Bevacizumab for Non-Ocular Indications
Number: 0685
Commercial CPB | Medicare CPB
Table Of Contents
PolicyApplicable CPT / HCPCS / ICD-10 Codes
Background
References
Brand Selection for Medically Necessary Indications
As defined in Aetna commercial policies, health care services are not medically necessary when they are more costly than alternative services that are at least as likely to produce equivalent therapeutic or diagnostic results. Avastin (bevacizumab), Alymsys (bevacizumab-maly), Vegzelma (bevacizumab-adcd), and Zirabev (bevacizumab-bvzr) are more costly to Aetna than other vascular endothelial growth factor inhibitors for certain indications. There is a lack of reliable evidence that Avastin (bevacizumab), Alymsys (bevacizumab-maly), Vegzelma (bevacizumab-adcd), and Zirabev (bevacizumab-bvzr) are superior to the lower cost vascular endothelial growth factor inhibitor for oncology indications: Mvasi (bevacizumab-awwb). Therefore, Aetna considers Avastin (bevacizumab), Alymsys (bevacizumab-maly), Vegzelma (bevacizumab-adcd), and Zirabev (bevacizumab-bvzr) to be medically necessary only for members who have a contraindication, intolerance, or ineffective response to the available equivalent alternative vascular endothelial growth factor inhibitor for oncology indications: Mvasi (bevacizumab-awwb).
Policy
Note: Requires Precertification:
Precertification of bevacizumab (Avastin), bevacizumab-maly (Alymsys), bevacizumab-awwb (Mvasi), bevacizumab-adcd (Vegzelma), and bevacizumab-bvzr (Zirabev), for oncology indications only, is required of all Aetna participating providers and members in applicable plan designs. For precertification of bevacizumab (Avastin), bevacizumab-awwb (Mvasi), and bevacizumab-bvzr (Zirabev), for oncology indications only, call (866) 752-7021 (Commercial), or fax (888) 267-3277. For Medicare Part B plans, call (866) 503-0857, or fax (844) 268-7263.
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Criteria for Initial Approval
Aetna considers bevacizumab (Avastin), bevacizumab-maly (Alymsys), bevacizumab–awwb (Mvasi), bevacizumab-adcd (Vegzelma), and bevacizumab-bvzr (Zirabev) medically necessary for the following non-ocular indications:
- Ampullary adenocarcinoma - for treatment of intestinal-type ampullary adenocarcinoma that is progressive, unresectable, or metastatic
- Breast cancer - for treatment of recurrent or metastatic breast cancer
- Central Nervous System (CNS) cancers - for treatment of the following types of CNS cancer:
- Glioblastoma
- Intracranial and Spinal Ependymoma (excludes subependymoma)
- Anaplastic Gliomas
- Low-Grade (WHO Grade 1 or 2) Glioma
- Medulloblastoma
- Primary Central Nervous System Lymphoma
- Meningiomas
- Limited and Extensive Brain Metastases
- Metastatic Spine Tumors
- Cervical / Vaginal cancer - for treatment of persistent, recurrent, or metastatic cervical or vaginal cancer
- Colorectal cancer, including appendiceal adenocarcinoma, and anal adenocarcinoma
- Hepatocellular carcinoma - for treatment of unresectable or metastatic hepatocellular carcinoma, when the requested medication will be used as initial treatment in combination with atezolizumab
- Malignant pleural mesothelioma, malignant peritoneal mesothelioma, pericardial mesothelioma, tunica vaginalis testis mesothelioma
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For treatment of malignant pleural mesothelioma, malignant peritoneal mesothelioma, pericardial mesothelioma, or tunica vaginalis testis mesothelioma when any of the following criteria are met:
- As first-line therapy for unresectable disease in combination with pemetrexed and either cisplatin, followed by single- agent maintenance bevacizumab; or
- As subsequent therapy in combination with pemetrexed and either cisplatin or carboplatin if immunotherapy was administered as first-line treatment;
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For treatment of malignant peritoneal mesothelioma, pericardial mesothelioma, or tunica vaginalis testis mesothelioma when used in combination with atezolizumab as subsequent therapy.
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- Non-small cell lung cancer (NSCLC) - for recurrent, unresectable, advanced, or metastatic non-squamous NSCLC
- Ovarian cancer/Fallopian tube cancer/Primary peritoneal cancer - for treatment of the following types of ovarian cancer, fallopian tube cancer, and primary peritoneal cancer:
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Epithelial Ovarian Cancer, including:
- Carcinosarcoma (malignant mixed Müllerian tumors)
- Clear cell carcinoma
- Mucinous carcinoma
- Endometrioid carcinoma
- Serous carcinoma
- Malignant sex cord-stromal tumors
- Fallopian Tube Cancer
- Primary Peritoneal Cancer
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- Renal cell carcinoma (RCC) - for treatment of relaspsed or stage IV renal cell carcinoma
- Small bowel adenocarcinoma, including advanced ampullary cancer
- Soft tissue sarcoma
- For treatment of angiosarcoma, as single agent therapy
- For treatment of solitary fibrous tumor or hemangiopericytoma, in combination with temozolomide
- Uterine neoplasms / Endometrial carcinoma - for treatment of progressive, advanced, recurrent, or metastatic uterine neoplasms or endometrial carcinoma
- Vulvar squamous cell carcinoma - for unresectable locally advanced, recurrent, or metastatic vulvar squamous cell carcinoma.
For intravitreal bevacizumab for neovascular (wet) age-related macular degeneration and other ophthalmologic indications, see CPB 0701 - Vascular Endothelial Growth Factor Inhibitors for Ocular Indications or CPB 0701m - Vascular Endothelial Growth Factor Inhibitors for Ocular Indications [Medicare].
Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).
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Continuation of Therapy
Aetna considers continuation of bevacizumab (Avastin), bevacizumab-maly (Alymsys), bevacizumab–awwb (Mvasi), bevacizumab-adcd (Vegzelma), and bevacizumab-bvzr (Zirabev) therapy medically necessary in members requesting reauthorization for an indication listed in Section I when there is no evidence of an unacceptable toxicity or disease progression while on the current regimen.
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Related Policies
For bevacizumab for ocular indications, see CPB 0701 - Vascular Endothelial Growth Factor Inhibitors for Ocular Indications or CPB 0701m - Vascular Endothelial Growth Factor Inhibitors for Ocular Indications [Medicare].
See also:
Dosage and Administration
Avastin
Bevacizumab is available as Avastin in an intravenous solution: 25 MG/ML (100mg and 400mg vials), for intravenous use.
Metastatic colorectal cancer:
- 5 mg/kg every 2 weeks with bolus-IFL
- 10 mg/kg every 2 weeks with FOLFOX4
- 5 mg/kg every 2 weeks or 7.5 mg/kg IV every 3 weeks with fluoropyrimidine-irinotecan or fluoropyrimidine-oxaliplatin based chemotherapy after progression on a first-line Avastin containing regimen.
First-line non−squamous non−small cell lung cancer: 15 mg/kg every 3 weeks with carboplatin and paclitaxel.
Recurrrent glioblastoma: is 10 mg/kg every 2 weeks.
Metastatic renal cell carcinoma (mRCC): 10 mg/kg every 2 weeks with interferon alfa.
Persistent, recurrent, or metastatic cervical cancer: 15 mg/kg every 3 weeks with paclitaxel and cisplatin, or paclitaxel and topotecan.
Platinum-resistant recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer:
- 10 mg/kg every 2 weeks with paclitaxel, pegylated liposomal doxorubicin or weekly topotecan
- 15 mg/kg every 3 weeks with topotecan given every 3 weeks.
Stage III or IV epithelial ovarian, fallopian tube or primary peritoneal cancer following initial surgical resection: 15 mg/kg every 3 weeks with carboplatin and paclitaxel for up to 6 cycles, followed by 15 mg/kg every 3 weeks as a single agent, for a total of up to 22 cycles.
Platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer:
- 15 mg/kg every 3 weeks with carboplatin and paclitaxel for 6-8 cycles, followed by 15 mg/kg every 3 weeks as a single agent
- 15 mg/kg every 3 weeks with carboplatin and gemcitabine for 6-10 cycles, followed by 15 mg/kg every 3 weeks as a single agent
Hepatocellular carcinoma: 15 mg/kg after administration of 1,200 mg of atezolizumab every 3 weeks.
Please consult the Full Prescribing Information for complete details for recommended dose adjustments
Source: Genentech, 2021
Alymsys, Mvasi, Vegzelma, and Zirabev
Bevacizumab is available as Alymsys, Mvasi, Vegzelma, or as Zirabev as single-dose vials in the following strengths: 100 mg/4 mL and 400 mg/16 mL. Do not administer Alymsys, Mvasi, or Zirabev for 28 days following major surgery and until surgical wound is fully healed.
Metastatic colorectal cancer
- 5 mg/kg every 2 weeks with bolus-IFL
- 10 mg/kg every 2 weeks with FOLFOX4
- 5 mg/kg every 2 weeks or 7.5 mg/kg every 3 weeks with fluoropyrimidine-irinotecan or fluoropyrimidine-oxaliplatin based chemotherapy after progression on a first-line bevacizumab product-containing regimen
First-line non-squamous non-small cell lung cancer
- 15 mg/kg every 3 weeks with carboplatin and paclitaxel
Recurrent glioblastoma
- 10 mg/kg every 2 weeks
Metastatic renal cell carcinoma
- 10 mg/kg every 2 weeks with interferon-alfa
Persistent, recurrent, or metastatic cervical cancer
- 15 mg/kg every 3 weeks with paclitaxel and cisplatin or paclitaxel and topotecan
Platinum-resistant recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer:
- 10 mg/kg every 2 weeks with paclitaxel, pegylated liposomal doxorubicin or weekly topotecan
- 15 mg/kg every 3 weeks with topotecan given every 3 weeks.
Stage III or IV epithelial ovarian, fallopian tube or primary peritoneal cancer following initial surgical resection (Mvasi, Vegzelma, and Zirabev only): 15 mg/kg every 3 weeks with carboplatin and paclitaxel for up to 6 cycles, followed by 15 mg/kg every 3 weeks as a single agent, for a total of up to 22 cycles.
Platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer (Mvasi and Zirabev only):
- 15 mg/kg every 3 weeks with carboplatin and paclitaxel for 6-8 cycles, followed by 15 mg/kg every 3 weeks as a single agent
- 15 mg/kg every 3 weeks with carboplatin and gemcitabine for 6-10 cycles, followed by 15 mg/kg every 3 weeks as a single agent
Administer as an intravenous infusion.
Please consult the Full Prescribing Information for complete details for recommended dose adjustments.
Source: Amgen, 2021; Pfizer, 2021; Amneal Pharmaceuticals, 2022a ; Celltrion, 2022b
Experimental and Investigational
Aetna considers bevacizumab (Avastin), bevacizumab-maly (Alymsys), bevacizumab–awwb (Mvasi), bevacizumab-adcd (Vegzelma), and bevacizumab-bvzr (Zirabev) experimental and investigational for the treatment of the following non-ocular indications (not an all-inclusive list) as its effectiveness for these indications has not been established.
- Acoustic neuroma
- Adrenocortical carcinoma
- Apocrine adenocarcinoma
- Bladder cancer
- Brain arterio-venous malformations (AVMs)
- Cancer of unknown origin (primary occult)
- Carcinoid tumors
- Cholangiocarcinoma
- Coat's disease
- Desmoid tumor (e.g., fibromatosis and fibrosarcoma)
- Desmoplastic small round blue cell tumor
- Diffuse leptomeningeal glio-neuronal tumor
- Esophageal cancer
- Gallbladder cancer
- Gastric cancer
- Gastroesopheal junction adenocarcinoma
- Gastrointestinal stromal tumors
- Hemangioblastoma (including retinal capillary hemangioblastoma)
- Hereditary hemorrhagic telangiectasia (HHT) and HHT-related epistaxis
- Hydatidiform mole
- Islet cell cancer
- Laryngeal papillomatosis
- Melanoma
- Meningeal melanoma metastases
- Mucoepidermoid carcinoma of the salivary gland
- Multiple myeloma
- Neuroendocrine tumors
- Neurofibromatosis
- Olfactory neuroblastoma (esthesioneuroblastoma)
- Pancreatic cancer
- Pelvic bone cancer
- Pineal gland malignancy
- Prostate cancer
- Pseudomyxoma peritonei
- Radiation-induced myelopathy
- Radiation necrosis
- Respiratory papillomatosis
- Sarcomas (e.g., Ewing sarcoma, Kaposi's sarcoma, leiomyosarcoma, liposarcoma, and osteosarcoma) other than angiosarcoma, solitary fibrous tumors, and hemangiopericytoma
- Squamous cell carcinoma of the head and neck
- Small cell carcinoma of the lung
- Squamous cell carcinoma of the lung
- Urachal carcinoma
- Urothelial carcinoma
- Uveal ciliary melanocytoma
- Vogt-Koyanagi-Harada syndrome
- von Hippel Lindau disease.
Aetna considers bevacizumab in combination with cetuximab (Erbitux) or panitumumab (Vectibix) experimental and investigational because the effectiveness and safety of these combinations has not been established.
Aetna considers bevacizumab in combination with atezolizumab for the treatment of renal cell carcinoma experimental and investigational.
Aetna considers bevacizumab in combination with pemetrexed as maintenance therapy for non-squamous non-small cell lung cancer experimental and investigational.
Background
U.S. Food and Drug Administration (FDA)-Approved Indications
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Metastatic Colorectal Cancer (mCRC)
- Avastin, Alymsys, Mvasi, Vegzelma, or Zirabev, in combination with intravenous fluorouracil-based chemotherapy, is indicated for the first- or second-line treatment of patients with metastatic colorectal cancer.
- Avastin, Alymsys, Mvasi, Vegzelma, or Zirabev, in combination with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy, is indicated for the second-line treatment of patients with metastatic colorectal cancer who have progressed on a first-line bevacizumab product-containing regimen.
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First-Line Non-Squamous Non-Small Cell Lung Cancer (NSCLC)
Avastin, Alymsys, Mvasi, Vegzelma, or Zirabev, in combination with carboplatin and paclitaxel, is indicated for the first-line treatment of patients with unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer.
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Recurrent Glioblastoma (RGM)
Avastin, Alymsys, Mvasi, Vegzelma, or Zirabev, is indicated for the treatment of recurrent glioblastoma in adults.
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Metastatic Renal Cell Carcinoma (mRCC)
Avastin, Alymsys, Mvasi, Vegzelma, or Zirabev, in combination with interferon alfa, is indicated for the treatment of metastatic renal cell carcinoma.
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Persistent, Recurrent, or Metastatic Cervical Cancer
Avastin, Alymsys, Mvasi, Vegzelma, or Zirabev, in combination with paclitaxel and cisplatin or paclitaxel and topotecan, is indicated for the treatment of patients with persistent, recurrent, or metastatic cervical cancer.
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Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer
- Avastin, Mvasi, Vegzelma, or Zirabev, in combination with carboplatin and paclitaxel, followed by Avastin, Mvasi, or Zirabev as a single agent, is indicated for the treatment of patients with stage III or IV epithelial ovarian, fallopian tube, or primary peritoneal cancer following initial surgical resection.
- Avastin, Alymsys, Mvasi, Vegzelma, or Zirabev, in combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan, is indicated for the treatment of patients with platinum-resistant recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer who received no more than 2 prior chemotherapy regimens.
- Avastin, Mvasi, Vegzelma, or Zirabev, in combination with carboplatin and paclitaxel, or with carboplatin and gemcitabine, followed by Avastin, Mvasi, or Zirabev as a single agent, is indicated for the treatment of patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer.
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Hepatocellular Carcinoma
Avastin, in combination with atezolizumab, is indicated for the treatment of patients with unresectable or metastatic hepatocellular carcinoma (HCC) who have not received prior systemic therapy.
Compendial Uses
- Breast Cancer for Recurrent or Stage IV (M1) Human Epidermal Growth Factor Receptor 2 (HER2)-Negative Disease
- Central Nervous System (CNS) Cancers
- Low-Grade (WHO Grade 1 or 2) Glioma
- Intracranial and Spinal Ependymoma (excluding subependymoma)
- Anaplastic Gliomas
- Medulloblastoma
- Primary Central Nervous System Lymphoma
- Meningiomas
- Limited and Extensive Brain Metastases
- Metastatic Spine Tumors
- Malignant Pleural Mesothelioma, Malignant Peritoneal Mesothelioma, Pericardial Mesothelioma, Tunica Vaginalis Testis Mesothelioma
- Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer
- Carcinosarcoma (malignant mixed Müllerian tumors)
- Clear Cell Carcinoma
- Mucinous Carcinoma
- Endometrioid Carcinoma
- Serous Carcinoma
- Malignant Sex Cord-Stromal Tumors
- Soft Tissue Sarcoma
- Angiosarcoma
- Solitary Fibrous Tumor/Hemangiopericytoma
- Uterine Neoplasms/Endometrial Carcinoma
- Vulvar Squamous Cell Carcinoma
- Small Bowel Adenocarcinoma
- Ampullary Adenocarcinoma
- Appendiceal Adenocarcinoma
- Anal Adenocarcinoma
- Renal Cell Carcinoma
- Ophthalmic Disorders
- Diabetic Macular Edema
- Neovascular (wet) Age-Related Macular Degeneration (AMD)
- Macular Edema following Retinal Vein Occlusion (RVO)
- Proliferative Diabetic Retinopathy
- Choroidal Neovascularization (CNV)
- Neovascular Glaucoma; adjunct
- Retinopathy of Prematurity
- Polypoidal Choroidal Vasculopathy
Avastin (bevacizumab) is 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. In the process, it prevents the proliferation of endothelial cells and formation of new blood vessels .Vascular endothelial growth factor (VEGF) is an important signaling protein involved in angiogenesis (the growth of blood vessels from pre‐existing vasculature). As its name implies, VEGF activity has been mostly studied on cells of the vascular endothelium, although it does have effects on a number of other cell types (e.g. stimulation monocyte/macrophage migration, neurons, cancer cells, kidney epithelial cells).
On September 14, 2017, the U.S. Food and Drug Administration (FDA) approved Mvasi (bevacizumab-awwb), a biosimilar to Avastin (bevacizumab). Mvasi is the first oncology therapeutic biosimilar approved by the U.S. Food and Drug Administration (FDA). Mvasi is a recombinant humanized monoclonal IgG1 antibody that binds vascular endothelial growth factor (VEGF) and prevents the interaction of VEGF to its receptors (Flt-1 and KDR) on the surface of endothelial cells. The interaction of VEGF with its receptors leads to endothelial cell proliferation and new blood vessel formation in in vitro models of angiogenesis. Administration of bevacizumab to xenotransplant models of colon cancer in nude (athymic) mice caused reduction of microvascular growth and inhibition of metastatic disease progression. Mvasi was proven to be highly similar to, and to have no clinically meaningful differences in terms of safety and effectiveness from Avastin, based on a totality of evidence, which included comparative analytical, clinical safety and efficacy data.
Subsequently, on June 28, 2019, the FDA approved Zirabev (bevacizumab-bvzr), another biosimilar to Avastin (bevacizumab), for the treatment of five types of cancer: metastatic colorectal cancer; unresectable, locally advanced, recurrent or metastatic non-squamous non-small cell lung cancer (NSCLC); recurrent glioblastoma; metastatic renal cell carcinoma (RCC); and persistent, recurrent or metastatic cervical cancer. Like Mvasi, Zirabev is also a recombinant humanized monoclonal IgG1 antibody VEGF inhibitor. The FDA approval was based on review of a comprehensive data package which demonstrated biosimilarity of Zirabev to the reference product. This includes results from the REFLECTIONS B7391003 clinical comparative study, which showed clinical equivalence and found no clinically meaningful differences between Zirabev and the reference product in patients with advanced non-squamous NSCLC.
On April 13, 2022, the U.S. Food and Drug Administration (FDA) approved Alymsys (bevacizumab-maly), a biosimilar referencing Avastin. The FDA's approval of Alymsys marks it as third bevacizumab biosimilar folllowing that of Mvasi and Zirabev in the U.S.Similar to Avastin and its prior bevacizumab biosimilar products, Alymsys is a vascular endothelial growth factor inhibitor used in oncology. It mediates its effect by preventing VEGF interaction with its receptors on the surface of endothelial cells, thereby, causing a reduction of microvascular growth and inhibition of metastatic disease progression. (Amneal Pharmaceuticals, 2022a; 2022b).
