Bevacizumab (Avastin) for Non-Ocular Indications

Number: 0685

Policy

Aetna considers bevacizumab (Avastin) medically necessary for the following non-ocular indications (see appendix for selection criteria):

AIDS-related Kaposi's sarcoma
Anal adenocarcinoma
Angiosarcoma - single agent therapy
Appendiceal cancer
Breast cancer - in combination with paclitaxel for recurrent or metastatic human epidermal growth factor receptor 2-negative disease
Central Nervous System Cancers (adult low-grade infiltrative supratentorial astrocytoma/oligodendroglioma, anaplastic gliomas, glioblastoma, adult intracranial and spinal ependymoma, adult medulloblastoma, primary CNS lymphoma, meningioma, brain metastases, leptomeningeal metastases, and metastatic spine tumors
Cervical cancer - first-line or second-line (if not previously used as first-line) therapy in combination with paclitaxel with cisplatin, carboplatin, or topotecan, or second-line therapy as a single agent
Colorectal cancer
Endometrial cancer (adenocarcinoma, serous, or clear cell; undifferentiated/dedifferntiated carcinoma; carcinosarcoma) - single agent therapy for members who have progressed on prior cytotoxic chemotherapy or in combination with carboplatin and paclitaxel for advanced or recurrent disease
Ovarian cancer, fallopian tube cancer, or primary peritoneal cancer
Hemangiopericytoma - in combination with temozolomide
Malignant Sex Cord-Stromal Tumors -single agent for clinical relapse
Malignant pleural mesothelioma - in combination with pemetrexed and cisplatin or carboplatin followed by single-agent maintenance therapy
Mucinous carcinoma of the ovary
Meningioma - Treatment for surgically inaccessible recurrent or progressive disease when radiation is not possible
Non-squamous, non-small cell lung cancer - first line chemotherapy in combination with cisplatin or carboplatin based chemotherapy for metastatic disease, or continuation maintenance therapy if given first line with chemotherapy in persons who achieve tumor response or stable disease following first-line chemotherapy
Peritoneal mesothelioma
Kidney Cancer- for relapse or stage IV disease
Small bowel adenocarcinoma
Solitary fibrous tumors - in combination with temozolomide
Vaginal cancer - first-line therapy in combination with paclitaxel with cisplatin, carboplatin, or topotecan, or second-line therapy as a single agent
Vulvar Cancer - Squamous Cell Carcinoma - In combination with cisplatin and paclitaxel (preferred regimen) or carboplatin and paclitaxel
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.

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 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
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
Hepatocellular cancer
Hereditary hemorrhagic telangiectasia
Hyatidiform mole
Islet cell cancer
Laryngeal papillomatosis
Melanoma
Mucoepidermoid carcinoma of the salivary gland
Multiple myeloma
Neuroendocrine tumors
Neurofibromatosis
Olfactory neuroblastoma (esthesioneuroblastoma)
Pancreatic cancer
Pelvic bone cancer
Pineal gland malignancy
Prostate cancer
Radiation-induced myelopathy
Sarcomas (e.g., Ewing sarcoma, Kaposi's sarcoma, leiomyosarcoma, liposarcoma, and osteosarcoma) other than AIDS-related Kaposi's sarcoma, 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
Vogt-Koyanagi-Harada syndrome
von Hippel Lindau disease

For bevacizumab for ocular indications, see CPB 0701 - Vascular Endothelial Growth Factor Inhibitors for Ocular Indications.

Background

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).

Avastin (bevacizumab) has been approved by the U.S. Food and Drug Administration (FDA) for:

metastatic colorectal cancer In combination with 5‐fluorouracil‐based chemotherapy as first‐line or second‐line therapy, or in combination with fluoropyrimidine‐irinotecan‐ or fluoropyrimidineoxaliplatin‐based chemotherapy as second‐line therapy in patients who have progressed on a first‐line bevacizumab‐containing regimen;
non‐squamous non‐small cell lung cancer, with carboplatin and paclitaxel for first line treatment of unresectable, locally advanced, recurrent or metastatic disease;
glioblastoma, as a single agent for patients with progressive disease following prior therapy (Effectiveness based on improvement in objective response rate. No data available demonstrating improvement in disease‐related symptoms or survival with bevacizumab);
metastatic renal cell carcinoma, in combination with interferon alfa;
cervical cancer, in combination with paclitaxel and cisplatin or paclitaxel and topotecan in persistent, recurrent, or metastatic disease; and
platinum‐resistant recurrent epithelial ovarian cancer, fallopian tube or primary peritoneal cancer, in combination with paclitaxel, pegylated liposomal doxorubicin or topotecan.

