Journal of Neuro-Oncology

, Volume 117, Issue 1, pp 133–139 | Cite as

Large volume reirradiation as salvage therapy for glioblastoma after progression on bevacizumab

  • William Magnuson
  • H. Ian Robins
  • Pranshu Mohindra
  • Steven Howard
Clinical Study

Abstract

Outcomes after bevacizumab failure for recurrent glioblastoma (GBM) are poor. Our analysis of 16 phase II trials (n = 995) revealed a median overall survival (OS) of 3.8 months (±1.0 month SD) after bevacizumab failure with no discernible activity of salvage chemotherapy. Thus, the optimal treatment for disease progression after bevacizumab has yet to be elucidated. This study evaluated the efficacy of reirradiation for patients with GBM after progression on bevacizumab. An IRB approved retrospective (2/2008–5/2013) analysis was performed of 23 patients with recurrent GBM (after standard radiotherapy/temozolomide) treated with bevacizumab (10 mg/kg) every 2 weeks until progression (median age 53 years; median KPS 80; median progression free survival on bevacizumab 3.7 months). Within 7–14 days of progression on bevacizumab, patients initiated reirradiation to a dose of 54 Gy in 27 fractions using pulsed-reduced dose rate (PRDR) radiotherapy. The median planning target volume was 424 cm3. At the start of reirradiation, bevacizumab (10 mg/kg) was given every 4 weeks for two additional cycles. The median OS and 6 month OS after bevacizumab failure was 6.9 months and 65 %, respectively. Reirradiation was well tolerated with no symptomatic grade 3–4 toxicities. Favorable outcomes of reirradiation after bevacizumab failure in patients with recurrent GBM suggest its role as a treatment option for large volume recurrences not amenable to stereotactic radiosurgery. As PRDR is easily accomplished from a technological standpoint, we are in the process of expanding this approach to a multi-institutional cooperative group trial.

Keywords

Radiotherapy Glioblastoma Bevacizumab Reirradiation 

Notes

Acknowledgments

Kathleen Reader Neuro-oncology Fund.