On September 28, 2022, the U.S. Food and Drug Administration (FDA) approved Vegzelma (bevacizumab-adcd), a biosimilar referencing Avastin for the treatment of six types of cancer: metastatic colorectal; recurrent or metastatic non-squamous non-small cell lung cancer (nsNSCLC); recurrent glioblastoma; metastatic renal cell carcinoma; persistent, recurrent, or metastatic cervical cancer; and epithelial ovarian, fallopian tube, or primary peritoneal cancer. The FDA approval of Vegzelma was based on supporting data from a pivotal phase 3 trial in patients with recurrent or metastatic nsNSCLC, which showed that Vegzelma is highly similar to the reference bevacizumab product with regard to efficacy, safety, and pharmacokinetics. Vegzelma marks the fourth bevacizumab biosimilar approval in the U.S., following the approvals of Mvasi (2017), Zirabev (2019), and Alymsys (2022) (Celltrion, 2022a).
Bevacizumab carries the following warnings and precautions:
- Gastrointestinal perforations and fistula
- Surgery and wound healing complications
- Hemorrhage
- Arterial thromboembolic events (ATE)
- Venous thromboembolic events (VTE)
- Hypertension
- Posterior reversible encephalopathy syndrome (PRES)
- Renal injury and proteinuria
- Infusion-related reactions
- Embryo-fetal toxicity
- Ovarian failure
- Congestive heart failure (CHF).
The most common adverse reactions incidence (incidence greater than 10%) include epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, hemorrhage, lacrimation disorder, back pain and exfoliative dermatitis.
Adrenocortical Carcinoma
Wortmann et al (2010) evaluated the effects of bevacizumab plus capecitabine as salvage therapy in advanced adrenocortical carcinoma (ACC). Patients registered with the German ACC Registry with refractory ACC progressing after cytotoxic therapies were offered treatment with bevacizumab (5 mg/kg body weight i.v. every 21 days) and oral capecitabine (950 mg/m(2) twice-daily for 14 days followed by 7 days of rest) in 2006 to 2008. Evaluation of tumor response was performed by imaging according to response evaluation criteria in solid tumours every 12 weeks. A total of 10 patients were treated with bevacizumab plus capecitabine. None of them experienced any objective response or stable disease. Two patients had to stop therapy after few weeks due to hand-foot syndrome, and 3 patients died on progressive disease within 12 weeks. Other adverse events were mild (grade I to grade II). Median survival after treatment initiation was 124 days. The authors concluded that bevacizumab plus capecitabine has no activity in patients with very advanced ACC. Hence, this regimen can not be recommended as a salvage therapy.
AIDS-related Kaposi's sarcoma
Uldrick et al (2012) stated alternatives to cytotoxic agents are desirable for patients with HIV-associated Kaposi's sarcoma (KS). Vascular endothelial growth factor-A (VEGF-A) contributes to KS pathogenesis. We evaluated the humanized anti-VEGF-A monoclonal antibody, bevacizumab, in patients with HIV-KS. Patients with HIV-KS who either experienced progression while receiving highly active antiretroviral therapy (HAART) for at least 1 month or did not regress despite HAART for at least 4 months were administered bevacizumab 15 mg/kg intravenously on days 1 and 8 and then every 3 weeks. The primary objective was assessment of antitumor activity using modified AIDS Clinical Trial Group (ACTG) criteria for HIV-KS. HIV-uninfected patients were also eligible and observed separately. Seventeen HIV-infected patients were enrolled. Fourteen patients had been receiving effective HAART for at least 6 months (median, 1 year). Thirteen patients had advanced disease (ACTG T(1)), 13 patients had received prior chemotherapy for KS, and seven patients had CD4 count less than 200 cells/μL. Median number of cycles was 10 (range, 1 to 37 cycles); median follow-up was 8.3 months (range, 3 to 36 months). Of 16 assessable patients, best tumor responses observed were complete response (CR) in three patients (19%), partial response (PR) in two patients (12%), stable disease in nine patients (56%), and progressive disease in two patients (12%). Overall response rate (CR + PR) was 31% (95% CI, 11% to 58.7%). Four of five responders had received prior chemotherapy for KS. Over 202 cycles, grade 3 to 4 adverse events at least possibly attributed to therapy included hypertension (n = 7), neutropenia (n = 5), cellulitis (n = 3), and headache (n = 2). The authors concluded that bevacizumab is tolerated in patients with HIV-KS and has activity in a subset of patients.
Brain Arterio-Venous Malformations
Williams and colleagues (2012) presented a case of an arterio-venous malformation (AVM) of the central sulcus treated with Gamma Knife surgery. The patient developed perilesional edema 9 months after treatment and experienced severe headache and hemiparesis. Her symptoms were refractory to corticosteroid therapy and pain management. She was subsequently treated with bevacizumab with striking improvement in her symptoms and results of neuroimaging studies. The authors concluded that this was the 1st time that bevacizumab has been used to control severe refractory perilesional edema related to an intra-cranial AVM.
Quan and associates (2018) examined delayed complications in patients with brain AVM (BAVM) after Gamma Knife stereotactic radiosurgery (GKSR) and presented the salvage therapy experiences of patients with BAVM with radiation-induced changes (RICs) or intra-cranial hemorrhage (ICH). This cohort consisted of 44 patients with BAVM who underwent failed GKSR between 2000 and 2015. These patients were further divided into an RIC group (23 patients) and an ICH group (21 patients) based on their post-GKSR complications. Patients' characteristics, treatment strategies, and long-term outcomes were analyzed. The modified Rankin Scale (mRS) was used to assess the neurologic status of each patient. The marginal dose and radiosurgery-based AVM score were not significantly different between the 2 groups. Craniotomy was performed in 26 patients (9 patients with ICH and 17 patients with RICs), and histologic examination showed cavernous angioma changes in 6 patients. In addition, 6 patients underwent repeat radiosurgery in the ICH group, and 7 patients used bevacizumab in the RIC group. A total of 30 patients showed good outcomes at the last follow-up (mRS score of less than 3). The authors concluded that salvage therapy for patients with BAVM should be performed based on the latency period and lesion characteristics of each individual; prompt treatment and a longer follow-up are recommended to achieve good clinical outcomes.
Furthermore, an UpToDate review on “Brain arteriovenous malformations” (Singer et al, 2019) does not mention bevacizumab as a therapeutic option.
Brain Metastases
Lin and DeAngelis (2015) noted that brain metastases (BMs) occur in 10 % to 20 % of adult patients with cancer, and with increased surveillance and improved systemic control, the incidence is likely to grow. Despite multi-modal treatment, prognosis remains poor. Current evidence supports use of whole-brain radiation therapy (WBRT) when patients present with multiple BMs. However, its associated cognitive impairment is a major deterrent in patients likely to live longer than 6 months. In patients with oligometastases (1 to 3 metastases) and even some with multiple lesions less than 3 to 4 cm, especially if the primary tumor is considered radiotherapy resistant, stereotactic radiosurgery is recommended; if the BMs are greater than 4 cm, surgical resection with or without post-operative WBRT should be considered. There is increasing evidence that systemic therapy, including targeted therapy and immunotherapy, is effective against BM and may be an early choice, especially in patients with sensitive primary tumors. In patients with progressive systemic disease, limited therapeutic options, and poor performance status, best supportive care may be appropriate. These investigators stated that small prospective studies of bevacizumab, in combination with other systemic agents, demonstrated activity against BM from heavily pre-treated HER2-positive breast cancer, NSCLC, melanoma, and SCLC. Currently, there is an ongoing phase III trial examining the effectiveness of bevacizumab, in addition to cisplatin and pemetrexed, in patients with NSCLC with asymptomatic BM (NCT02162537). Phase II trials of bevacizumab in BM from breast cancer (NCT02185352), melanoma (NCT02065466), and any solid tumor (NCT01898130) are also under way.
Breast Cancer
Preliminary results from a NCI-sponsored multi-center 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 PFS of 4 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 PFS. 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 2 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 PFS or OS (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 % versus 9.1 %; p = 0.001); however, this did not result in a longer PFS (4.86 versus 4.17 months; hazard ratio [HR]= 0.98). Overall survival (15.1 versus 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 % versus 0.5 %) was more frequent in patients receiving bevacizumab.
In July 2010, Federal health scientists said that follow-up studies of Avastin showed that it failed to extend patient lives, opening the door for it to be potentially withdrawal for use in treating that disease. The FDA approved Avastin in 2008 based on a trial showing it slowed growth of tumors caused by breast cancer. The decision was controversial because drugs for cancer patients who have never been treated before must usually show evidence they extend lives. Avastin's so-called "accelerated approval" was based on the condition that later studies would show a survival benefit. But in briefing documents posted online, FDA reviewers said 2 follow-up studies recently submitted by Roche failed to show that Avastin significantly extended lives compared to chemotherapy alone. Additionally, the FDA said that in follow-up studies the drug did not slow tumor growth to the same degree as in earlier studies. Furthermore, patients taking Avastin showed significantly more side effects, including high blood pressure, fatigue and abnormal white blood cell levels.
On July 20, 2010, an advisory panel has voted 12 to 1 to recommend that the FDA remove the advanced breast cancer indication from Avastin. The Oncologic Drugs Advisory Committee voted that bevacizumab, when added to standard chemotherapy, does not extend PFS long enough to be clinically meaningful in patients with human epidermal growth factor receptor 2 (HER2)-negative, metastatic breast cancer. If the FDA follows the advice of its advisory committee -- and it usually does -- bevacizumab would still be indicated for the treatment of colon, kidney, and lung cancer. The FDA will make a final decision by September 17 (Walker, 2010).
In a multi-center, randomized, open-label, phase III clinical trial, Martin et al (2015) examined if combining bevacizumab with endocrine therapy (ET) could potentially delay the emergence of resistance to ET in patients with breast cancer. This bi-national (Spain and Germany) study added bevacizumab (15 mg/kg every 3 weeks) to ET (ET-B; letrozole or fulvestrant) as first-line therapy in post-menopausal patients with HER2-negative and hormone receptor-positive advanced breast cancer. These researchers compared PFS, OS, ORR, response duration (RD), time to treatment failure (TTF), clinical benefit rate (CBR), and safety. From 380 patients recruited (2007 to 2011), 374 were analyzed by intent to-treat (184 patients on ET and 190 patients on ET-B). Median age was 65 years, 270 patients (72 %) had ECOG performance status of 0, 178 patients (48 %) had visceral metastases, and 171 patients (46 %) and 195 patients (52 %) had received prior chemotherapy or ET, respectively. Median PFS was 14.4 months in the ET arm and 19.3 months in the ET-B arm (hazard ratio [HR], 0.83; 95 % CI: 0.65 to 1.06; p = 0.126); ORR, CBR, and RD with ET versus ET-B were 22 % versus 41 % (p < 0.001), 67 % versus 77 % (p = 0.041), and 13.3 months versus 17.6 months (p = 0.434), respectively; TTF and OS were comparable in both arms. Grade 3 to 4 hypertension, aminotransferase elevation, and proteinuria were significantly higher in the ET-B arm; 8 patients (4.2 %) receiving ET-B died during study or within 30 days of end of treatment. The authors concluded that the addition of bevacizumab to ET in first-line treatment failed to produce a statistically significant increase in PFS or OS in women with HER2-negative/hormone receptor-positive advanced breast cancer. They stated that ET-B should not be recommended in the treatment of advanced hormone receptor-positive/HER2-negative breast cancer.
Cancer of Unknown Primary
In a phase II clinical study, Hainsworth et al (2009) evaluated the efficacy and toxicity of the combination of paclitaxel, carboplatin, bevacizumab, and erlotinib in the first-line treatment of patients with carcinoma of unknown primary site (CUP). Patients with previously untreated CUP (adenocarcinoma, poorly differentiated carcinoma, poorly differentiated squamous carcinoma) without clinical or pathological characteristics of a well-defined treatable subset were eligible. All patients received paclitaxel, carboplatin, bevacizumab, and erlotinib. Treatment cycles were repeated at 21-day intervals. After 4 cycles, paclitaxel and carboplatin were discontinued; bevacizumab-erlotinib treatment was continued until tumor progression. Patients were initially evaluated for response after completion of 2 treatment cycles; re-evaluations occurred every 6 weeks thereafter. Overall, 49 of 60 patients (82 %) completed 4 cycles of therapy, and 44 patients (73 %) subsequently received maintenance bevacizumab and erlotinib. Thirty-two patients (53 %) had major responses to treatment; an additional 18 patients had stable disease. After a median follow-up of 19 months, the median PFS time was 8 months, with 38 % of patients progression free at 1 year. The median survival time and 2-year OS rate were 12.6 months and 27 %, respectively. Treatment was generally well-tolerated, with a toxicity profile as predicted based on the known toxicities of each treatment component. The authors concluded that empiric treatment with paclitaxel, carboplatin, bevacizumab, and erlotinib is effective and well-tolerated as first-line treatment for patients with CUP. They stated that further development of this regimen is warranted.
Cervical Cancer
The American College of Radiology Expert Panel on Radiation Oncology-Gynecology’s Appropriateness Criteria® on “Advanced cervical cancer” (Gaffney et al, 2012) stated that “The combinations of cisplatin and topotecan have demonstrated an improvement in overall survival, and recently bevacizumab has shown promising activity in recurrent or metastatic cervix cancer”.
Vici and colleagues (2014) noted that cervical cancer is the 3rd most common cancer worldwide, and the development of new diagnosis, prognostic, and treatment strategies is a major interest for public health. Cisplatin, in combination with external beam irradiation for locally advanced disease, or as monotherapy for recurrent/metastatic disease, has been the cornerstone of treatment for more than 2 decades. Other investigated cytotoxic therapies include paclitaxel, ifosfamide and topotecan, as single agents or in combination, revealing unsatisfactory results. In recent years, much effort has been made towards evaluating new drugs and developing innovative therapies to treat cervical cancer. Among the most investigated molecular targets are EGFR and VEGF signaling pathways; both playing a critical role in the development of cervical cancer. Studies with bevacizumab or VEGF receptor tyrosine kinase have given encouraging results in terms of clinical efficacy, without adding significant toxicity.
Goey and Figg (2014) stated that the VEGF-A binding monoclonal antibody bevacizumab is a widely prescribed angiogenesis inhibitor and indicated for many types of cancer. As shown by 3 randomized phase III trials recently published in the New England Journal of Medicine, novel indications for this drug are still being explored. In the RTOG 0825 and AVAglio trials the effect of bevacizumab addition to standard therapy in newly diagnosed glioblastoma (radiotherapy plus temozolomide) was investigated, while in GOG 240 the combination of platinum-based chemotherapy plus bevacizumab was explored in advanced cervical cancer. In RTOG 0825, addition of bevacizumab to standard therapy did not result in survival benefit, and moreover, quality of life was more deteriorated in the bevacizumab arm. In AVAglio, however, PFS was significantly increased in the bevacizumab group and these patients also experienced a longer deterioration-free survival. These conflicting results do not fully support the incorporation of bevacizumab in the first-line treatment of glioblastoma. In contrast, in GOG 240 the bevacizumab group (including paclitaxel plus topotecan or paclitaxel) experienced a significant longer PFS and OS, and quality of life was not negatively affected in these patients. Thus, these results favor the use of bevacizumab in the treatment of advanced cervical cancer.
Tewari and colleagues (2014) evaluated the effectiveness of bevacizumab and non-platinum combination chemotherapy in patients with recurrent, persistent, or metastatic cervical cancer. Using a 2-by-2 factorial design, these researchers randomly assigned 452 patients to chemotherapy with or without bevacizumab at a dose of 15 mg/kg of body weight. Chemotherapy consisted of cisplatin at a dose of 50 mg/m2 of body-surface area, plus paclitaxel at a dose of 135 or 175 mg/m2 or topotecan at a dose of 0.75 mg/m2 on days 1 to 3, plus paclitaxel at a dose of 175 mg/m2 on day 1. Cycles were repeated every 21 days until disease progression, the development of unacceptable toxic effects, or a CR was documented. The primary end-point was OS; a reduction of 30 % in the hazard ratio for death was considered clinically important. Groups were well-balanced with respect to age, histologic findings, performance status, previous use or non-use of a radio-sensitizing platinum agent, and disease status. Topotecan-paclitaxel was not superior to cisplatin-paclitaxel (hazard ratio [HR] for death, 1.20). With the data for the 2 chemotherapy regimens combined, the addition of bevacizumab to chemotherapy was associated with increased OS (17.0 months versus 13.3 months; HR for death, 0.71; 98 % CI: 0.54 to 0.95; p = 0.004 in a 1-sided test) and higher response rates (48 % versus 36 %, p = 0.008). Bevacizumab, as compared with chemotherapy alone, was associated with an increased incidence of hypertension of grade 2 or higher (25 % versus 2 %), thrombo-embolic events of grade 3 or higher (8 % versus 1 %), and gastro-intestinal fistulas of grade 3 or higher (3 % versus 0 %). The authors concluded that the addition of bevacizumab to combination chemotherapy in patients with recurrent, persistent, or metastatic cervical cancer was associated with an improvement of 3.7 months in median OS.
On August 14, 2014, the FDA approved Avastin (bevacizumab) to treat patients with persistent, recurrent or late-stage (metastatic) cervical cancer. The FDA reviewed Avastin for treatment of patients with cervical cancer under its priority review program because the drug demonstrated the potential to be a significant improvement in safety or effectiveness over available therapy in the treatment of a serious condition. Priority review provides an expedited review of a drug’s application. The safety and effectiveness of bevacizumab for treatment of patients with cervical cancer was evaluated in a clinical study involving 452 patients with persistent, recurrent, or late-stage disease. Subjects were randomly assigned to receive paclitaxel and cisplatin with or without Avastin or paclitaxel and topotecan with or without Avastin. Results showed an increase in OS to 16.8 months in participants who received chemotherapy in combination with Avastin as compared to 12.9 months for those receiving chemotherapy alone.
Colorectal Cancer
Colorectal cancer is the second-leading cause of cancer death in the United States. It is the nation's third most common cancer accounting for approximately 15 % of all new cancer cases. Metastatic disease is present at diagnosis in 30 % of the patients, and about 50 % of early-stage patients will eventually present with metastatic disease. For many years, standard treatment of colorectal cancer was 5-fluorouracil (5-FU)-based therapy. Recent availability of newer agents, including capecitabine, irinotecan, oxaliplatin, and cetuximab has significantly expanded the options available for the management of patients with advanced colorectal cancer, with consequent improvements in survival.
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. In clinical trials, bevacizumab has been shown to extend patients' lives by approximately 5 months when given intravenously as a combination treatment along with standard chemotherapy drugs for colon cancer (e.g., the "Saltz regimen", also known as IFL, which includes irinotecan, 5-FU and leucovorin).
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.
In a phase II clinical study (n = 104), Kabbinavar and colleagues (2003) examined the safety and effectiveness of two doses of bevacizumab, in combination with 5-FU)/leucovorin (LV) versus 5-FU/LV alone in patients with metastatic colorectal cancer. Previously untreated patients with measurable metastatic colorectal cancer were randomly assigned to one of the following three treatment groups:- 5-FU (500 mg/m2)/LV (500 mg/m2) alone (n = 36),
- 5-FU/LV plus low-dose bevacizumab (5 mg/kg every 2 weeks) (n = 35), and
- 5-FU/LV plus high-dose bevacizumab (10 mg/kg every 2 weeks) (n = 33).
5-FU/LV was given weekly for the first 6 weeks of each 8-week cycle. Compared with the 5-FU/LV control arm, treatment with bevacizumab (at both dosages) plus 5-FU/LV resulted in higher response rates (control arm, 17 %, 95 % confidence interval [CI]: 7 to 34 %; low-dose arm, 40 %, 95 % CI: 24 to 58 %; high-dose arm, 24 %, 95 % CI: 12 to 43 %), longer median time to disease progression (control arm, 5.2 months, 95 % CI: 3.5 to 5.6 months; low-dose arm, 9.0 months, 95 % CI: 5.8 to 10.9 months; high-dose arm, 7.2 months, 95 % CI: 3.8 to 9.2 months), and longer median survival (control arm, 13.8 months; 95 % CI: 9.1 to 23.0 months; low-dose arm, 21.5 months, 95 % CI: 17.3 to undetermined; high-dose arm, 16.1 months; 95 % CI: 11.0 to 20.7 months). After cross-over, 2 of 22 patients had a partial response to bevacizumab alone. The authors concluded that the encouraging results of this randomized trial support further study of bevacizumab 5 mg/kg plus chemotherapy as first-line therapy for metastatic colorectal cancer.
The FDA approval of bevacizumab is based on the findings of a large, randomized, double-blind, placebo-controlled study (more than 800 patients) showing prolongation in the median survival of patients treated with bevacizumab plus the IFL chemotherapy regimen by about 5 months, compared to patients treated with the IFL chemotherapy regimen alone (20.3 months versus 15.6 months). The overall response rate to the treatment was 45 % compared to 35 % for the control arm of the trial.
