Antivascular Endothelial Growth Factor Antibody for Treatment of Glioblastoma Multiforme
Perm J 2013 Fall;17(4):68-74
Despite aggressive investigation, glioblastoma multiforme (GBM) remains one of the deadliest cancers, with low progression-free survival and high one-year mortality. Current first-line therapy includes surgery with adjuvant radiation therapy and cytotoxic chemotherapy, but virtually all tumors recur. Given the highly vascular nature of GBM and its high expression of vascular endothelial growth factor and other angiogenic factors, recent investigation has turned to bevacizumab, an antivascular endothelial growth factor monoclonal antibody, for treatment of recurrent GBM. Phase 2 studies demonstrated the efficacy and safety of bevacizumab therapy for recurrent GBM, which led to its approval by the US Food and Drug Administration in 2009 for use in recurrent GBM. Since then, several new Phase 2 studies and retrospective series have demonstrated that bevacizumab significantly increased six-month progression-free survival in patients with recurrent GBM and may do so in new-onset GBM. The objective of this review is to provide a collective resource for these materials, highlighting the efficacy and safety of bevacizumab and calling for increased investigation toward its optimal application in the management of high-grade glioma.
Glioblastoma multiforme (GBM) is a highly aggressive tumor with a rapid progression and poor prognosis. This tumor comprises nearly 50% of gliomas and 25% of all primary brain tumors.1-3 According to the most recent report from the Central Brain Tumor Registry of the United States, there are approximately 10,000 new cases of GBM recorded annually in the US.3 The development of GBM is positively correlated with age, reaching a peak in gross incidence at 45 to 64 years4 and highest per capita incidence at ages 74 to 85 years.3
Unfortunately, GBM is the most deadly form of glioma, classified as Stage 4 infiltrative glioma by the World Health Organization.5 The median overall survival is poor, ranging from 9 to 19 months in maximally treated patients,6,7 and the 1-year survival rate has been recorded at approximately 32%.2 Survival rates have historically increased with the advent of new surgical techniques and chemotherapeutic options,2 and they continue to slowly rise.4 GBM, however, recurs almost universally regardless of treatment regimen.
The extent of surgical resection is an independent risk factor for survival, with gross total resection increasing survival.6,8,9 However, even those patients with radiographically demonstrated resection in excess of 98% tumor volume experience nearly 100% recurrence, presumably because of the persistence of quiescent glioblastoma tumorigenic stem cells.8,10
Standard therapy for GBM involves surgical resection to the maximal extent possible with adjuvant radiotherapy and chemotherapy. Initial studies examined nitrosourea-based compounds to target GBM because of their lipophilicity and ability to cross the blood-brain barrier. Large meta-analyses have revealed that lomustine and carmustine in combination with whole-brain radiation or stereotactic radiotherapy yielded only modest results, with 1-year survival up to 35%, a 6% increase compared with radiotherapy alone.11 Phase 2 trials for combinations of carboplatin, procarbazine, and fluorouracil were similarly unimpressive, reaching a 1-year survival proportion of 32%.12
Temozolomide (Temodar, Schering-Plough Corp, Kenilworth, NJ) is an alkylating agent approved by the US Food and Drug Administration (FDA) for use in newly diagnosed GBM,13 which has been successfully used in the treatment of GBM. The Stupp protocol demonstrated increased survival of 2.5 months (12.2 months to 14.6 months) with the addition of temozolomide at dosages of 75 mg/m2/day for 7 days during radiotherapy and not exceeding 49 days.7,14,15 Following a 4-week break in therapy, temozolomide was administered again for 5 days in 28-day cycles for between 1 and 6 cycles. The study demonstrated a survival benefit at 2 years of 27.2% for patients receiving adjuvant temozolomide after maximal surgical resection, up from 10.9% in patients with adjuvant radiotherapy alone.7 The survival benefit at 5 years was 9.8% for patients with combination therapy compared with 1.9% for patients who received radiation therapy alone.7,14,15
With the advent of temozolomide for the treatment of GBM, a new gene product was identified that conferred survival advantage. Expression of O6-methylguanine-DNA methyltransferase (MGMT), an enzyme involved in DNA repair, was linked to shorter survival.16 The epigenetic silencing of the MGMT expression by methylation of the promoter was linked with a survival advantage in patients receiving temozolomide, with an overall survival of 18.2 months in patients with MGMT methylation compared with 12.2 months in patients without MGMT methylation.16
Despite chemotherapy and radiation, GBM universally recurs, and at recurrence the disease rapidly becomes lethal.12 Some of the treatments considered at recurrence were repeated surgery, repeated irradiation, or other chemotherapies,17,18 which all have yielded less than modest results. Because of the altered signaling pathways and frequent mutations found in GBM, the focus of therapy has shifted toward the use of biologics and target-specific molecular drugs for treatment.18 Bevacizumab (Avastin, Genentech, South San Francisco, CA) is a humanized antivascular endothelial growth factor (anti-VEGF) immunoglobulin G1 monoclonal antibody that was granted accelerated FDA approval in 2009 as a single-agent therapy for use in recurrent GBM refractory to prior chemotherapy or radiotherapy (Figure 1).19 This review will evaluate the theoretical mechanism of bevacizumab and its use and efficacy in treating glioma, to demonstrate the benefits it yields for well-selected patients with newly diagnosed or recurrent GBM.
