Journal of Neuro-Oncology

, Volume 99, Issue 2, pp 237–242 | Cite as

Rebound tumour progression after the cessation of bevacizumab therapy in patients with recurrent high-grade glioma

  • Richard M. Zuniga
  • Roy Torcuator
  • Rajan Jain
  • John Anderson
  • Thomas Doyle
  • Lonni Schultz
  • Tom Mikkelsen
Clinical Study - Patient Study


After withdrawal of bevacizumab in patients with recurrent high-grade glioma, we have observed a rapid tumour re-growth or “rebound” radiographic phenomenon with accelerated clinical decline. We retrospectively reviewed 11 patients treated at the Henry Ford Hermelin Brain Tumor Center with recurrent high-grade glioma who demonstrated a rebound progression pattern after the discontinuation of bevacizumab. The original tumour area-of-enhancement increased by a mean of 158%, when compared to the rebound magnetic resonance imaging. After rebound, no patients (0/8) showed a response to next-line treatments that did not include bevacizumab. The median survival of those re-treated with bevacizumab was 149 and 32 days for those who received other regimens. Abrupt discontinuation of bevacizumab after recurrence often leads to a dramatic rebound phenomenon and rapid clinical decline. Slow tapering of the bevacizumab dose after tumour progression may prevent this from occurring and improve responsiveness to next-line therapies.