A recent randomized controlled clinical study has shown that the addition of bevacizumab to a standard chemotherapy regimen for colorectal cancer has not resulted in an improvement in disease-free survival. Wolmark et al (2009) reported on the results of a 2-arm randomized prospective study to determine whether infusional 5-FU, leucovorin, and oxaliplatin (mFOLFOX6) plus bevacizumab (mFF6+B) would prolong disease-free survival (DFS) compared to mFOLFOX6 (mFF6) alone. Between September 2004 and October 2006, 2,672 patients with follow-up (1,338 and 1,334 in respective arms) with stage II (24.9 %) or III carcinoma of the colon were randomized to receive either mFF6 or mFF6+B. The primary end point was DFS. Events were defined as first recurrence, second primary cancer, or death. The median follow-up for patients still alive was 36 months. The hazard ratio (HR: FF6+B versus. mFF6) was 0.89; 95 % CI: 0.76 to 1.04; p = 0.15. The investigators reported that data censored at intervals disclosed an initial benefit for bevacizumab that diminished over time: The smoothed estimate of the DFS HR over time indicated that bevacizumab significantly reduced the risk of a DFS event during the interval from 0.5 to 1.0 year. There was no evidence that patients receiving bevacizumab had a worse DFS compared to those receiving mFF6 alone following treatment. The addition of bevacizumab to mFF6 did not result in an overall statistically significant prolongation in DFS. There was a transient benefit in DFS during the 1-year interval that bevacizumab was utilized. Consideration may be given to clinical trials assessing longer duration of bevacizumab administration.
Fluoropyrimidine-based chemotherapy plus the anti-VEGF antibody bevacizumab is standard first-line treatment for metastatic colorectal cancer. Tol and colleagues (2009)studied the effect of adding the anti-epidermal growth factor receptor (EGFR) antibody cetuximab to a combination of capecitabine, oxaliplatin, and bevacizumab for metastatic colorectal cancer. These investigators randomly assigned 755 patients with previously untreated metastatic colorectal cancer to capecitabine, oxaliplatin, and bevacizumab (CB regimen, 378 patients) or the same regimen plus weekly cetuximab (CBC regimen, 377 patients). The primary endpoint was progression-free survival (PFS). The mutation status of the KRAS gene was evaluated as a predictor of outcome. The median PFS was 10.7 months in the CB group and 9.4 in the CBC group (p = 0.01). Quality-of-life scores were lower in the CBC group. The overall survival (OS) and response rates did not differ significantly in the 2 groups. Treated patients in the CBC group had more grade 3 or 4 adverse events, which were attributed to cetuximab-related adverse cutaneous effects. Patients treated with cetuximab who had tumors bearing a mutated KRAS gene had significantly decreased PFS as compared with cetuximab-treated patients with wild-type-KRAS tumors or patients with mutated-KRAS tumors in the CB group. The authors concluded that the addition of cetuximab to capecitabine, oxaliplatin, and bevacizumab resulted in significantly shorter PFS and inferior quality of life. Mutation status of the KRAS gene was a predictor of outcome in the cetuximab group.
In an accompanying editorial of the afore-mentioned article, Mayer (2009) stated that the findings of Tol et al (2009) serve as a reminder that anti-tumor activity observed in pre-clinical and also uncontrolled clinical contexts may not be validated when examined in randomized trials. Furthermore, the data suggest that combining multiple forms of targeted therapies may not be analogous to combining different types of cytotoxic chemotherapy, presumably because of subtle interactions in intra-cellular signaling. Finally, these results underscore the fundamental importance of subjecting hypotheses to carefully conducted clinical trials. As was observed in this situation, more is not always better.
The addition of bevacizumab to oxaliplatin or irinotecan based doublet chemotherapy has shown benefit in metastatic colorectal cancer. Capecitabine (Cap) with or without mitomicin C (MMC) are alternate chemotherapy regimens suitable for patients who are either unfit for or who do not require initial oxaliplatin/irinotecan. Tebbutt et al (2009) reported on a phase III study comparing Cap with Cap Bev and Cap Bev MMC. The aim of this study was to develop a low toxicity regimen suitable for a broad population of patients with metastatic colorectal cancer. Previously untreated patients with unresectable metastatic colorectal cancer considered suitable for Cap monotherapy were randomised to arm A (Cap), arm B (Cap Bev) or arm C (Cap Bev MMC). The primary endpoint was progression free survival (PFS); secondary endpoints were response rate (RR), toxicity, overall survival (OS), and quality of life (QOL). Randomization was stratified by age, performance status (PS), center and Cap dose. Response was assessed every 6 weeks. A total of 471 patients were randomized from July 2005 to June 2007. The most common grade 3/4 toxicities were dermatologic (palmar-plantar erythrodysesthesia, PPE) (16 %, 26 %, 28 %) and diarrhea (11 %, 17 %, 16 %) for arms (A, B, C). However, adjusted rates per cycle were similar as arms B and C received more cycles of Cap (A = 8.3, B = 10.8, and C = 10.5). Other toxicity rates were generally less than 10 %. The study achieved its primary endpoint with a highly significant improvement in PFS for arms B and C. However, OS was similar in all arms. The authors concluded that all treatment regimens were well-tolerated. The addition of Bev +/- MMC to Cap significantly improved PFS without significant additional toxicity. However, OS was similar for all arms.
There is a lack of evidence to support the combinational use of bevacizumab with cetuximab for metastatic colorectal cancer (Tol et al, 2009; Mayer, 2009).
Desmoplastic Small Round Cell Tumor
Desmoplastic small round cell tumor (DSRCT), a rare malignant cancer, is a soft tissue sarcoma that usually affects young boys and men and is found most often in the abdomen. Its name means that it is formed by small, round cancer cells surrounded by scar-like tissue. The most common symptoms include abdominal pain, abdominal mass and symptoms of gastro-intestinal obstruction. Patients with DSRCTs are treated first with chemotherapy, then with surgery to remove the tumor, if possible. Radiation therapy is sometimes given, depending on the tumor. In addition, some patients with DSRCT are candidates for bone marrow transplantation. There is insufficient evidence regarding the clinical value of bevacizumab for the treatment of DSRCT.
de Araujo and Araujo (2014) presented 2 case reports of patients with DSRCT and discussed 2 therapeutic options for this sarcoma. This report focused on men aged 22 and 37 years, respectively. The first patient presented with an abdomino-pelvic mass that was not suitable for surgery. He underwent chemotherapy (adriblastina and cisplatin) with a brief partial remission and survival time of 13 months. The second patient presented with an abdominal mass and underwent partial resection. He received chemotherapy and bevacizumab, resulting in a partial remission and a survival time of 34 months. The extent of surgery and monoclonal antibody use probably had a positive impact on survival. The authors concluded that it is necessary to include specific targeted therapies in an attempt to improve survival.
Endometrial Cancer
Kamat and colleagues (2007) examined the clinical and therapeutic significance of VEGF in endometrial carcinoma using patient samples and an endometrioid orthotopic mouse model. Following Institutional Review Board approval, VEGF expression and microvessel density (MVD) counts were evaluated using immunohistochemistry in 111 invasive endometrial cancers by 2 independent investigators. Results were correlated with clinicopathologic characteristics. For the animal model, Ishikawa or Hec-1A cancer cell lines were injected directly into the uterine horn. Therapy experiments with bevacizumab alone or in combination with docetaxel were done and samples were analyzed for markers of angiogenesis and proliferation. Of 111 endometrial cancers, high expression of VEGF was seen in 56 % of tumors. There was a strong correlation between VEGF expression and MVD (p < 0.001). On multi-variate analysis, stage (p = 0.04), grade (p = 0.003), VEGF levels (p = 0.03), and MVD (p = 0.037) were independent predictors of shorter disease-specific survival. In the murine model, whereas docetaxel and bevacizumab alone resulted in 61 % to 77 % tumor growth inhibition over controls, combination therapy had the greatest efficacy (85 % to 97 % inhibition over controls; p < 0.01) in both models. In treated tumors, combination therapy significantly reduced MVD counts (50 % to 70 % reduction over controls; p < 0.01) and percent proliferation (39 % reduction over controls; p < 0.001). The authors concluded that increased levels of VEGF and angiogenic markers are associated with poor outcome in endometrioid endometrial cancer patients. Using a novel orthotopic model of endometrioid endometrial cancer, these researchers showed that combination of anti-vascular therapy with docetaxel is highly efficacious and should be considered for future clinical trials.
Epithelial Ovarian Cancer and Primary Peritoneal Cancer
Guidelines from the National Comprehensive Cancer Network (NCCN, 2006) stated that bevacizumab is an acceptable alternative chemotherapeutic regimen for recurrent epithelial ovarian cancer for stage II, III, and IV patients with partial responses to their primary paclitaxel and platinum-based chemotherapeutic regimens. The guidelines noted that bevacizumab has been demonstrated to be active in recurrent epithelial ovarian cancer, although it may cause arterial thrombosis and intestinal perforation. NCCN guidelines also indicate bevacizumab as therapy for clinical relapse in patients with stage II to IV granulosa-cell tumors of the ovary.
Primary peritoneal carcinoma (also known as papillary serous carcinoma of the peritoneum) is an entity closely associated with, but distinct from, epithelial ovarian carcinoma (EOC). Histologically, this tumor is indistinguishable from papillary serous ovarian carcinoma, but morphologic distinctions have been described. The criteria established by the Gynecologic Oncology Group (GOG) to define primary peritoneal carcinoma are:
- A predominantly serous histology
- Extra-ovarian involvement greater than ovarian involvement
- Ovaries normal in size (4.0 cm in largest diameter) or enlarged by a benign process
- Surface involvement of less than 5 mm depth and width.
Using these criteria, between 7 and 20 % of patients previously identified with primary EOC may be re-classified as having primary peritoneal carcinoma. In some cases, they may be classified as adenocarcinomas of unknown primary site. The pattern of spread is similar to that in women with EOC. Women with papillary serous carcinoma of the peritoneum are treated similarly to those with EOC. Optimal surgical cytoreduction may be more difficult to achieve in the setting of widespread peritoneal disease without a predominant ovarian or pelvic mass. Chemotherapy regimens and response rates are similar to EOC (NCCN, 2009).
Gastric Cancer
Shad et al (2006) assessed the safety and effectiveness of the addition of bevacizumab to chemotherapy in the treatment of gastric and gastro-esophageal junction (GEJ) adenocarcinoma. A total of 47 patients with metastatic or unresectable gastric/GEJ adenocarcinoma were treated with bevacizumab 15 mg/kg on day 1, irinotecan 65 mg/m2, and cisplatin 30 mg/m2 on days 1 and 8, every 21 days. The primary end point was to demonstrate a 50 % improvement in time to progression over historical values. Secondary end points included safety, response, and survival. Patient characteristics were as follows: median age 59 years (range of 25 to 75 years); Karnofsky performance status 90 % (70 to 100 %); male:female, 34:13; and gastric/GEJ, 24:23. With a median follow-up of 12.2 months, median time to progression was 8.3 months (95 % CI: 5.5 to 9.9 months). In 34 patients with measurable disease, the overall response rate was 65 % (95 % CI: 46 to 80 %). Median survival was 12.3 months (95 % CI: 11.3 to 17.2 months). These researchers observed no increase in chemotherapy related toxicity. Possible bevacizumab-related toxicity included a 28 % incidence of grade 3 hypertension, 2 patients with a gastric perforation and 1 patient with a near perforation (6 %), and 1 patient with a myocardial infarction (2 %). Grade 3 to 4 thromboembolic events occurred in 25 % of patients. Although the primary tumor was unresected in 40 patients, these investigators observed only 1 patient with a significant upper gastrointestinal bleed. The authors concluded that bevacizumab can be safely given with chemotherapy even with primary gastric and GEJ tumors in place. The response rate, time to disease progression (TTP), and OS are encouraging, with TTP improved over historical controls by 75 %. Moreover, they stated that further development of bevacizumab in gastric and GEJ cancers is needed.
Abad (2008) noted that bevacizumab has been used to treat patients with gastric cancer in phase I and II clinical trials with good results, which need to be confirmed in new phase III studies. Also, Ohtsu (2008) stated that several targeting agents such as trastuzumab, bevacizumab, and lapatinib are now under investigation in international randomized studies to examine their effects on metastatic gastric cancer.
Gliomas
Bevacizumab appears to be an effective treatment for gliomas. Vredenburgh et al (2007) reported on a phase II clinical trial of bevacizumab and irinotecan in 32 patients with recurrent gliomas, 23 with grade IV gliomas and 9 with grade III gliomas. Radiographical responses were noted in 63 % of patients (14 of 23 grade IV patients and 6 of 9 grade III patients); 1 was a complete response and 19 were partial responses. The median PFS was 23 weeks for all patients (95 % CI: 15 to 30 weeks; 20 weeks for grade IV patients and 30 weeks for grade III patients). The 6-month PFS probability was 38 % overall, and 56 % in the grade III glioma patients and 30 % in the grade IV glioma patients. The 6-month OS probability was 72 %. The response and survival rates in this study are higher than what would have been expected.
In May 2009, the FDA approved bevacizumab for the treatment of patients with glioblastoma multiforme when this form of brain cancer continues to progress following standard therapy.
Packer et al (2009) noted that chemotherapy has taken on a prominent role in the treatment of pediatric low-grade gliomas not amenable to gross total resections; however, there are few proven effective options for children with multiply recurrent tumors. Bevacizumab and irinotecan have been used with some success in adults with malignant gliomas. A total of 10 children with multiply recurrent low-grade gliomas were treated with the combination of bevacizumab and irinotecan. Patients received treatment at a median of 5.2 years of age, range of 1.5 to 11.1 years. The majority of patients had diencephalic tumors, 3 had neurofibromatosis type 1, and 2 had disseminated disease at the time of treatment. Nine of 10 patients had progressed after 3 or greater chemotherapy regimens and 1 patient also had received radiation therapy. Seven patients had an objective neuro-radiographical response, which was a complete response in 1, partial response in 3, and minor response in 3. Clinical improvements were noted in 7, including improved visual acuity (n = 2), improved motor function (n = 2), weight gain in 4 with a diencephalic syndrome, and reversal of psychomotor retardation (n = 3). Dose-limiting toxicities included transient leukoencephalopathy (n = 1) and grade 3 proteinuria (n = 1). Response was durable in the majority of patients and 6 remained on treatment, for up to 22 months. The authors concluded that multiple recurrent low-grade gliomas in children are responsive to the combination of bevacizumab and irinotecan. The drug combination of bevacizumab and irinotecan has been relatively well-tolerated, including in patients with neurofibromatosis type 1, and warrants further study.
Gonzalez et al (2007) reported the findings of 15 patients with malignant brain tumors who were treated with bevacizumab or bevacizumab in combination with other agents on either a 5 mg/kg/2-week or 7.5 mg/kg/3-week schedule. Radiation necrosis was diagnosed in 8 of these patients on the basis of magnetic resonance imaging (MRI) and biopsy; MRI studies were obtained before treatment and at 6-week to 8-week intervals. Of the 8 patients with radiation necrosis, post-treatment MRI performed an average of 8.1 weeks after the start of bevacizumab therapy showed a reduction in all 8 patients in both the MRI fluid-attenuated inversion-recovery (FLAIR) abnormalities and T1-weighted post-Gd-contrast abnormalities. The average area change in the T1-weighted post-Gd-contrast abnormalities was 48 % (+/- 22 SD), and the average change in the FLAIR images was 60 % (+/- 18 SD). The average reduction in daily dexamethasone requirements was 8.6 mg (+/- 3.6). The authors concluded that bevacizumab, alone and in combination with other agents, can reduce radiation necrosis by decreasing capillary leakage and the associated brain edema. Moreover, they stated that these findings will need to be confirmed in a randomized trial to determine the optimal duration of treatment.
Liu et al (2009) stated that diffuse pontine gliomas are a pediatric brain tumor that is fatal in nearly all patients. Given the poor prognosis for patients with this tumor, their quality of life is very important. Radiation therapy provides some palliation, but can result in radiation necrosis and associated neurologic decline. The typical treatment for this necrosis is steroid therapy. Although steroids are effective, they have many adverse effects that can often significantly compromise quality of life. Bevacizumab has been suggested as a treatment for radiation necrosis. These investigators reported on their initial experience with bevacizumab therapy for radiation necrosis in pediatric pontine gliomas. A total of 4 children with pontine gliomas treated at the Children's Hospital in Denver and the University of Colorado Denver developed evidence of radiation necrosis both clinically and on imaging. They received bevacizumab as a treatment for the radiation necrosis. These researchers reviewed the clinical outcome and imaging findings. After bevacizumab therapy, 3 children had significant clinical improvement and were able to discontinue steroid use. One child continued to decline, and, in retrospect, had disease progression, not radiation necrosis. In all cases, bevacizumab was well-tolerated. The authors concluded that in children with pontine gliomas, bevacizumab may provide both therapeutic benefit and diagnostic information. They stated that more formal evaluation of bevacizumab in these children is needed.
In a randomized, double-blind, placebo-controlled trial, Gilbert et al (2014) treated adults who had centrally confirmed glioblastoma with radiotherapy (60 Gy) and daily temozolomide. Treatment with bevacizumab or placebo began during week 4 of radiotherapy and was continued for up to 12 cycles of maintenance chemotherapy. At disease progression, the assigned treatment was revealed, and bevacizumab therapy could be initiated or continued. The trial was designed to detect a 25 % reduction in the risk of death and a 30 % reduction in the risk of progression or death, the 2 co-primary end-points, with the addition of bevacizumab. A total of 978 patients were registered, and 637 underwent randomization. There was no significant difference in the duration of OS between the bevacizumab group and the placebo group (median of 15.7 and 16.1 months, respectively; hazard ratio [HR] for death in the bevacizumab group, 1.13). Progression-free survival was longer in the bevacizumab group (10.7 months versus 7.3 months; HR for progression or death, 0.79). There were modest increases in rates of hypertension, thrombo-embolic events, intestinal perforation, and neutropenia in the bevacizumab group. Over time, an increased symptom burden, a worse QOL, and a decline in neurocognitive function were more frequent in the bevacizumab group. The authors concluded that first-line use of bevacizumab did not improve OS in patients with newly diagnosed glioblastoma; PFS was prolonged but did not reach the pre-specified improvement target.
In a phase III clinical trial, Chinot et al (2014) evaluated the effect of the addition of bevacizumab to radiotherapy-temozolomide for the treatment of newly diagnosed glioblastoma. These researchers randomly assigned patients with supratentorial glioblastoma to receive intravenous bevacizumab (10 mg/kg of body weight every 2 weeks) or placebo, plus radiotherapy (2 Gy 5 days a week; maximum of 60 Gy) and oral temozolomide (75 mg/square meter of body-surface area/day) for 6 weeks. After a 28-day treatment break, maintenance bevacizumab (10 mg/kg intravenously every 2 weeks) or placebo, plus temozolomide (150 to 200 mg/square meter/day for 5 days), was continued for six 4-week cycles, followed by bevacizumab monotherapy (15 mg/kg intravenously every 3 weeks) or placebo until the disease progressed or unacceptable toxic effects developed. The co-primary end-points were investigator-assessed PFS and OS. A total of 458 patients were assigned to the bevacizumab group, and 463 patients to the placebo group. The median PFS was longer in the bevacizumab group than in the placebo group (10.6 months versus 6.2 months; stratified hazard ratio [HR] for progression or death, 0.64; 95 % CI: 0.55 to 0.74; p < 0.001). The benefit with respect to PFS was observed across subgroups. Overall survival did not differ significantly between groups (stratified HR for death, 0.88; 95 % CI: 0.76 to 1.02; p = 0.10). The respective OS rates with bevacizumab and placebo were 72.4 % and 66.3 % at 1 year (p = 0.049) and 33.9 % and 30.1 % at 2 years (p = 0.24). Baseline health-related QOL and performance status were maintained longer in the bevacizumab group, and the glucocorticoid requirement was lower. More patients in the bevacizumab group than in the placebo group had grade 3 or higher adverse events (66.8 % versus 51.3 %) and grade 3 or higher adverse events often associated with bevacizumab (32.5 % versus 15.8 %). The authors concluded that the addition of bevacizumab to radiotherapy-temozolomide did not improve survival in patients with glioblastoma. Improved PFS and maintenance of baseline quality of life and performance status were observed with bevacizumab; however, the rate of adverse events was higher with bevacizumab than with placebo.
Mansour et al (2014) stated that glioblastoma multiforme (GBM) is the most aggressive subtype of malignant gliomas. Current standard treatment for GBM involves a combination of cyto-reduction through surgical resection, followed by radiation with concomitant and adjuvant chemotherapy (temozolomide). Despite aggressive treatment, these tumors remain undoubtedly fatal, especially in the elderly. Furthermore, tumors present in the pineal gland are extremely rare, accounting for only 0.1 to 0.4 % of all adult brain tumors, with this location adding to the complexity of treatment. These researchers presented a case of GBM, at the rare location of pineal gland, in an elderly patient who was refractory to initial standard of care treatment with radiation and concomitant and adjuvant temozolomide, but who developed a significant response to anti-angiogenic therapy using bevacizumab.
