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Keywords:

  • antiangiogenesis;
  • bevacizumab;
  • glioma;
  • glioblastoma;
  • vascular endothelial growth factor

Abstract

  1. Top of page
  2. Abstract
  3. Angiogenesis and Malignant Gliomas
  4. Bevacizumab for the Treatment of Malignant Gliomas
  5. Efficacy of Bevacizumab
  6. Safety Profile of Bevacizumab
  7. Practical Issues Surrounding Bevacizumab Administration
  8. Forward Outlook
  9. DISCUSSION
  10. CONFLICT OF INTEREST DISCLOSURES
  11. REFERENCES

Despite advances in adjuvant therapy, the prognosis for most patients with high-grade glioma (HGG) is poor, and almost all HGGs have a likelihood of disease recurrence. HGGs are highly vascularized tumors with elevated expression levels of vascular endothelial growth factor (VEGF), an important mediator of angiogenesis. A compelling biologic rationale, a pressing need for improved therapeutics and positive results from studies of bevacizumab in other tumor types, led to the evaluation of bevacizumab in the treatment of HGG. It was demonstrated previously that bevacizumab, which is a humanized monoclonal antibody that targets VEGF, improved outcomes when combined with chemotherapy (most commonly irinotecan) in patients with recurrent HGG; and, on the basis of an improved objective response rate in 2 prospective phase 2 studies, bevacizumab was granted accelerated approval by the US Food and Drug Administration as a single agent in patients with previously treated glioblastoma (GB). Bevacizumab-containing therapy has been associated with manageable, class-specific toxicity; however, severe treatment-related adverse events are observed in a minority of patients. Preliminary data on bevacizumab-based therapy in recurrent anaplastic gliomas, in the frontline treatment of GB, and in additional patient populations are also encouraging. With the goal of addressing unanswered questions regarding the optimal use of bevacizumab, the objective of the current review was to provide a summary of the clinical efficacy and safety data on bevacizumab in patients with HGG, the practical issues surrounding the administration of bevacizumab, and ongoing investigations of bevacizumab in additional brain tumor treatment settings. Cancer 2010. © 2010 American Cancer Society.

Glioblastoma (GB) is the most aggressive subtype of high-grade glioma (HGG) and is associated with a median survival of less than 15 months.1 Patients with anaplastic gliomas (AG) have a modestly better prognosis, with an estimated median survival of between 3 years (for anaplastic astrocytoma [AA]) and 7 years (for anaplastic oligodendroglial tumors).2, 3 Responses to treatment are observed in <10% of patients with recurrent GB, and the median progression-free survival (PFS) is estimated at 9 weeks and 13 weeks for patients with recurrent GB and AA, respectively.4 In 2005, a randomized phase 3 trial demonstrated that the addition of temozolomide (TMZ) to adjuvant radiation therapy was associated with an improvement in the median survival of patients with newly diagnosed GB from 12.1 months to 14.6 months.1 Although this treatment regimen is currently the standard of therapy for GB, there is still no clearly established standard of care for recurrent HGG.

Nearly all HGGs recur after initial therapy, and most patients do not survive beyond 1 year after the diagnosis of recurrent disease.4 In historic phase 2 trials of a variety of chemotherapeutics in patients with previously treated GB, response rates have not exceeded 6%, and 6-month PFS (PFS-6) rates have ranged between 9% and 28%.4-7 By contrast, therapies for recurrent AG have been associated with response rates of approximately 35%, and PFS-6 rates have ranged between 17% and 47%.4, 5, 7

Because reoperation and reradiation are treatment options for only a subset of patients, the majority of patients with progressive HGG are offered chemotherapy (investigational or best available) at the time of recurrence. Data from clinical trials have established antiangiogenic therapy with the humanized antivascular endothelial growth factor (anti-VEGF) monoclonal antibody bevacizumab (Avastin; Genentech, South San Francisco, Calif), with or without cytotoxic chemotherapy, as an active treatment option for patients with recurrent GB who have failed previous TMZ therapy,8 leading to the recent US. Food and Drug Administration (FDA) approval of single-agent bevacizumab in previously treated GB.9 Preliminary efficacy and safety data describing bevacizumab-based therapy in recurrent AG and additional neuro-oncology treatment settings, although emerging, also are of interest. This review will provide an overview of the role of angiogenesis in HGG and the development of bevacizumab-based treatment, the clinical efficacy and safety data on bevacizumab in this tumor setting, practical insights into bevacizumab administration, and a forward outlook on bevacizumab in other brain tumor treatment settings.