Black Box Warnings

Gastrointestinal perforations:

Bevacizumab administration can result in the development of gastrointestinal perforation, in some instances resulting in fatality. Gastrointestinal perforation, sometimes associated with intra‐abdominal abscess, occurred throughout treatment with bevacizumab (i.e. was not correlated to duration of exposure). The incidence of gastrointestinal perforation (gastrointestinal perforation, fistula formation, and/or intra‐abdominal abscess) in patients with colorectal cancer and in patients with non-small cell lung cancer (NSCLC) receiving bevacizumab was 2.4% and 0.9%, respectively. The typical presentation was reported as abdominal pain associated with symptoms such as constipation and vomiting. In patients with persistent, recurrent, or metastatic cervical cancer, gastrointestinal perforations were reported in 3.2% of Avastin treated patients, all of whom had a history of prior pelvic radiation. Gastrointestinal perforation should be included in the differential diagnosis of patients presenting with abdominal pain on bevacizumab. Bevacizumab therapy should be permanently discontinued in patients with gastrointestinal perforation.
Wound Healing Complications

Bevacizumab administration can result in the development of wound dehiscence, in some instances resulting in fatality. Bevacizumab therapy should be permanently discontinued in patients with wound dehiscence requiring medical intervention. The appropriate interval between termination of bevacizumab and subsequent elective surgery required to avoid the risks of impaired wound healing/wound dehiscence has not been determined. Bevacizumab should be discontinued at least 28 days prior to elective surgery.
Hemorrhage

Fatal pulmonary hemorrhage can occur in patients with NSCLC treated with chemotherapy and bevacizumab. The incidence of severe or fatal hemoptysis was 31% in patients with squamous histology and 4% in patients with NSCLC excluding predominant squamous histology. Patients with recent hemoptysis (1/2 teaspoonful or more of red blood) should not receive bevacizumab.

Avastin (bevacizumab) should not be used in persons with any of the following:

Hypersensitivity to bevacizumab or any component of the product
Grade 4 proteinuria (nephrotic syndrome).
Recent hemoptysis or untreated brain metastases due to increased risk of hemorrhage.
Gastrointestinal perforation.
Fistula formation involving internal organs.

Bevacizumab should not be used in members experiencing:

a hypertensive crisis or hypertensive encephalopathy.
a severe arterial thrombotic event.

Bevacizumab should not be used for at least 28 days following major surgery or until surgical incision is fully healed.

Risk versus benefit must be discussed with patients that are pregnant or breast feeding.

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). Current guidelines from the National Comprehensive Cancer Network (2009) recommends or lists as an option the addition of bevacizumab or cetuximab, but not both, to some regimens for metastatic colorectal cancer, based upon available data.

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.

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 (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.

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; 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 indicaetd 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, overall response rate (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 (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.

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).

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; 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 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.

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 (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.

Furthermore, NCCN’s clinical practice guideline on “Cervical cancer” (Version 1.2015) lists cisplatin/paclitaxel/bevacizumab (category 1) and topotecan/paclitaxel/bevacizumab (category 2B) as 1st-line combinational therapy; as well as bevacizumab (category 2B) as 2nd-line single-agent therapy.

Ependymomas

Guidelines from the NCCN (2010) indicated bevacizumab as a single agent for disease progression after radiation therapy for spine or brain ependymoma recurrence.

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 (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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Hereditary Hemorrhagic Telangiectasia

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).

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.

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.