Head and Neck Cancer
In a phase II clinical trial, Argiris et al (2011) hypothesized that bevacizumab will potentiate the activity of pemetrexed in squamous cell carcinoma of the head and neck (SCCHN). Patients with previously untreated, recurrent, or metastatic SCCHN were treated with pemetrexed 500 mg/m(2) and bevacizumab 15 mg/kg given intravenously every 21 days with folic acid and B-12 supplementation until disease progression. Primary end point was time-to-progression (TTP). DNA was isolated from whole blood samples for the detection of polymorphisms in thymidylate synthase, methylenetetrahydrofolate reductase (MTHFR), and VEGF. A total of 40 patients were enrolled. The median TTP was 5 months, and the median OS was 11.3 months. In 37 evaluable patients, the overall response rate was 30 %, including a complete response rate of 5 %, and the disease control rate was 86 %. Grade 3 to 5 bleeding events occurred in 6 patients (15 %): 4 were grade 3, and 2 were fatal. Other serious toxicities in 10 % or more of patients included neutropenia (10 %) and infection (12.5 %). One patient died of sepsis after receiving 8 cycles of therapy. For the MTHFR A1298C (rs1801131) single nucleotide polymorphisms, homozygote patients with AA had worse OS (p = 0.034). The authors concluded that the addition of bevacizumab to pemetrexed resulted in promising efficacy outcomes in SCCHN. Bleeding events were frequent but some may have been due to natural history of disease. Polymorphisms in MTHFR may offer potential for treatment individualization. They stated that bevacizumab-containing regimens should be further investigated in SCCHN.
Hemangioblastoma
Riklin and colleagues (2012) stated that hemangioblastomas represent rare benign tumors of the CNS. In the case of metastatic spread and limited surgical options, systemic treatment may be considered. However there is no standard of care beyond surgery. These investigators reported the cases of 2 patients with progressive multi-locular hemangioblastomas, who showed clinical benefit and radiological stabilization of tumor growth after treatment with bevacizumab. The authors concluded the findings of these case reports suggested activity of bevacizumab in hemangioblastomas after failure of standard therapeutic options
Furthermore, an UpToDate review on “Hemangioblastoma” (Wong et al, 2018) does not mention bevacizumab as a therapeutic option.
Hepatocellular Carcinoma
In a phase II clinical trial, Siegel et al (2008) determined the clinical and biologic effects of bevacizumab in unresectable hepatocellular carcinoma (HCC). Adults with organ-confined HCC, ECOG performance status of 0 to 2, and compensated liver disease were eligible. Patients received bevacizumab 5 mg/kg (n = 12) or 10 mg/kg (n = 34) every 2 weeks until disease progression or treatment-limiting toxicity. The primary objective was to determine whether bevacizumab improved the 6-month PFS rate from 40 % to 60 %. Secondary end points included determining the effects of bevacizumab on arterial enhancement and on plasma cytokine levels and the capacity of patients' plasma to support angiogenesis via an in vitro assay. The study included 46 patients, of whom 6 had objective responses (13 %; 95 % CI: 3 % to 23 %), and 65 % were progression-free at 6 months. Median PFS time was 6.9 months (95 % CI: 6.5 to 9.1 months); OS rate was 53 % at 1 year, 28 % at 2 years, and 23 % at 3 years. Grade 3 to 4 adverse events included hypertension (15 %) and thrombosis (6 %, including 4 % with arterial thrombosis). Grade 3 or higher hemorrhage occurred in 11 % of patients, including 1 fatal variceal bleed. Bevacizumab was associated with significant reductions in tumor enhancement by dynamic contrast-enhanced magnetic resonance imaging and reductions in circulating VEGF-A and stromal-derived factor-1 levels. Functional angiogenic activity was associated with VEGF-A levels in patient plasma. The authors concluded that these findings revealed significant clinical and biologic activity for bevacizumab in non-metastatic HCC and achieved the primary study end point. Serious bleeding complications occurred in 11 % of patients. They stated that further evaluation is needed in carefully selected patients (e.g., unresectable HCC).
In another phase II study, Thomas et al (2009) determined the proportion of patients with HCC treated with the combination of bevacizumab (B) and erlotinib (E) who were alive and progression free at 16 weeks (16-week PFS [PFS16]) of continuous therapy. Secondary objectives included response rate, median PFS, survival, and toxicity. Patients who had advanced HCC that was not amenable to surgical or regional therapies, up to 1 prior systemic treatment; Childs-Pugh score A or B liver function; ECOG performance status 0, 1, or 2 received B 10 mg/kg every 14 days and E 150 mg orally daily, continuously, for 28-day cycles. Tumor response was evaluated every 2 cycles by using Response Evaluation Criteria in Solid Tumors Group criteria. A total of 40 patients were treated. The primary end point of PFS16 was 62.5 %; 10 patients achieved a partial response for a confirmed overall response rate (intent-to-treat) of 25 %. The median PFS event was 39 weeks (95 % CI: 26 to 45 weeks; 9.0 months), and the median OS was 68 weeks (95 % CI: 48 to 78 weeks; 15.65 months). Grades 3 to 4 drug-related toxicity included fatigue (n = 8; 20 %), hypertension (n = 6; 15 %), diarrhea (n = 4; 10 %) elevated transaminases (n = 4; 10 %), gastrointestinal hemorrhage (n = 5; 12.5 %), wound infection (n = 2; 5 %), thrombocytopenia (n = 1; 2.5 %), and proteinuria, hyper-bilirubinemia, back pain, hyperkalemia, and anorexia (n = 1 each). The authors concluded that the combination of B + E in patients who had advanced HCC showed significant, clinically meaningful antitumor activity. They stated that bevacizumab plus erlotinib warrant additional evaluation in randomized controlled trials.
Hereditary Hemorrhagic Telangiectasia (HHT) / HHT-Related Epistaxis
In a single-center, phase 2 clinical trial, Dupuis-Girod et al (2012) examined the effectiveness of bevacizumab in reducing high cardiac output (CO) in severe hepatic forms of hereditary hemorrhagic telangiectasia (HHT) and evaluated improvement in epistaxis duration and quality of life. Patients were 18 to 70 years old and had confirmed HHT, severe liver involvement, and a high cardiac index related to HHT. Bevacizumab, 5 mg/kg of body weight, every 14 days for a total of 6 injections. The total duration of the treatment was 2.5 months; patients were followed-up for 6 months after the beginning of the treatment. Main outcome measure was decrease in CO at 3 months after the first injection, evaluated by echocardiography. A total of 25 patients were included between March 2009 and November 2010. Of the 24 patients who had echocardiograms available for re-read, there was a response in 20 of 24 patients with normalization of cardiac index (complete response [CR]) in 3 of 24, partial response (PR) in 17 of 24, and no response in 4 cases. Median cardiac index at beginning of the treatment was 5.05 L/min/m(2) (range of 4.1 to 6.2) and significantly decreased at 3 months after the beginning of the treatment with a median cardiac index of 4.2 L/min/m(2) (range of 2.9 to 5.2; p < 0.001). Median cardiac index at 6 months was significantly lower than before treatment (4.1 L/min/m(2); range of 3.0 to 5.1). Among 23 patients with available data at 6 months, these researchers observed CR in 5 cases, PR in 15 cases, and no response in 3 cases. Mean duration of epistaxis, which was 221 mins/month (range of 0 to 947) at inclusion, had significantly decreased at 3 months (134 mins; range of 0 to 656) and 6 months (43 mins; range of 0 to 310) (p = 0.008). Quality of life had significantly improved. The most severe adverse events were 2 cases of grade 3 systemic hypertension, which were successfully treated. The authors concluded that in this preliminary study of patients with HHT associated with severe hepatic vascular mal-formations and high CO, administration of bevacizumab was associated with a decrease in CO and reduced duration and number of episodes of epistaxis. Drawbacks of this study included small sample size and lack of a control group. The authors stated that it is unclear if this treatment could be definitive or a bridging therapy while patients are waiting for a liver transplant. They noted that longer follow-up studies are needed to determine the duration of HHT efficacy and whether maintenance therapy is needed.
Stokes and Rimmer (2018) performed a systematic review of the efficacy of bevacizumab in local treatment of epistaxis in patients with HHT based on epistaxis duration, frequency, severity and impact on QOL. A systematic search was performed using the PubMed, Medline and Embase databases. The Preferred Items for Systematic Reviews and Meta-Analyses guidelines were followed. Studies that measured the efficacy of intranasal bevacizumab treatment of epistaxis in patients with HHT were included for qualitative analysis. A total of 13 studies (4 RCTs, 3 prospective studies, 3 retrospective studies, 1 case-series study and 2 case reports) with a total of 357 patients were included. Local administration (either by submucosal injection or topically) did not have a significant impact on epistaxis duration, frequency, severity or QOL compared to placebo or other local treatments. The authors concluded that the available evidence suggested that intra-nasal bevacizumab treatment did not have a significant effect on epistaxis in patients with HHT. There are several limitations that require further investigation to confidently rule out local bevacizumab as an effective therapy in HHT related epistaxis.
Halderman and colleagues (2018) stated that bevacizumab has been used in several forms to treat epistaxis in HHT; however thus far, evidence-based recommendations are limited. These investigators performed a systematic review with evidence-based recommendations. A systematic review of the literature following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines was performed using Embase, Medline, Medline In-Process/Epub, and Cochrane databases. English language abstracts were reviewed for relevance. Results Eleven manuscripts met inclusion criteria and were analyzed. Submucosal injection, submucosal injection plus laser coagulation, intravenous (IV), and topical formulations of bevacizumab were evaluated for their therapeutic impact on epistaxis in patients with HHT. A total of 3 RCTs failed to show topical bevacizumab to be more effective in controlling epistaxis than saline or other moisturizers. The authors concluded that the use of submucosal and IV bevacizumab shows promise, but further study is needed to determine the true efficacy in the treatment of epistaxis as only grade C level of evidence exists currently. Based on the available literature, the use of topical bevacizumab is not recommended (grade B).
Guilhem et al (2017) noted that bevacizumab has recently emerged as a new option for severe forms of hereditary hemorrhagic telangiectasia (HHT). Its utilization in this orphan disease has rapidly spread despite the lack of randomized trials and international guidelines. These researchers reported the main clinical data (baseline characteristics, dose schedule, efficacy, adverse events [AEs] and deaths) of HHT patients treated by intravenous (IV) bevacizumab in France. This was a retrospective, observational study of HHT patients treated with bevacizumab for a severe form of the disease in the 14 centers of the French HHT network. A total of 46 patients (median age of 68 years) were treated between March 2009 and May 2015; 10 patients were treated for high-output cardiac failure, 20 patients for severe hemorrhages, and 16 for both indications. The standard protocol (6 infusions of 5 mg/kg every 2 weeks) was initially used in 89 % of the cases; but diverse strategies were subsequently applied. A clinical improvement was noted by the referent physician for 74 % of the patients with a median effect's duration of 6 months. Wound healing complications led to 2 amputations. Arthralgia/arthritis and arterial hypertension occurred in 5 patients each; 1/3 of the patients were dead at the time of the final update, coherently with age and the poor prognosis of these highly symptomatic patients. The authors concluded that IV bevacizumab appeared to provide a clinical benefice in severe HHT patients. Moreover, they stated that precautions concerning wound healing and vascular pathologies must be respected; prospective, double-blinded versus placebo trials are needed.
The authors stated that this study suffered from drawbacks inherent to its retrospective, non-interventional and open design. The retrospective data collection and the diversity of participating centers did not allowed these investigators to obtain standardized objective parameters for the efficacy assessment. Nevertheless, they thought that these data honestly reflected the daily practice and provided valuable information to apprehend the risk/benefit ratio of this new drug. It constituted a preliminary step to conducting a large, prospective, and randomized versus placebo trial, which is deeply needed. The lack of consensual modalities of bevacizumab use, especially for long-term treatments, was another concern. It has generated a high level of heterogeneity in these researchers’ data. Most of physicians had initially followed the "standard protocol" of 6 injections of 5 mg/kg, by analogy with the oncological use and the prospective trial. Other protocols with lower doses had also been proposed and could be more appropriate in some cases, notably for frail patients. Concerning the subsequent treatment (maintenance or re-treatment), a pharmacological study based on a mathematical model suggested a systematic monthly injection. A re-treatment strategy individually adapted to the clinical needs has been applied for 24 % of the cohort. This strategy could be pertinent but requires to be sustained by further clinical and biopharmaceutical investigations.
Iyer et al (2018) presented a multi-year clinical experience with IV bevacizumab for the management of severe gastro-intestinal (GI) bleeding and/or epistaxis in patients with HHT. All patients treated with IV bevacizumab for severe HHT-related bleeding from June 1, 2013, through January 31, 2017, were included in this report. Severity of epistaxis (determined using the Epistaxis Severity Score questionnaire); hemoglobin (Hb), iron, and ferritin levels; and quality of life (QOL) data were collected serially in all patients. Intravenous bevacizumab was administered to 34 patients using a standardized treatment protocol. Anemia was primarily related to severe epistaxis (n = 15, 44 %), severe GI bleeding (n = 4, 12 %), or both (n = 15, 44 %), with a median baseline Hb level of 9.1 g/dL (range of 8.3 to 10.5 gm/dL; to convert to mmol/L, multiply by 0.62). Red blood cell (RBC) transfusions had been administered to 28 patients (82 %). Of these, 16 patients (47 %) were RBC transfusion-dependent and had received a median of 75 RBC transfusions (range of 4 to greater than 500 RBC units) before initiation of bevacizumab. The median length of follow-up was 17.6 months from the beginning of bevacizumab treatment (range of 3 to 42.5 months). There was a significant reduction in epistaxis severity scores (p < 0.001) and RBC transfusion requirements (p = 0.007) after completion of the initial bevacizumab treatment cycle. New-onset or worsened hypertension was noted in 4 patients, with 1 patient experiencing hypertensive urgency with a temporary decline in renal function. The authors concluded that IV bevacizumab was an effective therapeutic option for patients with severe anemia related to epistaxis and/or GI bleeding. Moreover, these researchers stated that further studies are needed to establish a dose-response relationship as well as clinical, genetic, and biomarker predictors of response.
In what appeared to be an accompanying editorial, Gossage (2018) stated that “The study by Iyer et al is a semi-prospective study that finds a remarkable improvement in ESS score, quality of life, and transfusion need. Although one can attribute changes in ESS score or quality of life to the placebo effect, it is much harder to attribute so dramatic a change in transfusion need to placebo. It is still desirable to have a randomized placebo controlled trial. However, until we have those data in hand, I agree with Iyer et al that “systemic bevacizumab should be considered as a first-line therapy for the treatment of refractory bleeding in patients with HHT”. At this point, the bulk of the literature suggests that the initial course of treatment should be 4 to 6 infusions of 5 mg/kg bevacizumab every 2 to 3 weeks. Some have reported success with doses as low as 0.125 mg/kg, but most of the literature and informal polling of North American HHT Center Directors (James R. Gossage, MD, oral communication, 2015-2017) favor a dose of 5 mg/kg for most patients. In terms of maintenance therapy, the literature is less clear. Some have advocated a routine infusion every 1 to 6 months, whereas others have based additional infusions on recurrence of symptoms. Finally, although this therapy seems to be well tolerated by patients with HHT, serious adverse effects have been reported in patients with HHT, and therefore careful patient selection along with close monitoring of blood pressure, blood chemistry, and urine protein is advised”.
Al-Samkari et al (2019) stated that HHT is a rare hereditary multi-system vascular disorder causing visceral arterio-venous malformations (AVMs) and mucocutaneous bleeding. Chronic GI bleeding and epistaxis often produce profound anemia refractory to conventional treatment. Bevacizumab may be effective in treatment of bleeding in HHT. All HHT patients treated with systemic bevacizumab for chronic bleeding were selected for retrospective analysis. Data collected included demographics, baseline HHT characteristics, epistaxis grade, surgical interventions, bevacizumab dosing, AEs, Hb, RBC transfusions, intravenous iron infusions, and other anemia and/or bleeding-directed therapies. A total of 13 HHT patients were treated with bevacizumab for a median of 13.9 (range of 4.9 to 30.1) months. Compared with pre-treatment values, bevacizumab treatment increased the mean Hb by 4.0 g/dL (95 % CI: 2.6 to 5.3 g/dL) [mean (95 % CI: hemoglobin 8.5 (7.8 to 9.9) g/dL versus 12.5 (11.2 to 13.7) g/dL, p < 0.001)], reduced RBC units transfused by 92 % [median of 6 (range of 0 to 59) units versus 0 (range of 0 to 15) units, p = 0.004], and reduced quantity of iron infused by 73 % [mean (95 % CI: 462 (257 to 668) mg/month versus 126 (75 to 178) mg/month, p = 0.002]. Epistaxis control was achieved in 85 % with bevacizumab, versus 0 % before treatment (p < 0.001). No patient required nasal or GI procedures during the maintenance period; 2 patients (15 %) developed grade 3 hypertension requiring medical management. The authors concluded that systemic bevacizumab was highly effective to treat chronic bleeding in HHT. Moreover, they stated that further study is needed to confirm the magnitude of benefit and further define optimal dosing, treatment duration, and long-term safety.
An UpToDate review on “Management of hereditary hemorrhagic telangiectasia” (Shovlin, 2019) states that “Epistaxis affects over 95 % of individuals with hereditary hemorrhagic telangiectasia (HHT). A number of topical, systemic, and surgical treatments are available. As a general rule, we try to use local preventive therapies (e.g., nasal humidification, ointments) and other modifications such as dietary changes in order to avoid potential toxicities of systemic therapy; however, management is individualized. Some individuals with bleeding from localized vascular lesions may require subspecialist management, and some may require medical systemic therapies such as tamoxifen, tranexamic acid, or bevacizumab if epistaxis is recurrent or localized interventions are insufficient. Systemic agents should be used with caution if there is a propensity to venous or arterial thromboemboli … Hepatic AVMs are almost always asymptomatic. In our experience, a major risk is of misdiagnoses as metastases and clinician education is required. In less than 10 % of patients, symptoms may develop, attributable to portal hypertension, biliary disease, and/or high-output heart failure. For individuals with symptomatic liver involvement, treatment is generally supportive and directed at optimizing cardiac status and iron stores. If medical management fails, liver transplantation is the treatment of choice. The angiogenesis inhibitor bevacizumab may also be helpful, but data are too preliminary to support routine use in this setting”.
Stokes and Rimmer (2018) HHT remains a difficult disease for the ear, nose, and throat (ENT) specialist to manage. Affected patients often report recurrent epistaxis as the most debilitating symptom. The pathogenesis of the disease is due to genetic mutations affecting angiogenesis. For this reason, the anti-angiogenic therapy bevacizumab has gained popularity in the local treatment of epistaxis in patients with HHT. These investigators carried out a systematic review of the efficacy of bevacizumab in local treatment of epistaxis in patients with HHT based on epistaxis duration, frequency, severity and impact on QOL. A systematic search was performed using the PubMed, Medline and Embase databases. The Preferred Items for Systematic Reviews and Meta-Analyses guidelines were followed. Studies that measured the efficacy of intra-nasal bevacizumab treatment of epistaxis in patients with HHT were included for qualitative analysis. A total of 13 studies (4 RCTs, 3 prospective studies, 3 retrospective studies, 1 case series and 2 case reports) with a total of 357 patients were included. Local administration (either by submucosal injection or topically) did not have a significant impact on epistaxis duration, frequency, severity or QOL compared to placebo or other local treatments. The authors concluded that available evidence suggested that intra-nasal bevacizumab treatment did not have a significant effect on epistaxis in patients with HHT. These researchers noted that there were several limitations that need further investigation to confidently rule out local bevacizumab as an effective therapy in HHT-related epistaxis.
Halderman and co-workers (2018) stated that epistaxis is a primary complaint in 90 % to 96 % of patients with HHT. Numerous surgical and medical treatments aim to decrease the frequency and severity of epistaxis in this patient population. Bevacizumab has been used in several forms to treat epistaxis in HHT but thus far, evidence-based recommendations are limited. These investigators performed a systematic review of the literature following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines using Embase, Medline, Medline In-Process/Epub, and Cochrane databases. English language abstracts were reviewed for relevance. A total of 11 manuscripts met inclusion criteria and were analyzed. Submucosal injection, submucosal injection plus laser coagulation, intravenous (IV), and topical formulations of bevacizumab were evaluated for their therapeutic impact on epistaxis in patients with HHT; 3 RCTs failed to show topical bevacizumab to be more effective in controlling epistaxis than saline or other moisturizers. The authors concluded that the use of submucosal and IV bevacizumab showed promise, however, further study is needed to determine the true efficacy in the treatment of epistaxis as only grade C level exists currently. These researchers stated that based on the available literature, the use of topical bevacizumab is not recommended (grade B).
