Advertisement

Journal of Neuro-Oncology

, 91:359 | Cite as

Salvage chemotherapy with bevacizumab for recurrent alkylator-refractory anaplastic astrocytoma

  • Marc C. ChamberlainEmail author
  • Sandra Johnston
Clinical study - patient study

Abstract

A retrospective study of bevacizumab only in adults with recurrent temozolomide (TMZ)-refractory anaplastic astrocytoma (AA) with a primary objective of determining progression free survival (PFS). There is no standard therapy for alkylator-resistant AA and hence a need exists for new therapies. Twenty-five patients (15 men; 10 women) ages 26–63 (median 50), with radiographically recurrent AA were treated. All patients had previously been treated with surgery, involved-field radiotherapy, and alkylator-based chemotherapy. Fourteen patients underwent repeat surgery. Patients were treated at second recurrence with bevacizumab (10 mg/kg), once every 2 weeks (defined as a single cycle). Neurological evaluation was performed every 2 weeks and neuroradiographic assessment following the initial two cycles of bevacizumab and subsequently after every four cycles of bevacizumab. All patients were evaluable for toxicity and response. A total of 360 cycles of bevacizumab (median 14 cycles; range 2–40) was administered. Bevacizumab-related toxicity included fatigue (14 patients; 2 grade 3), leukopenia (7; 1 grade 3), deep vein thrombosis (5; 2 grade 3), hypertension (5; 1 grade 3), anemia (4; 0 grade 3) and wound dehiscence (1; 1 grade 3). Sixteen patients (64%) demonstrated a partial radiographic response, 2 (8.0%) stable disease and 7 (28%) progressive disease following two cycles of bevacizumab. Time to tumor progression ranged from 1 to 20 months (median: 7). Survival ranged from 2 to 23 months (median: 9.0). 6-month and 12-month PFS were 60 and 20%, respectively. Bevacizumab demonstrated efficacy and acceptable toxicity in this cohort of adults with recurrent alkylator refractory AA.

Keywords

Bevacizumab Recurrent anaplastic astrocytoma Alkylator chemotherapy refractory 

Notes

Acknowledgments

Marc Chamberlain and Sandra K. Johnston conducted the statistical analysis for this manuscript. Both authors listed above collected and analyzed data.

