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Review

Role of bevacizumab therapy in the management of glioblastoma

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Pages 97-104 | Published online: 22 Apr 2010

Abstract

Glioblastoma is one of the most common primary brain tumors and one of the most difficult to treat. In population-based studies only 30% of patients will survive 1 year and in the most efficacious surgery, irradiation, and chemotherapy clinical trials approximately 20% will live 2 years. Bevacizumab is a recombinant, antivascular epidermal growth factor receptor (VEGF) monoclonal antibody with 6 VEGF-binding residues that binds to VEGF, preventing VEGF from binding to its target, VEGFR-1 and VEGFR-2, on endothelial cells. Through its binding to VEGF ligands bevacizumab reduces tumor angiogenesis and vasogenic brain edema; the consequences are that bevacizumab reduces the rate of glioblastoma tumor growth and its associated tumoral edema, thereby improving quality of life and survival for patients suffering from cerebral glioblastoma. In this review, we will summarize the studies that led to the use of bevacizumab in glioblastoma and the potential side-effects and complications that can be associated with its use and, finally, new opportunities for drug combinations with bevacizumab.

Introduction

Glioblastoma multiforme (GBM) is a primary brain tumor arising from cells of astrocytic lineage. GBM is one of the most common and aggressive malignancies of the central nervous system (CNS). Despite its aggressiveness, there are molecular differences among all glioblastomas that result in a range of responsiveness to treatment. Primary glioblastomas arise without a preceding low grade glioma, often show amplification of epidermal growth factor receptor (EGFR) and murine double minute 2 (MDM2), along with inactivation of phosphatase and tensin homolog (PTEN) and p16 tumor suppressor genes. Secondary glioblastomas often have loss of p53 and pRB, as well as an increase in CDK4/6 expression. In 2005, Hegi and colleagues were able to show that outcome for patients with newly diagnosed glioblastomas depended on the methylation status of O6-methylguanine DNA methyltransferase (MGMT), with median survival increasing to 21.7 months in those with methylation of MGMT treated with both external beam irradiation and temozolomide.Citation1 As a result, molecular profiling of glioblastoma tissue collected at surgery is becoming important to patient treatment considerations and care.

The incidence rate of GBM is 3.1 per 100,000 person-years,Citation2 overall incidence of gliomas is greater in males (7.2 per 100,000 person-years) compared to females (5.0 per 100,000 person-years) and increases with age to 14/100,000 over age 65. The incidence rate is also greater amongst Caucasians compared to other ethnicities, and 18.5% of all brain tumors are GBM.Citation2

The median age at diagnosis of GBM is 64 years, and GBM is the second most common primary brain tumor behind only meningioma in patients at least 45 years of age.Citation2 Based on general tumor registry data, approximately 29.6% of patients with GBM will survival 1 year, whereas only 3.4% will survive 5 years with treatment.Citation2

Studies evaluating risk factors for brain tumors have thus far shown previous exposure to ionizing radiation as a statistically significant risk factor, but no conclusive evidence yet supports electromagnetic fields, cell phones, neurocarcinogens or metals as increasing risk of brain tumor development.Citation3 There are specific genetic disorders that are associated with an increased risk for developing malignancies, including brain tumors, and these include Li-Fraumeni syndrome, Neurofibromatosis, Tuberous Sclerosis, von Hippel-Lindau syndrome, and Turcot syndrome, but only 5% to 10% of brain tumors are inherited.Citation4

Vascular endothelial growth factor (VEGF) pathways and high-grade gliomas

VEGF is a potent endothelial cell mitogen and key regulator of both physiologic vasculogenesis in the embryonic circulatory systemCitation5 and pathologic angiogenesis leading to the growth of blood vessels from existing vasculature.Citation6,Citation7 VEGF has also been shown to stimulate monocyte/macrophage migration,Citation8Citation10 stimulate tumor cell migration,Citation11Citation15 and enhance vascular permeability in tight-junction endothelial environments such as those of the intact blood-brain barrier.Citation16Citation18

There are five known subtypes of VEGF (VEGF-A, -B, -C, -D and -E) and three known VEGF receptors (VEGFR-1, -2 and -3), all of which are tyrosine kinases.Citation19 VEGF A, VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1) are all highly expressed in the CNS. For CNS tumors, VEGF-A appears to bind to VEGFR-1 and VEGFR-2 and serve a particularly critical role for both angiogenesis and regulation of vascular permeability of the blood – brain barrier.Citation6,Citation16Citation18 VEGF-A stimulates endothelial proliferation via binding to VEGFR-2, and VEGFR-1 is involved in recruitment of macrophages/monocytes that in turn secrete pro-angiogenic factors. VEGF-A is known to stimulate vascular leakage, in particular through VEGFR-1 and VEGFR-2,Citation19 and this may contribute to the destabilization (increasing leakiness) of the blood – brain barrier that is often seen in malignant gliomas. Malignant gliomas as well as many other cancers are known to secrete VEGF as a means to stimulate the development of tumor vascular supply (angiogenesis). In turn, expression of VEGF appears to be upregulated by hypoxia as well as a variety of signal and transcription factors.Citation19 Specifically upregulated by hypoxia are:

  1. HIF-1αCitation20,Citation21

  2. STAT3Citation22,Citation23

  3. SrcCitation20,Citation24

  4. EGFR pathwayCitation25,Citation26

  5. FoxM1B transcription factorCitation27

  6. Hurl suppresses degradation of VEGF-A mRNACitation28,Citation29

While it is important to identify increased expression of VEGF-A, VEGFR-1 and VEGFR-2 in malignant gliomas, correlation to tumor growth is instrumental as well. Kerber and colleagues studied mice with transplanted glioma cells and mice transplanted with either wild-type bone marrow cells or with VEGFR-1 lacking a tyrosine kinase domain.Citation30 They found, using an original glioma cell line and a VEGF-A overexpressing cell line, that a significant reduction in growth of tumor was observed in those mice lacking wild-type VEGFR-1. Studies such as this suggest that VEGF-A and VEGFR-1 may be critical pathways in the growth of malignant gliomas.

Preclinical pharmacology studies

Bevacizumab is a recombinant, anti-VEGF monoclonal antibody with 6 VEGF-binding residues that binds to VEGF, preventing VEGF from binding to its target, VEGFR-1 and VEGFR-2, on endothelial cells.Citation31 Bao and colleagues examined stem cell-like glioma cells (SCLGC) to determine if such cells may be involved in angiogenesis and tumor development.Citation32 SCLGC were isolated from human glioblastoma tissue and implanted intracranially into mice. SCLGC, when compared to matched non-SCLGC controls, exhibited higher concentrations of VEGF, and hypoxia seemed to induce VEGF expression. Bevacizumab eliminated angiogenesis and suppressed growth of SCLGC, when compared to matched non-SCLGC controls. The authors concluded that stem-cell like tumors cells could contribute to angiogenesis in certain forms of cancer, such as gliomas.

Preclinical evaluation of antiangiogenic protein expression in four glioma cell lines after treatment with temozolomide found that levels of HIF-1a, ID-1, ID-2 and c-Myc were all reduced. Since these four factors are believed to be involved in angiogenesis and hypoxic metabolism, it was hypothesized that by reducing the levels of these factors, temozolomide may contribute to the reduction of angiogenesis in glioma. The authors also found that, when bevacizumab was added to temozolomide, the survival of mice with glioma improved, compared to mice treated with either compound alone.Citation33

To test the hypothesis that inhibition of hypoxia inducible factor-1 (HIF-1), when given with antiangiogenic agents, might be more efficacious, bevacizumab was given alone or with topotecan, a topoisomerase inhibitor, with HIF-1α inhibitor activity.Citation34 Using U251-HRE xenografts, the authors showed that bevacizumab reduced microvessel density and increased hypoxia and expression of the HIF-1 dependent gene in the tumor, but it did not induce apoptosis. The addition of topotecan to bevacizumab significantly reduced tumor growth, compared to mice treated with topotecan or bevacizumab alone. Topotecan also reduced expression of HIF-1 and inhibited proliferation while inducing apoptosis. Since the cytotoxic benefit of topotecan did not change with the addition of bevacizumab, the authors concluded that topotecan exerted its effect by HIF-1 inhibition. Furthermore, they hypothesized that bevacizumab, functioning as an anti-angiogenesis agent, may represent a potentially beneficial two-drug treatment strategy.Citation34

Clinical phase II studies at tumor recurrence

It is apparent from preclinical studies that VEGF is important for growth of endothelial cells and regulation of tumor angiogenesis; treatment with bevacizumab in vascular tumors like malignant gliomas was anticipated for many years prior to the initiation of formal clinical studies. Nonetheless, the first documented usage of bevacizumab in patients with glioblastoma was in an uncontrolled clinical trial by Stark-Vance in 2005. She presented a series of 29 patients, all with recurrent malignant glioma, treated with bevacizumab in combination with irinotecan.Citation35 Stark-Vance used bevacizumab 5 mg/kg and irinotecan 125 mg/m2 together, intravenously, every 2 weeks, with a 1- to 2-week break between each cycle. There were 3 complete responses (CR), 16 partial responses (PR) and 7 stable diseases (SD); thus, at least 65% of patients in this case series achieved a response to treatment. Toxicities attributed to bevacizumab included 1 intracranial hemorrhage, 1 bowel perforation, 2 wound-healing abnormalities and 5 cases of epistaxis.Citation35

The schedule of most phase 2 studies was based on an intravenous treatment with bevacizumab on a once every 14-day schedule. This was established by Genentech based on the plasma clearance half-life of approximately 21 days. While toxicity secondary to bevacizumat is generally mild, nevertheless, since bevacizumab may interfere with wound healing, it is recommended today to wait a minimum of 28 days before or after a major surgical procedure to administer bevacizumab to lower the risk of adverse events such as wound hemorrhage and breakdown. Bevacizumab was approved by the US Food and Drug Administration for recurrent glioblastoma in May 2009. Below we will chronicle some of the studies that led to that approval.

