Journal of Neuro-Oncology

, Volume 99, Issue 1, pp 49–56 | Cite as

Bevacizumab-induced diffusion-restricted lesions in malignant glioma patients

  • Johannes RiegerEmail author
  • Oliver Bähr
  • Klaus Müller
  • Kea Franz
  • Joachim Steinbach
  • Elke Hattingen
Clinical Study - Patient Study


Bevacizumab is an anti-vascular endothelial growth factor (VEGF) antibody with activity against recurrent malignant glioma inducing high rates of objective responses as assessed by magnetic resonance imaging (MRI). However, the mechanisms of the anti-tumor action of bevacizumab are controversial. In particular, it is unclear whether and when bevacizumab induces hypoxia in gliomas. Vascular normalization with hyperperfusion and enhanced oxygen delivery to the tumor has been suggested as an alternative mechanism. We analyzed diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) maps in 18 consecutive patients with recurrent malignant glioma before and after exposure to bevacizumab. Stroke-like lesions with diffusion restriction on DWI and corresponding ADC decrease were induced by bevacizumab within the previously enhancing tumor area in 13 of 18 patients. These lesions were detectable as early as 4 weeks after initiation of therapy and were maintained for up to 80 weeks. In one patient, an ADC-decreased lesion was biopsied, and histology showed atypical necrosis and nuclear hypoxia-inducible factor 1alpha upregulation but no tumor recurrence. Normalized regional cerebral blood flow (rCBF) and regional cerebral blood volume (rCBV) were analyzed in selected patients. Both parameters were decreased in responders with diffusion-restricted lesions. Within the tumor bed, bevacizumab induces diffusion-restricted lesions in the presence of reduced rCBF and rCBV. The cause of these alterations is unclear but may involve atypical necrosis and chronic hypoxia.


ADC Glioma Bevacizumab Irinotecan Perfusion 



Apparent diffusion coefficient


Complete response


Diffusion-weighted imaging


Hypoxia-inducible factor-1α


Minor response


Progressive disease


Progression-free survival


Partial response


Regional cerebral blood flow


Regional cerebral blood volume


Stable disease


Vascular endothelial growth factor



The Dr. Senckenberg Institute of Neurooncology is supported by the Dr. Senckenberg Foundation and the Hertie Foundation. J.S. is “Hertie Professor of Neurooncology”.


Prof. Steinbach has served as a consultant for Roche, the European distributor of bevacizumab (Avastin). The other authors report no disclosures.