References

  1. 1.
    The Medical Research Council Brain Tumor Working Party (2000) Randomized trial of procarbazine, lomustine, and vincristine in the adjuvant treatment of high-grade astrocytoma: a medical research council trial. J Clin Oncol 19:509–518Google Scholar
  2. 2.
    Prados MD, Scott C, Curran WJ et al (1999) Procarbazine, lomustine, and vincristine (PCV) chemotherapy for anaplastic astrocytoma: a retrospective review of radiation therapy oncology group protocols comparing survival with carmustine or PCV adjuvant chemotherapy. J Clin Oncol 17:3389–3395PubMedGoogle Scholar
  3. 3.
    Westphal M, Hilt DC, Bortey E et al (2003) A phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (gliadel wafers) in patients with primary malignant glioma. Neuro-Oncology 5(2):79–88. doi: 10.1215/15228517-5-2-79 PubMedCrossRefGoogle Scholar
  4. 4.
    Grossman SA, O’Neill A, Grunnet M, Mehta M et al (2003) Phase III study comparing three cycles of infusional carmustine and cisplatin followed by radiation therapy with radiation therapy and concurrent carmustine in patients with newly diagnosed supratentorial glioblastoma multiforme: Eastern Cooperative Oncology Group Trial 2394. J Clin Oncol 21:1485–1491. doi: 10.1200/JCO.2003.10.035 PubMedCrossRefGoogle Scholar
  5. 5.
    Prados MD, Levin V (2000) Biology and treatment of malignant glioma. Semin Oncol 27(Suppl 3):1–10PubMedGoogle Scholar
  6. 6.
    Gutin PH, Prados MD, Phillips TL et al (1991) External irradiation followed by an interstitial high activity iodine-125 implant “boost” in the initial treatment of malignant gliomas: NCOG study 6G82-2. Int J Radiat Oncol Biol Phys 21:601–606PubMedGoogle Scholar
  7. 7.
    Kornblith PD, Welch WC, Bradley MK (1993) The future of therapy for glioblastoma. Surg Neurol 39:538–543. doi: 10.1016/0090-3019(93)90041-X PubMedCrossRefGoogle Scholar
  8. 8.
    Loeffler JS, Alexander E, Shea WM et al (1992) Radiosurgery as part of the initial management of patients with malignant gliomas. J Clin Oncol 10(9):1379–1385PubMedGoogle Scholar
  9. 9.
    Prados MD, Gutin PH, Phillips TL et al (1992) Interstitial brachytherapy for newly diagnosed patients with malignant gliomas: the UCSF experience. Int J Radiat Oncol Biol Phys 24:593–597PubMedGoogle Scholar
  10. 10.
    Levin VA, Silver P, Hannigan J et al (1990) Superiority of post-radiotherapy adjuvant chemotherapy with CCNU, procarbazine, and vincristine (PCV) over BCNU for anaplastic gliomas: NCOG 6G61 final report. Int J Radiat Oncol Biol Phys 18:321–324PubMedGoogle Scholar
  11. 11.
    Stewart LA (2002) Chemotherapy in adult high-grade glioma: a systemic review and meta-analysis of individual patient data from 12 randomized trials. Lancet 359:1011–1018. doi: 10.1016/S0140-6736(02)08091-1 PubMedCrossRefGoogle Scholar
  12. 12.
    Fine HA, Dear KB, Loeffler JS et al (1993) Meta-analysis of radiation therapy and without chemotherapy for malignant gliomas in adults. Cancer 71:2585–2597. doi:10.1002/1097-0142(19930415)71:8<2585::AID-CNCR2820710825>3.0.CO;2-SPubMedCrossRefGoogle Scholar
  13. 13.
    Wong ET, Hess KR, Gleason MJ et al (1999) Outcomes and prognostic factors in recurrent glioma patients enrolled onto phase II clinical trials. J Clin Oncol 17:2572–2578PubMedGoogle Scholar
  14. 14.
    Yung WKA, Mechtler L, Gleason MJ (1991) Intravenous carboplatin for recurrent malignant gliomas: a phase II study. J Clin Oncol 9:860–864PubMedGoogle Scholar
  15. 15.
    Allen JC, Walker R, Luks E et al (1987) Carboplatin and recurrent childhood brain tumors. J Clin Oncol 5:759–763Google Scholar
  16. 16.
    Yung WK, Prados MD, Yaya-Tur R, Rosenfeld SS, Brada M et al (1999) Multicenter phase II trial of temozolomide in patients with anaplastic astrocytoma or anaplastic oligoastrocytoma at first relapse. J Clin Oncol 17:2762–2771PubMedGoogle Scholar
  17. 17.
    See SJ, Levin VA, Yung A et al (2004) 13-cis-Retinoic acid in the treatment of recurrent glioblastoma multiforme. Neuro-Oncology 6:253–258. doi: 10.1215/S1152851703000607 PubMedCrossRefGoogle Scholar
  18. 18.
    Allen JC, Helson L (1981) High-dose cyclophosphamide chemotherapy for recurrent CNS tumors in children. J Neurosurg 55:749–756PubMedCrossRefGoogle Scholar
  19. 19.
    Longee DC, Friedman HS, Albright RE, Burger PC et al (1990) Treatment of patients with recurrent gliomas with cyclophosphamide and vincristine. J Neurosurg 72:583–588PubMedGoogle Scholar
  20. 20.
    Chamberlain MC, Tsao-Wei D (2004) Recurrent glioblastoma multiforme: salvage therapy with cyclophosphamide. Cancer 100:1213–1220. doi: 10.1002/cncr.20072 PubMedCrossRefGoogle Scholar
  21. 21.
    Macdonald DR, Cascino TL, Schold SC et al (1990) Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol 8:1277–1280PubMedGoogle Scholar
  22. 22.
    Prados MD, Gutin PH, Phillips TL et al (1992) Highly anaplastic astrocytoma: a review of 357 patients treated between 1977 and 1989. Int J Radiat Oncol Biol Phys 23:3–8PubMedGoogle Scholar
  23. 23.
    Tortosa A, Vinolas N, Villa S, Verger E, Gil JM et al (2003) Prognostic implications of clinical, radiologic, and pathologic features in patients with anaplastic gliomas. Cancer 97:1063–1071. doi: 10.1002/cncr.11120 PubMedCrossRefGoogle Scholar
  24. 24.
    Voges J, Reszka R, Grossman A, Dittmar C, Richter R et al (2003) Image-guided convection-enhanced delivery and gene therapy of glioblastoma. Ann Neurol 54:479–487. doi: 10.1002/ana.10688 PubMedCrossRefGoogle Scholar