Conflict of interest

HIR has served as a consultant to Novocure and Genentech

References

  1. 1.
    Zhou YH, Tan F, Hess KR, Yung WK (2003) The expression of PAX6, PTEN, vascular endothelial growth factor, and epidermal growth factor receptor in gliomas: relationship to tumor grade and survival. Clin Cancer Res 9:3369–3375PubMedGoogle Scholar
  2. 2.
    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 27:4733–4740. doi:10.1200/JCO.2008.19.8721 PubMedCrossRefGoogle 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 27:740–745. doi:10.1200/JCO.2008.16.3055 PubMedCrossRefGoogle Scholar
  4. 4.
    Ram Z, Stupp R, et al (2010) Subgroup and quality of life analyses of the phase III clinical trial of NovoTTF-100A versus best standard chemotherapy for recurrent glioblastoma. Neuro Oncol Society for Neuro-Oncology (SNO) Abstract No-55, pages iv 48–49Google Scholar
  5. 5.
    Bokstein F, Shpigel S, Blumenthal DT (2008) Treatment with bevacizumab and irinotecan for recurrent high-grade glial tumors. Cancer 112:2267–2273. doi:10.1002/cncr.23401 PubMedCrossRefGoogle Scholar
  6. 6.
    Iwamoto FM, Abrey LE, Beal K, Gutin PH, Rosenblum MK, Reuter VE, DeAngelis LM, Lassman AB (2009) Patterns of relapse and prognosis after bevacizumab failure in recurrent glioblastoma. Neurology 73:1200–1206. doi:10.1212/WNL.0b013e3181bc0184 PubMedCrossRefGoogle Scholar
  7. 7.
    Lu-Emerson C, Norden AD, Drappatz J, Quant EC, Beroukhim R, Ciampa AS, Doherty LM, Lafrankie DC, Ruland S, Wen PY (2011) Retrospective study of dasatinib for recurrent glioblastoma after bevacizumab failure. J Neurooncol 104:287–291. doi:10.1007/s11060-010-0489-x PubMedCrossRefGoogle Scholar
  8. 8.
    Nghiemphu PL, Liu W, Lee Y, Than T, Graham C, Lai A, Green RM, Pope WB, Liau LM, Mischel PS, Nelson SF, Elashoff R, Cloughesy TF (2009) Bevacizumab and chemotherapy for recurrent glioblastoma: a single-institution experience. Neurology 72:1217–1222. doi:10.1212/01.wnl.0000345668.03039.90 PubMedCrossRefGoogle Scholar
  9. 9.
    Omuro A, Chan TA, Abrey LE, Khasraw M, Reiner AS, Kaley TJ, DeAngelis LM, Lassman AB, Nolan CP, Gavrilovic IT, Hormigo A, Salvant C, Heguy A, Kaufman A, Huse JT, Panageas KS, Hottinger AF, Mellinghoff I (2013) Phase II trial of continuous low-dose temozolomide for patients with recurrent malignant glioma. Neuro Oncol 15:242–250. doi:10.1093/Neuonc/Nos295 PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Quant EC, Norden AD, Drappatz J, Muzikansky A, Doherty L, Lafrankie D, Ciampa A, Kesari S, Wen PY (2009) Role of a second chemotherapy in recurrent malignant glioma patients who progress on bevacizumab. Neuro Oncol 11:550–555. doi:10.1215/15228517-2009-006 PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Raizer JJ, Grimm S, Chamberlain MC, Nicholas MK, Chandler JP, Muro K, Dubner S, Rademaker AW, Renfrow J, Bredel M (2010) A phase 2 trial of single-agent bevacizumab given in an every-3-week schedule for patients with recurrent high-grade gliomas. Cancer 116:5297–5305. doi:10.1002/cncr.25462 PubMedCrossRefGoogle Scholar
  12. 12.
    Reardon DA, Desjardins A, Peters KB, Vredenburgh JJ, Gururangan S, Sampson JH, McLendon RE, Herndon JE 2nd, Coan A, Threatt S, Friedman AH, Friedman HS (2011) Phase 2 study of carboplatin, irinotecan, and bevacizumab for recurrent glioblastoma after progression on bevacizumab therapy. Cancer 117:5351–5358. doi:10.1002/cncr.26188 PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Sathornsumetee S, Desjardins A, Vredenburgh JJ, McLendon RE, Marcello J, Herndon JE, Mathe A, Hamilton M, Rich JN, Norfleet JA, Gururangan S, Friedman HS, Reardon DA (2010) Phase II trial of bevacizumab and erlotinib in patients with recurrent malignant glioma. Neuro Oncol 12:1300–1310. doi:10.1093/neuonc/noq099 PubMedCentralPubMedGoogle Scholar
  14. 14.
    Selfridge J, Piccioni D, Zurayk M, et al. (2012) Deferred use of bevazicumab for recurrent glioblastoma is not associated with diminished efficacy. Neuro Oncol Society for Neuro-Oncology (SNO) Abstract NO-97, page vi 84Google Scholar
  15. 15.
    Vredenburgh JJ, Desjardins A, Herndon JE 2nd, 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 25:4722–4729. doi:10.1200/JCO.2007.12.2440 PubMedCrossRefGoogle Scholar
  16. 16.
    Wen PY, Schiff D, Cloughesy TF, Raizer JJ, Laterra J, Smitt M, Wolf M, Oliner KS, Anderson A, Zhu M, Loh E, Reardon DA (2011) A phase II study evaluating the efficacy and safety of AMG 102 (rilotumumab) in patients with recurrent glioblastoma. Neuro Oncol 13:437–446. doi:10.1093/neuonc/noq198 PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    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 91:329–336. doi:10.1007/s11060-008-9718-y PubMedCrossRefGoogle Scholar
  18. 18.
    Cabrera AR, Cuneo KC, Desjardins A, Sampson JH, McSherry F, Herndon JE 2nd, Peters KB, Allen K, Hoang JK, Chang Z, Craciunescu O, Vredenburgh JJ, Friedman HS, Kirkpatrick JP (2013) Concurrent stereotactic radiosurgery and bevacizumab in recurrent malignant gliomas: a prospective trial. Int J Radiat Oncol Biol Phys 86:873–879. doi:10.1016/j.ijrobp.2013.04.029 PubMedCrossRefGoogle Scholar
  19. 19.