Angiogenesis and Malignant Gliomas

  1. Top of page
  2. Abstract
  3. Angiogenesis and Malignant Gliomas
  4. Bevacizumab for the Treatment of Malignant Gliomas
  5. Efficacy of Bevacizumab
  6. Safety Profile of Bevacizumab
  7. Practical Issues Surrounding Bevacizumab Administration
  8. Forward Outlook
  9. DISCUSSION
  10. CONFLICT OF INTEREST DISCLOSURES
  11. REFERENCES

Angiogenesis is the process by which new blood vessels form from existing vasculature by endothelial cell migration and proliferation. Although angiogenesis is a natural physiologic process, it is also required for tumor growth beyond 0.125 mm because of to the limits of oxygen and nutrient diffusion.10 Antiangiogenic strategies may be effective in the treatment of cancer in part because of the accessibility and genetic stability of endothelial cells, the finding that angiogenesis largely is absent in healthy adults, allowing for therapeutic selectivity, and the residence of tumor stem cells in the (potentially targeted) microvascular niche.11

Glioblastoma is 1 of the most vascularized cancers,12 and many preclinical studies use GB as a tumor model of angiogenesis.13 VEGF is an important regulator of angiogenesis that is highly expressed within brain tumors14; in GB, the highest levels of VEGF expression are observed in areas of necrosis and regions of endothelial proliferation.15, 16 The degree of both vasculature density and VEGF expression is correlated with the malignancy and aggressiveness of these tumors as well as with outcomes, such as clinical recurrence and survival.17-20

The antiangiogenic agents that were evaluated first in GB included the oral inhibitors thalidomide, lenalidomide (an analog of thalidomide), and carboxyamidotriazole as well as the copper-chelating drug penicillamine. The results with these first-generation antiangiogenic therapies, however, were disappointing—the demonstrated no additional clinical benefit compared with the standard of care, weak inhibition of VEGF-mediated angiogenesis, or a lack of survival benefit.21-25 Consequently, more recent investigations have focused on newer, more potent antiangiogenic agents.

Bevacizumab for the Treatment of Malignant Gliomas

  1. Top of page
  2. Abstract
  3. Angiogenesis and Malignant Gliomas
  4. Bevacizumab for the Treatment of Malignant Gliomas
  5. Efficacy of Bevacizumab
  6. Safety Profile of Bevacizumab
  7. Practical Issues Surrounding Bevacizumab Administration
  8. Forward Outlook
  9. DISCUSSION
  10. CONFLICT OF INTEREST DISCLOSURES
  11. REFERENCES

Initially, the addition of bevacizumab to standard chemotherapy produced significant clinical benefit (PFS and/or overall survival [OS]) in patients with previously untreated and pretreated metastatic colorectal cancer, advanced nonsmall cell lung cancer, and metastatic breast cancer.26-29 Despite the exclusion of patients with untreated central nervous system (CNS) metastases from the majority of early trials of bevacizumab, the combination of proven clinical activity in other solid tumors and the pressing need for improved therapeutics in patients with HGG resulted in considerable interest in evaluating bevacizumab for the treatment of HGG. Notably, a recent meta-analysis reported that patients with CNS metastases who received bevacizumab have had low rates of tumor-associated CNS hemorrhage consistent with historic rates in this patient population, providing subsequent evidence of the safety of these investigations.30 Bevacizumab was evaluated first in previously treated and recurrent HGG in combination with irinotecan, a topoisomerase I inhibitor, because of its activity with irinotecan-containing regimens in patients with metastatic colorectal cancer.26 An encouraging response rate (43%) was reported in an initial retrospective study in HGG,31 prompting the investigation of bevacizumab with irinotecan in subsequent phase 2 studies.32-37 Several mechanisms of action have been suggested for the antiglioma effect of antiangiogenic agents, including direct inhibition of tumor-associated neoangiogenesis, a direct antiglial effect on VEGF receptor-expressing tumor cells, disruption of the tumor stem cell microvascular niche, and improved vascular function or normalization (Fig. 1).13, 39, 42, 44 The tumor stem cell microvascular niche may represent an important target of antiangiogenic agents, because the resident glioma stem cells are a population of CD133-positive, nestin-positive, self-renewing, multipotent tumor-initiating cells that are relatively radioresistant and chemoresistant.38, 39

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Figure 1. Proposed mechanisms of antiangiogenic agents in malignant gliomas are illustrated. Tumor stem cells represent a potential target for antiangiogenic agents.38, 39 It is hypothesized that vascular normalization mediates multiple effects: reduced peritumoral edema, reduced contrast enhancement of the tumor, improved oxygen and drug delivery, and decreased tumor interstitial pressure.40-42 Antiangiogenic therapy also may sensitize endothelial cells to cytotoxic therapies.43

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Efficacy of Bevacizumab

  1. Top of page
  2. Abstract
  3. Angiogenesis and Malignant Gliomas
  4. Bevacizumab for the Treatment of Malignant Gliomas
  5. Efficacy of Bevacizumab
  6. Safety Profile of Bevacizumab
  7. Practical Issues Surrounding Bevacizumab Administration
  8. Forward Outlook
  9. DISCUSSION
  10. CONFLICT OF INTEREST DISCLOSURES
  11. REFERENCES

