Journal of Neuro-Oncology

, Volume 119, Issue 1, pp 101–109 | Cite as

Bevacizumab treatment leads to observable morphological and metabolic changes in brain radiation necrosis

  • Shingo YonezawaEmail author
  • Kazuhiro Miwa
  • Jun Shinoda
  • Yuichi Nomura
  • Yoshitaka Asano
  • Noriyuki Nakayama
  • Naoyuki Ohe
  • Hirohito Yano
  • Toru Iwama
Clinical Study


We investigated morphological and metabolic changes of radiation necrosis (RN) of the brain following bevacizumab (BEV) treatment by using neuroimaging. Nine patients with symptomatic RN, who had already been treated with radiation therapy for malignant brain tumors (6 glioblastomas, 1 anaplastic oligodendroglioma, and 2 metastatic brain tumors), were enrolled in this prospective clinical study. RN diagnosis was neuroradiologically determined with Gd-enhanced MRI and 11C-methionine positron emission tomography (MET-PET). RN clinical and radiological changes in MRI, magnetic resonance spectroscopy (MRS) and PET were assessed following BEV therapy. Karnofsky performance status scores improved in seven patients (77.8 %). Both volumes of the Gd-enhanced area and FLAIR-high area from MRI decreased in all patients after BEV therapy and the mean size reduction rates of the lesions were 80.0 and 65.0 %, respectively. MRS, which was performed in three patients, showed a significant reduction in Cho/Cr ratio after BEV therapy. Lesion/normal tissue (L/N) ratios in MET- and 11C-choline positron emission tomography (CHO-PET) decreased in 8 (89 %) and 9 patients (100 %), respectively, and the mean L/N ratio reduction rates were 24.4 and 60.7 %, respectively. BEV-related adverse effects of grade 1 or 2 (anemia, neutropenia and lymphocytopenia) occurred in three patients. These results demonstrated that BEV therapy improved RN both clinically and radiologically. BEV therapeutic mechanisms on RN have been suggested to be related not only to the effect on vascular permeability reduction by repairing the blood–brain barrier, but also to the effect on suppression of tissue biological activity, such as immunoreactions and inflammation.


Bevacizumab Radiation necrosis Positron emission tomography Magnetic resonance imaging Magnetic resonance spectroscopy 



Conflict of interest

None declared.


