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Neurological Review |

Bevacizumab for Malignant Gliomas FREE

Fabio M. Iwamoto, MD; Howard A. Fine, MD
[+] Author Affiliations

Section Editor: David E. Pleasure, MD
Author Affiliations:Neuro-Oncology Branch, National Cancer Institute and National Institute for Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland.

More Author Information
Arch Neurol. 2010;67(3):285-288. doi:10.1001/archneurol.2010.11.
Text Size: A A A
Published online

Malignant gliomas are the most common and aggressive primary brain tumors in adults. Despite optimal treatment with surgery, radiotherapy, and temozolomide, tumor recurrences are frequent and patients with malignant gliomas continue to have poor prognoses. Malignant gliomas are often highly vascularized, and significant advances have been made in the last few decades in our understanding of the mechanisms of tumor angiogenesis. Recently, bevacizumab, an antibody against vascular endothelial growth factor, has demonstrated significant activity in recurrent glioblastomas, resulting in US Food and Drug Administration approval and raising the prospect for other antiangiogenic drugs now entering clinical trials.

Approximately 14 000 new cases of malignant gliomas are diagnosed each year in the United States; glioblastomas (GBMs) (grade 4 gliomas) account for approximately 70% of such cases, while anaplastic, or grade 3, gliomas represent the other 30% of cases.1Although this incidence may seem relatively small compared with other cancers, malignant gliomas are associated with significant morbidity and mortality. Despite standard treatment with maximal safe resection, radiotherapy, and temozolomide chemotherapy, median survival of patients with GBM is less than 15 months.2The median survival of patients with grade 3 glioma is only slightly better, ranging from 2 to 5 years.1

Tumor growth is highly dependent on the acquisition of a new vascular supply, as demonstrated by studies published by Judah Folkman and colleagues beginning in the 1960s. They showed that a tumor may survive with preexisting blood vessel supply only until it reaches a size of a few milimeters.3After that, angiogenesis, ie, growth of new blood vessels, is required for further tumor expansion. Glioma angiogenesis was demonstrated more than 30 years ago by showing that transplantation of human and experimental gliomas in rabbit corneas elicited intense neovascularization and tumor growth, while glioma transplantation into the avascular aqueous humor of the eye was incapable of growing beyond a very small size.4Since then, our understanding of the multiple pathways involved in the angiogenesis process has grown significantly. More recently, multiple anti-angiogenic drugs have entered clinical trials for malignant gliomas, and bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor (VEGF), received US Food and Drug Administration accelerated approval for recurrent or progressive GBM in May 2009.

The VEGF family of growth factors and their respective receptors are the best characterized proangiogenic proteins in human gliomas. Several groups have shown that glioma cells express and secrete VEGF, whose expression correlates with tumor vascularization and aggressiveness.57Vascular endothelial growth factor production and secretion by tumor cells is stimulated mainly by hypoxia, and malignant gliomas are rapidly growing and innately hypoxic tumors. More specifically, VEGF-A binds to VEGF receptors-2 expressed in blood vessels, which promotes endothelial cell migration and proliferation and consequently new blood vessel formation. In addition, both hypoxia and VEGF recruit bone marrow–derived cells that also contribute to the angiogenesis process.

There are multiple reasons for believing that anti-angiogenic drugs could play a significant role in the treatment of malignant gliomas. Malignant gliomas are often highly vascularized tumors, and vascular proliferation is one of the pathological hallmarks of GBM. One of the difficulties of developing effective treatments for gliomas has been poor drug penetration through the blood-brain barrier. By targeting the tumor vasculature, it is theoretically possible to bypass this dependence on drugs to cross the blood-brain barrier to reach their target. Finally, there is also both experimental8and clinical9,10evidence that anti-angiogenic drugs can decrease vasogenic edema and patients' requirement for corticosteroids, which is a significant cause of morbidity in this population.