Mesothelioma

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). In this French multicenter randomized phase 3 trial, eligible patients had unresectable, histologically proved MPM, age less than 76, no prior chemotherapy, performance score (PS) 0-2, no thrombosis, nor bleeding. Randomized patients (1:1) received pemetrexed 500 mg/m², cisplatin 75 mg/m² at day 1, with (arm B) or without bevacizumab (arm A), 15 mg/kg every 21 days, for 6 cycles. Arm B non-progressive patients received bevacizumab maintenance therapy until progression or toxicity. The primary endpoint was overall survival (OS). 445 patients were to be randomized, and 385 events observed, to show a significant OS improvement, with 80% statistical power, 5% a-risk. From February 2008 to January 2014, 448 patients were included in 73 centers. Males comprised 75.4% of subjects, median age was 65.7 years (range 34.7-75.9), and 96.7% had PS 0-1. The IDMC recommended a second interim analysis after 85% of events. On January 1, 2015, the duration since last news was less than 30 days in 105 out of 106 still living patients. Overall survival was significantly longer in the experimental arm (median: 18.8 months, 95%CI[15.9-22.6] versus 16.1 months, 95% CI [14.0-17.9] for the reference arm, (adj.HR = 0.76, 95% CI [0.61; 0.94], p = 0.012). With only 46/448 non-progressive patients at the date of analysis, median progression free survival (PFS) was 9.6 months, 95% CI [8.5-10.6] in bevacizumab arm versus 7.5 months, 95% CI [6.8-8.1] (adj.HR = 0.62, 95% CI [0.50-0.75], p < 0.0001). G3-4 hematological toxicities did not significantly differ in the two arms (49.5% versus 47.3%). Significantly more G3 proteinuria (0.0 versus 3.1%), G3 hypertension (0.0 versus 23%), G3-4 arterial thrombotic events (0.0 versus 2.7%) were observed in bevacizumab arm. The authors concluded that bevacizumab addition to pemetrexed/cis-platin provides a significantly longer survival in patients with MPM, with acceptable toxicity, making this triplet a new treatment paradigm.

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 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.

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.

Pineal Gland Malignancy

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.

An UpToDate review on “Pineal gland masses” (Moschovi and Chrousos, 2015) does not mention bevacizumab as a therapeutic option. Furthermore, according to National Comprehensive Cancer Network’s Drugs & Biologics Compendium (2015), pineal gland tumor is not a recommended indication of bevacizumab.

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) and the NCCN’s clinical practice guideline on “Bladder cancer” (Version 2.2015) do 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.

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.

Furthermore, National Comprehensive Cancer Network’s Drugs & Biologics Compendium (2017) does not list esthesioneuroblastoma/olfactory neuroblastoma as a recommended indication of bevacizumab.

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”.

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 adverse events (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.

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.

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.

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 postinitiation 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.

Appendix

Recommended Dosing for FDA-Approved Indications

Bevacizumab is available as Avastin in an Intravenous Solution: 25 MG/ML (100mg and 400mg vials).

According to the FDA-approved labeling of Avastin, the dosing for metastatic colorectal cancer is:

5 mg/kg IV every 2 weeks with bolus-IFL
10 mg/kg IV every 2 weeks with FOLFOX4
5 mg/kg IV 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.

The recommended dosing of Avastin for non−squamous non−small cell lung cancer is 15 mg/kg IV every 3 weeks with carboplatin/paclitaxel.

The recommended dosing of Avastin for glioblastoma is 10 mg/kg IV every 2 weeks.

The recommended dosing of Avastin for metastatic renal cell carcinoma (mRCC) is 10 mg/kg IV every 2 weeks with interferon alfa.

The recommended dosing for persistent, recurrent, or metastatic carcinoma of the cervix is 15 mg/kg IV every 3 weeks with paclitaxel/cisplatin or paclitaxel/topotecan.

The recommended dosing of Avastin for platinum-resistant recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer is:

10 mg/kg IV every 2 weeks with paclitaxel, pegylated liposomal doxorubicin or weekly topotecan
15 mg/kg IV every 3 weeks with topotecan given every 3 weeks.

Please consult the Full Prescribing Information for complete details for recommended dose adjustments.

Selection Criteria

The National Comprehensive Cancer Network Drug and Biologics Compendium (NCCN, 2017) recommends bevacizumab for the following indications:

AIDS-Related Kaposi Sarcoma - Subsequent systemic therapy given with antiretroviral therapy (ART) for relapsed/refractory advanced, cutaneous, oral, visceral, or nodal disease that has progressed on or not responded to first-line systemic therapy, and progressed on alternate first-line systemic therapy
Invasive breast cancer - In combination with paclitaxel for recurrent or metastatic human epidermal growth factor receptor 2 (HER2)-negative disease
- with symptomatic visceral disease or visceral crisis
- that is hormone receptor-negative or hormone receptor-positive and endocrine therapy refractory
Central Nervous System Cancers disease
- Adult low-grade infiltrative supratentorial astrocytoma/oligodendroglioma, anaplastic gliomas, glioblastoma, adult intracranial and spinal ependymoma, adult medulloblastoma, primary CNS lymphoma, meningioma, brain metastases, leptomeningeal metastases, and metastatic spine tumors) - Consider short-course single agent therapy for management of symptoms driven by RT necrosis, poorly controlled vasogenic edema, or mass effect
- Adult Intracranial and Spinal Ependymoma (Excluding Subependymoma) - Consider as single-agent treatment for disease progression
- Anaplastic Gliomas - Treatment of recurrent disease as a single agent or in combination with irinotecan, carmustine, lomustine, temozolomide, or carboplatin
- Glioblastoma - Treatment of recurrent disease as a single agent or in combination with irinotecan, carmustine, lomustine, temozolomide, or carboplatin
- Meningioma - Treatment for surgically inaccessible recurrent or progressive disease when radiation is not possible
Cervical Cancer - First-line therapy or second-line (if not previously used as first-line) in combination with paclitaxel with cisplatin, carboplatin, or topotecan, or second-line therapy as a single agent for
- local/regional recurrence
- distant metastases
Colon Cancer
- Therapy in combination with capecitabine or with FOLFOX (fluorouracil, leucovorin, and oxaliplatin), FOLFIRI (fluorouracil, leucovorin, and irinotecan), CapeOX (capecitabine and oxaliplatin), FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan), or 5-FU/LV (fluorouracil and leucovorin) regimen
  - as primary treatment for locally unresectable or medically inoperable disease
  - for unresectable synchronous liver and/or lung metastases that remain unresectable after primary systemic therapy
  - as primary treatment for synchronous abdominal/peritoneal metastases that are nonobstructing, or following local therapy for patients with imminent or existing obstruction
  - for unresectable synchronous metastases of other sites
  - as primary treatment for unresectable metachronous metastases in patients who have not received previous adjuvant FOLFOX or CapeOX within the past 12 months
  - for unresectable metachronous metastases that remain unresectable after primary treatment
- Initial treatment for unresectable synchronous liver and/or lung metastases in combination with
  - FOLFOX (fluorouracil, leucovorin, and oxaliplatin) regimen
  - FOLFIRI (fluorouracil, leucovorin, and irinotecan) regimen
  - FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin and irinotecan) regimen
  - CapeOX (capecitabine and oxaliplatin) regimen
- Therapy in combination with capecitabine or with FOLFOX (fluorouracil, leucovorin, and oxaliplatin), FOLFIRI (fluorouracil, leucovorin and irinotecan), CapeOX (capecitabine and oxaliplatin), FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin and irinotecan) or 5-FU/LV (fluorouracil and leucovorin) regimen
  - as adjuvant treatment following synchronized or staged resection for synchronous liver and/or lung metastases that converted from unresectable to resectable disease (2B recommendation)
  - as adjuvant treatment (following resection and/or local therapy) for resectable metachronous metastases in patients who have received previous chemotherapy or had growth on neoadjuvant chemotherapy (2B recommendation)
  - as adjuvant treatment for unresectable metachronous metastases that converted to resectable disease (2B recommendation)
- Preferred anti-angiogenic therapy as primary treatment for patients with unresectable metachronous metastases and previous adjuvant FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CapeOX (capecitabine and oxaliplatin) within the past 12 months
  - in combination with irinotecan
  - in combination with FOLFIRI (fluorouracil, leucovorin, and irinotecan) regimen
- Subsequent therapy after first progression of unresectable advanced or metastatic disease
  - as the preferred anti-angiogenic agent in combination with irinotecan or FOLFIRI (fluorouracil, leucovorin, and irinotecan) regimen for disease previously treated with oxaliplatin-based therapy without irinotecan
