease that has progressed on prior cytotoxic chemotherapy

3)    High-dose bevacizumab (both Avastin and biosimilar products) may be used on an emergency basis to stop severe, intractable bleeding that has not responded to other measures—only for patients with an inherited syndrome called Hereditary Hemorrhagic Telangiectasia (HHT).

a)    High-dose bevacizumab (both Avastin and biosimilar products)  requires pre-authorization when used to prevent severe, recurrent bleeding for patients with HHT.

High-dose bevacizumab (both Avastin and biosimilar products)  is considered medically necessary for prevention of bleeding in patients with HHT when the following criteria are met:

i)  Definite confirmation of HHT diagnosis through genetic testing or consensus clinical criteria (at least 3 out of the following 4—spontaneous, recurrent episodes of epistaxis; multiple telangiectasias at characteristic sites; visceral telangiectasias or arteriovenous malformations and family history of a first degree relative with confirmed HHT) with EITHER

·         Hemoglobin levels < 8 despite 3 months of adequate treatment with intravenous  iron products OR

·         More than three documented episodes of severe epistaxis or gastrointestinal bleeding requiring treatment in an ER or inpatient hospital setting.

Codes Used In This BI:



Q5118            Injection, bevacizumab-bvzr, biosimilar (Zirabev), 10mg

J9035             High-dose Bevacizumab injection (Avastin), 10 mg

C9257            Low-dose Bevacizumab injection, 0.25mg


Avastin (bevacizumab) is considered experimental and investigational for treatment of other cancers.


Bevacizumab is a recombinant humanized monoclonal antibody to vascular endothelial growth factor (VEGF). It is designed to bind to and inhibit VEGF, which plays an important role in tumor angiogenesis, a process critical for tumor growth and metastasis. On February 26, 2004, the U.S. Food and Drug Administration (FDA) approved bevacizumab (Avastin) (Genentech, Inc., South San Francisco, CA) for use in combination with intravenous 5-FU based chemotherapy as a first-line treatment for patients with metastatic colorectal cancer. It is the first FDA-approved therapy designed to inhibit angiogenesis. Bevacizumab is administered intravenously. In clinical trials, the most common side effects associated with the use of bevacizumab were asthenia, pain, abdominal pain, headache, hypertension, diarrhea, nausea, vomiting, anorexia, stomatitis, constipation, upper respiratory infection, epistaxis, dyspnea, exfoliative dermatitis, and proteinuria. The most serious adverse events were gastrointestinal perforations/wound healing complications, hemorrhage, hypertensive crises, nephrotic syndrome, and congestive heart failure.


Preliminary results from a National Cancer Institute-sponsored multicenter randomized controlled clinical trial conducted by the Eastern Cooperative Oncology Group (ECOG) of 722 women with previously untreated recurrent or metastatic breast cancer show that women who received bevacizumab in combination with paclitaxel had a statistically significant increase in progression-free survival of four months than women who received paclitaxel alone. The data monitoring committee overseeing the trial recommended that the results of a recent interim analysis be made public because the study had met its primary endpoint of increasing progression-free survival. Women whose tumors over-expressed HER-2 were not included in the study unless they had previously received trastuzumab (Herceptin) or were unable to receive trastuzumab. Also excluded were women who had received preventive chemotherapy treatment with paclitaxel within the previous 12 months, as well as women with a prior history of thrombosis or who were on anticoagulants. Serious hemorrhage and thrombosis were rare in this study. Women receiving the combination of paclitaxel and bevacizumab had small increases in rates of neuropathy, hypertension, and proteinuria than women receiving paclitaxel alone. Other side effects were similar between the two treatment groups.


A previous Phase III study of bevacizumab in metastatic breast cancer found that the addition of bevacizumab to capecitabine produced a significant increase in response rates, but this did not translate into improved progression free survival or overall survival (Miller, et al., 2005).  This randomized phase III trial compared the efficacy and safety of capecitabine with or without bevacizumab in 462 patients with metastatic breast cancer previously treated with an anthracycline and a taxane. Patients were randomly assigned to receive capecitabine (2,500 mg/m2/d) twice daily on day 1 through 14 every 3 weeks, alone or in combination with bevacizumab (15 mg/kg) on day 1.  Combination therapy significantly increased the response rates (19.8% v 9.1%; P = .001); however, this did not result in a longer PFS (4.86 v 4.17 months; hazard ratio = 0.98). Overall survival (15.1 v 14.5 months) and time to deterioration in quality of life as measured by the Functional


Assessment of Cancer Treatment-Breast were comparable in both treatment groups.  The investigators reported that bevacizumab was well tolerated in this heavily pretreated patient population (Miller, et al., 2005).  No significant differences were found in the incidence of diarrhea, hand-foot syndrome, thromboembolic events, or serious bleeding episodes between treatment groups. Of other grade 3 or 4 adverse events, only hypertension requiring treatment (17.9% v 0.5%) was more frequent in patients receiving bevacizumab.


NOTE: In December 2010, the FDA recommended removal of the breast cancer indication from the product labeling. This recommendation came after reviewing the results of four clinical studies of bevacizumab in women with breast cancer and determining that the data indicate that the drug does not prolong overall survival in breast cancer patients or provide a sufficient benefit in slowing disease progression to outweigh the significant risk to patients (see Adverse Reactions). Under the accelerated approval process, Genentech has the opportunity to request a hearing to appeal this decision. If the appeal is unsuccessful, the indication will be removed.