Bevacizumab, a humanized monoclonal antibody that targets VEGF, was first approved in combination with chemotherapy for colorectal, lung, and breast cancers. Despite initial reluctance to evaluate bevacizumab in patients with brain tumors owing to concerns of intracranial hemorrhage, a series of 29 patients with recurrent malignant gliomas treated with bevacizumab and irinotecan showed no significant hemorrhage and an astounding radiographic response rate of 66%11compared with historical rates of 9%.12This led to more rigorous prospective clinical trials of bevacizumab in recurrent malignant gliomas (Table). The combination of bevacizumab and irinotecan was studied in single-arm phase 2 trials for recurrent anaplastic gliomas (n = 33) and GBM (n = 35), respectively, and showed response rates of 61% and 57% and progression-free survival (PFS) at 6 months of 55% and 46%.13,21These results compared favorably with historical rates of PFS at 6 months of 9% to 15% for recurrent GBM and 17% to 31% for recurrent anaplastic gliomas.12,20However, irinotecan had been previously tested as a single agent in phase 2 trials and showed radiographic response rates of only 2.5% to 6% and no improvement in PFS.22,23These studies raised the question of irinotecan's contribution to the bevacizumab combination regimen. We therefore conducted a phase 2 trial of single-agent bevacizumab for recurrent GBM. Forty-eight heavily pretreated patients were included and the radiographic response was 35% and the PFS at 6 months was 29%.10A large phase 2 trial randomized 167 patients with recurrent GBM to either single-agent bevacizumab or bevacizumab with irinotecan. This noncomparative randomized study showed response rates of 28% and 38%, respectively, and a PFS at 6 months of 43% and 50%, respectively.9In addition to the radiographic responses and prolongation of PFS, patients treated with bevacizumab often had less vasogenic edema and decreased corticosteroid dependence secondary to neutralization of VEGF, a known vascular permeability factor. Our data10combined with those of the single-agent bevacizumab arm of the randomized phase 2 trial9supported the accelerated approval of bevacizumab for recurrent or progressive GBM by the Food and Drug Administration.

Table Graphic Jump LocationTable. Prospective Studies of Bevacizumab for Recurrent Glioblastoma

Bevacizumab is usually well tolerated, with the most common adverse effects being hypertension and minor bleeding, such as epistaxis. Intracranial hemorrhage occurred in less than 4% of patients and was severe in only approximately 1% of patients. Other uncommon but serious adverse events with bevacizumab include wound-healing complications, thromboembolic events, proteinuria, bowel perforation, and posterior reversible encephalopathy syndrome.9

Given that irinotecan does not seem to improve efficacy of single-agent bevacizumab in recurrent malignant gliomas and has significant toxicity effects, such as diarrhea and myelosuppression, other agents and strategies have been tried in conjunction with bevacizumab in this patient population. Phase 2 studies with bevacizumab and daily low-dose temozolomide, oral etoposide, erlotinib, or nitrosourea did not seem to improve outcomes in recurrent GBM when compared with studies with single-agent bevacizumab. A pilot study of bevacizumab with repeated irradiation included 20 patients with recurrent GBM and found a response rate of 50% and a PFS at 6 months of 65%, but selection of patients with smaller tumors make comparisons with other studies difficult.15Multiple trials combining bevacizumab with either cytotoxic agents or newer targeted drugs are ongoing for recurrent gliomas, and enrollment in these studies should be encouraged. Patients with recurrent malignant GBM who are not candidates for ongoing clinical trials should receive the Food and Drug Administration–approved single-agent bevacizumab regimen if medically appropriate.

Owing to these promising results of bevacizumab as a single agent in recurrent GBM, there is growing interest in evaluating the use of the drug as part of the initial treatment strategy for patients with newly diagnosed GBM. Early results from phase 2 trials showed that incorporation of bevacizumab into the standard upfront treatment for newly diagnosed GBM increased median PFS, but prolongation of overall survival is still unclear. To definitely address this question, 2 large phase 3 trials for newly diagnosed GBM are currently randomizing patients to standard radiotherapy and temozolomide with or without bevacizumab.