Glioma Bevacizumab Rebound Recurrent glioma Glioblastoma 


  1. 1.
    Stupp R, Mason WP, van den Brent MJ, Weller M, Fischer B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer R, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Esenhauer E, Mirimanoff R (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996CrossRefPubMedGoogle Scholar
  2. 2.
    Wong ET, Hess KR, Gleason MJ, Jaeckle KA, Prados MD, Levin VA, Yung WK (1999) Outcomes and prognostic factors in recurrent glioma patients enrolled onto phase II clinical trials. J Clin Oncol 17:2572–2578PubMedGoogle Scholar
  3. 3.
    Ferrara N (2005) VEGF as a therapeutic target in cancer. Oncology 69(Suppl 3):11–16CrossRefPubMedGoogle Scholar
  4. 4.
    Pradeep CR, Sunila ES, Kuttan G (2005) Expression of vascular endothelial growth factor (VEGF) and VEGF receptors in tumor angiogenesis and malignancies. Integr Cancer Ther 4:315–321CrossRefPubMedGoogle Scholar
  5. 5.
    Kargiotis O, Rao JS, Kyritsis AP (2006) Mechanism of angiogenesis in gliomas. J Neurooncol 78:281–283CrossRefPubMedGoogle Scholar
  6. 6.
    Poon RT-P, Fan S-T, Wong J (2001) Clinical implications of circulating angiogenic factors in cancer patients. J Clin Oncol 19:1207–1225PubMedGoogle Scholar
  7. 7.
    Yang JC, Haworth L, Sherry RM, Hwu P, Schwartzentruber DJ, Topalian SL, Steinberg SM, Chen HX, Rosenberg SA (2003) A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 349:427–434CrossRefPubMedGoogle Scholar
  8. 8.
    Hurwitz H, Fehrenbacker L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F (2004) Bevacizumab plus irinotecan, fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335–2342CrossRefPubMedGoogle Scholar
  9. 9.
    Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, Johnson DH (2006) Paclitaxel-carboplatin alone or with bevacizumab for non-small cell lung cancer. N Engl J Med 355:2542–2550CrossRefPubMedGoogle Scholar
  10. 10.
    Miller KD, Wang M, Gralow J, Dickler M, Cobleigh MA, Perez EA, Shenkier TN, Cella D, Davidson NE (2007) Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 357:2666–2676CrossRefPubMedGoogle Scholar
  11. 11.
    Vredenburgh JJ, Desjardins A, Herndon JE, Dowell JM, Reardon DA, Quinn JA, Rich JN, Sathornsumetee S, Gururangan S, Wagner M, Bigner DD, Friedman AH, Friedman HS (2007) Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma. Clin Cancer Res 13:1253–1259CrossRefPubMedGoogle Scholar
  12. 12.
    Cloughesy T, Prados M, Wen P, Mikkelsen T, Abrey LE, Schiff D, Yung WK, Maoxia Z, Dimery I, Friedman HS (2008) A phase II, randomized, non-comparative clinical trial of the effect of bevacizumab alone or in combination with irinotecan on 6-month progression free survival in recurrent, treatment-refractory glioblastoma. J Clin Oncol, ASCO Annual meeting proceedings (Post-meeting edn), vol 26, no 15S (May 20 Suppl), 2010bGoogle Scholar
  13. 13.
    Zuniga RM, Torcuator R, Jain R, Anderson J, Doyle T, Ellika S, Schultz L, Mikkelsen T (2009) Efficacy, safety and patterns of response and recurrence in patients with recurrent high-grade gliomas treated with bevacizumab plus irinotecan. J Neurooncol 91:329–336CrossRefPubMedGoogle Scholar
  14. 14.
    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
  15. 15.
    Torcuator R, Zuniga RM, Doyle T, Anderson J, Mikkelsen T et al (2008) Salvage concurrent chemotherapy with bevacizumab for recurrent malignant gliomas previously treated with bevacizumab and irinotecan. Neuro-oncology 10(5):829. doi: 10.1215/15228517-2008-051 (abstract)Google Scholar
  16. 16.
    Mancuso MR, Davis R, Norberg SM, O’Brien S, Sennino B, Nakahara T, Yao V, Inai T, Brooks P, Freimark B, Shalinsky DR, Hu-Lowe D, McDonald DM (2006) Rapid vascular regrowth in tumors after reversal of VEGF inhibition. J Clin Invest 116:2610–2621CrossRefPubMedGoogle Scholar
  17. 17.
    MacDonald DR, Cascino TL, Schold SC Jr, Cairncross JG (1990) Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol 8:1277–1280PubMedGoogle Scholar
  18. 18.
    Cacheux W, Boisserie T, Staudacher L, Vignaux O, Dousset B, Soubrane O, Terris B, Mateus C, Chaussade S, Goldwasser F (2008) Reversible tumor growth acceleration following bevacizumab interruption in metastatic colorectal cancer patients scheduled for surgery. Ann Oncol 19:1651–1661CrossRefGoogle Scholar
  19. 19.
    Matsumoto Y, Freund F, Peiretti E, Cooney MJ, Ferrara D, Yannuzzi LA (2007) Rebound macular edema following bevacizumab (avastin) therapy for retinal venous occlusive disease. Retina 27:426–431CrossRefPubMedGoogle Scholar
  20. 20.
    Ananthnarayan S, Bahng J, Roring J, Nghiemphu P, Lai A, Cloughesy T, Pope W (2008) Time course of imaging changes of GBM during extended bevacizumab treatment. J Neuro-oncol 88:339–347CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2010

Authors and Affiliations

  • Richard M. Zuniga
    • 1
  • Roy Torcuator
    • 1
    • 2
  • Rajan Jain
    • 3
  • John Anderson
    • 4
  • Thomas Doyle
    • 4
  • Lonni Schultz
    • 5
  • Tom Mikkelsen
    • 1
    • 2
  1. 1.Henry Ford Health SystemHermelin Brain Tumor CenterDetroitUSA
  2. 2.Department of NeurosurgeryHenry Ford Health SystemDetroitUSA
  3. 3.Department of NeuroradiologyHenry Ford Health SystemDetroitUSA
  4. 4.Department of Medical OncologyHenry Ford Health SystemDetroitUSA
  5. 5.Department of Biostatistics and Research EpidemiologyHenry Ford Health SystemDetroitUSA

Personalised recommendations