  - in combination with FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CapeOX (capecitabine and oxaliplatin) regimen for disease previously treated with irinotecan-based therapy without oxaliplatin
  - as the preferred anti-angiogenic agent in combination with irinotecan or FOLFIRI for patients previously treated with fluoropyrimidine therapy without irinotecan or oxaliplatin
  - in combination with FOLFOX, CapeOX, or irinotecan and oxaliplatin for patients previously treated with fluoropyrimidine therapy without irinotecan or oxaliplatin
Kidney Cancer - for relapse or stage IV disease
- in combination with interferon alfa-2b as first-line therapy for predominant clear cell histology
- as preferred single-agent subsequent therapy for predominant clear cell histology (2B recommendation)
- as single agent systemic therapy for non-clear cell histology
- in combination with erlotinib for non-clear cell histology in selected patients with advanced papillary renal cell carcinoma including hereditary leiomyomatosis and renal cell cancer (HLRCC)
- in combination with everolimus as systemic therapy for non-clear cell histology
Malignant Pleural Mesothelioma - Used in combination with pemetrexed and cisplatin or carboplatin followed by single-agent maintenance therapy as treatment of
- unresectable clinical stage I-III disease and tumors of epithelial or mixed histology
- clinical stage IV disease, tumors of sarcomatoid histology, or medically inoperable tumors in patients with performance status (PS) 0-2
Non-Small Cell Lung Cancer (NSCLC)
- Treatment in combination with carboplatin and paclitaxel or pemetrexed or in combination with cisplatin and pemetrexed for recurrence or metastases in patients with performance status 0-1, tumors of nonsquamous cell histology, and no history of recent hemoptysis as
  - first-line therapy for EGFR, ALK, ROS1, BRAF and PD-L1 negative or unknown
  - first-line or subsequent therapy for BRAF V600E-mutation positive tumors
  - subsequent therapy for sensitizing EGFR mutation-positive tumors and prior erlotinib, afatinib, gefitinib, or osimertinib therapy
  - subsequent therapy for ALK rearrangement-positive tumors and prior crizotinib, ceritinib, alectinib, or brigatinib therapy
  - subsequent therapy for ROS1 rearrangement-positive tumors and prior crizotinib therapy
  - subsequent therapy for PD-L1 expression-positive (≥50%) tumors and EGFR, ALK, ROS1, and BRAF negative or unknown and prior pembrolizumab therapy
- Continuation maintenance therapy if given first line with chemotherapy for recurrence or metastasis in patients with performance status 0-2, tumors of nonsquamous cell histology, and no history of recent hemoptysis who achieve tumor response or stable disease following first-line chemotherapy
  - as a single agent
  - in combination with pemetrexed if previously used with a first-line pemetrexed/platinum chemotherapy regimen
Ovarian Cancer
- Borderline and Low-Grade (Grade 1) Serous/Endometrioid Epithelial Carcinoma - Adjuvant treatment in combination with carboplatin and paclitaxel for pathologic stage II-IV low-grade disease or borderline epithelial tumors with invasive implants (2B recommendation)
- Carcinosarcoma (Malignant Mixed Müllerian Tumors) - Preferred adjuvant treatment in combination with carboplatin and paclitaxel for pathologic stage I-IV disease (2A recommendation)
- Clear Cell Carcinoma of the Ovary - Adjuvant treatment in combination with carboplatin and paclitaxel for pathologic stage II-IV disease (2A recommendation)
Epithelial Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer
- Consider as neoadjuvant chemotherapy in combination with paclitaxel and carboplatin for bulky stage III-IV disease or poor surgical candidates (2A recommendation)
- Used in combination with paclitaxel and carboplatin for
  - primary treatment for incompletely staged (stage II-IV) patients with suspected unresectable residual disease (2A recommendation)
  - primary treatment for patients with incomplete previous surgery and/or staging with stage II-IV and suspected unresectable residual disease (2A recommendation)
  - primary adjuvant therapy for pathologic stage IA-IB (grade 2 serous/endometrioid or grade 3), stage IC (grades 1-3), or stage II-IV disease (2A recommendation)
- In combination with paclitaxel and carboplatin for rising CA-125 levels or clinical relapse in patients who have received no prior chemotherapy (2B recommendation)
- Therapy for persistent disease or recurrence
  - as preferred therapy if platinum-sensitive, in combination with carboplatin and gemcitabine
  - if platinum-sensitive, in combination with carboplatin and paclitaxel
  - as preferred therapy if platinum-resistant, in combination with liposomal doxorubicin, weekly paclitaxel, or topotecan