Kini and associates (2019) reviewed the current literature regarding the use of bevacizumab for the treatment of epistaxis in patients with HHT and provided guidance on its usage for this indication. These investigators carried out a narrative literature review to analyze various methods and dosages of bevacizumab administration for the treatment of HHT-related epistaxis, along with a review of current treatment modalities and their drawbacks. The current standard of care for HHT-related epistaxis consists of treatments that are largely ineffective or invasive with significant potential complications. Submucosal bevacizumab has demonstrated efficacy in reducing frequency, duration, and severity of epistaxis in those with HHT. The authors concluded that given the inadequacies and potential drawbacks of current treatments for epistaxis in HHT, there is a need for new therapeutic options. Submucosal bevacizumab has been effective with a limited risk profile in a number of studies and should now be considered as a therapeutic option for refractory epistaxis. Moreover, these researchers stated that controlled studies are recommended to quantify optimal dosing, treatment schedule, and specific sub-populations that will respond best to this treatment.
Leiomyosarcoma
In a phase III, double-blind, placebo-controlled trial, Hensley et al (2015) examined if the addition of bevacizumab to gemcitabine-docetaxel increases PFS in patients with uterine leiomyosarcoma (uLMS). Patients with chemotherapy-naive, metastatic, unresectable uLMS were randomly assigned to gemcitabine-docetaxel plus bevacizumab or gemcitabine-docetaxel plus placebo. Progression-free survival, OS, and ORRs were compared to determine superiority. Target accrual was 130 patients to detect an increase in median PFS from 4 months (gemcitabine-docetaxel plus placebo) to 6.7 months (gemcitabine-docetaxel plus bevacizumab). Treatment effects on PFS and OS were described by hazard rations (HRs), median times to event, and 95 % CIs. In all, 107 patients were accrued: gemcitabine-docetaxel plus placebo (n = 54) and gemcitabine-docetaxel plus bevacizumab (n = 53). Accrual was stopped early for futility. No statistically significant differences in grade 3 to 4 toxicities were observed. Median PFS was 6.2 months for gemcitabine-docetaxel plus placebo versus 4.2 months for gemcitabine-docetaxel plus bevacizumab (HR, 1.12; p = 0.58). Median OS was 26.9 months for gemcitabine-docetaxel plus placebo and 23.3 months for gemcitabine-docetaxel plus bevacizumab (HR, 1.07; p = 0.81). Objective responses were observed in 17 (31.5 %) of 54 patients randomly assigned to gemcitabine-docetaxel plus placebo and 19 (35.8 %) of 53 patients randomly assigned to gemcitabine-docetaxel plus bevacizumab. Mean duration of response was 8.6 months for gemcitabine-docetaxel plus placebo versus 8.8 months for gemcitabine-docetaxel plus bevacizumab. The authors concluded that the addition of bevacizumab to gemcitabine-docetaxel for first-line treatment of metastatic uLMS failed to improve PFS, OS, or ORR. Gemcitabine-docetaxel remains a standard first-line treatment for uLMS.
Leptomeningeal Metastases
Burger et al (2016) stated that leptomeningeal dissemination of a primary brain tumor is a condition which is challenging to treat, as it often occurs in rather late disease stages in highly pre-treated patients. Its prognosis is dismal and there is still no accepted standard of care. These researchers reported here a good clinical effect with a partial response (PR) in 3 out of 9 patients and a stable disease(SD) with improvement on symptoms in 2 more patients following systemic anti-angiogenic treatment with bevacizumab (BEV) alone or in combination with chemo- and/or radiotherapy in a series of patients with leptomeningeal dissemination from primary brain tumors (diffuse astrocytoma WHO°II, anaplastic astrocytoma WHO°III, anaplastic oligodendroglioma WHO°III, primitive neuro-ectodermal tumor and glioblastoma, both WHO°IV). This translated into effective symptom control in 5 out of 9 patients, but only moderate progression-free survival (PFS) and overall survival (OS) times were reached; PRs as assessed by RANO criteria were observed in 3 patients (each 1 with anaplastic oligodendroglioma, primitive neuro-ectodermal tumor and glioblastoma). In these patients PFS intervals of 17, 10 and 20 weeks were achieved. In 3 patients (each with diffuse astrocytoma, anaplastic astrocytoma and primitive neuro-ectodermal tumor) SD was observed with PFS of 13, 30 and 8 weeks. Another 3 patients (all with glioblastoma) were primary non-responders and deteriorated rapidly with PFS of 3 to 4 weeks. No severe AEs were seen. The authors concluded that these experiences suggested that the combination of BEV with more conventional therapy schemes with chemo- and/or radiotherapy may be a palliative therapeutic option for patients with leptomeningeal dissemination of brain tumors. (This was a small study; and its findings were confounded by the combinational use of bevacizumab with chemo- and/or radiotherapy).
Sakata et al (2016) noted that leptomeningeal metastasis is a severe complication of non-small cell lung cancer. Its prognosis is very poor and conventional treatments have limited efficacy. However, epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors have exhibited high response rates in EGFR mutation-positive lung cancer patients with central nervous system (CNS) metastases. It has been postulated that this could be due to the penetration of agents into the CNS and a high cerebro-spinal fluid (CSF) concentration is a key consideration in measuring treatment effect. Bevacizumab has also been used as an effective therapeutic agent in patients with CNS metastases. However, the efficacy of EGFR-tyrosine kinase inhibitor doublet therapy for leptomeningeal metastases and the CSF penetration of EGFR-tyrosine kinase inhibitors have yet to be determined. Moreover, the safety of this doublet regimen in patients with a poor general condition is not known. These researchers reported on a case treated with erlotinib plus bevacizumab for leptomeningeal metastases from EGFR mutation-positive non-small cell lung cancer. The patient's performance status significantly improved and the CSF penetration rate of erlotinib plus bevacizumab was equal to or greater than the past reports of erlotinib alone. (This was a single-case study; and its findings were confounded by the combinational use of bevacizumab and erlotinib).
Matsuda et al (2017) stated that although promising preliminary results have been widely observed with bevacizumab for recurrent malignant gliomas, many unanswered questions remain to be resolved to achieve an optimal outcome. No predictive biomarkers of a survival benefit from bevacizumab have been established, and no consensus exists about the response or survival benefit regarding the prior recurrence pattern or tumor location. These researchers retrospectively analyzed the clinical benefit from bevacizumab for recurrent malignant gliomas in relation to the prior recurrence pattern or tumor location. A total of 31 consecutive patients with recurrent malignant gliomas who were treated with bevacizumab were investigated. The treatment response and survival benefit from bevacizumab were analyzed in association with age, sex, Karnofsky performance status (KPF), prior pathological diagnosis, prior recurrence pattern, primary location of tumor, recurrence status, and expression of angiogenic and hypoxic markers. The group with leptomeningeal dissemination had a significantly shorter median OS with bevacizumab (OSBev) (6.0 months, 95 % confidence interval (CI): 1.4 to 10.7) compared to those in the local/distant group (11.8 months, 95 % CI: 6.1 to 17.4). The median OSBev of the infra-tentorial tumor group and supra-tentorial tumor group were 9.2 months (95 % CI: 5.0 to 13.4) and 10.4 months (95 % CI: 6.6 to 14.3), respectively. With multi-variate analysis, the prior recurrence pattern was the only independent prognostic factor of OSBev. The authors concluded that patients with leptomeningeal dissemination of recurrent malignant glioma experienced minimal benefit from bevacizumab.
Melanoma
In a pilot study, Guenterberg and associates (2011) hypothesized that administration of bevacizumab in combination with high-dose interferon-alpha2b (IFN-α2b) would have clinical activity in patients with metastatic ocular melanoma. Patients with metastatic ocular melanoma received bevacizumab (15 mg/kg intravenously every 2 weeks) plus IFN-α2b (5 MU/m subcutaneously 3 times weekly for 2 weeks followed by a dose of 10 MU/m subcutaneously thereafter). Patients exhibiting a clinical response or stabilization of disease were treated until disease progression. A total of 5 patients were treated (3 men and 2 women) with a mean age of 63.8 years (range of 53 to 71 years). Overall, the regimen was well-tolerated. The following adverse events were noted: grade 3 dyspnea (n = 2), grade 3 and 4 fatigue (n = 2), grade 3 muscle weakness (n = 1), grade 3 anorexia (n = 1), grade 1 and 2 proteinuria (n = 2), and grade 3 diarrhea (n = 1). All adverse events resolved with a treatment holiday or dose reduction. One patient had reduction in tumor burden of 23 % by Response Evaluation Criteria in Solid Tumors criteria and 2 patients had stabilization of disease lasting 28 and 36 weeks, respectively. Two patients failed to respond and progressed after 6 and 7 weeks of therapy. The authors concluded that bevacizumab and IFN-α2b were well-tolerated in this patient population, and clinical activity was observed. They stated that further study of high-dose IFN-α2b in combination with bevacizumab in this setting is warranted.
Gonzalez-Cao et al (2008) assessed the activity of the combination of weekly paclitaxel and bevacizumab in previously treated metastatic melanoma. Patients with previously treated metastatic melanoma received paclitaxel 70 mg/m(2) weekly and bevacizumab 10 mg/kg biweekly for 5 consecutive weeks every 6 weeks. A total of 12 patients were treated. Two patients (16.6 %) achieved a partial response and 7 patients (58.3 %) stable disease. Responses were seen in soft tissue, lung and brain metastases. Median disease-free and OS times were 3.7 and 7.8 months, respectively. Treatment was well-tolerated. Main toxicities were grade 3 asymptomatic lymphopenia in 6 patients, grade 3 leucopenia in 2 patients, and grade 3 thrombocytopenia in 1 patient. The authors concluded that these preliminary results suggested that the combination of bevacizumab and weekly paclitaxel is active and safe in patients with metastatic melanoma, warranting further investigation.
Meningeal Melanoma Metastases
Simonsen and colleagues (2020) stated that melanoma patients with metastatic growth in the meninges have poor prognosis and few therapeutic options. Although treatment with BRAF inhibitors or immune checkpoint inhibitors has provided promising results, most patients with advanced melanoma are resistant to these treatments and develop severe side effects. Novel treatment strategies are needed for patients with meningeal melanoma metastases, and the potential of anti-angiogenic therapy was examined in this pre-clinical study. Two GFP-transfected melanoma models (A-07 and D-12) differing substantially in VEGF-A expression were included in the study, and the anti-VEGF-A antibody bevacizumab was used as therapeutic agent. Meningeal metastases were initiated in BALB/c nu/nu mice by intra-cranial inoculation of melanoma cells, and bevacizumab treatment was given twice-weekly in intra-peritoneal (i.p.) doses of 10 mg/kg until the mice became moribund. Therapeutic effects were evaluated by determining tumor host survival time, assessing tumor growth and angiogenic activity by quantitative analyses of histological preparations, and measuring the expression of angiogenesis-related genes by quantitative PCR. Meningeal A-07 melanomas showed higher expression of VEGF-A than meningeal D-12 melanomas, whereas the expression of ANGPT2 and IL8, 2 important angiogenesis drivers in melanoma, was much higher in D-12 than in A-07 tumors. Bevacizumab treatment inhibited tumor angiogenesis and prolonged host survival in mice with A-07 tumors but not in mice with D-12 tumors. Meningeal A-07 tumors in bevacizumab-treated mice compensated for the reduced VEGF-A activity by up-regulating a large number of angiogenesis-related genes, including ANGPT2 and its receptors TIE1 and TIE2. Melanoma cells migrated from meningeal tumors into the cerebrum, where they initiated metastatic growth by vessel co-option. In the A-07 model, the density of cerebral micro-metastases was higher in bevacizumab-treated than in untreated mice, either because bevacizumab treatment increased mouse survival or induced increased tumor gene expression. The authors concluded that bevacizumab treatment inhibited tumor angiogenesis and prolonged tumor host survival in mice with meningeal A-07 tumors, but had no effect on the angiogenic activity of meningeal D-12 tumors. Meningeal A-07 tumors compensated for reduced VEGF-A-mediated angiogenic activity by up-regulating the expression of a large number of other angiogenesis-related genes, including genes governing the ANGPT/TIE pathway. Melanoma cells migrated from meningeal tumors into the cerebral parenchyma and formed micro-metastases vascularized by vessel co-option, and in the A-07 model, bevacizumab-treated mice developed more and larger cerebral micro-metastases than untreated mice. These discoveries suggest that anti-angiogenic therapy may have the potential to inhibit the growth of meningeal melanoma metastases, but emphasize the need to target multiple angiogenic pathways and to individualize the treatment based on the angiogenic signature of the tumor tissue. Furthermore, anti-angiogenic therapy cannot be expected to improve the outcome of meningeal melanoma metastases without being combined with therapeutic strategies for preventing tumor cell migration, vessel co-option, and metastatic growth in the cerebral parenchyma.
Meningioma
In their review, Franke et al (2018) state meningiomas are the most prevalent primary tumor of the central nervous system (CNS), and although the majority of these neoplasms are classified as benign, nearly one fourth of the lesions display an aggressive profile characterized by pleomorphic histology, high recurrence rates, and overall resistance to standard treatment. Despite the ubiquitous nature of these tumors, no adjuvant therapeutic regimen has been identified which effectively controls disease recurrence and progression after surgery and radiation, leading to a dismal prognosis in this patient population. The primary focus of this research study is, hence, to assess the recently emerging use of bevacizumab, an anti-angiogenic agent, in the treatment of meningiomas. This systematic literature review analyzes the efficacy and safety of therapeutic bevacizumab for treatment-refractory meningiomas. A systematic PubMed search was conducted according to PRISMA guidelines to identify all relevant reports investigating the anti-angiogenic agent bevacizumab in the treatment of intracranial meningiomas. The reported parameters from pertinent retrospective reviews, prospective studies, and case studies were volumetric reduction, radiographic response, clinical stability, overall survival (OS), and progression free survival (PFS) measured at 6 and 12 months post-initiation of treatment. Complications were cataloged based on the range and severity of the therapy-related toxicities. A total of 11 articles, 5 retrospective series, 2 prospective trials, and 4 case reports, reporting on a total of 92 patients, were included in this review. The use of bevacizumab therapy for intracranial meningiomas demonstrated median overall PFS of 16.8 months (range: 6.5-22 months) and PFS-6 of 73% (range: 44%-93%). The authors concluded that therapeutic bevacizumab, either alone or with combination chemotherapies, for select patient populations with recurrent or progressive meningiomas, offers a treatment option that confers improved overall progression-free survival. To assess OS parameters, larger randomized controlled trials assessing the use of anti-angiogenic agents for recurrent/progressive meningiomas are warranted.
Shih et al (2016) stated meningiomas that progress after standard therapies are challenging with limited effective chemotherapy options. This phase II trial evaluated the efficacy of everolimus plus bevacizumab in patients with recurrent, progressive meningioma after treatment with surgical resection and local radiotherapy when appropriate. Patients with recurrent meningioma (WHO grade I, II, or III) following standard treatments with surgical resection and radiotherapy received bevacizumab (10 mg/kg IV days 1 and 15) and everolimus (10 mg PO daily) each 28 day cycle. Evaluation of response occurred every 2 cycles. The primary endpoint was progression-free survival (PFS). Secondary endpoints included response rate, overall survival and safety. Seventeen patients with a median age of 59 years (29-84) received study treatment. WHO grades at study entry included: I, 5 (29 %); II, 7 (41 %); III, 4 (24 %); unknown, 1 (6 %). Patients received a median of 8 cycles (1-37); all patients are off study treatment. A best response of SD was observed in 15 patients (88 %), and 6 patients had SD for >12 months. Overall median PFS was 22 months (95 % CI 4.5-26.8) and was greater for patients with WHO grade II and III compared to grade I tumors (22.0 months vs 17.5 months). Four patients discontinued treatment due to toxicity (proteinuria, 2; colitis, 1, thrombocytopenia, 1). However, other grade 3 toxicity was uncommon, and no patient had grade 4 toxicity. The authors concluded that the combination of everolimus and bevacizumab was well-tolerated, and produced stable disease in 88 % of patients; the median duration of disease stabilization of 10 months (2-29). The median PFS from this prospective trial was similar to previous retrospective reports of bevacizumab in the treatment of recurrent meningioma.
Mesothelioma: Peritoneal, Pleural, Pericardium, and Tunica Vaginalis Testes
Malignant mesothelioma is a highly lethal malignancy of the serosal membranes of the pleura, peritoneum, pericardium, or tunica vaginalis testes. This is a rare disease, with the pleural variant being the most common, followed by peritoneal mesothelioma (Alexander 2019; UpToDate).Pericardial mesothelioma is a rare form of mesothelioma that develops in the pericardium. Symptoms include chest pain and difficulty breathing. Pericardial mesothelioma is rare, accounting for less than 1% of mesothelioma cases. Although a causal relationship between asbestos exposure and pleural mesotheliomas is well established, the relationship between asbestos exposure and pericardial mesothelioma is less certain. Mesotheliomas arising in the pericardium produce tamponade and constriction. Resection is the treatment of choice for mesothelioma, but the prognosis with malignant pericardial mesotheliomas is very poor. The addition of radiation and/or chemotherapy has been attempted but has not been shown to be of value (Gaasch and Vander Salm 2019; UpToDate).
Chekol and Sun (2012) stated malignant mesothelioma of the tunica vaginalis testis is an extremely rare tumor representing 0.3% to 5% of all malignant mesotheliomas. Gross examination of testicular mesotheliomas typically reveals tumor nodules studding the thickened tunica vaginalis and, in some cases, infiltrating the testicular parenchyma, leading to diagnostic challenges. Microscopically, the tumor is characterized by epithelioid cells arising from the tunica vaginalis with papillary, tubulopapillary, or solid architectural patterns. The papillae are usually lined by a single layer of cells with relatively bland cytologic features. An epithelial cell phenotype admixed with a sarcomatoid pattern has also been described in a few cases. Immunohistochemically, the tumor is usually positive for calretinin, Wilms tumor-1, epithelial membrane antigen, D2-40, thrombomodulin, cytokeratin 7, and cytokeratin 5/6. Electron microscopic studies reveal epithelial cells joined by tight junctions, forming lumina, and displaying long microvilli with length to width ratios often greater than 10. The most important differential diagnostic considerations include florid mesothelial hyperplasia, adenomatoid tumor, carcinoma of the rete testis, and serous papillary tumors. In addition, the various types of testicular germ cell tumors should be considered, including seminomas, embryonal carcinomas, and intratubular germ cell tumors, particularly in tumors with testicular parenchymal involvement. Pleomorphic sarcomas should also be considered, particularly when dealing with the biphasic variant. The prognosis for this entity is grave, with a median survival of 23 months. Aggressive therapy with radical orchiectomy remains the mainstay of treatment.
The addition of bevacizumab to the pemetrexed-cisplatin regimen improved both progression-free and overall survival compared with pemetrexed plus cisplatin without bevacizumab in the large phase III MAPS trial conducted exclusively in patients with malignant pleural mesothelioma. It is reasonable to extrapolate this experience to patients with malignant peritoneal mesothelioma, although care should be taken in patient selection for bevacizumab (i.e., patients should have no poorly controlled hypertension, deep venous thrombosis, recent surgery, or viscus perforation, and they must have a good performance status) (Alexander and Kindler 2019; UpToDate).
NCCN guidelines (2015) added the first-line combination chemotherapy regimen of pemetrexed/cisplatin/bevacizumab followed by maintenance bevacizumab as a treatment option for patients with unresectable malignant pleural mesothelioma (MPM). This is a category 2A recommendation, based upon a study by Zalcman, et al. (2015; 2016). Zalcman et al (2016) stated malignant pleural mesothelioma is an aggressive cancer with poor prognosis, linked to occupational asbestos exposure. Vascular endothelial growth factor is a key mitogen for malignant pleural mesothelioma cells, therefore targeting of vascular endothelial growth factor might prove effective. The authors aimed to assess the effect on survival of bevacizumab when added to the present standard of care, cisplatin plus pemetrexed, as first-line treatment of advanced malignant pleural mesothelioma. This randomised, controlled, open-label, phase 3 trial recruited patients aged 18-75 years with unresectable malignant pleural mesothelioma who had not received previous chemotherapy, had an Eastern Cooperative Oncology Group performance status of 0-2, had no substantial cardiovascular comorbidity, were not amenable to curative surgery, had at least one evaluable (pleural effusion) or measurable (pleural tumour solid thickening) lesion with CT, and a life expectancy of >12 weeks from 73 hospitals in France. Exclusion criteria were presence of central nervous system metastases, use of antiaggregant treatments (aspirin ≥325 mg per day, clopidogrel, ticlopidine, or dipyridamole), anti-vitamin K drugs at a curative dose, treatment with low-molecular-weight heparin at a curative dose, and treatment with non-steroidal anti-inflammatory drugs. The authors randomly allocated patients (1:1; minimization method used [random factor of 0·8]; patients stratified by histology [epithelioid vs sarcomatoid or mixed histology subtypes], performance status score [0-1 vs 2], study centre, or smoking status [never smokers vs smokers]) to receive intravenously 500 mg/m(2) pemetrexed plus 75 mg/m(2) cisplatin with (PCB) or without (PC) 15 mg/kg bevacizumab in 21 day cycles for up to six cycles, until progression or toxic effects. The primary outcome was overall survival (OS) in the intention-to treat population. Treatment was open label. From Feb 13, 2008, to Jan 5, 2014, the authors randomly assigned 448 patients to treatment (223 [50%] to PCB and 225 [50%] to PC). OS was significantly longer with PCB (median 18·8 months [95% CI 15·9-22·6]) than with PC (16·1 months [14·0-17·9]; hazard ratio 0·77 [0·62-0·95]; p=0·0167). Overall, 158 (71%) of 222 patients given PCB and 139 (62%) of 224 patients given PC had grade 3-4 adverse events. The authors noted more grade 3 or higher hypertension (51 [23%] of 222 vs 0) and thrombotic events (13 [6%] of 222 vs 2 [1%] of 224) with PCB than with PC. The authors concluded that the addition of bevacizumab to pemetrexed plus cisplatin significantly improved OS in malignant pleural mesothelioma at the cost of expected manageable toxic effects, therefore it should be considered as a suitable treatment for the disease (MAPS Trial; NCT00651456) (MAPS Trial; NCT00651456).).