Combination therapy for recurrent glioblastoma

To date, the available clinical data for bevacizumab in GB are derived from phase 2 and retrospective studies (Table 1). In the first completed, prospectively designed, single-institution, phase 2 trial of bevacizumab and irinotecan for recurrent GB, 20 of 35 patients (57%) had at least a partial response (PR), and the PFS-6 rate was 46% (95% confidence interval [CI], 32%-66%).33 Investigators in the large, multicenter, randomized, noncomparative phase 2 BRAIN study evaluating bevacizumab with or without irinotecan in previously treated and recurrent GB subsequently reported a response rate of 38% (31 of 82 patients) with combination therapy and a median response duration of 4.3 months.34 The combination of bevacizumab and irinotecan was associated with a PFS-6 rate of 50% and a median OS of 8.7 months (95% CI, 7.8-10.9 months).34 In retrospective analyses and additional phase 2 studies, response rates with bevacizumab-based combination therapy have ranged between 38% and 62%, and PFS-6 rates have ranged between 30% and 46% in patients with recurrent GB, representing a significant improvement compared with historic outcomes in this patient population.31, 32, 37, 46, 47 An improvement in median OS (ranging from 31 weeks to 42 weeks) also has been observed with bevacizumab-based regimens relative to historic controls.33, 34, 46, 47 In a recent pilot study, investigators demonstrated that the combination of bevacizumab and concurrent radiotherapy was active and well tolerated in patients with recurrent, malignant glioma.48 In patients with recurrent GB (n = 20) who received bevacizumab and hypofractionated stereotactic radiotherapy, the overall response rate was 50%, the PFS-6 rate was 65%, and the median OS was 12.5 months.

Table 1. Outcomes With Bevacizumab-Containing Therapy in Recurrent Glioblastoma and Anaplastic Glioma
StudyTumor TypeRegimenRadiographic Response, %PFSMedian OS, mob
CR/PRaSDMedian, mobPFS-6, %PFS-12, %
  • PFS indicates progression-free survival; OS, overall survival; CR, complete response; PR, partial response; SD, stable disease; PFS-6, 6-month PFS rate; PFS-12, 12-month PFS rate; BV, bevacizumab; CT, chemotherapy; GB, glioblastoma; HGG, high-grade glioma; NA, not available; AG, anaplastic glioma; HFSRT; hypofractionated stereotactic radiotherapy; AO, anaplastic oligodendroglioma; AOA, anaplastic oligoastrocytoma.

  • a

    A single value indicates the combined CR+PR percentage.

  • b

    Median PFS and median OS (reported in weeks) were standardized to months using the following formula: weeks/52×12.

Key studies in recurrent GB        
 BV+CT        
  Stark-Vance 200531GB (n=11), other HGG (n=10)BV+irinotecan5/3852NANANANA
  Pope 200645GB (n=10), AG (n=4)BV+irinotecan or etoposide0/5021NANANANA
  Vredenburgh 200732GB (n=23), AG (n=9)BV+irinotecan3/5934NAOverall, 38; GB, 30NAGB, 9.23
  Vredenburgh 200733GB (N=35)BV+irinotecan57245.546209.7
  Friedman 200934GB (N=167)BV alone (n=85), BV+irinotecan (n=82)BV+irinotecan, 38NANABV+irinotecan, 50.2NABV+irinotecan, 8.7
  Norden 200846GB (N=33)BV+CTNA5.542NAGB+AG, 8.2 
  Nghiemphu 200947GB (N=123)BV+CT (n=44), CT or other agent(s) (control; n=79)NABV+CT, 4.25; control, 1.82BV+CT, 41; control, 18NABV+CT, 9.0; control, 6.1 
  Gilbert 200937GB (N=57)BV+irinotecanNANA37NANA 
 BV+radiotherapy        
  Gutin 200948GB (n=20)BV+HFSRT50NANA65NA12.5
 Single-agent BV        
  Friedman 200934GB (N=167)BV alone (n=85), BV+irinotecan (n=82)BV alone, 28NANABV alone, 42.6NABV alone, 9.2
  Kreisl 200936GB (N=48)BV[RIGHTWARDS ARROW]BV+irinotecanLevin criteria, 71; MacDonald criteria, 35NA3.729NA7.2
 Chamberlain & Johnston 201049GB (N=50)BV4242NA42228.5
  Raizer 200950GB (n=50), AA (n=5), AO/AOA (n=6)BV0/25503.932NA6.6
Key studies in recurrent AG        
 BV+CT        
  Norden 200846AG (N=21)BV+CT3459GB+AG, 5.532NAGB+AG, 8.2
  Desjardins 200835AG (N=33)BV+irinotecan9/52338.1553915
 Single-agent BV        
  Chamberlain & Johnston 200951AA (N=25)BV0/6486.760209.0
  Chamberlain & Johnston 200952AO (N=22)BV0/6856.7568238.5