    Combs SE, Thilmann C, Edler L, Debus J, Schulz-Ertner D (2005) Efficacy of fractionated stereotactic reirradiation in recurrent gliomas: long-term results in 172 patients treated in a single institution. J Clin Oncol 23:8863–8869. doi:10.1200/JCO.2005.03.4157 PubMedCrossRefGoogle Scholar
  20. 20.
    Cuneo KC, Vredenburgh JJ, Sampson JH, Reardon DA, Desjardins A, Peters KB, Friedman HS, Willett CG, Kirkpatrick JP (2012) Safety and efficacy of stereotactic radiosurgery and adjuvant bevacizumab in patients with recurrent malignant gliomas. Int J Radiat Oncol Biol Phys 82:2018–2024. doi:10.1016/j.ijrobp.2010.12.074 PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Fogh SE, Andrews DW, Glass J, Curran W, Glass C, Champ C, Evans JJ, Hyslop T, Pequignot E, Downes B, Comber E, Maltenfort M, Dicker AP, Werner-Wasik M (2010) Hypofractionated stereotactic radiation therapy: an effective therapy for recurrent high-grade gliomas. J Clin Oncol 28:3048–3053. doi:10.1200/JCO.2009.25.6941 PubMedCrossRefGoogle Scholar
  22. 22.
    Gutin PH, Iwamoto FM, Beal K, Mohile NA, Karimi S, Hou BL, Lymberis S, Yamada Y, Chang J, Abrey LE (2009) Safety and efficacy of bevacizumab with hypofractionated stereotactic irradiation for recurrent malignant gliomas. Int J Radiat Oncol Biol Phys 75:156–163. doi:10.1016/j.ijrobp.2008.10.043 PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Niyazi M, Ganswindt U, Schwarz SB, Kreth FW, Tonn JC, Geisler J, la Fougere C, Ertl L, Linn J, Siefert A, Belka C (2012) Irradiation and bevacizumab in high-grade glioma retreatment settings. Int J Radiat Oncol Biol Phys 82:67–76. doi:10.1016/j.ijrobp.2010.09.002 PubMedCrossRefGoogle Scholar
  24. 24.
    Shapiro LQ, Beal K, Goenka A, Karimi S, Iwamoto FM, Yamada Y, Zhang Z, Lassman AB, Abrey LE, Gutin PH (2013) Patterns of failure after concurrent bevacizumab and hypofractionated stereotactic radiation therapy for recurrent high-grade glioma. Int J Radiat Oncol Biol Phys 85:636–642. doi:10.1016/j.ijrobp.2012.05.031 PubMedCrossRefGoogle Scholar
  25. 25.
    Adkison JB, Tome W, Seo S, Richards GM, Robins HI, Rassmussen K, Welsh JS, Mahler PA, Howard SP (2011) Reirradiation of large-volume recurrent glioma with pulsed reduced-dose-rate radiotherapy. Int J Radiat Oncol Biol Phys 79:835–841. doi:10.1016/j.ijrobp.2009.11.058 PubMedCrossRefGoogle Scholar
  26. 26.
    Hall EJ, Giaccia AJ (2006) Radiobiology for the radiologist. Lippincott Williams & Wilkins, PhiladelphiaGoogle Scholar
  27. 27.
    Harney J, Short SC, Shah N, Joiner M, Saunders MI (2004) Low dose hyper-radiosensitivity in metastatic tumors. Int J Radiat Oncol Biol Phys 59:1190–1195. doi:10.1016/j.ijrobp.2003.12.029 PubMedCrossRefGoogle Scholar
  28. 28.
    Joiner MC, Marples B, Lambin P, Short SC, Turesson I (2001) Low-dose hypersensitivity: current status and possible mechanisms. Int J Radiat Oncol Biol Phys 49:379–389PubMedCrossRefGoogle Scholar
  29. 29.
    Marples B, Wouters BG, Collis SJ, Chalmers AJ, Joiner MC (2004) Low-dose hyper-radiosensitivity: a consequence of ineffective cell cycle arrest of radiation-damaged G2-phase cells. Radiat Res 161:247–255PubMedCrossRefGoogle Scholar
  30. 30.
    Hochberg FH, Pruitt A (1980) Assumptions in the radiotherapy of glioblastoma. Neurology 30:907–911PubMedCrossRefGoogle Scholar
  31. 31.
    Kelly PJ, Daumas-Duport C, Kispert DB, Kall BA, Scheithauer BW, Illig JJ (1987) Imaging-based stereotaxic serial biopsies in untreated intracranial glial neoplasms. J Neurosurg 66:865–874. doi:10.3171/jns.1987.66.6.0865 PubMedCrossRefGoogle Scholar
  32. 32.
    Mohindra P, Robins HI, Tome WA, Hayes L, Howard SP (2013) Wide-field pulsed reduced dose rate radiotherapy (PRDR) for recurrent ependymoma in pediatric and young adult patients. Anticancer Res 33:2611–2618PubMedGoogle Scholar
  33. 33.
    Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996. doi:10.1056/NEJMoa043330 PubMedCrossRefGoogle Scholar
  34. 34.
    Wen PY, Macdonald DR, Reardon DA, Cloughesy TF, Sorensen AG, Galanis E, Degroot J, Wick W, Gilbert MR, Lassman AB, Tsien C, Mikkelsen T, Wong ET, Chamberlain MC, Stupp R, Lamborn KR, Vogelbaum MA, van den Bent MJ, Chang SM (2010) Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol 28:1963–1972. doi:10.1200/JCO.2009.26.3541 PubMedCrossRefGoogle Scholar
  35. 35.
    Levin VA, Bidaut L, Hou P, Kumar AJ, Wefel JS, Bekele BN, Grewal J, Prabhu S, Loghin M, Gilbert MR, Jackson EF (2011) Randomized double-blind placebo-controlled trial of bevacizumab therapy for radiation necrosis of the central nervous system. Int J Radiat Oncol Biol Phys 79:1487–1495. doi:10.1016/j.ijrobp.2009.12.061 PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    Dilworth JT, Krueger SA, Dabjan M, Grills IS, Torma J, Wilson GD, Marples B (2013) Pulsed low-dose irradiation of orthotopic glioblastoma multiforme (GBM) in a pre-clinical model: effects on vascularization and tumor control. Radiother Oncol. doi:10.1016/j.radonc.2013.05.022 PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • William Magnuson
    • 1
  • H. Ian Robins
    • 2
  • Pranshu Mohindra
    • 1
  • Steven Howard
    • 1
  1. 1.Department of Radiation OncologyUniversity of WisconsinMadisonUSA
  2. 2.Departments of Medicine, Human Oncology and Neurology, K4/534 Clinical Science CenterUniversity of WisconsinMadisonUSA

Personalised recommendations