Antiangiogenic therapy using bevacizumab in recurrent high-grade glioma: impact on local control and patient survival

Clinical article

Restricted access

Object

Antiangiogenic agents have recently shown impressive radiological responses in high-grade glioma. However, it is not clear if the responses are related to vascular changes or due to antitumoral effects. The authors report the mature results of a clinical study of bevacizumab-based treatment of recurrent high-grade gliomas.

Methods

Sixty-one patients with recurrent high-grade gliomas received treatment with bevacizumab at 10 mg/ kg every 2 weeks for 4 doses in an 8-week cycle along with either irinotecan or carboplatin. The choice of concomitant chemotherapeutic agent was based on the number of recurrences and prior chemotherapy.

Results

At a median follow-up of 7.5 months (range 1–19 months), 50 (82%) of 61 patients relapsed and 42 patients (70%) died of the disease. The median number of administered bevacizumab cycles was 2 (range 1–7 cycles). The median progression-free survival (PFS) and overall survival (OS) were 5 (95% confidence interval [CI] 2.3–7.7) and 9 (95% CI 7.6–10.4) months, respectively, as calculated from the initiation of the bevacizumab-based therapy. Radiologically demonstrated responses following therapy were noted in 73.6% of cases. Neither the choice of chemotherapeutic agent nor the performance of a resection prior to therapy had an impact on patient survival. Although the predominant pattern of relapse was local, 15 patients (30%) had diffuse disease.

Conclusions

Antiangiogenic therapy using bevacizumab appears to improve survival in patients with recurrent high-grade glioma. A possible change in the invasiveness of the tumor following therapy is worrisome and must be closely monitored.

Abbreviations used in this paper: CI = confidence interval; GBM = glioblastoma multiforme; GTR = gross-total resection; KPS = Karnofsky Performance Scale; OS = overall survival; PFS = progression-free survival; VEGF = vascular endothelial growth factor; WHO = World Health Organization.

Article Information

Address correspondence to: Ashwatha Narayana, M.D., Department of Radiation Oncology, New York University Medical Center, 550 First Avenue, New York, New York 11016. email: ashwatha.narayana@nyumc.org.

Please include this information when citing this paper: published online October 3, 2008; DOI: 10.3171/2008.4.17492.

© AANS, except where prohibited by US copyright law.

Headings

Figures

  • View in gallery

    Bar graph showing compliance to bevacizumab therapy.

  • View in gallery

    Graphs demonstrating PFS and its relationship with other factors. n = number of patients.

  • View in gallery

    Graphs revealing OS and its relationship with other factors. n = number of patients.

  • View in gallery

    Images obtained in a 19-year-old woman with recurrent GBM treated with bevacizumab and irinotecan. Magnetic resonance images obtained before (A–C) and 10 months after (D–F) the administration of bevacizumab, demonstrating a decrease in contrast enhancement on T1-weighted images (A and D), relative cerebral blood volume on perfusion images (B and E), and vascular permeability on diffusion sequences (C and F).

  • View in gallery

    Magnetic resonance images (A and E) and photomicrographs (B–D and F–H) obtained in a 36-year-old woman with recurrent anaplastic astrocytoma. Images show the tumor tissue before (A–D) and 4 months after (E–H) bevacizumab therapy. Black arrows indicate the recurrent tumor. White arrows indicate new areas of diffuse recurrence following therapy. Note the increased expression of D2-40 (podoplanin, B and F), CD34 (C and G), and fascin (D and H), markers of mesenchymal expression following bevacizumab therapy, suggesting transition to a more invasive mesenchymal phenotype.

References

  • 1

    Bao SWu QSathornsumetee SHao YLi ZHjelmeland AB: Stem cell-like glioma cells promote tumor angiogenesis through vascular endothelial growth factor. Cancer Res 66:784378482006

    • Search Google Scholar
    • Export Citation
  • 2

    Cha SKnopp EAJohnson GWetzel SGLitt AWZagzag D: Intracranial mass lesions: dynamic contrast-enhanced susceptibility-weighted echo-planar perfusion MR imaging. Radiology 223:11292002

    • Search Google Scholar
    • Export Citation
  • 3

    Chen WDelaloye SSilverman DHGeist CCzernin JSayre J: 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 25:471447212007

    • Search Google Scholar
    • Export Citation
  • 4

    Gruber MLBuster WP: Temozolomide in combination with irinotecan for treatment of recurrent malignant glioma. Am J Clin Oncol 27:33382004

    • Search Google Scholar
    • Export Citation
  • 5

    Hurwitz HFehrenbacher LNovotny WCartwright THainsworth JHeim W: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:233523422004

    • Search Google Scholar
    • Export Citation
  • 6

    Johnson DHFehrenbacher LNovotny WFHerbst RSNemunaitis JJJablons DM: Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol 22:218421912004

    • Search Google Scholar
    • Export Citation
  • 7

    Kassner ARoberts TP: Beyond perfusion: cerebral vascular reactivity and assessment of microvascular permeability. Top Magn Reson Imaging 15:58652004

    • Search Google Scholar
    • Export Citation
  • 8

    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
  • 9

    Law MYang SBabb JSKnopp EAGolfinos JGZagzag D: Comparison of cerebral blood volume and vascular permeability from dynamic susceptibility contrast-enhanced perfusion MR imaging with glioma grade. AJNR Am J Neuroradiol 25:7467552004