Angiogenesis, Vascular Endothelial Growth Factor, and Glioblastoma
Angiogenesis, the process of creating new blood vessels and vascular branches from preexisting tissues, is a vital component of tumorigenesis; it is required for solid tumor growth beyond a 0.125-mm radius because of limitations in nutrient and oxygen diffusion capacity.20 This process requires an abundance of unique growth factors and cell adhesion molecules, which include different isoforms of VEGF (VEGF-A, VEGF-B, VEGF-C, and VEGF-D) as well as platelet-derived growth factor.21 A receptor tyrosine kinase ligand, VEGF-A has been identified as a key promotor of tumor angiogenesis.22 In tumor microenvironments such as GBM, VEGF secretion is increased to promote abnormal angiogenesis.23 In GBM, the highest concentrations of VEGF are found in areas of necrosis and hypoxia in the tumor, because VEGF production is stimulated in tumorigenic glial cells by hypoxia and the concomitant upregulation of hypoxia inducible factor-1.24 The resultant vasculature is often abnormal, creating the potential for the development of new areas of necrosis and hypoxia, thus continuing the cycle.24 Both the density of the microvasculature and the level of VEGF secretion in glial tumors have been associated with tumor grade and clinical outcomes, with low overall survival scores for patients who expressed high levels of messenger RNA secretion.18,25-27 Therefore, the development of an antiangiogenic biologic therapy targeting VEGF-A for highly vascular tumors such as glioblastoma gained popularity.28 It is postulated that anti-VEGF-A immunoglobulin G acts by sequestering VEGF and therefore preventing the protein from initiating the signaling cascade, which will lead to recruitment of endothelial cells and proliferation of blood vessels (Figure 2).
In glioma models the preclinical data for the use of bevacizumab showed that the tumors exhibited microvascular regression, normalization of mature blood vessels, and inhibition of new vessel growth.29 Clinical trials demonstrated efficacy of bevacizumab and led to FDA approval for use in malignant colorectal cancer in 2004 and recurrent glioblastoma in 2009.22 Two independent, randomized, prospective trials of bevacizumab for recurrent GBM demonstrated an increase in progression-free survival (PFS) of 3.9 to 4.2 months in patients with recurrent disease already treated with prior surgery, radiotherapy, and temozolomide.19 Bevacizumab received accelerated approval as single-agent therapy for recurrent GBM refractory to surgical treatment, chemotherapy, and radiotherapy.19
Bevacizumab Use in Glioblastoma
Most investigations into bevacizumab therapy for GBM have consisted of Phase 2 trials to determine safety and efficacy of the biologic agent in patients who have recurrence of GBM after attempting first-line surgical resection followed by adjuvant radiotherapy and temozolomide chemotherapy. The primary endpoint for these studies was 6-month PFS30; the North American Brain Tumor Consortium uses 6-month PFS as the efficacy endpoint of therapeutic trials for adult patients with recurrent high-grade gliomas.31 Historic evidence suggests that 6-month PFS in absence of treatment of recurrent GBM ranges from 9%30 to 16%.31 These findings are based on retrospective data from pooled trials of nonefficacious therapies; most investigators usually tailor their studies to demonstrate the presence or lack of a significant difference from this baseline.