  - as preferred therapy as a single agent
- Maintenance therapy for platinum-sensitive persistent disease or recurrence following response to combination therapy with
  - carboplatin, gemcitabine, and bevacizumab
  - carboplatin, paclitaxel, and bevacizumab
Malignant Sex Cord-Stromal Tumors - Single agent for clinical relapse in patients with stage II-IV disease
Mucinous carcinoma of the ovary
- Adjuvant treatment in combination with
  - carboplatin and paclitaxel for pathologic stage II-IV disease (2A recommendation)
  - fluorouracil, leucovorin, and oxaliplatin (2B recommendation)
  - capecitabine and oxaliplatin (2B recommendation)
- Preferred therapy, if platinum-sensitive, for persistent disease or recurrence in combination with
  - fluorouracil, leucovorin, and oxaliplatin (2B recommendation)
  - capecitabine and oxaliplatin (2B recommendation)
Rectal Cancer
- Used in combination with capecitabine or with FOLFOX (fluorouracil, leucovorin, and oxaliplatin), FOLFIRI (fluorouracil, leucovorin, and irinotecan), FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) regimen, CapeOX (capecitabine and oxaliplatin), or fluorouracil and leucovorin regimen as
  - primary treatment for T3, N0, M0; any T, N1-2, M0; or T4 and/or locally unresectable or medically inoperable disease with no metastases if resection is contraindicated following neoadjuvant therapy
  - prinary treatment for unresectable synchronous metastases or medically inoperable disease
  - systemic therapy following primary treatment with chemoradiation or local therapy for symptomatic unresectable synchronous metastases or medically inoperable disease
  - adjuvant treatment (following resection and/or local therapy) for resectable metachronous metastases in patients who have received previous chemotherapy or had growth on neoadjuvant chemotherapy (2B recommendation)
  - primary treatment for unresectable metachronous metastases in patients who have not received previous adjuvant FOLFOX or CapeOX within the past 12 months
  - adjuvant treatment for unresectable metachronous metastases that converted to resectable disease (2B recommendation)
  - systemic therapy for unresectable metachronous metastases that remain unresectable after primary treatment
- Preferred anti-angiogenic therapy as primary treatment for patients with unresectable metachronous metastases and previous adjuvant FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CapeOX (capecitabine and oxaliplatin) within the past 12 months
  - in combination with irinotecan
  - in combination with FOLFIRI (fluorouracil, leucovorin, and irinotecan) regimen
- Subsequent therapy after first progression for unresectable advanced or metastatic disease
  - as the preferred anti-angiogenic agent in combination with irinotecan or FOLFIRI (fluorouracil, leucovorin, and irinotecan) regimen for disease previously treated with oxaliplatin-based therapy without irinotecan
  - in combination with FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CapeOX (capecitabine and oxaliplatin) regimen for disease previously treated with irinotecan-based therapy without oxaliplatin
  - as the preferred anti-angiogenic agent in combination with irinotecan or FOLFIRI for patients previously treated with fluoropyrimidine therapy without irinotecan or oxaliplatin
  - in combination with FOLFOX, CapeOX, or irinotecan and oxaliplatin for patients previously treated with fluoropyrimidine therapy without irinotecan or oxaliplatin
Angiosarcoma - Single agent therapy for angiosarcoma
Solitary Fibrous Tumor/Hemangiopericytoma - In combination with temozolomide for the treatment of solitary fibrous tumor and hemangiopericytoma
Endometrial Carcinoma
- as single agent therapy for members who have progressed on prior cytotoxic chemotherapy
- in combination with carboplatin and paclitaxel for advanced or recurrent disease
Endometroid adenocarcinoma - Single-agent therapy for disease that has progressed on prior cytotoxic chemotherapy
Serous or clear cell carcinoma; carcinosarcoma - Single-agent therapy for disease that has progressed on prior cytotoxic chemotherapy.
Vulvar Cancer - Squamous Cell Carcinoma - In combination with cisplatin and paclitaxel (preferred regimen) or carboplatin and paclitaxel
- as additional treatment for unresectable locally advanced disease clinically positive for residual tumor at the primary site and/or nodes
- as additional treatment for locally advanced disease with positive margins following resection
- as primary treatment for metastatic disease beyond the pelvis
- for isolated groin/pelvic recurrence if prior external beam radiation therapy (EBRT)
- for clinical nodal or distant recurrence with multiple pelvic nodes, distant metastasis, or prior pelvic EBRT