In an early phase II trial, 9 patients with malignant glioma and 23 with glioblastoma were treated with a combination of bevacizumab and irinotecan ().Citation36 Specifically, these patients were treated with bevacizumab 10 mg/kg IV every 2 weeks and irinotecan 125 mg/m2 for patients on enzyme-inducing antiepileptic medication (EIAED) or 340 mg/m2 for patients not on EIAED. Twenty patients (63%) achieved a radiographic response to treatment. Of the 23 glioblastomas, 14 patients (61%) achieved a partial response or better, with a median progression-free survival (PFS) of 20%. Three patients developed deep venous thromboses or pulmonary emboli, and 1 patient had a stroke. There were no cases of intracranial hemorrhages.Citation36

Table 1 Compilation of phase II studies using bevacizumab for recurrent glioblastoma

In another retrospective analysis of bevacizumab combined with cytotoxic chemotherapy (irinotecan, carboplatin, carboplatin with erlotinib, carmustine or temozolomide) for recurrent malignant gliomas, a total of 55 patients were reviewed and 63% showed a response to treatment and 30% had stable disease ().Citation37 The results of this trial included a 6-month PFS of 42% for glioblastoma and 32% for anaplastic glioma. Twenty-three patients, at progression, continued bevacizumab but changed chemotherapeutic agents, and this resulted in no radiographic responses, but 2 patients had prolonged PFS. The authors also noted a pattern of increased volume of infiltrative, nonenhancing tumor in those patients who progressed while on bevacizumab. The conclusion reached was that, while bevacizumab combined with cytotoxic chemotherapy is active in patients with malignant gliomas, changing chemotherapeutic agents at progression proved beneficial in only a small subset of patients and progression of tumor seemed to occur in a non-enhancing, infiltrative pattern.Citation37

In another phase II trial of patients with recurrent glioblastoma, 48 patients with recurrent glioblastoma were treated with bevacizumab 10 mg/kg every 2 weeks until tumor progression, then irinotecan was added to bevacizumab, either 340 mg/m2 or 125 mg/m2, depending on EIAED status ().Citation38 While on bevacizumab alone, 34 patients (71%) achieved a radiographic response based on Levin criteria,Citation39 compared to 17 patients (35%) when using Macdonald criteria.Citation40 The 6-month PFS was 29%, and 6-month overall survival (OS) was 57%. 19 patients were treated with bevacizumab and irinotecan at progression, and no radiographic responses were observed.

In a larger multi-institutional phase II trial of bevacizumab alone or in combination with irinotecan for recurrent glioblastoma, 167 patients were randomly assigned to bevacizumab 10 mg/kg every 2 weeks alone or with irinotecan 340 mg/m2 or 125 mg/m2, depending on EIAED status ().Citation41 For those patients on bevacizumab alone, 6-month PFS was 43%, objective response rates were 28% and median OS was 9 months. For those patients on bevacizumab and irinotecan, 6-month PFS was 50%, objective response rates were 38%, and median OS was 8.7 months. The bevacizumab-alone group experienced grade 3 or higher adverse events, including hypertension (8%) and seizures (6%). The bevacizumab and irinotecan group also experienced grade 3 or higher adverse events, including seizures (14%), neutropenia (9%) and fatigue (9%). Two patients in the bevacizumab-alone group had a grade 1 intracranial hemorrhage (2%), compared to 3 patients (4%) in the bevacizumab and irinotecan-group (grade 1, 2 and 4).Citation41

It is difficult to make a straightforward comparison of bevacizumab to cytotoxic agents used to treat GBM because of the unusual action of bevacizumab and the fact that it does not directly damage DNA of dividing tumor cells. In addition, bevacizumab reduces cerebral edema through a direct effect on brain capillary endothelial cells thus leading to a high “response rate”. On the other hand, alkylating agents only secondarily reduce peritumoral edema when they reduce tumor and neoplastic endothelial cell burden. Furthermore, for PFS, comparing bevacizumab and cytotoxic agents can also be misleading, especially since they are not mutually exclusive therapies but rather may be complementary. Lastly, much of the early single-agent cytotoxic chemotherapy literature occurred before the current magnetic resonance imaging (MRI) era became widespread. Nonetheless, for interest’s sake we will cite some conclusions from the cytotoxic literature for recurrent GBM.