Multiple Myeloma
In a phase II clinical trial, White and colleagues (2013) compared bevacizumab and bortezomib versus bortezomib in relapsed or refractory multiple myeloma (MM). Patients with relapsed or refractory MM were randomized to receive bortezomib (1.3 mg/m(2) on days 1, 4, 8, and 11 of each 21-day cycle) and either placebo or bevacizumab (15 mg/kg on day 1 of each cycle) for up to 8 cycles. At completion, patients in the bortezomib-plus-bevacizumab arm could continue bevacizumab until they developed progressive disease or unacceptable toxicity. The primary endpoint was PFS. The stratified hazard ratio of PFS for the bevacizumab-containing arm (n = 49) relative to the bortezomib monotherapy arm (n = 53) was 0.743 (95 % CI: 0.43 to 1.28; p = 0.2804); the median PFS was 6.2 months (95 % CI: 4.4 to 8.5 months) and 5.1 months (95 % CI: 4.2 to 7.2 months), respectively; the overall response rates were 51 % and 43.4 % (p = 0.4029), respectively; and the median response duration was 6.9 months (95 % CI: 4.73 to 11.83 months) and 6.0 months (95 % CI: 4.86 to 8.31 months), respectively. Frequent adverse events occurred at similar rates across treatment arms, but hypertension, fatigue, and neuralgia occurred more frequently in the bevacizumab-containing arm. The authors concluded that the addition of bevacizumab to bortezomib in unselected patients with pretreated MM did not result in significant improvements in efficacy outcomes.
Neuroendocrine Tumors
The NET Task Force of the National Cancer Institute GI Steering Committee (Kulke et al, 2011) convened a clinical trials planning meeting to identify key unmet needs, develop appropriate study end points, standardize clinical trial inclusion criteria, and formulate priorities for future neuroendocrine tumor (NET) studies for the United States cooperative group program. Emphasis was placed on the development of well-designed clinical trials with clearly defined efficacy criteria. Key recommendations include the evaluation of pancreatic NET separately from NETs of other sites and the exclusion of patients with poorly differentiated histologies from trials focused on low-grade histologies. Specific recommendations for ongoing and future studies on carcinoid tumors and pancreatic NETs are:- successful completion of the ongoing phase III study of bevacizumab and IFN in patients with advanced carcinoid tumors may define the role of bevacizumab in these patients, and
- everolimus is active in patients with advanced pancreatic NETs.
A randomized phase II study comparing everolimus alone with combination of everolimus plus bevacizumab in patients with pancreatic NET will build on the recent observation of activity with everolimus alone, and may help define the potential additive activity of bevacizumab in this setting.
In a multi-center, phase II trial, Hobday and colleagues (2015) evaluated the effectiveness of combination therapy of temsirolimus and bevacizumab in patients with pancreatic neuroendocrine tumors (PNET). These investigators conducted a 2-stage single-arm phase II trial of the mammalian target of rapamycin (mTOR) inhibitor temsirolimus 25 mg intravenously (IV) once-weekly and bevacizumab 10 mg/kg IV once every 2 weeks in patients with well or moderately differentiated PNETs and progressive disease by Response Evaluation Criteria in Solid Tumors (RECIST) within 7 months of study entry. Co-primary end-points were tumor response rate and 6-month PFS. A total of 58 patients were enrolled, and 56 patients were eligible for response assessment. Confirmed response rate (RR) was 41 % (23 of 56 patients); PFS at 6 months was 79 % (44 of 56). Median PFS was 13.2 months (95 % CI: 11.2 to 16.6). Median OS was 34 months (95 % CI: 27.1 to “not reached”). For evaluable patients, the most common grade 3 to 4 AEs attributed to therapy were hypertension (21 %), fatigue (16 %), lymphopenia (14 %), and hyperglycemia (14 %). The authors concluded that the combination of temsirolimus and bevacizumab had substantial activity and reasonable tolerability in a multi-center phase II trial, with RR of 41 %, well in excess of single targeted agents in patients with progressive PNETs. Six-month PFS was a notable 79 % in a population of patients with disease progression by RECIST criteria within 7 months of study entry. They stated that on the basis of this trial, continued evaluation of combination mTOR and VEGF pathway inhibitors is warranted.
Neurofibromatosis
Plotkin and co-workers (2009) determined the expression pattern of VEGF and 3 of its receptors, VEGFR-2, neuropilin-1, and neuropilin-2, in paraffin-embedded samples from 21 vestibular schwannomas associated with neurofibromatosis type 2 and from 22 sporadic schwannomas. A total of 10 consecutive patients with neurofibromatosis type 2 and progressive vestibular schwannomas who were not candidates for standard treatment were treated with bevacizumab. An imaging response was defined as a decrease of at least 20 % in tumor volume, as compared with baseline. A hearing response was defined as a significant increase in the word-recognition score, as compared with baseline. Vascular endothelial growth factor was expressed in 100 % of vestibular schwannomas and VEGFR-2 in 32 % of tumor vessels on immuno-histochemical analysis. Before treatment, the median annual volumetric growth rate for 10 index tumors was 62 %. After bevacizumab treatment in the 10 patients, tumors shrank in 9 patients, and 6 patients had an imaging response, which was maintained in 4 patients during 11 to 16 months of follow-up. The median best response to treatment was a volumetric reduction of 26 %. Three patients were not eligible for a hearing response; of the remaining 7 patients, 4 had a hearing response, 2 had stable hearing, and 1 had progressive hearing loss. There were 21 adverse events of grade 1 or 2. The authors concluded that VEGF blockade with bevacizumab improved hearing in some, but not all, patients with neurofibromatosis type 2 and was associated with a reduction in the volume of most growing vestibular schwannomas. They stated that additional research is needed to determine the optimal drug regimen, duration, and adverse-effect profile for long-term anti-VEGF therapy for vestibular schwannomas associated with neurofibromatosis.
Plotkin and colleagues (2019) stated that bevacizumab treatment at 7.5 mg/kg every 3 weeks resulted in improved hearing in approximately 35 % to 40 % of patients with neurofibromatosis type 2 (NF2) and progressive vestibular schwannomas (VSs). However, the optimal dose is unknown. In a multi-center, phase-II clinical trial, these researchers examined the safety and efficacy of high-dose bevacizumab in pediatric and adult patients with NF2 with progressive VS. Bevacizumab was given for 6 months at 10 mg/kg every 2 weeks, followed by 18 months at 5 mg/kg every 3 weeks. The primary end-point was hearing response defined by word recognition score (WRS) at 6 months. Secondary end-points included toxicity, radiographic response, QOL, and plasma biomarkers. A total of 22 subjects with NF2 (median age of 23 years) with progressive hearing loss in the target ear (median baseline WRS, 53 %) were enrolled; 9 (41 %) of 22 subjects achieved a hearing response at 6 months (1 of 7 children and 8 of 15 adults; p = 0.08). Radiographic response was observed in 7 (32 %) of 22 patients with VS at 6 months (7 of 15 adults and 0 of 7 children; p = 0.05). Common mild-to-moderate AEs included hypertension, fatigue, headache, and irregular menstruation. Improvement in NF2-related QOL and reduction in tinnitus-related distress were reported in 30 % and 60 % of subject, respectively. Paradoxically, high-dose bevacizumab treatment was not associated with a significant decrease in free VEGF but was associated with increased carbonic anhydrase IX, hepatocyte growth factor, placental growth factor, stromal cell-derived factor 1α, and basic fibroblast growth factor concentrations in plasma. The authors concluded that high-dose bevacizumab appeared to be no more effective than standard-dose bevacizumab for treatment of patients with NF2 with hearing loss. In contrast to adults, pediatric subjects did not experience tumor shrinkage. However, adult and pediatric subjects reported similar improvement in QOL during induction. These researchers stated that novel approaches using bevacizumab should be considered for children with NF2.
Non-Small Cell Lung Cancer
Preliminary results from a National Cancer Institute (NCI)-sponsored phase III randomized, controlled, multi-center clinical study of bevacizumab in patients with newly diagnosed non-small cell lung cancer (NSCLC) found that subjects treated with chemotherapy plus bevacizumab survived an average of 12.5 months, compared with 10.2 months among patients receiving paclitaxel and carboplatin alone (NCI, 2005). This difference was statistically significant. 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 improving overall survival. A total of 878 patients with advanced non-squamous, NSCLC who had not previously received systemic chemotherapy were enrolled in this study between July 2001 and April 2004. Patients were randomized to 1 of the 2 treatment arms. One patient group received standard treatment -- 6 cycles of paclitaxel and carboplatin. The second group received the same 6-cycle chemotherapy regimen with the addition of bevacizumab, followed by bevacizumab alone until disease progression. Patients with squamous cell carcinoma of the lung were excluded from in the study because previous clinical experience suggested that these patients had a higher risk of serious bleeding from the lung after bevacizumab therapy. Patients with a prior history of frank hemoptysis were also excluded from the trial. The most significant adverse event observed in this study was life-threatening or fatal bleeding, primarily from the lungs. This infrequent adverse event was more common in the patient group that received bevacizumab in combination with chemotherapy than in the patient group that received only chemotherapy. In October 2006, the FDA approved the use of bevacizumab in combination with carboplatin and paclitaxel for the initial systemic treatment of patients with unresectable, locally advanced, recurrent or metastatic, non-squamous, NSCLC. This approval was based on an improvement in survival time when bevacizumab was added to a standard chemotherapy regimen.
A randomized phase III study (BeTa Lung) evaluating bevacizumab in combination with erlotinib (Tarceva) in patients with advanced NSCLC whose disease had progressed following platinum-based chemotherapy did not meet its primary endpoint of improving OS compared to erlotinib in combination with placebo (Genentech, 2008). This multi-center, randomized, controlled phase III study enrolled 636 patients with advanced NSCLC who experienced disease progression during or following first-line standard chemotherapy or chemoradiotherapy. Patients who had received previous treatment with an epidermal growth factor receptor (EGFR) inhibitor or anti-angiogenesis agent were not eligible for this trial. Patients were randomized to receive erlotinib in combination with bevacizumab or erlotinib in combination with placebo. The primary endpoint of the study was improvement in OS. Secondary endpoints included PFS, objective response and an evaluation of exploratory biomarkers. Median survival was reported to be similar in both arms of this study. However, the study found improvements in the secondary endpoints of PFS and response rate when bevacizumab was added to erlotinib compared to erlotinib alone in this study.
Zhang and associates (2016) stated that bevacizumab and erlotinib inhibit different tumor growth pathways, and both exhibit beneficial effects in the treatment of NSCLC. However, the efficacy of bevacizumab in combination with erlotinib remains controversial. These researchers carried out a meta-analysis to compare combination treatment with bevacizumab and erlotinib to bevacizumab or erlotinib monotherapy in the treatment of NSCLC; RCTs published in PubMed, Web of Science and EMBASE were systematically reviewed. The main outcome measures included OS, PFS, overall response rate (ORR) and adverse events (AEs). Results were expressed as hazard ratios [HRs] or RRs with 95 % CIs. A total of 5 RCTs involving a total of 1,736 patients were included in this meta-analysis. The combination of bevacizumab and erlotinib significantly improved PFS (HR = 0.63, 95 % CI: 0.53 to 0.75; p = 0.000) and the ORR (RR = 1.91, 95 % CI: 1.19 to 3.06; p = 0.007) in the 2nd-line treatment of NSCLC compared with bevacizumab or erlotinib alone. However, no significant difference in OS was observed between the combination and monotherapy groups (HR = 0.96, 95 % CI: 0.83 to 1.11; p = 0.573). A subgroup analysis has shown that the greatest PFS benefit was associated with an age of less than 65 years (HR = 0.74, 95 % CI: 0.57 to 0.96; p = 0.026), Asian/Pacific Islander ethnicity (HR = 0.23, 95 % CI: 0.10 to 0.54; p = 0.001), Eastern Cooperative Oncology Group performance status (ECOG PS) 1 (HR = 0.82, 95 % CI: 0.68 to 0.98; p = 0.033), stage IIIB or IV disease (HR = 0.68, 95 % CI: 0.57 to 0.82; p = 0.000) and no history of smoking (HR = 0.48, 95 % CI: 0.32 to 0.71; p = 0.000). The incidence of grade 3/4 AEs such as rash and diarrhea was higher in the combination group than in the monotherapy group. The authors concluded that the addition of bevacizumab to erlotinib can significantly improve PFS and the ORR in the 2nd-line treatment of NSCLC with an acceptable and manageable risk of rash and diarrhea. Moreover, these researchers stated that further well-conducted, large-scale trials are needed to verify their findings and examine the efficacy of the combined therapy in patients with non-squamous NSCLC with EGFR mutations.
The authors stated that this meta-analysis had several drawbacks. First, this study included only 5 RCTs, and some of these trials had relatively small sample sizes. Although all of these studies were high-quality, well-performed trials, the conclusions of this meta-analysis should be interpreted with caution because smaller trials were more likely to result in over-estimation of the treatment effect than larger trials. Second, the examination of the effect of Bev in combination with Erl in patients with NSCLC with EGFR mutations was insufficient because of sparse reporting among the included studies. Finally, it should be noted that all of these trials were partly funded by the pharmaceutical industry, and their results might have been affected by the inherent conflict of interest and possible bias. However, these trials were all high-quality studies that were conducted well, and they were the only eligible studies that evaluated the efficacy of the combination treatment.
Zhao and colleagues (2018) noted that a role for erlotinib and bevacizumab as single agents has been established in the treatment of NSCLC. However, the safety and efficacy of erlotinib in combination with bevacizumab compared with single agents remain unclear. In a meta-analysis, these investigators examined the status of this combined strategy in NSCLC. They systematically searched relevant databases for RCTs on the use of erlotinib plus bevacizumab in NSCLC. The main outcomes analysis reported OS, PFS, ORR, and AEs. Random-effects models were used to estimate pooled hazard ratio [HR] and RR. A total of 10 studies with 2,802 participants were eligible for meta-analysis, the results of which suggested that erlotinib plus bevacizumab failed to significantly enhance either OS (95 % CI: 0.87 to 1.12; p = 0.825) or ORR (95 % CI: 0.69 to 1.67; p = 0.758). Although PFS was modestly improved, there was no statistical significance (5.55 months versus 4.67 months, 95 % CI: 0.63 to 1.15; p = 0.297). Incidence of rash or diarrhea was higher in the combination group than in the single-agent group. Subgroup analysis showed encouraging OS (95 % CI: 0.29 to 0.69; p < 0.001) in EGFR-mutant patients treated with combination therapy, no such benefits were found in groups restricting on KRAS status. The authors concluded that erlotinib plus bevacizumab enhanced OS for EGFR-mutant patients, with rash and diarrhea common but acceptable adverse effects; combination treatment can be recommended as the preferable option for EGFR-mutant patients. Moreover, these researchers stated that further large-scale, well-designed RCTs are needed to confirm their validation.
In a systematic review and meta-analysis, Shan and colleagues (2018) examined the effect of combination maintenance therapy of pemetrexed plus bevacizumab for patients with advanced NSCLC. These researchers identified relevant studies by electronic search (Embase, PubMed, Cochrane, and Web of Science from January 1, 1960 to October 29, 2016) and manual search. The primary outcome of interest was PFS and secondary end-point included OS and toxicities. Data were pooled for quantitative analysis and the final effect size was reported as hazard ratio [HR] for survival outcomes and RR for safety outcomes, both with a random-effects model. A total of 3 RCTs enrolling 1,302 patients with advanced NSCLC were included in this meta-analysis. An evident PFS improvement (HR = 0.73, 95 % CI: 0.63 to 0.83, p < 0.01) was observed in patients with pemetrexed and bevacizumab combination maintenance therapy compared with single-agent maintenance therapy, yet it did not subsequently lead to a significant improvement in OS (HR = 0.97, 95 % CI: 0.84 to 1.10, p = 0.66). This analysis also showed statistically increased risks for provoking grade 3 to 4 AEs in patients managed using pemetrexed plus bevacizumab combination (RR = 1.59, 95 % CI: 1.07 to 2.36, p = 0.022). The authors concluded that pemetrexed plus bevacizumab combination maintenance therapy led to significant improvement in PFS but not in OS for patients with advanced NSCLC, which also increased the risks of grade 3 to 4 AE. These researchers stated that because of the limitation of existing studies and this meta-analysis, there is insufficient evidence to support routine use of pemetrexed-bevacizumab combination as maintenance therapy.
The authors stated that this study had several drawbacks. First, the data extracted were merely from previous publication, whereas original data and individual patient data were unavailable, which make these researchers unable to perform more detailed analysis and obtain more comprehensive results. Second, this analysis was limited by substantial heterogeneity across included trials, which was possibly attributed to the variation in trial design, inclusion and exclusion criteria, and treatment regimen involving induction modalities and agents' dosage. Third, even though most of the included trials were published in journals with high impact factor, open-label design and pharmaceutical industry funding as potential risks of bias still exist. Finally, this meta-analysis was limited by lack of available studies. Thus, these results should be interpreted with caution.
Olfactory Neuroblastoma (Esthesioneuroblastoma)
Dunbar et al (2012) stated that olfactory neuroblastomas (ONBs) are rare malignant tumors that arise from olfactory epithelium and typically present with symptoms attributable to locally invasive disease. Kadish radiographic staging and Hyams' histopathologic grading are prognostic. Overall survival rates, averaging 60 to 70 % at 5 years, remain limited by high rates of delayed loco-regional and distant progression. At initial presentation, the available evidence supports the use of multi-modality therapy, historically surgery and radiation, to improve disease-free and overall survival. At recurrence/progression, the available evidence supports the use of therapy to improve disease control and symptoms (palliation), but patient heterogeneity dictates individualization of modalities. Although the ideal use of chemotherapy as a modality remains undefined, the available evidence supports its use, historically platinum-based, for palliation. However, recent insights into the molecular-genetic aberrations of ONBs, coupled with the emergence chemotherapeutic agents capable of targeting such aberrations, suggest an expanded role. The authors reported a case of a 60-year old man, heavily pre-treated for metastatic ONB, presenting with profound central nervous system as well as head-and-neck symptoms. He experienced unexpectedly durable palliation with bevacizumab. Additionally, he experienced localized palliation with an Ommaya reservoir. The authors reviewed the literature regarding historical and emerging therapies for ONB to emphasize the needs for individualization and translational clinical studies.
An UpToDate review on “Olfactory neuroblastoma (esthesioneuroblastoma)” (Synderman et al, 2017) does not list bevacizumab as a therapeutic option.
Pancreatic Cancer
Bevacizumab is being investigated as a treatment for pancreatic cancer. An assessment by the BlueCross BlueShield Technology Evaluation Center (TEC) (BCBSA, 2006) concluded that bevacizumab for pancreatic cancer does not meet the TEC criteria. Regarding use of bevacizumab as first-line therapy, TEC assessment notes "On June 26, 2006, the drug's manufacturer announced that, after interim analysis of a phase III randomized controlled trial (RCT; n = 602) comparing gemcitabine with versus without bevacizumab as first-line therapy for pancreatic cancer, the trial's data safety monitoring board concluded that it was .... very unlikely that significant differences in overall survival will be shown as the data mature. Consequently, the trial was stopped early." Regarding use of bevacizumab as second line therapy, the TEC assessment identified 2 published uncontrolled studies on pancreatic cancer. One study on pancreatic cancer also included radiation therapy. Each study used bevacizumab as part of a combination regimen, but none provided data for comparison on concurrent or historical controls managed with the same regimen minus bevacizumab. The TEC assessment concluded that current evidence does not permit conclusions on outcomes of bevacizumab for any stage of pancreatic carcinoma.
