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Salvage chemotherapy with bevacizumab for recurrent alkylator-refractory anaplastic astrocytoma

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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.

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References

  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 19:509–518

    Google Scholar 

  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 17:3389–3395

    PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  5. Prados MD, Levin V (2000) Biology and treatment of malignant glioma. Semin Oncol 27(Suppl 3):1–10

    PubMed  CAS  Google Scholar 

  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 21:601–606

    PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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):1379–1385

    PubMed  CAS  Google Scholar 

  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 24:593–597

    PubMed  CAS  Google Scholar 

  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 18:321–324

    PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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-S

    Article  PubMed  CAS  Google Scholar 

  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 17:2572–2578

    PubMed  CAS  Google Scholar 

  14. Yung WKA, Mechtler L, Gleason MJ (1991) Intravenous carboplatin for recurrent malignant gliomas: a phase II study. J Clin Oncol 9:860–864

    PubMed  CAS  Google Scholar 

  15. Allen JC, Walker R, Luks E et al (1987) Carboplatin and recurrent childhood brain tumors. J Clin Oncol 5:759–763

    Google Scholar 

  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 17:2762–2771

    PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  18. Allen JC, Helson L (1981) High-dose cyclophosphamide chemotherapy for recurrent CNS tumors in children. J Neurosurg 55:749–756

    Article  PubMed  CAS  Google Scholar 

  19. Longee DC, Friedman HS, Albright RE, Burger PC et al (1990) Treatment of patients with recurrent gliomas with cyclophosphamide and vincristine. J Neurosurg 72:583–588

    PubMed  CAS  Google Scholar 

  20. Chamberlain MC, Tsao-Wei D (2004) Recurrent glioblastoma multiforme: salvage therapy with cyclophosphamide. Cancer 100:1213–1220. doi:10.1002/cncr.20072

    Article  PubMed  CAS  Google Scholar 

  21. Macdonald DR, Cascino TL, Schold SC et al (1990) Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol 8:1277–1280

    PubMed  CAS  Google Scholar 

  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 23:3–8

    PubMed  CAS  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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 22:1s

    Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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. Stark-Vance V (2005) Bevacizumab and CPT-11 in the treatment of relapsed malignant glioma. Neuro-Oncology 7(3):369

    Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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. 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

    Article  PubMed  CAS  Google Scholar 

  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] 135:201–203

    Google Scholar 

  40. Lawless JF (1982) Statistical models and methods for lifetime data. Wiley, New York, pp 345–354

    Google Scholar 

  41. Miller RG Jr (1981) Survival analysis. Wiley, New York, pp 114–118

    Google Scholar 

  42. Kaplan EL, Meier P (1958) Nonparametric estimation form incomplete observations. J Am Stat Assoc 53:457–481. doi:10.2307/2281868

    Article  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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-E

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  47. Simanek R, Vormittag R, Hassler M et al (2007) Venous thromboembolism and survival in patients with high-grade glioma. J Neurooncol 9(2):89–95

    Google Scholar 

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Acknowledgments

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

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Correspondence to Marc C. Chamberlain.

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Chamberlain, M.C., Johnston, S. Salvage chemotherapy with bevacizumab for recurrent alkylator-refractory anaplastic astrocytoma. J Neurooncol 91, 359–367 (2009). https://doi.org/10.1007/s11060-008-9722-2

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