Note: Vaginal cancer should be treated according to guidelines for cervical cancer, and small bowel adenocarcinoma, anal adenocarcinoma and appendiceal carcinoma should be treated according to the guidelines for colorectal cancer.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes
Code	Code Description
*Information in the [brackets] below has been added for clarification purposes. Codes requiring a 7th character are represented by "+"*:
Other CPT codes related to the CPB:
67028	Intravitreal injection of a pharmacologic agent (separate procedure)
96401 - 96450	Chemotherapy administration
HCPCS codes covered if selection criteria are met:
J9035	Injection, bevacizumab, 10 mg [for neovascular (wet) age related macular degeneration see C9257]
C9257	Injection, bevacizumab, 0.25 mg [covered for neovascular (wet) age related macular degeneration]
Other HCPCS codes related to the CPB:
J8700	Temozolomide, oral, 5 mg
J9035	Injection, pemetrexed, 10 mg
J9045	Injection, carboplatin, 50 mg
J9050	Injection, carmustine, 100 mg
J9060	Injection, cisplatin, powder or solution, 10 mg
J9190	Injection, fluorouracil, 500 mg
J9206	Injection, irinotecan, 20 mg
J9214	Injection, interferon, alfa-2b, recombinant, 1 million units
J9267	Injection, paclitaxel, 1 mg
J9328	Injection, temozolomide, 1 mg
Q0083 - Q0085	Chemotherapy administration
S0178	Lomustine, oral, 10mg
ICD-10 codes covered if selection criteria are met [See CPB 701 for ocular indications]:
B39.4 [H32 also required]	Histoplasmosis capsulati, retinitis
B39.5 [H32 also required]	Histoplasmosis duboisli, retinitis
B39.9 [H32 also required]	Histoplasmosis, unspecified , retinitis
C17.0 - C17.9	Malignant neoplasm of small intestine, including duodenum
C18.0 - C21.8	Malignant neoplasm of colon, rectum, rectosigmoid junction and anus
C22.3	Angiosarcoma of liver
C34.00 - C34.92	Malignant neoplasm of the bronchus and lung [non-squamous, non-small cell] [covered for non- small cell lung cancer and non -squamous cell lung cancer]
C38.4	Malignant neoplasm of pleura [solitary fibrous tumors]
C45.0	Mesothelioma of pleura
C45.1	Mesothelioma of peritoneum
C46.0 - C46.9	Kaposi's sarcoma [AIDS-related Kaposi's sarcoma]
C48.0 - C48.8	Malignant neoplasm of retroperitoneum and peritoneum
C49.0 - C49.9	Malignant neoplasm of other connective and soft tissue, [angiosarcoma][hemangiopericytoma] [not covered for desmoplastic small round blue cell tumor]
C50.011 - C50.929	Malignant neoplasm of breast
C51.0 - C51.9	Malignant neoplasm of vulva
C52	Malignant neoplasm of vagina
C53.0 - C53.9	Malignant neoplasm of cervix uteri
C54.1 - C54.3, C54.9	Malignant neoplasm of corpus uteri, except isthmus [recurrent, metastatic endometrial cancer in members who have progressed on prior cytotoxic chemotherapy]
C56.1 - C56.9	Malignant neoplasm of ovary [epithelial and mucinous]
C57.00 - C57.02	Malignant neoplasm of fallopian tube
C64.1 - C64.9	Malignant neoplasm of kidney [renal cell carcinoma]
C71.0 - C71.9	Malignant neoplasm of brain [not covered for diffuse leptomeningeal glio-neuronal tumor]
C72.0 - C72.9	Malignant neoplasm of spinal cord, cranial nerves and other parts of central nervous system [not covered for diffuse leptomeningeal glio-neuronal tumor]
D32.0 - D32.9	Benign neoplasm of meninges [treatment for surgically inaccessible recurrent or progressive disease when radiation is not possible]
E08.311, E08.3211 - E08.3219, E08.3311 - E08.3319, E08.3411 - E08.3419, E08.3511 - E08.3559, E09.311, E09.3211 - E09.3219, E09.3311 - E09.3319, E09.3411 - E09.3419, E09.3511 - E09.3559, E10.311, E10.3211 - E10.3219, E10.3311 - E10.3319, E10.3411 - E10.3419, E10.3511 - E10.3559, E11.311, E11.3211 - E11.3219, E11.3311 - E11.3319, E11.3411 - E11.3419, E11.3511 - E11.3559, E13.311, E13.3211 - E13.3219, E13.3311 - E13.3319, E13.3411 - E13.3419, E13.3511 - E13.3559	Diabetic macular edema
G93.6	Cerebral edema
H30.001 - H30.049	Focal chorioretinal inflammaton
H30.101 - H30.149	Disseminated chorioretinal inflammation
H30.891 - H30.93	Other and unspecified chorioretinal inflammation