Much of what we have learned regarding the biological basis for glioma angiogenesis is based on the standard animal model of human xenografts grown orthotopically in immunodeficient mice. These generally develop as encapsulated balls of tumor that because of their encapsulated nature require de novo vascular supply to grow.24By contrast, human gliomas grow in situ as highly infiltrative individual tumor cells that may or may not have a central area of tumor bulk with associated vascular proliferation and high angiogenic activity. For many gliomas, particularly anaplastic gliomas, there is often little evidence for vascular proliferation, as the individual infiltrative tumors cells tend to grow along preestablished normal cerebral vasculature, and thus there is no need for tumor-associated angiogenesis. Indeed, there is at least a theoretical concern that inhibiting malignant glioma angiogenesis may prevent the establishment of tumor bulk but has little effect on the infiltrative component of the disease and therefore has little impact on the overall survival of the patient. Early clinical and radiographic observations of patients treated with bevacizumab suggest that this may be the case.25,26Possibly more concerning is recent laboratory evidence that suggests that inhibition of VEGF may actually increase the invasive nature of tumor cells.27These data are very disturbing, for it is the infiltrative tumor cells that are most often responsible for clinical relapse and ultimately the death of patients with gliomas. Clinical studies will need to be devised to either corroborate or negate these experimental observations. If true, the use of antiangiogenic agents may have to be restricted to patients with tumors that are clearly highly vascular rather than those that are mostly infiltrative.

The recent Food and Drug Administration approval of single-agent bevacizumab for recurrent GBM represents a significant therapeutic advance, considering the few therapeutic options available for this aggressive tumor. Two ongoing phase 3 clinical trials will provide essential data on the value of adding bevacizumab to standard treatment for newly diagnosed GBM. Because anti-angiogenic agents can rapidly normalize leaky abnormal tumor vessels and decrease enhancement on scans after treatment initiation, additional studies are needed on how to best evaluate radiographic response in patients treated with anti-angiogenic drugs.28Furthermore, mechanisms of resistance to antiangiogenic therapies should be investigated.25,29Clinical,30molecular,31and/or radiographic markers32to identify patients more likely to respond to antiangiogenic therapies need to be validated. Finally, because patients with malignant glioma continue to have a poor prognosis despite optimal treatment, enrollment in clinical trials involving rational drug combinations with newer drugs that are directed against validated molecular targets should be encouraged.

Correspondence:Howard A. Fine, MD, Neuro-Oncology Branch, National Cancer Institute, National Institute for Neurological Disorders and Stroke, National Institutes of Health, 9030 Old Georgetown Rd, Bloch Bldg 82, Room 225, Bethesda, MD 20892 (hfine@mail.nih.gov).

Accepted for Publication:January 5, 2010.

Author Contributions:Both authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Fine. Acquisition of data: Iwamoto. Analysis and interpretation of data: Iwamoto and Fine. Drafting of the manuscript: Iwamoto and Fine. Critical revision of the manuscript for important intellectual content: Fine. Administrative, technical, and material support: Fine. Study supervision: Fine.

Financial Disclosure:None reported.

Funding/Support:This research was supported by the Intramural Research Program of the National Institutes of Health (Center for Cancer Research of the National Cancer Institute and National Institute of Neurological Disorders and Stroke).