Monotherapy for recurrent glioblastoma

In addition to its activity when combined with chemotherapeutics, it also has been demonstrated that bevacizumab increases response and PFS when administered as a single agent in patients with recurrent GB (Table 1).9, 34, 36 In the phase 2 BRAIN study of patients with GB who developed recurrent disease after TMZ treatment, the objective response rate with single-agent bevacizumab was 28% (24 of 85 patients), and the median response duration was 5.6 months.34 When responses in that study were calculated on the basis of radiographic criteria and stable or decreasing corticosteroid use, 25.9% of patients (95% CI, 17%-36.1%) responded to bevacizumab monotherapy.9 The PFS-6 rate with single-agent bevacizumab was 42.6% (95% CI, 29.6%-55.5%), and the median OS was 9.2 months (95% CI, 8.2-10.7 months).34 In the single-institution, prospective phase 2 National Cancer Institute (NCI) NCI 06-C-0064E study of 48 patients with recurrent GB who received single-agent bevacizumab, 71% and 35% of patients achieved a radiographic response based on Levin criteria and MacDonald criteria, respectively.36 When using radiographic criteria and stable or decreasing corticosteroid use as a measure of response, the objective response rate was 19.6% (11 of 56 patients; 95% CI, 10.9%-31.3%),9 the median PFS was 16 weeks (95% CI, 12-26 weeks), the PFS-6 rate was 29% (95% CI, 18%-48%), and the median OS was 31 weeks (95% CI, 21-54 weeks).36 The improved objective response rates observed in the BRAIN and NCI 06-C-0064E studies resulted in the accelerated approval of single-agent bevacizumab for patients with progressive GB after previous, upfront, TMZ-based therapy. Two additional studies (a phase 2 trial and a retrospective analysis) have evaluated single-agent bevacizumab in recurrent GB—response rates in those trials were 25% and 42%, respectively, and the PFS-6 rates were 32% and 42%, respectively.49, 50

Therapy for recurrent anaplastic gliomas

Bevacizumab treatment in patients with recurrent AG also has achieved favorable outcomes compared with historic controls, with response rates ranging between 34% and 68% and PFS-6 rates ranging between 32% and 68% for patients who received bevacizumab and chemotherapy.35, 46, 51, 52 Despite the improvements in response rates reported in those studies, no apparent survival benefit was observed: The median OS ranged between 36 weeks and 65 weeks in patients with recurrent AG who received bevacizumab treatment.35, 46, 51, 52

Safety Profile of Bevacizumab

  1. Top of page
  2. Abstract
  3. Angiogenesis and Malignant Gliomas
  4. Bevacizumab for the Treatment of Malignant Gliomas
  5. Efficacy of Bevacizumab
  6. Safety Profile of Bevacizumab
  7. Practical Issues Surrounding Bevacizumab Administration
  8. Forward Outlook
  9. DISCUSSION
  10. CONFLICT OF INTEREST DISCLOSURES
  11. REFERENCES

Overall, bevacizumab treatment is generally well tolerated in patients with recurrent GB, and the bevacizumab-related toxicities are similar to those that have been characterized in other solid tumor types. Reported rates of grade 3 or greater adverse events with bevacizumab in patients with recurrent GB have ranged between 18% and 66%, and it appears that the rate of serious treatment-related adverse events is lower when bevacizumab is used as a single agent.34, 36, 37, 49 In the randomized, noncomparative phase 2 BRAIN study in patients with progressive GB, the rate of grade 3 or greater adverse events was 46% in patients who received bevacizumab monotherapy and 66% in patients who received combined bevacizumab plus irinotecan.34 Cross-trial comparisons also have suggested that single-agent bevacizumab is associated with a lower rate of grade 3 adverse events than bevacizumab-containing combinations for GB; however, those observations were subject to differences in study design and patient populations.37, 49

The most common adverse events with bevacizumab treatment in recurrent GB include low-grade bleeding, hypertension, impaired wound healing, and proteinuria,32-34 which also were associated with bevacizumab in other cancer types.26, 28, 29 The majority of these toxicities appear to be caused by on-target, class-specific actions of antiangiogenic agents and reflect the disruption of VEGF in normal tissue. The rates of serious adverse events, such as gastrointestinal perforation, reversible posterior leukoencephalopathy syndrome, and wound-healing complications studies are low in GB studies(each ≤4% incidence) (Fig. 2).31-34, 46, 48, 50, 53 Although the reported rate of grade 2 or greater bleeding events has been as high as 5.3%, life-threatening intracranial hemorrhages have occurred in only a small percentage of patients (≤3%) treated with bevacizumab.31-34, 37, 46, 50 This latter incidence rate falls within the expected range for spontaneous events in patients with HGG (approximately 2%-3%).54, 55 Relatively high rates of thromboembolism have been reported in studies that evaluated bevacizumab-containing therapy in recurrent GB (ranging from 1.6% to 12.5%) (Fig. 2); however, these rates must be considered in the context of the significant risk of thromboembolic events that is inherent in patients with HGG.56 Thus, the cumulative data from clinical trials suggest that, despite small risks of life-threatening complications, including intracranial hemorrhages and thromboembolic events, bevacizumab-containing therapy is well tolerated with manageable, class-specific toxicities.