Patient populations are typically selected on the basis of performance status, failure of first-line therapy with radiologic proof of disease progression, and lack of major comorbidities in light of a histologic diagnosis of Grade 4 glioma. Exclusion criteria generally include previous treatment with carmustine wafer or anti-VEGF agents; history of bleeding diathesis, intracranial hemorrhage, or coagulopathy; clinically significant cardiovascular disease; recent arterial thromboembolism; uncontrolled hypertension; and Karnofsky performance score less than 70.19,32,33
In the first prospective Phase 2 trial of bevacizumab, Vredenburgh et al34 administered irinotecan, a topoisomerase inhibitor, as conjunctive adjuvant therapy because of the combination's history of success in colorectal cancer. They observed partial or complete response in 20 (57%) of 35 patients, with a 6-month PFS rate of 46% (n = 16; 95% confidence interval [CI], 32%-66%),34 in excess of the baseline 6-month PFS rate of 9% to 16% in 345 untreated patients with recurrent GBM.30,31 A study sponsored by Genentech demonstrated similar findings, noting a 6-month PFS rate of 36.0% (n = 31; CI, 25.0%-47.0%) in a Phase 2 trial of bevacizumab and irinotecan in 85 patients.19 Since that time, multiple authors have documented 6-month PFS rates for bevacizumab and irinotecan combination therapy between 25% and 40% (Table 1).35-38 Friedman et al32 performed a large trial both with and without combination irinotecan therapy. They found a 6-month PFS rate of 42.6% (CI, 29.6%-55.5%) in patients receiving combination irinotecan-bevacizumab therapy and a 6-month PFS rate of 50.3% (CI, 36.8%-63.9%) in those receiving single-agent bevacizumab, with no significant difference in 6-month PFS or median PFS between the 2 arms. Investigation into bevacizumab monotherapy has yielded similar results. Kreisl et al39 recorded a 6-month PFS rate of 29% (n = 14; CI, 18%-48%) in a Phase 2 trial of 48 patients, and Chamberlain and Johnston40 found a 6-month PFS rate of 42% (n = 21) in a retrospective review of 50 patients using bevacizumab monotherapy. Overall, the results between single-agent bevacizumab and combination therapy with cytotoxic agents, specifically irinotecan, have been similar to date, with no clear superiority among either regimen.
New combination therapies are currently under clinical investigation as well. Hasselbalch et al33 combined adjuvant bevacizumab therapy with irinotecan and cetuximab, a monoclonal anti-epidermal growth factor antibody also used in colorectal cancer, and reported a 6-month PFS of 33% (n = 14; CI 19%-48%) among 43 patients. Gutin et al41 administered hypofractionated stereotactic radiotherapy in combination with bevacizumab for treatment of recurrent GBM in 20 patients and reported a 65% (n = 13; CI unreported) 6-month PFS. Additionally, Sathornsumetee et al42 combined bevacizumab with erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor, in 25 patients with recurrent GBM and found a 6-month PFS rate of 29.2% (n = 7).
These studies are noncomparative, Phase 2 safety studies, and there is no statistically significant evidence to indicate the comparative effectiveness of bevacizumab in single-agent or combination therapy for recurrent GBM. However, all studies in our literature search, regardless of combination therapy, reported 6-month PFS rates in excess of 25% (Table 1), suggesting that there may be benefit to bevacizumab therapy in delaying disease progression.