    • Search Google Scholar
    • Export Citation
  • 10

    Liu GYuan XZeng ZTunici PNg HAbdulkadir IR: Analysis of gene expression and chemoresistance of CD133+ cancer stem cells in glioblastoma. Mol Cancer 5:672006

    • Search Google Scholar
    • Export Citation
  • 11

    Macdonald DRCascino TLSchold SC JrCairncross JG: Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol 8:127712801990

    • Search Google Scholar
    • Export Citation
  • 12

    Mason WPCairncross JG: Drug Insight: temozolomide as a treatment for malignant glioma–impact of a recent trial. Nat Clin Pract Neurol 1:88952005

    • Search Google Scholar
    • Export Citation
  • 13

    Medical Research Council Brain Tumor Working Party: Randomized trial of procarbazine, lomustine, and vincristine in the adjuvant treatment of high-grade astrocytoma. A Medical Research Council trial. J Clin Oncol 19:5095182001

    • Search Google Scholar
    • Export Citation
  • 14

    Narayana AChheang SKnopp EPeccerelli NBabb JJohnson G: Comparing cerebral blood volume and vascular permeability measurements with tumor volume measurements following anti-angiogenesis therapy in recurrent gliomas. J Clin Oncol 25:18 Suppl20302007. (Abstract)

    • Search Google Scholar
    • Export Citation
  • 15

    Narayana ALeibel SAPrimary and metastatic brain tumors in adults. Leibel SPhilips TL: Textbook of Radiation Oncology ed 2PhiladelphiaSaunders2004. 471495

    • Search Google Scholar
    • Export Citation
  • 16

    Narayana AYamada JBerry SShah PHunt MGutin PH: Intensity-modulated radiotherapy in high-grade gliomas: clinical and dosimetric results. Int J Radiat Oncol Biol Phys 64:8928972006

    • Search Google Scholar
    • Export Citation
  • 17

    Pope WBLai ANghiemphu PMischel PCloughesy TF: MRI in patients with high-grade gliomas treated with bevacizumab and chemotherapy. Neurology 66:125812602006

    • Search Google Scholar
    • Export Citation
  • 18

    Raizer JJCallot LCohn RChandler JLevy RGetch C: A phase II safety study of bevacizumab in patients with multiple recurrent or progressive malignant gliomas. J Clin Oncol 25:18 Suppl20792007. (Abstract)

    • Search Google Scholar
    • Export Citation
  • 19

    Sakariassen Prestegarden LWang JSkaftnesmo KOMahesparan RMolthoff C: Angiogenesis-independent tumor growth mediated by stem-like cancer cells. Proc Natl Acad Sci U S A 103:16466164712006

    • Search Google Scholar
    • Export Citation
  • 20

    Santarelli JGUdani VYung YCCheshier SWagers ABrekken RA: Incorporation of bone marrow-derived Flk-1-expressing CD34+ cells in the endothelium of tumor vessels in the mouse brain. Neurosurgery 59:3743822006

    • Search Google Scholar
    • Export Citation
  • 21

    Stefanik DFFellows WKRizkalla LRRizkalla WMStefanik PPDeleo AB: Monoclonal antibodies to vascular endothelial growth factor (VEGF) and the VEGF receptor, FLT-1, inhibit the growth of C6 glioma in a mouse xenograft. J Neurooncol 55:911002001

    • Search Google Scholar
    • Export Citation
  • 22

    Stupp RMason WPVan den Bent MJWeller MFisher BTaphoom MJ: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:9879962005

    • Search Google Scholar
    • Export Citation
  • 23

    Traina TARugo HSDickler M: Bevacizumab for advanced breast cancer. Hematol Oncol Clin North Am 21:3033192007

  • 24

    Vignjevic DSchoumacher MGavert NJanssen KPJih GLaé M: Fascin, a novel target of beta-catenin-TCF signaling, is expressed at the invasive front of human colon cancer. Cancer Res 67:684468532007

    • Search Google Scholar
    • Export Citation
  • 25

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

    • Search Google Scholar
    • Export Citation
  • 26

    Vredenburgh JJDesjardins AHerndon JE IIMarcello JReardon DAQuinn JA: bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol 25:4722 47292007

    • Search Google Scholar
    • Export Citation
  • 27

    Wicki ALehembre FWick NHantusch BKerjaschki DChristofori G: Tumor invasion in the absence of epithelialmesenchymal transition: podoplanin-mediated remodeling of the actin cytoskeleton. Cancer Cell 9:2612722006

    • Search Google Scholar
    • Export Citation
  • 28

    Wong ETHess KRGleason MJJaeckle KAKyritsis APPrados MD: Outcomes and prognostic factors in recurrent glioma patients enrolled onto phase II clinical trials. J Clin Oncol 17:257225781999

    • Search Google Scholar
    • Export Citation

Cited By

Metrics

Metrics

All Time Past Year Past 30 Days
Abstract Views 191 191 12
Full Text Views 193 193 0
PDF Downloads 91 91 0
EPUB Downloads 0 0 0

PubMed

Google Scholar