For this purpose, we selected BCNU,Citation42Citation44 procarbazine,Citation45,Citation46 carboplatin,Citation47 and temozolomideCitation46 data that were analyzed for a prior review.Citation48 Since response to these therapies is under 50% the median will generally be about 8 weeks for all studies. Therefore, in order to better understand and compare alkylating agent therapy to bevacizumab, we elected to combine response and stable disease patients in order to look at duration of therapy benefit. As summarized in , those studies show combined response (PR, CR) and stable disease (minor response [MR], SD) rates of 27% to 46% with median time to progression (MTP) of 22 to 30 weeks.Citation48 Thus, even though the metrics used in and are different (PFS at 6 months vs. MTP) and the response criteria differ between the study groups (MR + PR + CR vs. SD + MR + PR + CR) summarized in the two tables, one can appreciate that bevacizumab therapy benefits more patients than the cytotoxic drugs, and the durability of a benefit appears to be somewhat longer. That bevacizumab can be combined with some cytotoxic drugs without increasing myelotoxicity should be viewed as encouraging.

Table 2 Compilation of selected phase II studies of cytotoxic drugs for treatment of recurrent glioblastoma

Clinical phase II studies and translational research

A retrospective review of 44 patients treated with bevacizumab for recurrent glioblastoma were compared to 79 patients who were not treated with bevacizumab.Citation49 The authors found a significant improvement in PFS and OS in the group treated with bevacizumab. In addition, patients age 55 years or older and those with a Karnofsky Performance Status of 80 or less had an improved PFS when treated with bevacizumab. VEGF expression in glioblastoma specimens collected on all patients, analyzed with DNA microarray analysis, was higher in patients at least 55 years of age. Lastly, those patients treated with bevacizumab required a lower dose of dexamethasone, and retained their level of function longer when treated with bevacizumab.Citation49

Sathornsumetee and colleagues conducted a phase II trial, searching for biomarkers that could predict outcome and response to treatment in patients with recurrent malignant astrocytomas.Citation50 Tumor tissue was collected from 27 patients with GBM and 18 with anaplastic astrocytoma at initial diagnosis. The tissue was studied using immunohistochemistry to semi-quantitate expression of VEGF, VEGF receptor 2, CD31, hypoxia-inducible carbonic anhydrase 9 (CA9), and HIF-2α. A total of 58% experienced PR or more. Elevated expression of VEGF was associated with a greater likelihood of response to treatment, but not a survival benefit. Elevated CA9 expression was associated with a poor outcome, and thus hypoxia, not angiogenesis, ultimately determined survival in this patient population. Median survival for patients with elevated CA9 expression was 37 weeks, while those with low CA9 expression was 74 weeks. The best prognosis was associated with patients whose tumor tissue was negative for CA9 and HIF-2α, whereas those who expressed both CA9 and HIF-2α had the worst prognosis. There were no significant differences in survival for angiogenic markers VEGF, VEGFR-2 or CD31.Citation50

Lucio-Eterovic and colleagues compared U87 glioblastoma cell lines and NSC23 glioma stem cell lines with respect to the effects of bevacizumab on in vitro and in vivo invasion, and sought to identify potential mechanisms of resistance to treatment.Citation14 These authors were able to show that both cell lines treated with bevacizumab were able to upregulate expression of molecules important for angiogenesis, such as fibroblastic growth factors, interleukins and angiogenins, thereby bypassing the antiangiogenic effect of bevacizumab. Furthermore, there were increased levels of invasion-related proteins (MMP-2, MMP-9, MMP-12, SPARC and TIMPs), suggesting both cell lines treated with bevacizumab may use this as a mechanism for increasing tumor invasiveness.Citation14

Clinical phase II studies with irradiation

A phase II pilot study of bevacizumab in combination with temozolomide and radiation therapy was reported for patients with newly diagnosed glioblastoma multiforme.Citation51 In this study, all patients were treated with standard external beam irradiation (60 Gy in 30 fractions, 3 to 5 weeks followed surgery), concurrent temozolomide (75 mg/m2 for 42 days during radiation therapy), and bevacizumab 10 mg/kg every 2 weeks, starting on day 1 of radiation therapy (RT). After RT was completed, adjuvant temozolomide chemotherapy was continued at 150 to 200 mg/m2, days 1 to 5 every 28 days, and bevacizumab was continued at 10 mg/kg every 2 weeks. Though preliminary data analysis was encouraging, the routine use of this regimen was not advocated pending completion of a larger, ongoing phase II trial.Citation51

Gutin and colleagues studied the safety and efficacy of bevacizumab in patients with recurrent malignant gliomas who also received stereotactic radiation therapy.Citation52 25 patients with recurrent malignant glioma, who already received standard radiation therapy, were treated with bevacizumab 10 mg/kg every 2 weeks until tumor recurrence. These patients were also treated with 30 Gy of stereotactic radiation therapy in 5 fractions after the first course of bevacizumab. Three patients discontinued bevacizumab due to grade 3 intratumoral hemorrhage, wound dehiscence, and/or bowel perforation. No radiation necrosis was seen in any patients. In patients with GBM, the response rate was 50%, with a 6-month PFS of 65%, and a median OS of 12.5 months.Citation52