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Figure 2. Selected adverse events reported in large (≥35 patients) phase 2 studies and retrospective analyses of bevacizumab with33, 34, 37, 46 and without34, 36, 49, 52 chemotherapeutics in patients with recurrent glioblastoma are shown. BV indicates bevacizumab; CT, chemotherapy; An asterisk indicates clinical trials that also included patients with recurrent anaplastic gliomas (21 of 55 patients46 and 11 of 61 patients50); dagger, clinical trials that reported only grade ≥3 adverse events.

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Practical Issues Surrounding Bevacizumab Administration

  1. Top of page
  2. Abstract
  3. Angiogenesis and Malignant Gliomas
  4. Bevacizumab for the Treatment of Malignant Gliomas
  5. Efficacy of Bevacizumab
  6. Safety Profile of Bevacizumab
  7. Practical Issues Surrounding Bevacizumab Administration
  8. Forward Outlook
  9. DISCUSSION
  10. CONFLICT OF INTEREST DISCLOSURES
  11. REFERENCES

There are several practical issues related to treatment administration, combination therapy, contraindications and other safety-related issues, response evaluation, and disease course that are relevant to the use of bevacizumab for HGG (Table 2). With regard to administration, the recommended dose and schedule of single-agent bevacizumab is 10 mg/kg intravenously every 2 weeks in patients with recurrent GB.9 Although most studies in recurrent HGG have evaluated bevacizumab (in combination with irinotecan) on a schedule of 10 mg/kg every 2 weeks or a weekly equivalent dose of 15 mg/kg every 3 weeks, the ideal treatment schedule or dosage of bevacizumab is unclear, because no direct comparisons of different treatment schedules or dose-response studies have been conducted.57, 58 Consequently, until a benefit in efficacy and/or tolerability has been established with an alternative dosing regimen, bevacizumab should be administered as a single agent according to the prescribing information at a dose of 10 mg/kg every 2 weeks.

Table 2. Clinical Pearls: Practical Issues Regarding Bevacizumab Treatment in Patients with High-Grade Glioma
  1. GB indicates glioblastoma; NCI CTC, National Cancer Institute Common Toxicity Criteria; RANO, Response Assessment in Neuro-Oncology; HGG, high-grade gliomas; FLAIR, fluid-attenuated inversion recovery; MRI, magnetic resonance imaging.

Administration and concomitant treatment
 • The recommended dose and schedule of single-agent bevacizumab in patients with recurrent GB is 10 mg/kg intravenously every 2 wk until disease progression or unacceptable toxicity.
 • Dose reductions of bevacizumab are not required in patients who are receiving enzyme-inducing, antiepileptic drugs.
 • There appears to be no increased risk of intracranial hemorrhage with the concurrent use of bevacizumab and anticoagulants.
Safety considerations
 • Treatment with bevacizumab should be discontinued for specific severe adverse events, including symptomatic intracranial hemorrhage, wound dehiscence, and bowel perforation. Other important adverse events that warrant discontinuation of bevacizumab include medically refractory hypertension, proteinuria (NCI CTC grade >2), and arterial/venous thrombosis.
 • Bevacizumab-based therapy should be suspended within 4 to 6 wk of surgery.
 • Blood pressure should be assessed before each bevacizumab administration and proteinuria should be monitored by urine protein/creatinine ratio every cycle or every other cycle.
Response to therapy and disease course
 • It is not yet established which brain tumor radiographic response criteria (ie, Levin, MacDonald, or RANO) are best for evaluating antiangiogenic therapies.
 • Bevacizumab therapy is associated with a clinically meaningful corticosteroid sparing effect in >33% of patients with HGG.
 • The results of a recent retrospective analysis support the inclusion of older patients (aged ≥55 y) in studies of bevacizumab in HGG.
 • Antiangiogenic therapy appears to be cytostatic and likely requires long-term, continuous treatment.
 • An increased FLAIR MRI signal appears to be the best indicator of progressive disease, although this is best appreciated retrospectively and by serial imaging.
 • The appropriate options are unclear for patients with HGG who develop disease progression after antiangiogenic treatment; the current data do not support the use of bevacizumab with irinotecan for patients with progressive disease after single-agent bevacizumab nor bevacizumab with carboplatin after treatment with bevacizumab and irinotecan.

