A clinical trial of bevacizumab, temozolomide, and radiation for newly diagnosed glioblastoma

Clinical article

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Object

The presence of angiogenesis is a hallmark of glioblastoma (GBM). Vascular endothelial growth factor (VEGF), which drives angiogenesis, provides an additional target for conventional therapy. The authors conducted a prospective clinical trial to test the effectiveness of bevacizumab, an inhibitor of VEGF, in newly diagnosed GBM.

Methods

From 2006 through 2010, 51 eligible patients with newly diagnosed GBM were treated with involved-field radiation therapy and concomitant temozolomide (75 mg/m2 daily for 42 days) along with bevacizumab (10 mg/kg every 2 weeks), starting 29 days after surgery. This was followed by 6 cycles of adjuvant temozolomide therapy (150 mg/m2 on Days 1–7 of a 28-day cycle) with bevacizumab administered at 10 mg/kg on Days 8 and 22 of each 28-day cycle.

Results

The 6- and 12-month progression-free survival (PFS) rates were 85.1% and 51%, respectively. The 12- and 24-month overall survival (OS) rates were 85.1% and 42.5%, respectively. Grade III/IV toxicities were noted in 10 patients (19.6%). No treatment-related deaths were observed. Asymptomatic intracranial bleeding was noted in 5 patients.

Conclusions

The addition of bevacizumab to conventional therapy in newly diagnosed GBM appears to improve both PFS and OS in patients with newly diagnosed GBM, with acceptable morbidity. A shift toward diffuse relapse was noted in a significant number of patients. Ongoing Phase III clinical trials will show the true benefit of this antiangiogenic approach.

Abbreviations used in this paper: EORTC = European Organization for Research and Treatment of Cancer; GBM = glioblastoma; KPS = Karnofsky Performance Scale; OS = overall survival; PFS = progression-free survival; UCLA = University of California, Los Angeles; VEGF = vascular endothelial growth factor.

Article Information

Address correspondence to: Ashwatha Narayana, M.D., Department of Radiation Oncology, New York University Langone Medical Center, 550 1st Avenue, New York, New York 10016. email: ashwatha.narayana@nyumc.org.

Please include this information when citing this paper: published online October 28, 2011; DOI: 10.3171/2011.9.JNS11656.

© AANS, except where prohibited by US copyright law.

Headings

Figures

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    Kaplan-Meier analysis of PFS in 51 patients with newly diagnosed GBM. Cum = Cumulative.

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    Kaplan-Meier analysis of OS in 51 patients with newly diagnosed GBM.

References

  • 1

    Barcellos-Hoff MHNewcomb EWZagzag DNarayana A: Therapeutic targets in malignant glioblastoma microenvironment. Semin Radiat Oncol 19:1631702009

    • Search Google Scholar
    • Export Citation
  • 2

    Duda DGJain RKWillett CG: Antiangiogenics: the potential role of integrating this novel treatment modality with chemoradiation for solid cancers. J Clin Oncol 25:403340422007

    • Search Google Scholar
    • Export Citation
  • 3

    Folkman J: Tumor angiogenesis: therapeutic implications. N Engl J Med 285:118211861971

  • 4

    Friedman HSPrados MDWen PYMikkelsen TSchiff DAbrey LE: Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol 27:473347402009

    • Search Google Scholar
    • Export Citation
  • 5

    Grossman SAYe XPiantadosi SDesideri SNabors LBRosenfeld M: Survival of patients with newly diagnosed glioblastoma treated with radiation and temozolomide in research studies in the United States. Clin Cancer Res 16:244324492010

    • Search Google Scholar
    • Export Citation
  • 6

    Gruber MLRaza SGruber DNarayana A: Bevacizumab in combination with radiotherapy plus concomitant and adjuvant temozolomide for newly diagnosed glioblastoma: update progression-free survival, overall survival, and toxicity. ASCO Meeting Abstracts 27:20172009

    • Search Google Scholar
    • Export Citation
  • 7

    Iwamoto FMAbrey LEBeal KGutin PHRosenblum MKReuter VE: Patterns of relapse and prognosis after bevacizumab failure in recurrent glioblastoma. Neurology 73:120012062009