Clinical trials with anticoagulation

A retrospective review evaluated the safety of using anticoagulation in glioma patients who were also treated with bevacizumab.Citation53 In this report, 21 patients were treated with anticoagulation and bevacizumab for a median of 72 days. No large lobar hemorrhages were noted, although 14% (3/21) patients had small areas of hemorrhage and only 5% (1/21) developed symptoms from the small hemorrhage. No patients sustained permanent neurological impairments. Interestingly, 7 patients were also identified who developed symptomatic hemorrhages while on bevacizumab but were not receiving anticoagulation. The authors concluded that anticoagulation is not a contraindication to starting bevacizumab.Citation53

Bevacizumab and neuroimaging

A retrospective analysis of patterns of relapse and prognosis, once tumor progression has occurred, was reported for 37 patients with recurrent GBM on bevacizumab.Citation54 The median OS after tumor progression on bevacizumab was 4.5 months, with a pattern of progression characterized by an increase in enhancement at the original site of tumor (46%), a new enhancing lesion distant to the original tumor location (16%), and growth of nonenhancing tumor (35%). Additional chemotherapy was given to those with tumor progression on bevacizumab, and the median PFS for these patients was 2 months, with a median OS of 5.2 months and a 6-month PFS of 0%. The authors concluded that contrast MRI is not sufficient to fully assess treatment response of bevacizumab for recurrent GBM patients, especially since nonenhancing (T2 FLAIR) growth of tumor can be associated with a worse prognosis; additional chemotherapy following failure of bevacizumab provided only transient tumor control.Citation54

In another retrospective analysis, 27 patients with recurrent high-grade glioma were treated with irinotecan and bevacizumab and evaluated for safety and efficacy.Citation55 In this report, patients were treated with bevacizumab at 10 mg/kg every 2 weeks and irinotecan every 2 weeks (125 mg/m2 for those not on EIAEDs, 340 mg/m2 for those on EIAEDs). Six-month PFS was 46%, and median OS 13 months. Median number of prior therapies was 2 in this patient population. Interestingly, 12 patients had radiographic evidence for intracranial hemorrhage prior to receiving bevacizumab, yet only 1 patient required discontinuation of bevacizumab due to progression of hemorrhage. It was concluded that stable intracranial hemorrhage is probably not a contraindication to treatment with bevacizumab and irinotecan.Citation55

Another retrospective analysis of 51 patients with recurrent high-grade gliomas treated with bevacizumab and irinotecan was reported.Citation56 In this series, patients were treated with bevacizumab 10 mg/kg and irinotecan (125 mg/m2 for those not on EIAEDs, 340 mg/m2 for those on EIAEDs) IV every 2 weeks. The 6-month PFS for anaplastic glioma was 79% and 64% for glioblastoma. Of the 38 patients who experienced progression of disease, 23 showed distant progression, and 7 showed progression only on T2 FLAIR sequences. Twelve percent discontinued bevacizumab and irinotecan due to adverse events, including one with renal failure and another with gastric perforation. No intracranial hemorrhages were reported. The authors concluded that the high rate of distant progression may indicate an ability of the tumor to adapt to bevacizumab with a mechanism of infiltration.Citation56

In a retrospective review of MRI from patients with GBM who reviewed bevacizumab-containing regimens, and evaluated for the time course for imaging changes, 15 patients were identified who responded to a bevacizumab regimen and were available for MRI follow up for at least 7 months. The median time to best tumor response was 158 days (range, 16 to 261), and the median best response was a 72% reduction in tumor volume and vasogenic edema.Citation57

Bevacizumab and radiation necrosis

Bevacizumab appears to be active not only in the treatment of patients with glioblastomas, but for those with treatment-related changes from radiation therapy. The first paper to comment on this association was published in 2007.Citation58 Eight patients with malignant brain tumors (4 glioblastomas, 3 anaplastic gliomas and 1 hemangiopericytoma) were classified as having radiation necrosis using MRI criteria,Citation59 although radiation necrosis was confirmed in 2 patients by biopsy. Following treatment with bevacizumab, alone or in combination with other chemotherapy agents, there was an average reduction of MRI enhancement of 48% and FLAIR size of 60%. Furthermore, there was a reduction in the average dexamethasone dose of 8 mg.