Wen  PYKesari  S Malignant gliomas in adults. N Engl J Med 2008;359 (5) 492- 507
PubMed Link to Article
Stupp  RMason  WPvan den Bent  MJ  et al. European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group, Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352 (10) 987- 996
PubMed Link to Article
Folkman  JKlagsbrun  M Angiogenic factors. Science 1987;235 (4787) 442- 447
PubMed Link to Article
Brem  S The role of vascular proliferation in the growth of brain tumors. Clin Neurosurg 1976;23440- 453
PubMed
Lamszus  KUlbricht  UMatschke  JBrockmann  MAFillbrandt  RWestphal  M Levels of soluble vascular endothelial growth factor (VEGF) receptor 1 in astrocytic tumors and its relation to malignancy, vascularity, and VEGF-A. Clin Cancer Res 2003;9 (4) 1399- 1405
PubMed
Plate  KHBreier  GWeich  HARisau  W Vascular endothelial growth-factor is a potential tumor angiogenesis factor in human gliomas in vivo. Nature 1992;359 (6398) 845- 848
PubMed Link to Article
Samoto  KIkezaki  KOno  M  et al.  Expression of vascular endothelial growth factor and its possible relation with neovascularization in human brain tumors. Cancer Res 1995;55 (5) 1189- 1193
PubMed
Kamoun  WSLey  CDFarrar  CT  et al.  Edema control by cediranib, a vascular endothelial growth factor receptor-targeted kinase inhibitor, prolongs survival despite persistent brain tumor growth in mice. J Clin Oncol 2009;27 (15) 2542- 2552
PubMed Link to Article
Friedman  HSPrados  MDWen  PY  et al.  Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol 2009;27 (28) 4733- 4740
PubMed Link to Article
Kreisl  TNKim  LMoore  K  et al.  Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol 2009;27 (5) 740- 745
PubMed Link to Article
Stark-Vance  V Bevacizumab and CPT-11 in the treatment of relapsed malignant glioma [abstract]. Neuro Oncol 2005;7 (3) 369
Wong  ETHess  KRGleason  MJ  et al.  Outcomes and prognostic factors in recurrent glioma patients enrolled onto phase II clinical trials. J Clin Oncol 1999;17 (8) 2572- 2578
PubMed
Vredenburgh  JJDesjardins  AHerndon  JE  II  et al.  Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol 2007;25 (30) 4722- 4729
PubMed Link to Article
Gilbert  MRWang  MAldape  K  et al.  RTOG 0625: a phase II study of bevacizumab with irinotecan in recurrent glioblastoma (GBM) [abstract]. J Clin Oncol 2009;27 (15S) 2011
Link to Article
Gutin  PHIwamoto  FMBeal  K  et al.  Safety and efficacy of bevacizumab with hypofractionated stereotactic irradiation for recurrent malignant gliomas. Int J Radiat Oncol Biol Phys 2009;75 (1) 156- 163
PubMed Link to Article
Reardon  DDesjardins  AVredenburgh  JJGururangan  SPeters  KBNorfleet  JA Bevacizumab plus etoposide among recurrent malignant glioma patients: phase II study final results [abstract]. J Clin Oncol 2009;27 (15S) 2046
Link to Article
Sathornsumetee  SDesjardins  AVredenburgh  JJ  et al.  Phase II study of bevacizumab plus erlotinib for recurrent malignant gliomas [abstract]. J Clin Oncol 2009;27 (15S) 2045
Maron  RVredenburgh  JJDesjardins  A  et al.  Bevacizumab and daily temozolomide for recurrent glioblastoma multiforme (GBM) [abstract]. J Clin Oncol 2008;26 (15S) 2074
Soffietti  RRuda  RTrevisan  E  et al.  Phase II study of bevacizumab and nitrosourea in patients with recurrent malignant glioma: a multicenter Italian study [abstract]. J Clin Oncol 2009;27 (15S) 2012
Lamborn  KRYung  WKChang  SM  et al. North American Brain Tumor Consortium, Progression-free survival: an important end point in evaluating therapy for recurrent high-grade gliomas. Neuro Oncol 2008;10 (2) 162- 170
PubMed Link to Article
Desjardins  AReardon  DAHerndon  JE  II  et al.  Bevacizumab plus irinotecan in recurrent WHO grade 3 malignant gliomas. Clin Cancer Res 2008;14 (21) 7068- 7073
PubMed Link to Article
Prados  MDLamborn  KYung  WK  et al. North American Brain Tumor Consortium, A phase 2 trial of irinotecan (CPT-11) in patients with recurrent malignant glioma: a North American Brain Tumor Consortium study. Neuro Oncol 2006;8 (2) 189- 193
PubMed Link to Article
Batchelor  TTGilbert  MRSupko  JG  et al. NABTT CNS Consortium, Phase 2 study of weekly irinotecan in adults with recurrent malignant glioma: final report of NABTT 97-11. Neuro Oncol 2004;6 (1) 21- 27
PubMed Link to Article
Lee  JKotliarova  SKotliarov  Y  et al.  Tumor stem cells derived from glioblastomas cultured in bFGF and EGF more closely mirror the phenotype and genotype of primary tumors than do serum-cultured cell lines. Cancer Cell 2006;9 (5) 391- 403
PubMed Link to Article
Iwamoto  FMAbrey  LEBeal  K  et al.  Patterns of relapse and prognosis after bevacizumab failure in recurrent glioblastoma. Neurology 2009;73 (15) 1200- 1206
PubMed Link to Article
Norden  ADDrappatz  JMuzikansky  A  et al.  An exploratory survival analysis of anti-angiogenic therapy for recurrent malignant glioma. J Neurooncol 2009;92 (2) 149- 155
PubMed Link to Article
Pàez-Ribes  MAllen  EHudock  J  et al.  Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 2009;15 (3) 220- 231
PubMed Link to Article
van den Bent  MJVogelbaum  MAWen  PYMacdonald  DRChang  SM End point assessment in gliomas: novel treatments limit usefulness of classical Macdonald's Criteria. J Clin Oncol 2009;27 (18) 2905- 2908
PubMed Link to Article
Bergers  GHanahan  D Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer 2008;8 (8) 592- 603
PubMed Link to Article
Nghiemphu  PLLiu  WLee  Y  et al.  Bevacizumab and chemotherapy for recurrent glioblastoma: a single-institution experience. Neurology 2009;72 (14) 1217- 1222
PubMed Link to Article
Sathornsumetee  SCao  YMarcello  JE  et al.  Tumor angiogenic and hypoxic profiles predict radiographic response and survival in malignant astrocytoma patients treated with bevacizumab and irinotecan. J Clin Oncol 2008;26 (2) 271- 278
PubMed Link to Article
Chen  WDelaloye  SSilverman  DH  et al.  Predicting treatment response of malignant gliomas to bevacizumab and irinotecan by imaging proliferation with [18F] fluorothymidine positron emission tomography: a pilot study. J Clin Oncol 2007;25 (30) 4714- 4721
PubMed Link to Article