  25. 25.
    Stupp R, Mason WP, Van Den Bent MJ et al (2004) Concomitant and adjuvant temozolomide and radiotherapy for newly diagnosed glioblastoma multiforme. Conclusive results of a randomized phase III trial by the EORTC Brain & RT Groups and NCIC Clinical Trial Groups. J Clin Oncol 22:1sGoogle Scholar
  26. 26.
    Brem H, Piantadosi S, Burger PC, Walker M, Selker R et al (1995) Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas. Lancet 345:1008–1012. doi: 10.1016/S0140-6736(95)90755-6 PubMedCrossRefGoogle Scholar
  27. 27.
    Jaeckle KA, Hess KR, Yung A et al (2003) Phase II evaluation of temozolomide and 13-cis-retinoic acid for the treatment of recurrent and progressive malignant glioma: a North American Brain Tumor Consortium study. J Clin Oncol 21:2305–2311. doi: 10.1200/JCO.2003.12.097 PubMedCrossRefGoogle Scholar
  28. 28.
    Cairncross G, Berkey B, Shaw E et al (2006) Phase III trial of chemotherapy plus radiotherapy compared with radiotherapy alone for pure and mixed anaplastic oligodendroglioma: Intergroup Radiation Oncology Group trial 9402. J Clin Oncol 24(18):2707–2714. doi: 10.1200/JCO.2005.04.3414 PubMedCrossRefGoogle Scholar
  29. 29.
    van den Bent MJ, Carpentier AF, Brandes AA et al (2006) Adjuvant procarbazine, lomustine and vincristine improves progression free survival but not overall survival in newly diagnosed anaplastic oligodendrogliomas and oligoastrocytomas: a randomized European Organization for Research and Treatment of Cancer Phase III trial. J Clin Oncol 24(18):2715–2722. doi: 10.1200/JCO.2005.04.6078 PubMedCrossRefGoogle Scholar
  30. 30.
    Wick-Wolfgang W, Weller M (2008) Neuro-Oncology Working Group of the German Cancer Society. J Clin Oncol 26(15S):90s (abstract). doi: 10.1200/JCO.2007.11.9248 Google Scholar
  31. 31.
    Stark-Vance V (2005) Bevacizumab and CPT-11 in the treatment of relapsed malignant glioma. Neuro-Oncology 7(3):369Google Scholar
  32. 32.
    Pope WB, Lai A, Nghiemphu P, Mischel P, Cloughesy TF (2006) MRI in patients with high-grade gliomas treated with bevacizumab and chemotherapy. Neurology 66(8):1258–1260. doi: 10.1212/01.wnl.0000208958.29600.87 PubMedCrossRefGoogle Scholar
  33. 33.
    Vredenburgh JJ, Desjardins A, Herndon JEII et al (2007) Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma. Clin Cancer Res 13(4):1253–1259. doi: 10.1158/1078-0432.CCR-06-2309 PubMedCrossRefGoogle Scholar
  34. 34.
    Vredenburgh JJ, Desjardins A, Herndon JE et al (2007) Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol 25(30):4722–4729. doi: 10.1200/JCO.2007.12.2440 PubMedCrossRefGoogle Scholar
  35. 35.
    Chen C, Silverman DHS, Geist C et al (2007) 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(30):4714–4721. doi: 10.1200/JCO.2006.10.5825 PubMedCrossRefGoogle Scholar
  36. 36.
    Norden AD, Young GS, Setayesh K et al (2008) Bevacizumab for recurrent malignant glioma: efficacy, toxicity and patterns of recurrence. Neurology 70:779–787. doi: 10.1212/01.wnl.0000304121.57857.38 PubMedCrossRefGoogle Scholar
  37. 37.
    Cloughesy T, Prados MD, Mikkelsen T et al (2008) A phase 2 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 26:91s (abstract)Google Scholar
  38. 38.
    Berry G, Kitchin RM, Mock PA (1991) A comparison of two simple hazard ratio estimators based on the logrank test. Stat Med 10:749–755. doi: 10.1002/sim.4780100510 PubMedCrossRefGoogle Scholar
  39. 39.
    Pike MC (1972) Contribution to the discussion on the paper by R. Peto and J. Peto, ‘Asymptotically efficient rank invariant procedures’. J R Stat Soc [Ser A] 135:201–203Google Scholar
  40. 40.
    Lawless JF (1982) Statistical models and methods for lifetime data. Wiley, New York, pp 345–354Google Scholar
  41. 41.
    Miller RG Jr (1981) Survival analysis. Wiley, New York, pp 114–118Google Scholar
  42. 42.
    Kaplan EL, Meier P (1958) Nonparametric estimation form incomplete observations. J Am Stat Assoc 53:457–481. doi: 10.2307/2281868 CrossRefGoogle Scholar
  43. 43.
    Batchelor TT, Sorensen AG, di Tomaso E et al (2007) AZD2171, a Pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 11:83–95. doi: 10.1016/j.ccr.2006.11.021 PubMedCrossRefGoogle Scholar
  44. 44.
    Brandes AA, Scelzi E, Salmistraro G et al (1997) Incidence of risk of thromboembolism during treatment of high-grade gliomas: a prospective study. Eur J Cancer 33:1592–1596. doi: 10.1016/S0959-8049(97)00167-6 PubMedCrossRefGoogle Scholar
  45. 45.
    Marras LC, Geerts WH, Perry JR (2000) The risk of venous thromboembolism is increased throughout the course of malignant glioma: an evidence-based review. Cancer 89:640–646. doi:10.1002/1097-0142(20000801)89:3<640::AID-CNCR20>3.0.CO;2-EPubMedCrossRefGoogle Scholar
  46. 46.
    Semrad TJ, O’Donnell R, Wun T et al (2007) Epidemiology of venous thromboembolism in 9489 patients with malignant glioma. J Neurosurg 106(4):601–608. doi: 10.3171/jns.2007.106.4.601 PubMedCrossRefGoogle Scholar
  47. 47.
    Simanek R, Vormittag R, Hassler M et al (2007) Venous thromboembolism and survival in patients with high-grade glioma. J Neurooncol 9(2):89–95Google Scholar

Copyright information

© Springer Science+Business Media, LLC. 2008

Authors and Affiliations

  1. 1.Department of Neurology and Neurological SurgeryUniversity of Washington/Fred Hutchinson Cancer Center, Seattle Cancer Care AllianceSeattleUSA

Personalised recommendations