Another retrospective review of 6 patients (3 glioblastoma, 1 anaplastic astrocytoma, 1 anaplastic ependymoma and 1 astrocytoma), all with biopsy-proven radiation necrosis, were treated with bevacizumab. The average reduction in enhancement seen on MRI scans was 79%, and FLAIR images on MRI had an average signal reduction of 49%. The radiographic response rate reached 100%, and a response was maintained for a mean of 5.9 months (6 weeks to 18 months). The average number of bevacizumab infusions given was 6.8, and all patients were able to taper off dexamethasone.Citation60

One of the authors (VAL) has completed a randomized, double-blind, placebo-controlled trial of bevacizumab in non-GBM patients with radiation necrosis.Citation61 This study strongly confirms the retrospective studies of bevacizumab effectiveness in treating radiation necrosis of the CNS. It appears clear that bevacizumab can reduce capillary leakage, in a VEGF-dependent process, and thereby effectively manage vasogenic edema in patients with malignant brain tumors and radiation necrosis.Citation30 In addition, reduction of VEGF by bevacizumab appears to stop the progression of radiation necrosis in many cases. Cliniclas must be cognizant of the possibility that this may confound our ability to truly evaluate response when using neuroimaging criteria in patients with glioblastoma who have MRI scans that could represent tumor progression and/or radiation necrosis.

Concluding remarks

Bevacizumab has thus far been shown to be active in patients with glioblastoma, with acceptable toxicity. Most serious adverse events, defined as grade 3 or 4 based on Common Terminology Criteria for Adverse Events (CTCAE) v3.0, are 5% or less, with exception to hypertension (range 6% to 16%).Citation62 Bevacizumab has been shown to improve survival, both PFS and OS, compared to historical controls in glioblastoma patients, with the most impressive response rates thus far for any such therapy. There are data to support activity of bevacizumab alone in patients with recurrent glioblastoma.

The conundrum facing clinicians who use or would like to use bevacizumab to treat glioblastoma and anaplastic gliomas is how to best utilize its unique pharmacological actions on brain capillary permeability and its ability to interfere with tumor vessel formation. It is naïve to expect that bevacizumab combination with alkylating agents will achieve substantially more in terms of durable response since there is no unique interaction to be exploited. To date, most trials appear to be combinations of bevacizumab with DNA-damaging agents and/or irradiation. Emerging data to show benefit with bevacizumab used at diagnosis along with temozolomide have been judged encouraging based primarily on acceptable toxicity profiles when combining bevacizumab with standard conventional external beam irradiation or hypofractionated radiation therapy at recurrence. There are presently, however, a lack of randomized-controlled trials to provide definitive answers on the true impact of bevacizumab-containing regimens for patients with glioblastoma. Trials such as RTOG 0825, which is presently open and evaluating newly diagnosed glioblastoma patients treated with standard external beam irradiation plus temozolomide versus standard external beam irradiation, temozolomide and bevacizumab, will address some of these concerns, although it may also point out the propensity of bevacizumab to alter glioma tumors to a more invasive phenotype.Citation54

It is hoped that the continued identification of biomarkers and genetic patterns will identify patients who may benefit from anti-angiogenic agents such as bevacizumab, and these studies may also suggest other treatable cellular targets that may be critical to the advancement of treatment for glioblastoma patients. Lastly, given important issues of cost and toxicity, future randomized-controlled trials identifying optimal dose and length of treatment would be very helpful in optimizing use of bevacizumab for glioblastoma patients.

Disclosures

The authors declare no conflicts of interest.