In September 2009, the TEC assessment (BCBSA, 2009) on the off-label use of bevacizumab for advanced adenocarcinoma of the pancreas concluded that whether the addition of bevacizumab to chemotherapy regimens for advanced pancreatic adenocarcinoma improves health outcomes has not been established in the investigational settings. Thus, the use of bevacizumab for patients with advanced adenocarcinoma of the pancreas does not meet the TEC criteria.
In a phase III study, Van Cutsem et al (2009) examined the use of bevacizumab in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer. Patients were randomly assigned to receive gemcitabine (1,000 mg/m(2)/week), erlotinib (100 mg/day), and bevacizumab (5 mg/kg every 2 weeks) or gemcitabine, erlotinib, and placebo. Primary end point was OS; secondary end points included PFS, disease control rate, and safety. A total of 301 patients were randomly assigned to the placebo group and 306 to the bevacizumab group. Median OS was 7.1 and 6.0 months in the bevacizumab and placebo arms, respectively (hazard ratio [HR], 0.89; 95 % CI: 0.74 to 1.07; p = 0.2087); this difference was not statistically significant. Adding bevacizumab to gemcitabine-erlotinib significantly improved PFS (HR, 0.73; 95 % CI: 0.61 to 0.86; p = 0.0002). Treatment with bevacizumab plus gemcitabine-erlotinib was well-tolerated: safety data did not differ from previously described safety profiles for individual drugs. The authors concluded that the primary objective was not met. The addition of bevacizumab to gemcitabine-erlotinib did not lead to a statistically significant improvement in OS in patients with metastatic pancreatic cancer. However, PFS was significantly longer in the bevacizumab group compared with placebo.
In a phase II clinical trial, Crane et al (2009) evaluated the 1-year survival of patients with locally advanced, unresectable pancreatic cancer treated with the combination of bevacizumab, capecitabine, and radiation. Secondary end points were toxicity, PFS, and RR. Patients with locally advanced pancreatic cancer without duodenal invasion were treated with 50.4 Gy per 28 fractions to the gross tumor with concurrent capecitabine 825 mg/m(2) orally twice-daily on days of radiation and bevacizumab 5 mg/kg on days 1, 15, and 29 followed by maintenance gemcitabine 1 g/m(2) weekly for 3 weeks and bevacizumab 5 mg/kg every 2 weeks, both in 4-week cycles until progression. Treatment plans were reviewed for quality assurance (QA). Between January 2005 and February 2006, 82 eligible patients were treated. The median and 1-year survival rates were 11.9 months (95 % CI: 9.9 to 14.0 months) and 47 % (95 % CI: 36 % to 57 %). Median PFS was 8.6 months (95 % CI: 6.9 to 10.5), and RR was 26 %. Overall, 35.4 % of patients had grade 3 or greater treatment-related gastro-intestinal toxicity (22.0 % during chemoradiotherapy, 13.4 % during maintenance chemotherapy). Unacceptable radiotherapy protocol deviations (i.e., inappropriately generous volume contoured) correlated with grade 3 or greater gastrointestinal toxicity during chemoradiotherapy (45 % versus 18 %; adjusted odds ratio, 3.7; 95 % CI: 0.98 to 14.1; p = 0.05). The authors concluded that the addition of bevacizumab to a regimen of capecitabine-based chemoradiotherapy followed by gemcitabine did not result in an improvement in overall survival in patients with locally advanced pancreatic cancer.
Pineal Gland Malignancy
An UpToDate review on “Pineal gland masses” (Moschovi and Chrousos, 2015) does not mention bevacizumab as a therapeutic option.
Pseudomyxoma Peritonei
Winer and Buckanovich (2009) stated that pseudomyxoma peritonei (PMP) is a rare tumor syndrome that can be diagnosed in association with mucinous ovarian tumors of low malignant potential. Surgical debulking is the primary treatment modality as chemotherapy has generally proven ineffective in this slowly progressive tumor. When patients with PMP are not surgical candidates, there is no effective treatment, and patients will die of progressive disease. These investigators reported 2 patients with PMP with associated mucinous ovarian tumor of low malignant potential treated with bevacizumab. Both patients demonstrated disease response to bevacizumab. One patient had a prolonged response while on therapy, remained stable for 6 months when treatment was held, and then after progressing responded to a 2nd course of therapy. The authors concluded that while this phase-II study was encouraging, further management strategies for PMP are clearly necessary; the majority of patients in this study did not receive a clinical benefit. The authors’ experience with bevacizumab suggested a relatively non-toxic therapy with significant activity in ovarian PMP worthy of further study. Similar to the patients in the trial with mitomycin-C and capecitabine, the patients in this trial demonstrated tumor marker response that correlated with disease response. Patient 1 demonstrated a clear reduction in her ascites as well as tumor. Patient 2 had a clinical and biomarker response to both single agent bevacizumab a s well as bevacizumab in combination with chemotherapy. These researchers stated that the finding of this study provided an initial rationale for the use of bevacizumab in clinical trials in PMP. Given the improved activity observed with bevacizumab in combination with chemotherapy in other solid tumors and the recent report of an active chemotherapeutic regimen for PMP, trials with bevacizumab as a single agent or in combination with chemotherapy for unresectable PMP may be warranted.
Sun et al (2009) noted that effective systemic therapy for advanced PMP is the focus of investigation. These researchers described a case of PMP arising from an adenoma of the appendix in a 58-year old man. First, the patient underwent explorative laparotomy with ileo-coecal resection, but without possibility of major tumor debulking due to adhesive gross tumor masses. Subsequently, 6 cycles of Folfox IV chemotherapy were administered, without response, but with severe side effects. Upon progressive disease, a combination of bevacizumab and capecitabine led to a long-term stabilization of disease and obvious improvement of performance status. The authors concluded that he findings of this case suggested that modulation of tumor micro-environment and angiogenesis by bevacizumab, potentially augmented by capecitabine, may be beneficial in borderline tumors such as PMP. These researchers stated that their observation may encourage studies using bevacizumab based therapies in advanced borderline tumors. With such therapy, remission of PMP is not the primary goal in an advanced situation, but stabilization of disease and clinical improvement.
Dohan et al (2014) stated that PMP is an uncommon peritoneal mucinous carcinomatosis confined to the peritoneal cavity. The rarity of PMP in humans makes evaluation of the disease biological features and new therapeutic strategies difficult. Accordingly, there is a need for animal models of PMP. Human PMP tissue was intraperitoneally grafted and grown into nude mice, then constituted into reliable and reproducible orthotopic models. Histological and immunostaining analysis was performed. Bevacizumab was injected twice-weekly either during tumor growth or after cytoreductive surgery. In-vivo imaging of tumor angiogenesis was performed using barium sulfate or isolectin microangiography and Doppler ultrasonography (US) of the superior mesenteric artery. Tumor angiogenesis was confirmed by the presence of tortuous vascular networks with high levels of expression of CD31, vascular endothelial cadherin, and desmin. Doppler US of the superior mesenteric artery revealed a 2-fold increase in blood flow velocity compared with tumor-free mice (p < 0.001). Bevacizumab administration was correlated with the normalization of tumor vascularity when injected during tumor growth and with the stabilization of the histological and hemodynamic findings when injected after cyto-reductive surgery (CRS). The authors concluded that their PMP models mimicked human PMP; these findings confirmed the presence of tumor angiogenesis related to PMP growth; this murine model allowed researchers to actually bench test and evaluate, in pre-clinical studies, the efficacy of new therapeutic strategies and anti-angiogenic therapies.
Radiation-Induced Myelopathy
In a retrospective, case-series study, Psimaras and colleagues (2016) examined the effectiveness of bevacizumab for treatment of late-onset radiation-induced myelopathy. These investigators studied all patients diagnosed with radiation-induced myelopathy presenting to 2 neuro-oncology centers between 2008 and 2012. All patients were treated with bevacizumab, after no clinical or radiologic improvement was achieved with conventional (in particular steroid) treatment. This study included 4 patients (2 women) with late-onset radiation-induced myelopathy who were each treated with 4 cycles of bevacizumab. The median delay from radiotherapy to myelopathy was 19 months (range of 14 to 22 months). Initial treatment with steroids was unsuccessful in all 4 patients. Bevacizumab was introduced after a median of 4.8 months (range of 4 to 5 months) from the onset of the neurologic symptoms. These researchers observed stabilization of clinical outcome in 3 patients; radiologic findings improved in all 4 patients. The authors concluded that the use of bevacizumab resulted in radiologic improvement, but had only a modest effect on clinical outcome. The authors also noted that the discrepancy between the clinical and radiologic outcome called into question the effectiveness of the treatment and may suggest that the bevacizumab mechanism of action targeted the edema but did not treat the demyelination or the axonal loss. Nevertheless, the lack of clinical improvement in this study might be due to a number of factors, such as- late initiation of bevacizumab treatment, when the neurologic deficit was no longer reversible;
- the severity of the cases reported here, with 3 patients already bedridden; and
- more detailed assessment of disability and QOL assessment, which was not assessed here, may have revealed subtle clinical improvements.
The authors stated that these findings suggested that the use of bevacizumab in late-onset radiation-induced myelopathy deserves further study with a particular focus on the optimal timing of treatment. This study provided Class IV evidence that for patients with late radiation-induced myelopathy unresponsive to steroids, bevacizumab improved radiologic but not clinical outcomes.
Radiation Necrosis
Delishaj and colleagues (2017) stated that RN of brain tissue is a serious late complication of brain irradiation and recently bevacizumab has been suggested as therapeutic option of RN. There is a lack of data in the literature regarding the effectiveness of bevacizumab for the treatment of RN. These investigators performed a comprehensive analysis of all reported cases using bevacizumab for the treatment of brain RN. In September 2016, these researchers performed a comprehensive literature search of the following electronic databases: PubMed, Web of Science, Scopus and Cochrane Library. The research for the review was conducted using a combination of the keywords "radiation necrosis", "radiotherapy" and "bevacizumab" alongside the fields comprising article title, abstract and keywords. Randomized trials, non-randomized trials, prospective studies, retrospective studies and single-case reports were included in the review. The research generated 21 studies and 125 cases where bevacizumab had been used for the treatment of RN. The median follow-up was 8 months and the most frequent bevacizumab dose used was 7.5 mg/kg for 2 weeks with a median of 4 cycles. Low-dose bevacizumab resulted in effectiveness with improvement in both clinical and radiographic response. The median decrease in T1 contrast enhancement and in T2/FLAIR signal abnormality was 64 % and 6 0%, respectively. A reduction in steroidal therapy was observed in majority of patients treated. The authors concluded that based on the data of this review, bevacizumab appeared to be a promising agent for the treatment of brain RN. Moreover, they stated that future prospective studies are needed to evaluate the role of bevacizumab in RN and to define the optimal scheduling, dosage and duration of therapy.
The authors stated that the inherent drawbacks of this study were due to the retrospective studies analyzed, the small number of patients reported in the studies, the patients having been treated for different conditions, different radiation doses, different radiation modalities and with limited follow-up after bevacizumab therapy. Furthermore, the diagnosis of RN was made by radiologic evaluation in the majority of the studies analyzed in this review and the patients were treated in different institutions and countries. Furthermore, there was a publication bias present, because only patients who responded to bevacizumab were likely to be included in the published literature.
Furthermore, an UpToDate review on “Delayed complications of cranial irradiation” (Dietrich et al, 2018) states that “The optimal dose and duration of bevacizumab for treatment of radiation necrosis have not been established. In small series, symptomatic and/or radiographic relapse after discontinuation of bevacizumab has been described in 2 of 5 and 11 of 20 patients. Some of these patients may respond to retreatment with bevacizumab. While no serious adverse events were reported in the randomized trial, additional studies are needed to better determine the safety profile of bevacizumab in the management of radiation necrosis as well as the optimal dose and duration of treatment”.
Renal Cell Carcinoma
A randomized, double-blind, phase II trial was conducted comparing placebo with bevacizumab at doses of 3 and 10 mg per kilogram of body weight, given every 2 weeks in 166 patients with renal cancer (Yang et al, 2003). Subjects were randomized to 3 groups:- 40 to placebo,
- 37 to low-dose bevacizumab, and
- 39 to high-dose bevacizumab.
The investigators reported that there was a significant prolongation of the time to progression of disease in the high-dose-antibody group as compared with the placebo group (hazard ratio [HR], 2.55; p < 0.001). There was a small difference, of borderline significance, between the time to progression of disease in the low-dose-antibody group and that in the placebo group (HR, 1.26; p = 0.053). The probability of being progression-free for patients given high-dose antibody, low-dose-antibody, and placebo was 64 %, 39 %, and 20 %, respectively, at 4 months and 30 %, 14 %, and 5 % at 8 months. There was, however, no significant differences in OS between groups (p > 0.20 for all comparisons). Although there were no significant differences in survival, this study can not rule out such a benefit due to the fact that the study was too underpowered to detect differences in survival between treatment groups that may be clinically significant (Chen, 2004). A phase III study of bevacizumab in renal cell carcinoma is currently ongoing.
In July 2009, the FDA granted approval for the use of bevacizumab in combination with interferon alfa for the treatment of patients with metastatic renal cell carcinoma.
Respiratory Papillomatosis
In a retrospective review, Maturo and Hartnick (2010) described their initial experience with intra-lesional bevacizumab treatment for children with severe, recurrent respiratory papilloma (RRP). A total of 3 children, aged 3 to 6 years, with severe RRP requiring more than 4 operative interventions in 1 year whose parents (or legal guardians) consented to adjuvant treatment with intra-lesional bevacizumab. All 3 children were treated as follows: surgical debridement with a micro-debrider, pulsed KTP laser treatments, and adjuvant intra-lesional injections with bevacizumab (1.25 mg total). Main outcome measures were time interval between operative interventions, Derkay severity scale for RRP, and pediatric voice-related quality of life (PVRQOL) scores. All 3 children demonstrated increased time between operative interventions. Two children had a substantial decrease in their Derkay score and improved PVRQOL scores. One child, although time between operative interventions improved, did not have any change in Derkay score and required further adjuvant therapy. The authors concluded that injectable bevacizumab appears to show some efficacy in prolonging the time between treatments and therefore reducing the number of treatments per year in children with severe RRP. However, before any meaningful conclusions can be drawn, further studies must be conducted in the form of head-to-head trials looking specifically at the issues of time between treatment intervals, efficacy of one adjunct over another, vocal outcomes, and whether several adjunctive treatments confer advantage over 1 treatment.
Urothelial Carcinoma
In a phase II clinical trial, Hahn and colleagues (2011) evaluated the effectiveness and toxicity of bevacizumab in combination with cisplatin and gemcitabine (CGB) as first-line treatment for patients with metastatic urothelial cancer (UC). Chemotherapy-naive patients with metastatic or unresectable UC received cisplatin 70 mg/m(2) on day 1, gemcitabine 1,000 to 1,250 mg/m(2) on days 1 and 8, and bevacizumab 15 mg/kg on day 1, every 21 days. A total of 43 patients with performance status of 0 (n = 26) or 1 (n = 17) and median age of 66 years were evaluable for toxicity and response. Grade 3 to 4 hematologic toxicity included neutropenia (35 %), thrombocytopenia (12 %), anemia (12 %), and neutropenic fever (2 %). Grade 3 to 5 non-hematologic toxicity included deep vein thrombosis/pulmonary embolism (21 %), hemorrhage (7 %), cardiac (7 %), hypertension (5 %), and proteinuria (2 %). Three treatment-related deaths (central nervous system [CNS] hemorrhage, sudden cardiac death, and aortic dissection) were observed. Best response by RECIST was CR in 8 patients (19 %) and PR in 23 patients (53 %), for an ORR of 72 %. Stable disease lasting greater than or equal to 12 weeks occurred in 4 patients (9 %), and progressive disease occurred in 6 patients (14 %). With a median follow-up of 27.2 months (range of 3.5 to 40.9 months), median PFS was 8.2 months (95 % CI: 6.8 to 10.3 months) with a median OS time of 19.1 months (95 % CI: 12.4 to 22.7 months). The study-defined goal of 50 % improvement in PFS was not met. The authors concluded that CGB demonstrated promising OS and anti-angiogenic treatment-related toxicities in the phase II setting of metastatic UC. They stated that the full risk/benefit profile of CGB in patients with metastatic UC will be determined by an ongoing phase III inter-group trial.
Kurtoglu et al (2015) stated that despite recent advances in the identification of genomic alterations that lead to urothelial oncogenesis in-vitro, patients with advanced urothelial carcinomas continue to have poor clinical outcomes. These researchers focused on targeted therapies that have yielded the most promising results alone or combined with traditional chemotherapy, including the anti-angiogenesis agent bevacizumab, the human epidermal growth factor receptor 2 antibody trastuzumab, and the tyrosine kinase inhibitor cabozantinib. They also described ongoing and developing clinical trials that use innovative approaches, including dose-dense scheduling of singular chemotherapy combinations, prospective screening of tumor tissues for mutational targets and biomarkers to predict chemo-sensitivity before the determination of the therapeutic regimen, and novel agents that target proteins in the immune checkpoint regulation pathway (programmed cell death protein 1 [PD-1] and anti-PD-ligand 1) that have shown significant potential in pre-clinical models and early clinical trials. New agents and targeted therapies, alone or combined with traditional chemotherapy, will only be validated through accrual to developing clinical trials that aim to translate these therapies into individualized treatments and improved survival rates in urothelial carcinoma.
Furthermore, the National Cancer Institute’s PDQ on “Bladder cancer treatment -- for health professionals” (2015) do not mention bevacizumab as a therapeutic option.
Vaginal Cancer
According to information from the National Cancer Institute (NCI, 2015), no established anticancer drugs can be considered of proven clinical benefit in vaginal cancer, although patients are often treated with regimens used to treat cervical cancer.
Bevacizumab plus Paclitaxel, Albumin-Bound (Abraxane) for the Treatment of Metastatic Trophoblastic Tumor
Worley et al (2018) reported on the case of a 36-year old woman with metastatic and refractory choriocarcinoma following single- and multi-agent chemotherapy and surgical metastectomy experienced a durable remission after receiving therapy with an anti-endoglin monoclonal antibody and bevacizumab.
Yang et al (2019) stated that epithelioid trophoblastic tumors (ETTs) are the rarest type of gestational trophoblastic neoplasia. These investigators examined the clinical features, treatments, outcomes, and prognostic factors in patients with ETT, and explored potential therapeutic targets. They retrospectively analyzed the clinical features, treatments, survival, and prognostic factors of 21 ETT patients treated at the authors’ institution between January 2002 and December 2017. Expression levels of programmed cell death 1 (PD-1), PD-1 ligands (PD-L1and PD-L2), B7 family ligands (B7-H3, B7-H4, V-domain Ig suppressor of T cell activation [VISTA], and B7-H6), and CD105 expression were assessed by immunohistochemistry. A total of 14 patients with ETT (66.7 %) presented with irregular vaginal bleeding; 3 stage I patients (14.3 %) with normal β-human chorionic gonadotropin (β- hCG) levels underwent hysterectomy alone. Of the remaining 18 patients who had elevated β-hCG levels (85.7 %), 1 received chemotherapy and 17 underwent surgery and multi-agent chemotherapy. After treatment, 17 patients (81.0 %) achieved complete remission (CR; 2 of whom [11.8 %] later relapsed) and 4 (19.0 %) with stage IV died of their disease. On uni-variate and multi-variate analyses, stage IV disease was an independent prognostic factor for overall survival (OS) and disease-free survival (DFS) (p < 0.001). PD-L1, B7-H3, and CD105 were detected in 100 % of samples, PD-L2 and VISTA in 82 %, B7-H6 in 18 %, and B7-H4 was undetectable in ETT cells. The authors concluded that hysterectomy and metastatic lesion resection are essential for controlling ETT. Surgery plus chemotherapy are recommended for patients with abnormal β-hCG levels and metastatic disease; PD-L1, PD-L2, B7-H3, VISTA and CD105 were potential therapeutic targets for metastatic ETT.