    • Search Google Scholar
    • Export Citation
  • 8

    Jain RK: Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat Med 7:9879892001

  • 9

    Jain RKdi Tomaso EDuda DGLoeffler JSSorensen AGBatchelor TT: Angiogenesis in brain tumours. Nat Rev Neurosci 8:6106222007

    • Search Google Scholar
    • Export Citation
  • 10

    Kreisl TNKim LMoore KDuic PRoyce CStroud I: Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol 27:7407452009

    • Search Google Scholar
    • Export Citation
  • 11

    Lai ATran ANghiemphu PLPope WBSolis OESelch M: Phase II study of bevacizumab plus temozolomide during and after radiation therapy for patients with newly diagnosed glioblastoma multiforme. J Clin Oncol 29:1421482011

    • Search Google Scholar
    • Export Citation
  • 12

    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 9:139914052003

    • Search Google Scholar
    • Export Citation
  • 13

    Lee CGHeijn Mdi Tomaso EGriffon-Etienne GAncukiewicz MKoike C: Anti-Vascular endothelial growth factor treatment augments tumor radiation response under normoxic or hypoxic conditions. Cancer Res 60:556555702000

    • Search Google Scholar
    • Export Citation
  • 14

    Miyagami MKatayama Y: Angiogenesis of glioma: evaluation of ultrastructural characteristics of microvessels and tubular bodies (Weibel-Palade) in endothelial cells and immunohistochemical findings with VEGF and p53 protein. Med Mol Morphol 38:36422005

    • Search Google Scholar
    • Export Citation
  • 15

    Narayana AGolfinos JGFischer IRaza SKelly PParker E: Feasibility of using bevacizumab with radiation therapy and temozolomide in newly diagnosed high-grade glioma. Int J Radiat Oncol Biol Phys 72:3833892008

    • Search Google Scholar
    • Export Citation
  • 16

    Narayana AKelly PGolfinos JParker EJohnson GKnopp E: Antiangiogenic therapy using bevacizumab in recurrent high-grade glioma: impact on local control and patient survival. Clinical article. J Neurosurg 110:1731802009

    • Search Google Scholar
    • Export Citation
  • 17

    Narayana AKunnakkat SDMedabalmi PGolfinos JParker EKnopp E: Change in pattern of relapse after antiangiogenic therapy in high-grade glioma. Int J Radiat Oncol Biol Phys [epub ahead of print]2010

    • Search Google Scholar
    • Export Citation
  • 18

    Narayana ARecht LGutin PHCentral Nervous System Tumors. Hoppe RTPhilips TLRoach M: Textbook of Radiation Oncology PhiladelphiaSaunders2010. 421432

    • Search Google Scholar
    • Export Citation
  • 19

    Nghiemphu PLLiu WLee YThan TGraham CLai A: Bevacizumab and chemotherapy for recurrent glioblastoma: a single-institution experience. Neurology 72:121712222009

    • Search Google Scholar
    • Export Citation
  • 20

    Norden ADYoung GSSetayesh KMuzikansky AKlufas RRoss GL: Bevacizumab for recurrent malignant gliomas: efficacy, toxicity, and patterns of recurrence. Neurology 70:7797872008

    • Search Google Scholar
    • Export Citation
  • 21

    Nowicki MODmitrieva NStein AMCutter JLGodlewski JSaeki Y: Lithium inhibits invasion of glioma cells; possible involvement of glycogen synthase kinase-3. Neurooncol 10:6906992008

    • Search Google Scholar
    • Export Citation
  • 22

    Stupp RMason WPvan den Bent MJWeller MFisher BTaphoorn MJB: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:9879962005

    • Search Google Scholar
    • Export Citation
  • 23

    Vredenburgh JJDesjardins AHerndon JE JrDowell JMReardon DAQuinn JA: Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma. Clin Cancer Res 13:125312592007

    • Search Google Scholar
    • Export Citation
  • 24

    Willett CGBoucher Ydi Tomaso EDuda DGMunn LLTong RT: Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med 10:1451472004

    • Search Google Scholar
    • Export Citation
  • 25

    Zagzag DAmirnovin RGreco MAYee HHolash JWiegand SJ: Vascular apoptosis and involution in gliomas precede neovascularization: a novel concept for glioma growth and angiogenesis. Lab Invest 80:8378492000

    • Search Google Scholar
    • Export Citation

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