  1. 1.
    Glantz MJ, Burger PC, Friedman AH, Radtke RA, Massey EW, Schold SC Jr (1994) Treatment of radiation-induced nervous system injury with heparin and warfarin. Neurology 44:2020–2027PubMedCrossRefGoogle Scholar
  2. 2.
    Kohshi K, Imada H, Nomoto S, Yamaguchi R, Abe H, Yamamoto H (2003) Successful treatment of radiation-induced brain necrosis by hyperbaric oxygen therapy. J Neurol Sci 209:115–117PubMedCrossRefGoogle Scholar
  3. 3.
    McPherson CM, Warnick RE (2004) Results of contemporary surgical management of radiation necrosis using frameless stereotaxis and intraoperative magnetic resonance imaging. J Neurooncol 68:41–47PubMedCrossRefGoogle Scholar
  4. 4.
    Presta LG, Chen H, O’Connor SJ, Chisholm V, Meng YG, Krummen L et al (1997) Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders. Cancer Res 57:4593–4599PubMedGoogle Scholar
  5. 5.
    Nordal RA, Nagy A, Pintilie M, Wong CS (2004) Hypoxia and hypoxia-inducible factor-1 target genes in central nervous system radiation injury: a role for vascular endothelial growth factor. Clin Cancer Res 15:3342–3353CrossRefGoogle Scholar
  6. 6.
    Nonoguchi N, Miyatake S, Fukumoto M, Furuse M, Hiramatsu R, Kawabata S et al (2011) The distribution of vascular endothelial growth factor-producing cells in clinical radiation necrosis of the brain: pathological consideration of their potential roles. J Neurooncol 105:423–431PubMedCrossRefGoogle Scholar
  7. 7.
    Gonzalez J, Kumar AJ, Conrad CA, Levin VA (2007) Effect of bevacizumab on radiation necrosis of the brain. Int J Radiat Oncol Biol Phys 67:323–326PubMedCrossRefGoogle Scholar
  8. 8.
    Levin VA, Bidaut L, Hou P, Kumar AJ, Wefel JS, Bekele BN et al (2011) Randomized double-blind placebo-controlled trial of bevacizumab therapy for radiation necrosis of the central nervous system. Int J Radiat Oncol Biol Phys 79:1487–1495PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Furuse M, Kawabata S, Kuroiwa T, Miyatake S (2011) Repeated treatments with bevacizumab for recurrent radiation necrosis in patients with malignant brain tumors: a report of 2 cases. J Neurooncol 102:471–475PubMedCrossRefGoogle Scholar
  10. 10.
    Torcuator R, Zuniga R, Mohan YS, Rock J, Doyle T, Anderson J et al (2009) Initial experience with bevacizumab treatment for biopsy confirmed cerebral radiation necrosis. J Neurooncol 94:63–68PubMedCrossRefGoogle Scholar
  11. 11.
    Miwa K, Matsuo M, Shinoda J, Oka N, Kato T, Okumura A et al (2008) Simultaneous integrated boost technique by helical tomotherapy for the treatment of glioblastoma multiforme with 11C-methionine PET: report of three cases. J Neurooncol 87:333–339PubMedCrossRefGoogle Scholar
  12. 12.
    Matsuo M, Miwa K, Tanaka O, Shinoda J, Nishibori H, Tsuge Y et al (2012) Impact of [11C]methionine positron emission tomography for target definition of glioblastoma multiforme in radiation therapy planning. Int J Radiat Oncol Biol Phys 82:83–89PubMedCrossRefGoogle Scholar
  13. 13.
    Takenaka S, Asano Y, Shinoda J, Nomura Y, Yonezawa S, Miwa K, et al (2014) Comparison of 11C-methionine, 11C-choline, and 18F-fluorodeoxyglucose-PET for distinguishing glioma recurrence from radiation necrosis. Neurol Med Chir (Tokyo). 54(4):280–289Google Scholar
  14. 14.
    Shinoda J, Yano H, Ando H, Ohe N, Sakai N, Saio M et al (2002) Radiological response and histological changes in malignant astrocytic tumors after stereotactic radiosurgery. Brain Tumor Pathol 19:83–92PubMedCrossRefGoogle Scholar
  15. 15.
    Amin A, Moustafa H, Ahmed E, El-Toukhy M (2012) Glioma residual or recurrence versus radiation necrosis: accuracy of pentavalent technetium-99 m-di mercaptosuccinic acid [Tc-99 m (v) DMSA] brain SPECT compared to proton magnetic resonance spectroscopy (H1-MRS): initial results. J Neurooncol 106:579–587PubMedCrossRefGoogle Scholar
  16. 16.
    Matoba M, Kondou T, Tanaka T, Kitadate M, Oota K, Tonami H (2010) Noninvasive monitoring of radiation-induced early therapeutic response using high-resolution MR imaging and proton MR spectroscopy in VX2 carcinoma. J Radiat Res 51:690–705Google Scholar
  17. 17.
    Nakajima T, Kumabe T, Kanamori M, Saito R, Tashiro R, Watanabe M et al (2009) Differential diagnosis between radiation necrosis and glioma progression using sequential proton magnetic resonance spectroscopy and methionine positron emission tomography. Neurol Med Chir (Tokyo) 49:394–401CrossRefGoogle Scholar
  18. 18.
    Moravan MJ, Olschowka JA, Williams JP, O’Banion MK (2011) Cranial irradiation leads to acute and persistent neuroinflammation with delayed increases in T-cell infiltration and CD11c expression in C57BL/6 mouse brain. Radiat Res 176:459–473PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Zhao W, Robbins ME (2009) Inflammation and chronic oxdative stress in radiation-induced late normal tissue injury: therapeutic implications. Curr Med Chem 16:130–143PubMedCrossRefGoogle Scholar