It is also unclear which therapeutic agent, if any, should be combined with bevacizumab to improve efficacy in recurrent HGG. The similar response and PFS-6 rates observed with bevacizumab monotherapy relative to bevacizumab plus chemotherapy (predominantly irinotecan), combined with the limited single-agent activity of irinotecan in recurrent GB, have led investigators and the FDA to argue that it is unclear whether irinotecan contributes additional clinical benefit to bevacizumab-based regimens in recurrent HGG.36, 59-63 For these reasons, along with the observation that higher rates of grade 3 or greater adverse events are associated with the combination of chemotherapy and bevacizumab, the addition of irinotecan does not appear to be justified at this time. The identification of an alternative partner for bevacizumab currently is an active area of research; for example, phase 2 studies are evaluating bevacizumab with erlotinib (an epidermal growth factor receptor tyrosine kinase inhibitor), etoposide (a topoisomerase II inhibitor), and fotemustine (a second-generation nitrosourea) in recurrent HGG.20, 64, 65

Clinical experience suggests that bevacizumab is not contraindicated in patients who are receiving other concomitant medications, such as enzyme-inducing antiepileptic drugs (EIAEDs) or anticoagulants. Dose modifications of bevacizumab generally are not required, even when administered to patients who are receiving EIAEDs like phenytoin or carbamazepine.32, 33 In addition, there does not appear to be an increased risk of hemorrhage (intracranial or extracranial) with or without the concurrent use of bevacizumab with anticoagulants46, 66; in a retrospective review of thromboembolic events in 21 patients with HGG, the investigators concluded that the use of anticoagulants did not lead to any major hemorrhages and did not appear to prohibit the initiation or continuation of bevacizumab therapy.66

However, there are specific severe adverse events that occur at a relatively low incidence but that require dose delays or cessation of bevacizumab. Compelling indications for discontinuing bevacizumab therapy include intracranial hemorrhage (Common Toxicity Criteria grade 2 or greater), bowel perforation, and wound dehiscence53; and temporary suspension of bevacizumab is recommended 4 weeks before surgery and for patients who have evidence of moderate-to-severe proteinuria or severe hypertension that is not controllable with medication.9 It has been demonstrated that the blockade of VEGF impairs wound healing, and several studies have indicated a small risk of wound dehiscence, either at the site of the craniotomy or at the central venous line.31-34, 45, 46, 67 In practice, this observation mandates that antiangiogenic therapy not commence until the craniotomy (or surgical wound) is healed, which may require 4 to 6 weeks. It is noteworthy that there are differences in the frequency of monitoring for select bevacizumab-related side effects, such as proteinuria, between clinical trials and current clinical practice; based on clinical trial protocols, testing the urine protein/creatinine ratio is recommended either with every cycle or with every other cycle of bevacizumab.

Clinical experience has delineated the challenges of determining patient response and disease course after treatment with antiangiogenic agents in HGG. Currently, there are no clear guidelines for evaluating neuroradiographic response or progression because of limitations of standard MacDonald response criteria, and it remains unclear what constitutes the best response criteria for antiangiogenic therapies.36, 68 Proposed methods for measuring antiangiogenesis include assaying for angiogenic factors (eg, serum or urinary VEGF, basic fibroblast growth factor, matrix metalloproteinase, or urokinase plasminogen activator) or for ex vivo markers (eg, circulating endothelial cells); biopsy analysis (to determine tumor density and drug-target interactions); and radiographic assessment (calculating fluoro-L-thymidine-positron emission tomographic response, changes in the apparent diffusion coefficient, or the ratio of fluid-attenuated inversion-recovery [FLAIR] volume to contrast-enhancing tumor volume).67, 69-73 In addition, there is no current consensus regarding the most effective method for a priori determination of response to bevacizumab treatment. Common practice in patients with recurrent HGG who receive bevacizumab involves magnetic resonance imaging (MRI) evaluations after 2 cycles of treatment and, if the patient is stable or responding, then MRI evaluations after every subsequent 4 cycles of bevacizumab.

A secondary benefit of bevacizumab in patients with HGG is its demonstrated ability to decrease both tumoral and peritumoral edema in patients with HGG, thereby reducing the requirement for chronic corticosteroid use. Several studies have reported that corticosteroid reductions were feasible in 33% to 59% of patients with recurrent GB after bevacizumab treatment,32, 34, 36, 46, 49, 74 and 2 trials have reported average corticosteroid dose reductions of 72% and 59%,36, 74 respectively. The ability of bevacizumab-based therapy to reduce corticosteroid usage is an important benefit, because chronic corticosteroid use in patients with HGG is associated with significant morbidity and numerous side effects, including a Cushingoid pattern of weight gain, hyperglycemia, skin fragility, and bleeding; myopathy; lymphopenia; infection; and thromboembolism.75-77

It is noteworthy that a recent retrospective analysis in recurrent GB comparing outcomes between patients who received bevacizumab treatment (n = 44) and patients in a control group (n = 79) suggested that the effect of bevacizumab is greater in older patients.47 In the older cohort (patients aged ≥55 years), bevacizumab treatment was associated with a significant improvement in both PFS (P = .02) and OS (P = .03) relative to the control group. By contrast, no treatment-related differences in outcomes were observed in younger patients (aged <55 years). The authors hypothesized that this age-dependent response may be reflective of biologic differences (eg, VEGF expression levels) in GB between various age groups.47 At a minimum, these results support the applicability of bevacizumab for older patients with GB.