Bevacizumab for the Treatment of Respiratory Papillomatosis
Tkaczuk and colleagues (2021) noted that RRP is a rare, potentially life-threatening, disease that impacts the voice, breathing, and QOL of patients. Frequent surgical interventions may be needed to control symptoms. In a retrospective review, these researchers examined the safety and effectiveness of intravenous bevacizumab in the management of severe RRP in adults. This study included a group of patients with severe RRP defined as having a high disease burden, frequent need for debridement, and/or trachea-bronchial disease. Patients were initially treated with 15 mg/kg of bevacizumab at 3-week intervals. Bevacizumab dosing and frequency was then individually titrated down. A total of 14 adults received a median of 8.5 (range of 2 to 17) bevacizumab infusions over approximately 24 months. All had a history of laryngeal RRP with 6/14 having additional trachea-bronchial lesions. Patients required a median of 4 (range of 2 to 11) procedures in the year prior to treatment. Only 3/10 (30 %) patients who continued therapy required any additional procedures. Bevacizumab was generally well-tolerated, with 4 patients discontinuing therapy. Medical reasons included severe epistaxis and hypertension and thrombocytopenia in an individual with systemic lupus erythematosus (SLE). Common side effects included hypertension (grade 2), headache (grades 1 to 2), elevated creatinine (grades 1 to 2), and epistaxis (grade 3). The authors concluded that intravenous bevacizumab for the primary treatment of severe RRP in adults appeared clinically safe and effective; expected and typically mild side effects related to bevacizumab were observed. Moreover, these researchers stated that continued investigation of bevacizumab via a prospective clinical trial is needed. Level of Evidence = IV.
Benedict and Derkay (2021) stated that despite recent advancement RRP remains a rare but challenging benign airway neoplasm. In recent years there has been significant shifts in incidence of this disease due to changes in vaccination and prevention for human papilloma virus (HPV) and its related pathology. These investigators reviewed the epidemiology, prevention and treatment of RRP. The PubMed database was searched using relevant MeSH terms including "recurrent respiratory papillomatosis". The titles and abstracts were reviewed to evaluate relevance and unrelated articles were excluded. A full-text review for select articles was carried out, the data and discussions were interpreted and synthesized to create a concise update on the management of RRP. With the increasing use of the 9-valent and quadri-valent HPV vaccine in Australia, these researchers have observed a significant decrease in the incidence of RRP. Preliminary data in the U.S. showed a similar trend of decreased incidence after implementation of vaccination. Single-dose Gardasil in developing countries has shown sustained immunization for at least 7 years. Preliminary clinical trials and retrospective studies have shown the HPV vaccine may have benefit as a treatment method in addition to prevention for HPV related diseases. Bevacizumab has shown promise as a systemic treatment for RRP. The Corona Virus Disease 2019 (COVID-19) pandemic has affected peri-operative management of RRP. The authors concluded that RRP continues to decline in incidence since the implementation of HPV vaccination. Advancement in the medical management including bevacizumab show promise as an additional therapeutic option for the management of RRP.
Bevacizumab for the Treatment of Radiation Necrosis
Palmisciano and colleagues (2021) stated that radiation necrosis (RN) represents a serious post-radiotherapy complication in patients with brain metastases (BM). Bevacizumab and laser interstitial thermal therapy (LITT) are viable therapeutic options; however, direct comparative data are scarce. These investigators reviewed the literature to compare the 2 therapeutic strategies. PubMed, Embase, Scopus, and Cochrane databases were searched. All studies of patients with RN from BM treated with bevacizumab or LITT were included. Treatment outcomes were analyzed using indirect meta-analysis with random-effect modeling. Among the 18 studies included, 143 patients received bevacizumab and 148 underwent LITT. Both strategies were equally effective in providing post-treatment symptomatic improvement (p = 0.187, I2 = 54.8 %), weaning off steroids (p = 0.614, I2 = 25.5 %), and local lesion control (p = 0.5, I2 = 0 %). Mean number of lesions per patient was not statistically significant between the 2 groups (p = 0.624). Similarly, mean T1-contrast-enhancing pre-treatment volumes were not statistically different (p = 0.582). Patterns of radiological responses differed at 6-month follow-ups, with rates of partial regression significantly higher in the bevacizumab group (p = 0.001, I2 = 88.9 %), and SD significantly higher in the LITT group (p = 0.002, I2 = 81.9 %). Survival rates were superior in the LITT cohort, and statistical significance was reached at 18 months (p = 0.038, I2 = 73.7 %). Low rates of AEs were reported in both groups (14.7 % for bevacizumab and 12.2 % for LITT). The authors concluded that bevacizumab and LITT could be safe and effective treatments for RN from BM. Clinical and radiological outcomes were mostly comparable; however, LITT may relate with superior survival benefits in select patients. Moreover, these researchers stated that further studies are needed to identify the best patient candidates for each treatment group.
In a systematic review, Liao and associates (2021) examined the medical literature for studies reporting the safety and effectiveness of bevacizumab, as well as for studies comparing bevacizumab with corticosteroids for the treatment of radiation brain necrosis (RBN) in patients receiving radiotherapy for intra-cranial disease. These investigators searched PubMed, Cochrane library, Embase, and ClinicalTrials.gov from their inception through March 1, 2020 for studies that examined the safety and effectiveness of bevacizumab in patients with RBN. Two investigators independently carried out the study selection, data extraction, and data synthesis. A total of 12 studies (8 retrospective, 2 prospective, and 2 RCTs) involving 236 patients with RBN who were treated with bevacizumab were included for analysis. The 2 RCTs also had control arms comprising patients with RBN who were treated with corticosteroids/placebo (n = 57). Radiographic responses were recorded in 84.7 % (200/236) of patients, and radiographic progression was observed in 15.3 % (36/236). Clinical improvement was observed in 91 % (n = 127) of responding patients among 7 studies (n = 113). All 12 studies reported volume reduction on T1 gadolinium enhancement MRI (median of 50 %, range of 26 % to 80 %) and/or T2 FLAIR MRI images (median of 59 %, range of 48 % to 74 %). A total of 46 responding patients (34 %) had recurrence. The 2 RCTs revealed significantly improved radiographic response in patients treated with bevacizumab. Both also showed clinical improvement and significant reduction in edema volume on both T1 gadolinium enhancement MRI and T2 FLAIR MRI. Neurocognitive improvement was significantly better after 2 months of treatment in patients receiving bevacizumab than in those given corticosteroids, as examined by the MoCA scale (p = 0.028). The recurrence rate and side effects of the treatments showed no significant differences. The authors concluded that patients with RBN responded to bevacizumab, which could improve clinical outcomes and cognitive function; and bevacizumab appeared to be more effective than corticosteroid-based treatment. The safety profile was comparable to that of the corticosteroids. These researchers stated that currently, a RCT is ongoing, comparing bevacizumab plus corticosteroids with corticosteroids plus placebo. This trial will certainly provide more evidence for the comparative efficacy of bevacizumab (NCT02490878). There were no serious side effects associated with bevacizumab administration. They stated that the safety profile was comparable to that of the corticosteroids; and more well-designed and larger RCTs are needed to determine the role of bevacizumab in RBN treatment.
The authors stated that this review had several drawbacks. First, most of the studies were retrospective in nature and contained few patients. Retrospective studies are prone to selection bias, recall bias, and mis-classification bias, and they were subject to confounding. Second, patients had different conditions for undergoing radiotherapy; radiation modalities and doses also differed greatly among the studies and patients. Third, the follow-up following bevacizumab therapy also varied and was limited. Fourth, publication bias may also have been present, as patients responding to bevacizumab were more likely to be included in the studies. To assess comparative outcomes, only 2 RCTs were available. Fifth, even though it was classified as class I evidence, the 1st RCT comprised only 14 patients and a high cross-over from the placebo group. The 2nd RCT was down-graded one level as it was an open-label trial; it was then further down-graded due to concerns regarding detection bias and inadequate blinding in the trial.
Bevacizumab for the Treatment of Uveal Ciliary Melanocytoma
Kamisasanuk et al (2012) reported a case of choroidal neovascularization (CNV) associated with optic disk melanocytoma successfully treated with bevacizumab. A 63-year old man complained of visual impairment in his left eye. His visual acuity (VA) was 0.9 OS. Fundus examination showed optic disk melanocytoma associated with serous retinal detachment and mild hemorrhage. Fluorescein and indocyanine green angiography (ICGA) revealed CNV adjacent to the optic disc. Intra-vitreous bevacizumab (IVB) was performed 3 times. Choroidal neovascularization and serous retinal detachment disappeared at 5 months after IVB; VA recovered to 1.5 OS and has been stable for 1 year follow-up. No adverse events (AEs) were found related to IVB. The authors concluded that intra-vitreous bevacizumab could be a beneficial treatment for CNV associated with optic disc melanocytoma.
Al-Halafi (2013) stated that melanocytoma of the optic disc is a benign melanocytic tumor that rarely causes visual impairment. These investigators reported a rare case of CNV in association with optic disc melanocytoma and its response to intra-vitreal injection of bevacizumab. The choroidal neovascular membrane regressed following a single intra-vitreal bevacizumab injection with formation of a scar. CNV associated with optic disc melanocytoma is rare. Intra-vitreal anti-VEGF treatment may be an effective treatment for CNV associated with optic disc melanocytoma.
Urrets-Zavalia et al (2015) presented a case of a complicated posterior melanocytoma that was successfully treated with intra-vitreal bevacizumab. A 50-year old Caucasian man was referred with sudden-onset metamorphopsia and decreased vision in his right eye over the course of the last 2 months. His best-corrected visual acuity (BCVA) was 20/80 and poorer than Jaeger 14 in the right eye, and 20/20 and Jaeger 1 in his left eye. In the right fundus, there was a melanocytic lesion occupying the infero-temporal quadrant of the optic disk, extending to the adjacent choroid inferiorly; optic nerve edema, supero-temporal retinal vein dilatation, and subretinal fluid under the macula and nasal half of the posterior pole were observed, and a subretinal CNV complex was observed adjacent to the supero-temporal margin of the optic disk, confirmed by fluorescein angiography (FA), surrounded by a dense subretinal hemorrhage. Optical coherence tomography (OCT) showed retinal edema and detachment of neurosensory retina. The patient was treated with 3 consecutive doses on a monthly basis of intra-vitreal 1.25 mg/0.05 ml bevacizumab; VA recovered rapidly, and at 4 months after treatment, it was 20/20 and Jaeger 1, with complete resolution of macular edema and subretinal fluid and hemorrhage. After 3 years of follow-up, BCVA remained stable, macular area was normal, and there was no evident optic nerve edema, retinal vein caliber and aspect were normal, and there was no significant change of the tumor; FA only evidenced late staining of CNV scar, and OCT showed a normal macular anatomy. The authors concluded that intra-vitreal bevacizumab was effective in the treatment of CNV, optic nerve edema, venous dilatation, and local capillary telangiectasia, complicating an optic disk melanocytoma.
Ursu et al (2015) stated that TLR-9 agonists are immuno-stimulating agents that have anti-tumor effects in animal models. In a phase-I clinical trial, these researchers examined the safety profile of subcutaneous injections, combined with intrathecally administration of CpG-28, a TRL 9 agonist, in patients with neoplastic meningitis (NM). Cohorts of 3 to 6 patients with NM were treated for 5 weeks with escalating doses of CpG-28. The primary end-point was tolerance; secondary end-points were progression free survival (PFS) and overall survival (OS). A total of 29 patients were treated with CpG-28. The primary cancers were malignant glioma, lung carcinoma, breast cancer, melanoma or melanocytoma (n = 1), ependymoma, and colorectal cancer. The median age was 56 years and median Karnovsky Performance status (KPS) was 70 %. The treatment was well-tolerated. Adverse effects that were possibly or probably related to the studied drug were grade-2 lymphopenia, anemia and neutropenia, local erythema at injection sites, fever and seizure. There were 5 serious AEs: 2 confusions, 2 infections of ventricular devices and 1 grade-4 thrombopenia and neutropenia. The median PFS was 7 weeks and median OS was 15 weeks. Interestingly, the median survival was slightly (but not significantly) higher in the 8 patients who were concomitantly treated with bevacizumab (19 weeks versus 15 weeks; p = 0.11). The authors concluded that CpG-28 was well-tolerated at doses up to 0.3 mg/kg subcutaneously and 18 mg intrathecally. Moreover, these researchers stated that additional trials are needed.
An UpToDate review on “Initial management of uveal and conjunctival melanomas” (Harbour and Shih, 2021) states that “Radiation-induced cataracts and dry eye can be managed by conventional ophthalmic means. The management of radiation retinopathy, optic neuropathy, and neovascular glaucoma has been more challenging. Radiation causes endothelial cell loss and capillary closure, leading to retinal ischemia and the elaboration of vascular endothelial growth factor (VEGF) and other pro-angiogenic factors. Attempted treatments have included photodynamic therapy, laser photocoagulation, oral pentoxifylline, hyperbaric oxygen, periocular or intravitreal injection of corticosteroids, and intravitreal injection of anti-VEGF agents such as bevacizumab, ranibizumab, and aflibercept. While none of these treatments is curative or preventative, promising results have been observed for intravitreal anti-VEGF therapy in maintaining or improving visual function in some patients with radiation maculopathy”.
Furthermore, an UpToDate reviews on “Management of metastatic uveal melanoma” (Carvajal and Harbour, 2021) does not mention bevacizumab as a management / therapeutic option.
Bevacizumab Plus Atezolizumab for the Treatment of Renal Cell Carcinoma
Rini and colleagues (2019) noted that a phase-II clinical trial showed improved PFS for atezolizumab plus bevacizumab versus sunitinib in patients with metastatic RCC (mRCC) who express PD-L1. In a multi-center, open-label, phase-III RCT, these investigators compared atezolizumab plus bevacizumab versus sunitinib as 1st-line treatment for metastatic RCC. Patients with a component of clear cell or sarcomatoid histology and who were previously untreated, were recruited from 152 academic medical centers and community oncology practices in 21 countries, mainly in Europe, North America, and the Asia-Pacific region, and were randomly assigned 1:1 to either atezolizumab 1,200 mg plus bevacizumab 15 mg/kg intravenously once every 3 weeks or sunitinib 50 mg orally once-daily for 4 weeks on, 2 weeks off. A permuted-block randomization (block size of 4) was used to obtain a balanced assignment to each treatment group with respect to the stratification factors. Researchers and subjects were not masked to treatment allocation. Patients, investigators, independent radiology committee members, and the sponsor were masked to PD-L1 expression status. Co-primary endpoints were investigator-assessed PFS in the PD-L1 positive population and OS in the intention-to-treat (ITT) population. Of 915 patients enrolled between May 20, 2015 and October 12, 2016, a total of 454 were randomly assigned to the atezolizumab plus bevacizumab group and 461 to the sunitinib group; 362 (40 %) of 915 patients had PD-L1 positive disease. Median follow-up was 15 months at the primary PFS analysis and 24 months at the OS interim analysis. In the PD-L1 positive population, the median PFS was 11.2 months in the atezolizumab plus bevacizumab group versus 7.7 months in the sunitinib group (HR 0.74 [95 % CI: 0.57 to 0.96]; p = 0.0217). In the ITT population, median OS had an HR of 0.93 (0.76 to 1.14) and the results did not cross the significance boundary at the interim analysis; 182 (40 %) of 451 patients in the atezolizumab plus bevacizumab group and 240 (54 %) of 446 patients in the sunitinib group had treatment-related grade 3 to 4 AEs: 24 (5 %) in the atezolizumab plus bevacizumab group and 37 (8 %) in the sunitinib group had treatment-related all-grade AEs, which led to treatment-regimen discontinuation. The authors concluded that atezolizumab plus bevacizumab prolonged PFS versus sunitinib in patients with metastatic RCC and showed a favorable safety profile. Moreover, these researchers stated that longer-term follow-up is needed to establish whether a survival benefit will emerge.
In a phase-II clinical trial, Pal and associates (2020) examined patient-reported outcome (PRO) data from IMmotion150. The phase-II IMmotion150 study showed improved PFS with atezolizumab plus bevacizumab versus sunitinib in patients with PD-L1+ tumors and suggested activity of atezolizumab monotherapy in previously untreated mRCC. Patients with previously untreated mRCC were randomized to atezolizumab 1,200 mg intravenously (IV) every 3 weeks (n = 103), the atezolizumab regimen plus bevacizumab 15 mg/kg IV every 3 weeks (n = 101), or sunitinib 50 mg orally daily (4 weeks on, 2 weeks off; n = 101). MD Anderson Symptom Inventory (MDASI) and Brief Fatigue Inventory (BFI) were administered on days 1 and 22 of each 6-week cycle. Time to deterioration (TTD), change from baseline in MDASI core and RCC symptom severity, interference with daily life, and BFI fatigue severity and interference scores were reported for all comers. TTD was the first greater than or equal to 2-point score increase over baseline. Absolute effect size of greater than or equal to 0.2 suggested a clinically important difference with checkpoint inhibitor therapy versus sunitinib. Completion rates were greater than 90 % at baseline and greater than or equal to 80 % at most visits. Delayed TTD in core and RCC symptoms, symptom interference, fatigue, and fatigue-related interference was observed with atezolizumab (both alone and in combination) versus sunitinib. Improved TTD (HR [95 % CI]) was more pronounced with atezolizumab monotherapy: core symptoms, 0.39 (0.22 to 0.71); RCC symptoms, 0.22 (0.12 to 0.41); and symptom interference, 0.36 (0.22 to 0.58). Change from baseline by visit, evaluated by the MDASI, also showed a trend favoring atezolizumab monotherapy versus sunitinib. Small sample sizes may have limited the ability to draw definitive conclusions. The authors concluded that although not statistically significant, a trend towards improved QOL was observed in patients treated with atezolizumab plus bevacizumab versus sunitinib. Patients treated with the combination reported similar symptom burden versus sunitinib. Moreover, QOL results were more compelling with atezolizumab monotherapy, suggesting that monotherapy should be examined in selected settings (e.g., biomarker-selected populations in a metastatic setting, or as adjuvant treatment where immunotherapy is under investigation and use of sunitinib is controversial due to its low risk-benefit ratio).
Bevacizumab Plus Pemetrexed as Maintenance Therapy for Non-Squamous Non-Small Cell Lung Cancer
Kong and colleagues (2021) noted that when patients of advanced non-squamous non-small cell lung cancer (NSCLC) have achieved remission by induction therapy, it is controversial that combination with bevacizumab is used as maintenance therapy. Pemetrexed is a classic drug for maintenance therapy; whether bevacizumab is superior to pemetrexed is also unclear. In a meta-analysis, these researchers examined the safety and effectiveness of advanced non-squamous NSCLC in the maintenance treatment. From the establishment as of December 6, 2020, PubMed, Embase, and Cochrane electronic databases were searched and the American Society of Clinical Oncology (ASCO), European Society of Medical Oncology (ESMO), and NCCN databases in the past 10 years. The application of combination with bevacizumab, pemetrexed was studied in clinical trials of maintenance treatment for advanced NSCLC. The extracted data include PFS, OS, and grade 3 to 4 AEs. A total of 7 clinical trials were screened, 6 were phase-III RCTs, and a cohort trial, including 3,298 patients. Compared with bevacizumab and pemetrexed, PFS of combination with bevacizumab was significantly improved (HR = 0.71, 95 % CI: 0.65 to 0.77, p < 0.00001), but OS was not improved (HR = 0.93, 95 % CI: 0.85 to 1.01, p = 0.10). Compared with bevacizumab and pemetrexed, no significant difference of PFS (HR = 0.87, 95 % CI: 0.69 to 1.09, p = 0.21), and OS (HR = 0.87, 95 % CI: 0.72 to 1.05, p = 0.15) was found. A higher incidence of grade 3 to 4 AE occurred in combination with bevacizumab (odds ratio [OR] = 1.63, 95 % CI: 1.35 to 1.97, p < 0.00001). The authors concluded that this meta-analysis showed that combination with bevacizumab could significantly improve PFS in the maintenance treatment of non-squamous NSCLC, but it did not translate into the OS’ advantage; pemetrexed and bevacizumab compared with bevacizumab, no benefits of PFS and OS were found. The combination with the bevacizumab group and the pemetrexed group had a higher incidence of neutropenia, anemia, and hemorrhage (grade 3 to 4), and the bevacizumab group had a higher incidence of proteinuria (grade 3 to 4). In the incidence of thrombocytopenia, hypertension, and thromboembolic events (grade 3 to 4), no significant difference was found. Therefore, combination with bevacizumab is not recommended due to the lack of OS benefit and higher adverse reactions; bevacizumab is not more advantageous than pemetrexed. Due to the lack of the literature, further verification is needed.
The authors stated that this meta-analysis had several drawbacks. One was a non-randomized phase-II clinical trial, which had a random allocation sequence and allocation concealed bias. Furthermore, patients who received maintenance treatment in the Point Break study were randomized and induced. There is a limit to the possibility of induction therapy affecting the maintenance treatment plan. Only 1 clinical trial has clarified blinding, and there may be bias in blinding. Among the 7 clinical trials, 3 clinical trials did not describe the EGFR status, and the PD-L1 expression in the 7 clinical trials was unknown. Some patients may have EGFR mutations or positive PD-L1 expression, which may affect the research results. These trials have different therapeutic options, so the grouping meta-analysis only included a limited number of studies. Gruppo Oncologico Italia Meridionale does not use PFS and OS as the primary endpoints, so the sample size was small. In hematological toxicity analysis, the clinical sample size was small, and more clinical data are needed.
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The above policy is based on the following references:
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