References

  • HegiMEDiserensACGorliaTMGMT gene silencing and benefit from temozolomide in glioblastomaN Engl J Med200535210997100315758010
  • CBTRUSStatistical Report: Primary Brain Tumors in the United States, 2000–2004Central Brain Tumor Registry of the United States2008
  • BondyMLScheurerMEMalmerBBrain tumor epidemiology: consensus from the Brain Tumor Epidemiology ConsortiumCancer20081137 Suppl1953196818798534
  • NarodSAStillerCLenoirGMAn estimate of the heritable fraction of childhood cancerBr J Cancer19916369939992069856
  • ShibuyaMVascular endothelial growth factor-dependent and -independent regulation of angiogenesisBMB Rep200841427828618452647
  • DvorakHFSioussatTMBrownLFDistribution of vascular permeability factor (vascular endothelial growth factor) in tumors: concentration in tumor blood vesselsJ Exp Med19911745127512781940805
  • ShweikiDItinASofferDKeshetEVascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesisNature199235963988438451279431
  • RenYTsuiHTPoonRTMacrophage migration inhibitory factor: roles in regulating tumor cell migration and expression of angiogenic factors in hepatocellular carcinomaInt J Cancer20031071222912925952
  • ProescholdtMAHeissJDWalbridgeSVascular endothelial growth factor (VEGF) modulates vascular permeability and inflammation in rat brainJ Neuropathol Exp Neurol199958661362710374752
  • MarchioSPrimoLPaganoMVascular endothelial growth factor-C stimulates the migration and proliferation of Kaposi’s sarcoma cellsJ Biol Chem199927439276172762210488101
  • NagashimaGSuzukiRHokakuHGraphic analysis of microscopic tumor cell infiltration, proliferative potential, and vascular endothelial growth factor expression in an autopsy brain with glioblastomaSurg Neurol199951329229910086494
  • SandstromMJohanssonMSandstromJBergenheimATHenrikssonRExpression of the proteolytic factors, tPA and uPA, PAI-1 and VEGF during malignant glioma progressionInt J Dev Neurosci1999175–647348110571409
  • NordenADDrappatzJWenPYAntiangiogenic therapies for high-grade gliomaNat Rev Neurol200951161062019826401
  • Lucio-EterovicAKPiaoYde GrootJFMediators of glioblastoma resistance and invasion during antivascular endothelial growth factor therapyClin Cancer Res200915144589459919567589
  • VerhoeffJJvan TellingenOClaesAConcerns about anti-angiogenic treatment in patients with glioblastoma multiformeBMC Cancer2009944420015387
  • CriscuoloGRThe genesis of peritumoral vasogenic brain edema and tumor cysts: a hypothetical role for tumor-derived vascular permeability factorYale J Biol Med19936642773147516104
  • RisauWMolecular biology of blood-brain barrier ontogenesis and functionActa Neurochir Suppl199460109112
  • MonacciWTMerrillMJOldfieldEHExpression of vascular permeability factor/vascular endothelial growth factor in normal rat tissuesAm J Physiol19932644 Pt 1C99510028476026
  • ShibuyaMBrain angiogenesis in developmental and pathological processes: therapeutic aspects of vascular endothelial growth factorFebs J2009276174636464319664071
  • JiangBHAganiFPassanitiASemenzaGLv-Src induces expression of hypoxia-inducible factor 1 (Hif-1) and transcription of genes encoding vascular endothelial growth factor and enolase 1– involvement of Hif-1 in tumor progressionCancer Res19975723532853359393757
  • GrayMJZhangJEllisLMHIF-1alpha, STAT3, CBP/p300 and Ref-1/APE are components of a transcriptional complex that regulates Src-dependent hypoxia-induced expression of VEGF in pancreatic and prostate carcinomasOncogene200524193110312015735682
  • NiuGWrightKLHuangMConstitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesisOncogene200221132000200811960372
  • LoHWCaoXZhuHAli-OsmanFConstitutively activated STAT3 frequently coexpresses with epidermal growth factor receptor in high-grade gliomas and targeting STAT3 sensitizes them to Iressa and alkylatorsClin Cancer Res200814196042605418829483
  • MukhopadhyayDTsiokasLZhouXMFosterDBruggeJSSukhatmeVPHypoxic induction of human vascular endothelial growth factor expression through c-Src activationNature199537565325775817540725
  • ClarkeKSmithKGullickWJHarrisALMutant epidermal growth factor receptor enhances induction of vascular endothelial growth factor by hypoxia and insulin-like growth factor-1 via a PI3 kinase dependent pathwayBr J Cancer200184101322132911355942
  • FeldkampMMLauNRakJKerbelRSGuhaANormoxic and hypoxic regulation of vascular endothelial growth Factor (VEGF) by astrocytoma cells is mediated by RasInt J Cancer199981111812410077162
  • ZhangYZhangNDaiBFoxM1B transcriptionally regulates vascular endothelial growth factor expression and promotes the angiogenesis and growth of glioma cellsCancer Res200868218733874218974115
  • NaborsLBGillespieGYHarkinsLKingPHHuR, a RNA stability factor, is expressed in malignant brain tumors and binds to adenine- and uridine-rich elements within the 3’ untranslated regions of cytokine and angiogenic factor mRNAsCancer Res20016152154216111280780
  • IdoKNakagawaTSakumaTTakeuchiHSatoKKubotaTExpression of vascular endothelial growth factor-A and mRNA stability factor HuR in human astrocytic tumorsNeuropathology200828660461118498284