Despite clear evidence of bevacizumab activity in recurrent HGG, not all patients respond to treatment, and no biomarkers for patients who are responsive to antiangiogenic therapies have been identified. One explanation for the lack of response after bevacizumab treatment is that antiangiogenic therapy treats only 1 of several tumor compartments—the angiogenic-dependent, contrast-enhancing component—and does not target the highly infiltrative, migratory, angiogenic-independent compartment (eg, the leading edge of infiltrating glioma cells [FLAIR-defined tumor volume]).53, 68 In a retrospective analysis, a diffuse, infiltrative pattern of recurrence was observed in 8 or 40 patients (20%; 95% CI, 9%-36%) who received salvage bevacizumab treatment for recurrent GB.78 Although those authors noted that this pattern of recurrence appeared to be more prevalent with bevacizumab treatment, the analysis, because it lacked a control arm, did not provide a corresponding baseline value to establish a more definitive association for this recurrence pattern. It is known that abrupt cessation of anti-VEGF therapy may result in rebound edema and clinical deterioration (the so-called flare response), activation of non-VEGF proangiogenic stimuli, and the emergence of highly proliferative tumor clones, suggesting that antiangiogenic therapy is cytostatic rather than cytocidal.79 Consequently, in stable or responding patients who receive bevacizumab, long-term, continuous treatment is required.80 FLAIR MRI, in conjunction with clinical symptoms, appears to be the best indicator of progressive disease, and an increased FLAIR signal often precedes the re-emergence of contrast-enhancing tumor.45, 46, 51, 52

Determining appropriate treatment options for patients with HGG who progress after bevacizumab treatment is of significant clinical interest and is another area of active investigation. In 2 retrospective studies, it was observed that patients who progressed (after an initial response) on frontline treatment with a bevacizumab-containing regimen rarely responded to bevacizumab combined with alternative chemotherapy upon disease progression: The reported PFS-6 rate was 2%, and long-term disease control was achieved in 9.5% of patients, respectively.46, 81 Additional studies have reported that patients who received bevacizumab plus irinotecan or an alternative cytotoxic therapy after progression on single-agent bevacizumab had poor outcomes: Zero of 19 patients had radiographic responses in a prospective phase 2 study, and a median OS of 2 months (range, 1-5 months) was reported in a retrospective analysis.36, 49 In a recent study of 35 patients with GB who progressed after treatment with bevacizumab and irinotecan, continuous low-dose TMZ was added to bevacizumab and irinotecan. The authors concluded that this regimen appears to have activity in patients with previously treated GB (partial responses in 11.4%, stable disease for ≥2 months in 40%, and a median survival of 5 months [range, 2-13 months]).82 Further investigation is necessary, however, to confirm these preliminary results. Patients with GB who progress after an initial response to bevacizumab represent a challenging patient population. These patients are offered and increasingly will be offered novel investigational treatments, such as vascular-disrupting agents, therapies that target cell migration, and alternative antiangiogenic therapies (ie, therapeutics that target basic fibroblast growth factor; stromal cell-derived factor-1α; the TEK tyrosine kinase receptor, endothelial Tie2; hepatocyte growth factor; and the c-Met receptor83).

Forward Outlook

  1. Top of page
  2. Abstract
  3. Angiogenesis and Malignant Gliomas
  4. Bevacizumab for the Treatment of Malignant Gliomas
  5. Efficacy of Bevacizumab
  6. Safety Profile of Bevacizumab
  7. Practical Issues Surrounding Bevacizumab Administration
  8. Forward Outlook
  9. DISCUSSION
  10. CONFLICT OF INTEREST DISCLOSURES
  11. REFERENCES

Because of the positive clinical results observed in recurrent GB, bevacizumab continues to be evaluated in additional treatment settings. Data from clinical trials of bevacizumab in the treatment of recurrent AG are emerging, as discussed above, and suggest that bevacizumab may improve response and PFS-6 rates compared with historic controls.35, 46, 51, 52