Figures

Tables

Table Graphic Jump LocationTable. Prospective Studies of Bevacizumab for Recurrent Glioblastoma

References

Wen  PYKesari  S Malignant gliomas in adults. N Engl J Med 2008;359 (5) 492- 507
PubMed Link to Article
Stupp  RMason  WPvan den Bent  MJ  et al. European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group, Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352 (10) 987- 996
PubMed Link to Article
Folkman  JKlagsbrun  M Angiogenic factors. Science 1987;235 (4787) 442- 447
PubMed Link to Article
Brem  S The role of vascular proliferation in the growth of brain tumors. Clin Neurosurg 1976;23440- 453
PubMed
Lamszus  KUlbricht  UMatschke  JBrockmann  MAFillbrandt  RWestphal  M Levels of soluble vascular endothelial growth factor (VEGF) receptor 1 in astrocytic tumors and its relation to malignancy, vascularity, and VEGF-A. Clin Cancer Res 2003;9 (4) 1399- 1405
PubMed
Plate  KHBreier  GWeich  HARisau  W Vascular endothelial growth-factor is a potential tumor angiogenesis factor in human gliomas in vivo. Nature 1992;359 (6398) 845- 848
PubMed Link to Article
Samoto  KIkezaki  KOno  M  et al.  Expression of vascular endothelial growth factor and its possible relation with neovascularization in human brain tumors. Cancer Res 1995;55 (5) 1189- 1193
PubMed
Kamoun  WSLey  CDFarrar  CT  et al.  Edema control by cediranib, a vascular endothelial growth factor receptor-targeted kinase inhibitor, prolongs survival despite persistent brain tumor growth in mice. J Clin Oncol 2009;27 (15) 2542- 2552
PubMed Link to Article
Friedman  HSPrados  MDWen  PY  et al.  Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol 2009;27 (28) 4733- 4740
PubMed Link to Article
Kreisl  TNKim  LMoore  K  et al.  Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol 2009;27 (5) 740- 745
PubMed Link to Article
Stark-Vance  V Bevacizumab and CPT-11 in the treatment of relapsed malignant glioma [abstract]. Neuro Oncol 2005;7 (3) 369
Wong  ETHess  KRGleason  MJ  et al.  Outcomes and prognostic factors in recurrent glioma patients enrolled onto phase II clinical trials. J Clin Oncol 1999;17 (8) 2572- 2578
PubMed
Vredenburgh  JJDesjardins  AHerndon  JE  II  et al.  Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol 2007;25 (30) 4722- 4729
PubMed Link to Article
Gilbert  MRWang  MAldape  K  et al.  RTOG 0625: a phase II study of bevacizumab with irinotecan in recurrent glioblastoma (GBM) [abstract]. J Clin Oncol 2009;27 (15S) 2011
Link to Article
Gutin  PHIwamoto  FMBeal  K  et al.  Safety and efficacy of bevacizumab with hypofractionated stereotactic irradiation for recurrent malignant gliomas. Int J Radiat Oncol Biol Phys 2009;75 (1) 156- 163
PubMed Link to Article
Reardon  DDesjardins  AVredenburgh  JJGururangan  SPeters  KBNorfleet  JA Bevacizumab plus etoposide among recurrent malignant glioma patients: phase II study final results [abstract]. J Clin Oncol 2009;27 (15S) 2046
Link to Article
Sathornsumetee  SDesjardins  AVredenburgh  JJ  et al.  Phase II study of bevacizumab plus erlotinib for recurrent malignant gliomas [abstract]. J Clin Oncol 2009;27 (15S) 2045