Bevacizumab is typically well tolerated by patients, and its side effect profile in those with GBM is equivalent to the adverse events encountered in patients receiving bevacizumab therapy for malignant colorectal cancer, non-small-cell lung cancer, and metastatic breast cancer.43 In trials of bevacizumab for recurrent GBM, the most commonly encountered Grade 3 or 4 adverse events (graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0)44 include hypertension, hemorrhage (eg, epistaxis, intracranial), thromboembolic complications, and convulsions.32 Other serious adverse events reported in the literature include proteinuria, gastrointestinal tract perforation, wound healing complications, reversible posterior leukoencephalopathic syndrome, intractable convulsion, and neutropenia,32 but the frequency of such outcomes is generally very low (< 4% in large studies).19,32
The overall rate of Grade 3 or greater adverse events in studies of bevacizumab to date has ranged from 12% to 66%32,35 (Table 2). These events are hypothesized to be caused by the incidental effect of anti-VEGF blockade on the vasculature of normal healthy tissues or caused by postoperative wound healing complications presumably caused by inhibition of neovascularization of wound tissue in neurosurgical patients.18 Although there are no formal recommendations for the interval between surgery and initiation of bevacizumab therapy in patients after repeated surgical resection of GBM, most studies in the literature cite 3 to 4 weeks as an appropriately safe interval.41,45 Neurosurgeons and neuro-oncologists should be wary of the potential for adverse outcomes with premature repeated operation in patients using bevacizumab who require additional resection of tumor after initiation of adjuvant chemotherapy.
Grade 5 events (ie, those leading to death) are rare, occurring in less than 3.6% of patients (Table 2). Causes of mortality in clinical studies thus far include infection secondary to drug-induced neutropenia, pulmonary embolism, and intracranial hemorrhage.19,32,38 Even in studies in which fatal intracranial hemorrhage occurred,38 the rate of hemorrhage approaches the expected incidence of intracranial hemorrhage in patients with intracranial malignancy in the absence of treatment (approximately 2.5%).46
There is some evidence that single-agent bevacizumab is associated with lower rates of Grade 3 or higher adverse events than combination therapy with irinotecan.18,38,40 Chamberlain et al40 and Kreisl et al38 noted Grade 3 or greater adverse events in only 24.0% to 27.1% of enrolled patients receiving single-agent bevacizumab therapy, whereas benchmark studies for combined bevacizumab and irinotecan treatment, such as by Friedman et al,32 found rates of Grade 3 or greater adverse events as high as 65.8%. Regardless, these data are limited to cross-trial comparisons of different study populations. Friedman and colleagues' own single-agent bevacizumab arm had Grade 3 or greater adverse events in 46.4% of patients, and any differences in the safety profile of single-agent or combined therapies of bevacizumab are still speculative at this time.
Prospects for Future Use
More recent investigations have led to the experimental use of bevacizumab as combination therapy with first-line adjuvant radiotherapy and temozolomide after surgical resection of new-onset GBM. Vredenburgh et al47 treated 125 patients with bevacizumab, radiotherapy, and temozolomide beginning 4 weeks after surgical resection and found no increase in patient dropout compared with similar trials of radiotherapy and temozolomide in the absence of bevacizumab. They found that 93% of patients were able to tolerate combined adjuvant therapy of irradiation, temozolomide, and bevacizumab compared with an 83% completion rate in similar trials of temozolomide and irradiation alone.47 Importantly, less than 2% of patients enrolled experienced clinically significant intracranial hemorrhage or craniotomy wound dehiscence despite theoretical concerns of increased risks of wound healing complications.47 Furthermore, the median PFS was measured at 13.8 months, which compared favorably with the median PFS of 6.9 months in similar temozolomide and radiotherapy trials.14
Lai et al45 also treated 70 patients with adjuvant bevacizumab, temozolomide, and radiotherapy in new-onset GBM and recorded a statistically significant increase in 6-month PFS (range, 7.6 months to 13.6 months) without change in median overall survival compared with accumulated data of radiotherapy plus temozolomide without bevacizumab given at their institution.