  20. 20.
    Ogawa T, Shishido F, Kanno I, Inugami A, Fujita H, Murakami M et al (1993) Cerebral glioma: evaluation with methionine PET. Radiology 186:45–53PubMedCrossRefGoogle Scholar
  21. 21.
    Aki T, Nakayama N, Yonezawa S, Takenaka S, Miwa K, Asano Y et al (2012) Evaluation of brain tumors using dynamic 11C-methinone-PET. J Neurooncol 109:115–122PubMedCrossRefGoogle Scholar
  22. 22.
    De Witte O, Goldberg I, Wikler D, Rorive S, Damhaut P, Monclus M et al (2001) Positron emission tomography with injection of methionine as a prognostic factor in glioma. J Neurosurg 95:746–750PubMedCrossRefGoogle Scholar
  23. 23.
    Herholz K, Hölzer T, Bauer B, Schröder R, Voges J, Ernestus RI et al (1998) 11C-methionine PET for differential diagnosis of low grade gliomas. Neurology 50:1316–1322PubMedCrossRefGoogle Scholar
  24. 24.
    Kato T, Shinoda J, Nakayama N, Miwa K, Okumura A, Yano H et al (2008) Metabolic assessment of gliomas using 11C-methionine, 18F-fluorodeoxyglucose, and 11C-choline positron-emission tomography. AJNR Am J Neuroradiol 29:1176–1182PubMedCrossRefGoogle Scholar
  25. 25.
    Nariai T, Tanaka Y, Wakimoto H, Aoyagi M, Tamaki M, Ishiwata K et al (2005) Usefulness of l-[methyl-11C] methionine-positron emission tomography as a biological monitoring tool in the treatment of glioma. J Neurosurg 103:498–507PubMedCrossRefGoogle Scholar
  26. 26.
    Ogawa T, Inugami A, Hatazawa J, Kanno I, Murakami M, Yasui N et al (1996) Clinical positron emission tomography for brain tumors: comparison of fludeoxyglucose F 18 and L-methyl-11C-methionine. AJNR Am J Neuroradiol 17:345–353PubMedGoogle Scholar
  27. 27.
    Tovi M, Lilja A, Bergström M, Ericsson A, Bergström K, Hartman M (1990) Delineation of gliomas with magnetic resonance imaging using Gd-DTPA in comparison with computed tomography and positron emission tomography. Acta Radiol 31:417–429PubMedCrossRefGoogle Scholar
  28. 28.
    Ohtani T, Kurihara H, Ishiuchi S, Saito N, Oriuchi N, Inoue T et al (2001) Brain tumour imaging with carbon-11 choline: comparison with FDG PET and gadolinium-enhanced MR imaging. Eur J Nucl Med 28:1664–1670PubMedCrossRefGoogle Scholar
  29. 29.
    Kureshi SA, Hofman FM, Schneider JH, Chin LS, Apuzzo ML, Hinton DR (1994) Cytokine expression in radiation-induced delayed cerebral injury. Neurosurgery 35:822–830PubMedCrossRefGoogle Scholar
  30. 30.
    Chiang CS, McBride WH, Withers HR (1993) Radiation-induced astrocytic and microglial responses in mouse brain. Radiother Oncol 29:60–68PubMedCrossRefGoogle Scholar
  31. 31.
    Tsuyuguchi N, Sunada I, Iwai Y, Yamanaka K, Tanaka K, Takami T et al (2003) Methionine positron emission tomography of recurrent metastatic brain tumor and radiation necrosis after stereotactic radiosurgery: is a differential diagnosis possible? J Neurosurg 98:1056–1064PubMedCrossRefGoogle Scholar
  32. 32.
    Friedman HS, Prados MD, Wen PY, Mikkelsen T, Schiff D, Abrey LE et al (2009) Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol 27:4733–4740PubMedCrossRefGoogle Scholar
  33. 33.
    Kreisl TN, Kim L, Moore K, Duic P, Royce C, Stroud I et al (2009) Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol 27:740–745PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Lai A, Tran A, Nghiemphu PL, Pope WB, Solis OE, Selch M et al (2010) Phase II study of bevacizumab plus temozolomide during and after radiation therapy for patients with newly diagnosed glioblastoma multiforme. J Clin Oncol 29:142–148PubMedCentralPubMedCrossRefGoogle Scholar
  35. 35.
    Narayana A, Gruber D, Kunnakkat S, Golfinos JG, Parker E, Raza S et al (2012) A clinical trial of bevacizumab, temozolomide, and radiation for newly diagnosed glioblastoma. J Neurosurg 116:341–345PubMedCrossRefGoogle Scholar
  36. 36.
    Vredenburgh JJ, Desjardins A, Herndon JE II, Marcello J, Reardon DA, Quinn JA et al (2007) Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol 25:4722–4729PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Shingo Yonezawa
    • 1
    • 2
    • 3
    Email author
  • Kazuhiro Miwa
    • 1
    • 2
  • Jun Shinoda
    • 1
    • 2
  • Yuichi Nomura
    • 1
    • 2
    • 3
  • Yoshitaka Asano
    • 1
    • 2
  • Noriyuki Nakayama
    • 3
  • Naoyuki Ohe
    • 3
  • Hirohito Yano
    • 3
  • Toru Iwama
    • 3
  1. 1.Chubu Medical Center for Prolonged Traumatic Brain DysfunctionKizawa Memorial HospitalMinokamoJapan
  2. 2.Department of Clinical Brain SciencesGifu University Graduate School of MedicineMinokamoJapan
  3. 3.Department of NeurosurgeryGifu University Graduate School of MedicineGifuJapan

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