Maron  RVredenburgh  JJDesjardins  A  et al.  Bevacizumab and daily temozolomide for recurrent glioblastoma multiforme (GBM) [abstract]. J Clin Oncol 2008;26 (15S) 2074
Soffietti  RRuda  RTrevisan  E  et al.  Phase II study of bevacizumab and nitrosourea in patients with recurrent malignant glioma: a multicenter Italian study [abstract]. J Clin Oncol 2009;27 (15S) 2012
Lamborn  KRYung  WKChang  SM  et al. North American Brain Tumor Consortium, Progression-free survival: an important end point in evaluating therapy for recurrent high-grade gliomas. Neuro Oncol 2008;10 (2) 162- 170
PubMed Link to Article
Desjardins  AReardon  DAHerndon  JE  II  et al.  Bevacizumab plus irinotecan in recurrent WHO grade 3 malignant gliomas. Clin Cancer Res 2008;14 (21) 7068- 7073
PubMed Link to Article
Prados  MDLamborn  KYung  WK  et al. North American Brain Tumor Consortium, A phase 2 trial of irinotecan (CPT-11) in patients with recurrent malignant glioma: a North American Brain Tumor Consortium study. Neuro Oncol 2006;8 (2) 189- 193
PubMed Link to Article
Batchelor  TTGilbert  MRSupko  JG  et al. NABTT CNS Consortium, Phase 2 study of weekly irinotecan in adults with recurrent malignant glioma: final report of NABTT 97-11. Neuro Oncol 2004;6 (1) 21- 27
PubMed Link to Article
Lee  JKotliarova  SKotliarov  Y  et al.  Tumor stem cells derived from glioblastomas cultured in bFGF and EGF more closely mirror the phenotype and genotype of primary tumors than do serum-cultured cell lines. Cancer Cell 2006;9 (5) 391- 403
PubMed Link to Article
Iwamoto  FMAbrey  LEBeal  K  et al.  Patterns of relapse and prognosis after bevacizumab failure in recurrent glioblastoma. Neurology 2009;73 (15) 1200- 1206
PubMed Link to Article
Norden  ADDrappatz  JMuzikansky  A  et al.  An exploratory survival analysis of anti-angiogenic therapy for recurrent malignant glioma. J Neurooncol 2009;92 (2) 149- 155
PubMed Link to Article
Pàez-Ribes  MAllen  EHudock  J  et al.  Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 2009;15 (3) 220- 231
PubMed Link to Article
van den Bent  MJVogelbaum  MAWen  PYMacdonald  DRChang  SM End point assessment in gliomas: novel treatments limit usefulness of classical Macdonald's Criteria. J Clin Oncol 2009;27 (18) 2905- 2908
PubMed Link to Article
Bergers  GHanahan  D Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer 2008;8 (8) 592- 603
PubMed Link to Article
Nghiemphu  PLLiu  WLee  Y  et al.  Bevacizumab and chemotherapy for recurrent glioblastoma: a single-institution experience. Neurology 2009;72 (14) 1217- 1222
PubMed Link to Article
Sathornsumetee  SCao  YMarcello  JE  et al.  Tumor angiogenic and hypoxic profiles predict radiographic response and survival in malignant astrocytoma patients treated with bevacizumab and irinotecan. J Clin Oncol 2008;26 (2) 271- 278
PubMed Link to Article
Chen  WDelaloye  SSilverman  DH  et al.  Predicting treatment response of malignant gliomas to bevacizumab and irinotecan by imaging proliferation with [18F] fluorothymidine positron emission tomography: a pilot study. J Clin Oncol 2007;25 (30) 4714- 4721
PubMed Link to Article

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