NOTE:  On November 18, 2011, The FDA revoked the agency’s approval of the breast cancer indication for Avastin (bevacizumab) after concluding that the drug has not been shown to be safe and effective for that use.


Hereditary Hemorrhagic Telangiectasia (HHT) is an inherited genetic disorder (also known as Osler-Weber-Rendu syndrome) that affects the formation of blood vessels.  Depending on the population studied, the prevalence is about 1 in 5,000 to 1 in 10,000 people. While there are genetic tests that can confirm the diagnosis, the diagnosis is more commonly made using consensus clinical criteria. Complications of HHT are usually caused by bleeding from malformed blood vessels.  Recurrent epistaxis is seen in 75% of patients and recurrent gastrointestinal bleeding affects 25% of patients with HHT. Aside from requiring emergency interventions, these recurrent episodes of bleeding often lead to significant anemia requiring iron therapy or blood transfusions.  The presence of visceral arteriovenous malformations can sometimes lead to catastrophic complications. 


Elevated blood levels of vascular endothelial growth factor (VEGF) play a role in stimulating abnormal growth of blood vessels in patients with HHT. By attaching to VEGF, bevacizumab (Avastin) can decrease the growth of abnormal blood vessels in patients with HHT and has been shown to reduce or prevent some of the complications.


1)    National Comprehensive Cancer Network Drugs and Biologics Compendium.  Accessed 10/10/2014

2)    Sadick H, Riedel F, Naim R, et al. Patients with hereditary hemorrhagic telangiectasia have increased plasma levels of vascular endothelial growth factor and transforming growth factor-β1 as well as high ALK1 tissue expression. Haematologica 2005; 90:818-828.

3)    Flieger D, Hainke S, Fischbach W. Dramatic improvement in hereditary hemorrhagic telangiectasia after treatment with the vascular endothelial growth factor (VEGF) antagonist bevacizumab. Ann Hematol 2006; 85:631-632.

4)    Mitchell A, Adams LA, MacQuillan G, Tibballs J, vanden Driesen R, Delriviere L. Bevacizumab reverses need for liver transplantation in hereditary hemorrhagic telangiectasia. Liver Transpl 2008;14:210-213

5)    Jee Wan Wee, Young Woo Jeon, Jun Young Eun, Han Jo Kim, Sang Byung Bae, Kyu Taek Lee. . (2014) hereditary hemorrhagic telangiectasia treated with low dose intravenous bevacizumab. Blood Research 49, 192.

6)    Wenhao Li, Sreelakshmi Kotha, Deepak Joshi. . (2017) Upper Gastrointestinal Bleeding Caused by Hereditary Hemorrhagic Telangectasia. Clinical Gastroenterology and Hepatology 15:7, A25-A26.

7)    L. Robard et al. Guidelines of the French Society of Otorhinolaryngology (SFORL) (short version). Specific treatment of epistaxis in Rendu-Osler-Weber disease. European Annals of Otorhinolaryngology, Head, and Neck Diseases. 2017; 134:1, 37-41.

8)    Narendranath Epperla, Jonathan T. Kapke, Matthew Karafin, Kenneth D. Friedman, Patrick Foy. . (2016) Effect of systemic bevacizumab in severe hereditary hemorrhagic telangiectasia associated with bleeding. American Journal of Hematology 91:6, E313-E314.

9)    Natalia P. Arizmendez, Luke Rudmik, David M. Poetker. . (2015) Intravenous bevacizumab for complications of hereditary hemorrhagic telangiectasia: a review of the literature. International Forum of Allergy & Rhinology 5:10.1002/alr.2015.5.issue-11, 1042-1047.

10) Charles Alderman, Jonathan Corlett, Jonathan Cullis. . (2013) the treatment of recurrent epistaxis due to hereditary haemorrhagic telangiectasia with intranasal bevacizumab. British Journal of Haematology 162:10.1111/bjh.2013.162.issue-4, 547-548.

11) Alexandru Lupu, Carmen Stefanescu, Xavier Treton, Alain Attar, Olivier Corcos, Yoram Bouhnik. . (2013) Bevacizumab as Rescue Treatment for Severe Recurrent Gastrointestinal Bleeding in Hereditary Hemorrhagic Telangiectasia. Journal of Clinical Gastroenterology 47, 256-257.

12) Tom T. Karnezis, Terence M. Davidson. . (2011) Efficacy of intranasal bevacizumab (Avastin) treatment in patients with hereditary hemorrhagic telangiectasia-associated epistaxis. The Laryngoscope 121, 636-638.

13) Brinkerhoff, Brian T., Poetker, David M., Choong, Nicholas W.,. . (2011) Long-Term Therapy with Bevacizumab in Hereditary Hemorrhagic Telangiectasia. New England Journal of Medicine 364:7, 688-689.

Application to Products
This policy applies to all health plans administered by QualChoice, both those insured by QualChoice and those that are self-funded by the sponsoring employer, unless there is indication in this policy otherwise or a stated exclusion in your medical plan booklet. Consult the individual plan sponsor Summary Plan Description (SPD) for self-insured plans or the specific Evidence of Coverage (EOC) for those plans insured by QualChoice. In the event of a discrepancy between this policy and a self-insured customer’s SPD or the specific QualChoice EOC, the SPD or EOC, as applicable, will prevail. State and federal mandates will be followed as they apply.
Changes: QualChoice reserves the right to alter, amend, change or supplement benefit interpretations as needed.
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