H31.20 - H31.29	Hereditary choroidal dystrophies
H32 [use with B39.4, B39.5, B39.9]	Chorioretinal disorders in diseases classified elsewhere
H34.8110 - H34.8192	Central retinal vein occlusion
H34.8310 - H34.8392	Venous tributary(branch) occlusion
H35.011 - H35.019	Changes in retinal vascular appearance
H35.041 - H35.049	Retinal microaneurysms unspecified
H35.051 - H35.059	Retinal neovascularization unspecified
H35.061 - H35.069	Retinal vasculitis
H35.09	Other intraretinal microvascular abnormalities
H35.101 - H35.23	Retinopathy of prematurity and other non-diabetic proliferative retinopathy
H35.3110 - H35.3293	Age-related macular degeneration
H35.33	Angioid streaks of macula
H35.50 - H35.54	Hereditary retinal dystrophies
H40.50x0 - H40.53x4	Glaucoma secondary to other eye disorders
H44.20 - H44.23	Degenerative myopia
H44.2A1 - H44.2E9	Degenerative myopia with choroidal neovascularization, macular hole, retinal detachment foveoschisis or other maculopathy
Q82.8	Other specified congenital malformations of skin [pseudoxanthoma elasticum]
T66.xxxA - T66.xxxS	Radiation sickness, unspecified [radiation therapy necrosis]
Z85.038	Personal history of malignant neoplasm of large intestine
Z85.048	Personal history of malignant neoplasm of rectum, rectosigmoid junction, and anus
Z85.3	Personal history of malignant neoplasm of breast
Z85.43	Personal history of malignant neoplasm of ovary [epithelial]
Z85.528	Personal history of other malignant neoplasm of kidney [renal cell carcinoma]
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
A18.50 - A18.59	Tuberculosis of eye
A51.43	Secondary syphilitic oculopathy
B25.9	Cytomegaloviral disease, unspecified (retinitis)
B58.01	Toxoplasma chorioretinitis
C00.0 - C16.9 C22.0 - C33 C37 - C44.99 C46.0 - C47.9 C51.0 - C51.9 C54.0 C54.8 C55 C57.10 - C63.9 C66.1 - C70.9 C72.0 - C86.6 C88.2 - C94.32 C94.80 - C96.4 C96.a - C96.9	Malignant neoplasms [except those specifically listed as covered]
D3a.00 - D3a.8	Benign neuroendocrine tumors
D14.1	Benign neoplasm of larynx [laryngeal papillomatosis]
D18.00 - D18.09	Hemangioma [hemangioblastoma]
D21.4	Benign neoplasm of connective and other soft tissue of abdomen [stromal tumor]
D32.0	Benign neoplasm of cerebral meninges [meningioma]
D33.3	Benign neoplasm of cranial nerves [acoustic neuroma]
D48.1 - D48.2	Neoplasm of uncertain behavior of connective and other soft tissue [gastrointestinal stromal tumors]
D49.2	Neoplasm of unspecified behavior of bone, soft tissue, and skin [desmoid tumor]
E08.311 - E08.359 E09.311 - E09.359 E10.311 - E10.359 E11.311 - E11.359 E13.311 - E13.359	Diabetic retinopathy
E88.49	Other mitochondrial metabolism disorders [NARP syndrome]
G45.3	Amaurosis fugax
G93.6	Cerebral edema [radiation-induced]
G95.89	Other specified diseases of spinal cord
H16.241 - H16.249 H21.331 - H21.339 H44.001 - H44.9	Disorders of globe
H30.20 - H30.819 H31.001 - H31.129	Pars planitis, Harada's disease, chorioretinal scars and degenerations except angioid streaks
H31.301 - H31.9	Choroidal hemorrhage, detachment, and other disorders
H33.001 - H33.8	Retinal detachments and defects
H34.821 - H34.829 H35.70 - H35.739	Venous engorgement and separation of retinal layers
H35.021 - H35.029	Exudative retinopathy [Coat's disease]
H35.071 - H35.079	Retinal telangiectasis
H35.30 - H35.31 H35.351 - H35.359 H35.461 - H35.469	Degeneration of macula and posterior pole other than exudative senile macular degeneration and peripheral retinal degenerations.
H35.60 - H35.63 H35.81 - H35.9	Other retinal disorders
H40.001 - H42	Glaucoma
I78.0	Hereditary hemorrhagic telangiectasia
O01.0 - O01.9	Hydatidiform mole
Q15.0	Congenital glaucoma
Q85.00 - Q85.02	Neurofibromatosis [nonmalignant]
Q85.8	Other phakomatoses, not elsewhere classified [von Hippel Lindau disease]
T66.xxx+	Radiation sickness, unspecified [radiation necrosis]

The above policy is based on the following references:

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Last Review 12/21/2018

Effective: 05/14/2004

Next Review: 07/25/2019
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