  1. 1.
    Vredenburgh JJ, Desjardins A, Herndon JE, Marcello J, Reardon DA, Quinn JA, Rich JN, Sathornsumetee S, Gururangan S, Sampson J, Wagner M, Bailey L, Bigner DD, Friedman AH, Friedman HS (2007) Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol 25:4722–4729CrossRefPubMedGoogle Scholar
  2. 2.
    Norden AD, Young GS, Setayesh K, Muzikansky A, Klufas R, Ross GL, Ciampa AS, Ebbeling LG, Levy B, Drappatz J, Kesari S, Wen PY (2008) Bevacizumab for recurrent malignant gliomas: efficacy, toxicity, and patterns of recurrence. Neurology 70:779–787CrossRefPubMedGoogle Scholar
  3. 3.
    Kreisl TN, Kim L, Moore K, Duic P, Royce C, Stroud I, Garren N, Mackey M, Butman JA, Camphausen K, Park J, Albert PS, Fine HA (2009) Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol 27:740–745CrossRefPubMedGoogle Scholar
  4. 4.
    Friedman HS, Prados MD, Wen PY, Mikkelsen T, Schiff D, Abrey LE, Yung WK, Paleologos N, Nicholas MK, Jensen R, Vredenburgh J, Huang J, Zheng M, Cloughesy T (2009) Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol. 27:4733–4740CrossRefPubMedGoogle Scholar
  5. 5.
    Sathornsumetee S, Cao Y, Marcello JE, Herndon JE, McLendon RE, Desjardins A, Friedman HS, Dewhirst MW, Vredenburgh JJ, Rich JN (2008) Tumor angiogenic and hypoxic profiles predict radiographic response and survival in malignant astrocytoma patients treated with bevacizumab and irinotecan. J Clin Oncol 26:271–278CrossRefPubMedGoogle Scholar
  6. 6.
    Jain RK (2005) Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307:58–62CrossRefPubMedGoogle Scholar
  7. 7.
    Batchelor TT, Sorensen AG, di Tomaso E, Zhang W, Duda DG, Cohen KS, Kozak KR, Cahill DP, Chen P, Zhu M, Ancukiewicz M, Mrugala MM, Plotkin S, Drappatz J, Louis DN, Ivy P, Scadden DT, Benner T, Loeffler JS, Wen PY, Jain RK (2007) AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 11:83–95CrossRefPubMedGoogle Scholar
  8. 8.
    Macdonald DR, Cascino TL, Schold SCJ, Cairncross JG (1990) Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol 8:1277–1280PubMedGoogle Scholar
  9. 9.
    Server A, Kulle B, Maehlen J, Josefsen R, Schellhorn T, Kumar T, Langberg CW, Nakstad PH (2009) Quantitative apparent diffusion coefficients in the characterization of brain tumors and associated peritumoral edema. Acta Radiol 50:682–689CrossRefPubMedGoogle Scholar
  10. 10.
    Ostergaard L, Weisskoff RM, Chesler DA, Gyldensted C, Rosen BR (1996) High resolution measurement of cerebral blood flow using intravascular tracer bolus passages. Part I: mathematical approach and statistical analysis. Magn Reson Med 36:715–725CrossRefPubMedGoogle Scholar
  11. 11.
    Castillo M, Smith JK, Kwock L, Wilber K (2001) Apparent diffusion coefficients in the evaluation of high-grade cerebral gliomas. ANJR Am J Neuroradiol 22:60–64Google Scholar
  12. 12.
    Pope WB, Kim HJ, Huo J, Alger J, Brown S, Gjertson D, Sai V, Young JR, Tekchandani L, Cloughesy T, Mischel PS, Lai A, Nghiemphu P, Rahmanuddin S, Goldin J (2009) Recurrent glioblastoma multiforme: ADC histogram analysis predicts response to bevacizumab treatment. Radiology 252:182–189CrossRefPubMedGoogle Scholar
  13. 13.
    Sundgren PC, Fan X, Weybright P, Welsh RC, Carlos RC, Petrou M, McKeever PE, Chenevert TL (2006) Differentiation of recurrent brain tumor versus radiation injury using diffusion tensor imaging in patients with new contrast-enhancing lesions. Magn Reson Imaging 24:1131–1142CrossRefPubMedGoogle Scholar
  14. 14.
    Fischer I, Cunliffe CH, Bollo RJ, Raza S, Monoky D, Chiriboga L, Parker EC, Golfinos JG, Kelly PJ, Knopp EA, Gruber ML, Zagzag D, Narayana A (2008) High-grade glioma before and after treatment with radiation and Avastin: initial observations. Neurooncology 10:700–708Google Scholar
  15. 15.
    Kamoun WS, Ley CD, Farrar CT, Duyverman AM, Lahdenranta J, Lacorre DA, Batchelor TT, di Tomaso E, Duda DG, Munn LL, Fukumura D, Sorensen AG, Jain RK (2009) 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 27:2542–2552CrossRefPubMedGoogle Scholar
  16. 16.
    Erber R, Thurnher A, Katsen AD, Groth G, Kerger H, Hammes H, Menger MD, Ullrich A, Vajkoczy P (2004) Combined inhibition of VEGF and PDGF signaling enforces tumor vessel regression by interfering with pericyte-mediated endothelial cell survival mechanisms. FASEB J 18:338–340PubMedGoogle Scholar
  17. 17.
    Ronellenfitsch MW, Brucker DP, Burger MC, Wolking S, Tritschler F, Rieger J, Wick W, Weller M, Steinbach JP (2009) Antagonism of the mammalian target of rapamycin selectively mediates metabolic effects of epidermal growth factor receptor inhibition and protects human malignant glioma cells from hypoxia-induced cell death. Brain 132:1509–1522CrossRefPubMedGoogle Scholar
  18. 18.
    Pennacchietti S, Michieli P, Galluzzo M, Mazzone M, Giordano S, Comoglio PM (2003) Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene. Cancer Cell 3:347–361CrossRefPubMedGoogle Scholar
  19. 19.
    Zheng X, Jiang F, Katakowski M, Kalkanis SN, Hong X, Zhang X, Zhang ZG, Yang H, Chopp M (2007) Inhibition of ADAM17 reduces hypoxia-induced brain tumor cell invasiveness. Cancer Sci 98:674–684CrossRefPubMedGoogle Scholar
  20. 20.
    Pàez-Ribes M, Allen E, Hudock J, Takeda T, Okuyama H, Viñals F, Inoue M, Bergers G, Hanahan D, Casanovas O (2009) Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 15:220–231CrossRefPubMedGoogle Scholar
  21. 21.
    Lee CG, Heijn M, di Tomaso E, Griffon-Etienne G, Ancukiewicz M, Koike C, Park KR, Ferrara N, Jain RK, Suit HD, Boucher Y (2000) Anti-Vascular endothelial growth factor treatment augments tumor radiation response under normoxic or hypoxic conditions. Cancer Res 60:5565–5570PubMedGoogle Scholar
  22. 22.
    Winkler F, Kozin SV, Tong RT, Chae SS, Booth MF, Garkavtsev I, Xu L, Hicklin DJ, Fukumura D, di Tomaso E, Munn JJ, Jain RK (2004) Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases. Cancer Cell 6:553–563PubMedGoogle Scholar
  23. 23.
    Wick A, Felsberg J, Steinbach JP, Herrlinger U, Platten M, Blaschke B, Meyermann R, Reifenberger G, Weller M, Wick W (2007) Efficacy and tolerability of temozolomide in an alternating weekly regimen in patients with recurrent glioma. J Clin Oncol 25:3357–3361CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2009

Authors and Affiliations

  • Johannes Rieger
    • 1
    Email author
  • Oliver Bähr
    • 1
  • Klaus Müller
    • 2
  • Kea Franz
    • 3
  • Joachim Steinbach
    • 1
  • Elke Hattingen
    • 4
  1. 1.Dr. Senckenberg Institute of NeurooncologyGoethe-University FrankfurtFrankfurtGermany
  2. 2.Edinger InstituteGoethe-University FrankfurtFrankfurtGermany
  3. 3.Department of NeurosurgeryGoethe-University FrankfurtFrankfurtGermany
  4. 4.Institute for NeuroradiologyGoethe-University FrankfurtFrankfurtGermany

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