There also are several ongoing and planned studies evaluating bevacizumab in patients with newly diagnosed GB, and several studies recently reported preliminary data on the use of bevacizumab with chemoradiation in this treatment setting.84-89 The initial results suggest that the addition of bevacizumab to the upfront management of GB is associated with acceptable toxicity and promising activity. Early efficacy results in 2 studies evaluating bevacizumab with radiotherapy and TMZ for the treatment of newly diagnosed GB compare favorably with data from a historic European Organization for Research and Treatment of Cancer/National Cancer Institute of Canada Clinical Trials Group trial.1, 86, 87 One of those studies reported that the addition of bevacizumab resulted in an improved median PFS of 13 months (95% CI, 11.3-15.9 months) compared with 6.9 months (95% CI, 5.9-8.2 months) in the historic study.87 It is noteworthy that 2 large phase 3 trials—Radiation Therapy Oncology Group (RTOG) trial RTOG-0825 (a US-based study sponsored by the RTOG) and AVAglio (a global study sponsored by Roche Pharmaceuticals of bevacizumab combined with standard-of-care therapy after surgery in patients with GB multiforme)—have opened this year and will prospectively evaluate bevacizumab-containing regimens in patients with newly diagnosed GB. The results from those studies are needed to establish the safety (including the potential for wound-healing complications) and efficacy of combining bevacizumab with radiotherapy and TMZ in the frontline setting for newly diagnosed GB.

Because a secondary benefit of bevacizumab therapy is a marked improvement of peritumoral edema, leading to reductions in or discontinuance of chronic corticosteroid use, bevacizumab also may be useful in the management of symptomatic patients who have suspected pseudoprogression after concurrent TMZ and radiation for newly diagnosed GB90 and in patients who have inoperable, newly diagnosed GB complicated by large, corticosteroid-dependent tumor masses. In addition, there are indications that bevacizumab may be beneficial in patients with other brain tumors and CNS disorders, such as radiation-induced necrosis with mass effect,74, 91, 92 and highly angiogenic, nonglioma, recurrent primary brain tumors like meningioma, medulloblastoma, ependymoma,93 oligodendroglial tumors,52, 94, 95 neurofibromatosis 2-related vestibular schwannomas,96 and radiation-induced myelopathy.97

DISCUSSION

  1. Top of page
  2. Abstract
  3. Angiogenesis and Malignant Gliomas
  4. Bevacizumab for the Treatment of Malignant Gliomas
  5. Efficacy of Bevacizumab
  6. Safety Profile of Bevacizumab
  7. Practical Issues Surrounding Bevacizumab Administration
  8. Forward Outlook
  9. DISCUSSION
  10. CONFLICT OF INTEREST DISCLOSURES
  11. REFERENCES

Antiangiogenic agents hold great promise for the treatment of HGG—a malignant disease associated with poor patient prognosis. Bevacizumab is the best characterized antiangiogenic therapy and recently received FDA approval as a single agent for the treatment of patients with progressive GB after previous upfront, TMZ-based therapy. In addition to its use as monotherapy for recurrent GB, preliminary data with bevacizumab in recurrent AG and in additional treatment settings appear promising, and these are areas of active clinical investigation. Overall, treatment with bevacizumab in multiple GB studies appears to be well tolerated with toxicity (ie, bleeding, hypertension, wound dehiscence, proteinuria, intracranial hemorrhage, and thromboembolism) similar to that observed in other solid cancers treated with bevacizumab-containing therapies.

Because of the extensive clinical experience with bevacizumab, practical issues regarding its administration, safety profile, and response to treatment have been described. Notwithstanding this knowledge, several important questions about the use of bevacizumab in HGG remain unanswered—for example, the optimal therapeutic partner, dosage, treatment schedule, and radiographic response criteria of bevacizumab all are unknown, as are the treatment options that should be offered to patients who progress on bevacizumab-based therapy. Many of these unanswered questions are being addressed in on-going clinical trials, and the results from those trials likely will to continue to drive improvements in the treatment of patients with HGG.

CONFLICT OF INTEREST DISCLOSURES

  1. Top of page
  2. Abstract
  3. Angiogenesis and Malignant Gliomas
  4. Bevacizumab for the Treatment of Malignant Gliomas
  5. Efficacy of Bevacizumab
  6. Safety Profile of Bevacizumab
  7. Practical Issues Surrounding Bevacizumab Administration
  8. Forward Outlook
  9. DISCUSSION
  10. CONFLICT OF INTEREST DISCLOSURES
  11. REFERENCES

Support for third-party writing assistance for this article was provided by Genentech, Inc. Dr. Chamberlain participates as an advisory board member for Genentech, for which he has received honoraria.

REFERENCES

  1. Top of page
  2. Abstract
  3. Angiogenesis and Malignant Gliomas
  4. Bevacizumab for the Treatment of Malignant Gliomas
  5. Efficacy of Bevacizumab
  6. Safety Profile of Bevacizumab
  7. Practical Issues Surrounding Bevacizumab Administration
  8. Forward Outlook
  9. DISCUSSION
  10. CONFLICT OF INTEREST DISCLOSURES
  11. REFERENCES
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