These were noncomparative trials to determine the efficacy and safety of bevacizumab in combination with radiotherapy and temozolomide. Bevacizumab is currently labeled for use only in patients with recurrent GBM with progression after the options of surgical resection, radiotherapy, and temozolomide chemotherapy have been exhausted. Phase 2 studies of temozolomide have shown a 6-month PFS of 13% to 29% (95% CI) in temozolomide-treated patients48; these studies suggest that bevacizumab may provide clinical benefit above this benchmark. The potential safety of bevacizumab after a sufficient postoperative interval is theorized to increase the clinical benefit of angiogenic inhibition and to improve the clinical effect of bevacizumab.47
Glioblastoma multiforme is a highly aggressive and deadly class of malignancy. Patients receiving this diagnosis have on average less than a year to live, and even those who respond to first-line therapy will likely face most of that time neurologically impaired or debilitated. Furthermore, the financial expense of bevacizumab is daunting. One study estimated the cost per quality-adjusted life year for use in colorectal and breast cancer at approximately $300,000.49 Even for these neurologically intact patients, only 25% of surveyed oncologists believed that bevacizumab offered "good value."49 However, most surveyed oncologists believe that patients should have access to high-quality care despite the financial costs of treatment, as it is difficult to place a price tag on extending life.49
Options for patients with GBM are limited at tumor recurrence. Often, repeated irradiation and repeated surgery are not suitable options, and the tumors have already demonstrated resistance to first-line cytotoxic alkylating therapy with temozolomide.18 Despite the data supporting the safety and efficacy of bevacizumab (measured by increased 6-month PFS) in patients with recurrent GBM (Tables 1 and 2), some studies show only a very modest increase in median overall survival.36 Lai et al,45 in their study of bevacizumab in combination with adjuvant radiotherapy and temozolomide in new-onset GBM, also found a statistically significant difference in 6-month PFS among patients receiving bevacizumab compared with historic institutional data without corresponding change in median overall survival. This suggests that the use of bevacizumab delays progression. Although it has little effect on overall survival, bevacizumab therapy maintains the patient's Karnofsky performance score by increasing the PFS and consequently increasing the quality of life.
However, there exist no reliable a priori evaluations to determine whether a patient is suitable for bevacizumab therapy, or in which patients bevacizumab will provide optimal benefit.18 Increased age (> 55 years) and lower performance (Karnofsky performance score < 80) has been associated with greater benefit from bevacizumab, possibly because of the higher VEGF expression in these patients.50 Furthermore, patients treated with bevacizumab are able to maintain functional status longer than patients historically not treated with bevacizumab.50 Age at time of diagnosis is still the strongest prognostic indicator for survival in GBM, with median survival as low as 2 months in patients older than age 80 years.51 Although overall survival for patients with GBM has increased since the 1990s, the youngest (aged 20 to 44 years) and most functional patients have received the greatest benefit, achieving 2-year survival rates as high as 39%; the most elderly patients (aged > 80 years) have experienced minimal benefit and have achieved a disappointing 2-year survival rate of 1%.4
Recent studies of bevacizumab threaten to change this trend by increasing the median PFS and prolonging the functional status of patients whose disease was previously resistant to traditional radiotherapy and cytotoxic adjuvant therapies. Furthermore, recent studies have begun experimental investigation into the use of bevacizumab as adjuvant therapy for new-onset GBM.45,47 Given the antiangiogenic mechanism of bevacizumab, it is widely theorized that early administration of VEGF inhibitors will prevent wound healing and increase operative complications.52 These studies suggest not only that postoperative administration of bevacizumab (after an appropriate time window) is safe, it may actually be efficacious in prolonging median PFS and increasing six-month PFS.45,47 Preliminary results from the AVAglio study, the first prospective Phase 3 trial for the use of bevacizumab (Avastin) in recurrent glioma, were recently announced at the 2013 American Society of Clinical Oncology meeting. The study found that the addition of bevacizumab to treatment of newly diagnosed GBM did not improve overall survival, although it did improve the PFS but not to a significant statistical criterion.53 The study also found that the MGMT methylation profile did not identify to be a selective benefit, but instead was a risk subset. To date, the results of this study suggest that bevacizumab should not be used as first-line therapy for the treatment of GBM.
Bevacizumab has been shown to be safe in new-onset and recurrent disease. This is especially important for older patients (age > 55 years) for whom the prognosis is worse and the benefits of bevacizumab more promising. More prospective Phase 3 trials are needed to determine the appropriate patient population for bevacizumab therapy, the appropriate combination therapy, and the appropriate timing of therapy (adjuvant for new-onset vs recurrent disease). Although the effect on overall survival and the appropriate patient population is still unclear for bevacizumab, its ability to increase the number of patients who survive for 6 months without impairment should be cause for further investigation and clinical use.
The author(s) have no conflicts of interest to disclose.
Kathleen Louden, ELS, of Louden Health Communications provided editorial assistance.
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