  • KerberMReissYWickersheimAFlt-1 signaling in macrophages promotes glioma growth in vivoCancer Res200868187342735118794121
  • McCormackPLKeamSJBevacizumab: a review of its use in metastatic colorectal cancerDrugs200868448750618318567
  • BaoSWuQSathornsumeteeSStem cell-like glioma cells promote tumor angiogenesis through vascular endothelial growth factorCancer Res200666167843784816912155
  • MathieuVDe NeveNLe MercierMCombining bevacizumab with temozolomide increases the antitumor efficacy of temozolomide in a human glioblastoma orthotopic xenograft modelNeoplasia200810121383139219048117
  • RapisardaAHollingsheadMUranchimegBIncreased antitumor activity of bevacizumab in combination with hypoxia inducible factor-1 inhibitionMol Cancer Ther2009871867187719584228
  • Stark-VanceVBevacizumab and CPT-11 in the treatment of relapsed malignant gliomaNeuro Oncol20057369
  • VredenburghJJDesjardinsAHerndonJE2ndPhase II trial of bevacizumab and irinotecan in recurrent malignant gliomaClin Cancer Res20071341253125917317837
  • NordenADYoungGSSetayeshKBevacizumab for recurrent malignant gliomas: efficacy, toxicity, and patterns of recurrenceNeurology2008701077978718316689
  • KreislTNKimLMooreKPhase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastomaJ Clin Oncol200927574074519114704
  • LevinVACraftsDCNormanDMHofferPBSpireJPWilsonCBCriteria for evaluating patients undergoing chemotherapy for malignant brain tumorsJ Neurosurg1977473329335894339
  • MacdonaldDRCascinoTLScholdSCJrCairncrossJGResponse criteria for phase II studies of supratentorial malignant gliomaJ Clin Oncol199087127712802358840
  • FriedmanHSPradosMDWenPYBevacizumab alone and in combination with irinotecan in recurrent glioblastomaJ Clin Oncol200927284733474019720927
  • LevinVAChemotherapy of primary brain tumorsNeurol Clin1985348558663001491
  • WilsonCBGutinPBoldreyEBDraftsDLevinVAEnotKJSingle-agent chemotherapy of brain tumors. A five-year reviewArch Neurol19763311739744185991
  • LevinVAWilsonCBNitrosourea chemotherapy for primary malignant gliomasCancer Treat Rep1976606719724954010
  • RodriguezLAPradosMSilverPLevinVAReevaluation of procarbazine for the treatment of recurrent malignant central nervous system tumorsCancer19896412242024232555038
  • YungWKAlbrightREOlsonJA phase II study of temozolomide vs. procarbazine in patients with glioblastoma multiforme at first relapseBr J Cancer200083558859310944597
  • YungWKMechtlerLGleasonMJIntravenous carboplatin for recurrent malignant gliomas: a phase II studyJ Clin Oncol1991958601849986
  • BergerMSLeibelSABrunerJMFinlayJLLevinVAPrimary Cerebral TumorsLevinVACancer in the Nervous SystemSecond edNew YorkOxford University Press200275148
  • NghiemphuPLLiuWLeeYBevacizumab and chemotherapy for recurrent glioblastoma: a single-institution experienceNeurology200972141217122219349600
  • SathornsumeteeSCaoYMarcelloJETumor angiogenic and hypoxic profiles predict radiographic response and survival in malignant astrocytoma patients treated with bevacizumab and irinotecanJ Clin Oncol200826227127818182667
  • LaiAFilkaEMcGibbonBPhase II pilot study of bevacizumab in combination with temozolomide and regional radiation therapy for up-front treatment of patients with newly diagnosed glioblastoma multiforme: interim analysis of safety and tolerabilityInt J Radiat Oncol Biol Phys20087151372138018355978
  • GutinPHIwamotoFMBealKSafety and efficacy of bevacizumab with hypofractionated stereotactic irradiation for recurrent malignant gliomasInt J Radiat Oncol Biol Phys200975115616319167838
  • NghiemphuPLGreenRMPopeWBLaiACloughesyTFSafety of anticoagulation use and bevacizumab in patients with gliomaNeuro Oncol200810335536018436627
  • IwamotoFMAbreyLEBealKPatterns of relapse and prognosis after bevacizumab failure in recurrent glioblastomaNeurology200973151200120619822869
  • KangTYJinTElinzanoHPeereboomDIrinotecan and bevacizumab in progressive primary brain tumors, an evaluation of efficacy and safetyJ Neurooncol200889111311818438609
  • ZunigaRMTorcuatorRJainREfficacy, safety and patterns of response and recurrence in patients with recurrent high-grade gliomas treated with bevacizumab plus irinotecanJ Neurooncol200991332933618953493
  • AnanthnarayanSBahngJRoringJTime course of imaging changes of GBM during extended bevacizumab treatmentJ Neurooncol200888333934718389177
  • GonzalezJKumarAJConradCALevinVAEffect of bevacizumab on radiation necrosis of the brainInt J Radiat Oncol Biol Phys200767232332617236958
  • KumarAJLeedsNEFullerGNMalignant gliomas: MR imaging spectrum of radiation therapy- and chemotherapy-induced necrosis of the brain after treatmentRadiology2000217237738411058631
  • TorcuatorRZunigaRMohanYSInitial experience with bevacizumab treatment for biopsy confirmed cerebral radiation necrosisJ Neurooncol2009941636819189055
  • LevinVABidautLHouPRandomized double-blind placebo-controlled trial of bevacizumab therapy for radiation necrosis of the CNSInt J Radiat Oncol Biol Phys2010 In press.
  • HigaGMAbrahamJBiological mechanisms of bevacizumab-associated adverse eventsExpert Rev Anticancer Ther200997999100719589038