Journal of Neuro-Oncology

, Volume 106, Issue 2, pp 409–415 | Cite as

Phase II study of Gleevec® plus hydroxyurea (HU) in adults with progressive or recurrent meningioma

  • David A. ReardonEmail author
  • Andrew D. Norden
  • Annick Desjardins
  • James J. Vredenburgh
  • James E. HerndonII
  • April Coan
  • John H. Sampson
  • Sridharan Gururangan
  • Katherine B. Peters
  • Roger E. McLendon
  • Julie A. Norfleet
  • Eric S. Lipp
  • Jan Drappatz
  • Patrick Y. Wen
  • Henry S. Friedman
Clinical Study – Patient Study


We prospectively evaluated the efficacy and safety of imatinib plus hydroxyurea in patients with progressive/recurrent meningioma. A total of 21 patients with progressive/recurrent meningioma were enrolled in this dual center, single-arm, phase II trial. All patients received 500 mg of hydroxyurea twice a day. Imatinib was administered at 400 mg/day for patients not on CYP3A enzyme inducing anti-epileptic drugs (EIAEDs) and at 500 mg twice a day for patients on EIAEDs. The primary endpoint was progression-free survival at 6 months (PFS-6) and secondary endpoints were safety, radiographic response rate, and overall survival (OS). Best radiographic response was stable disease and was observed in 14 patients (67%). PFS-6 for all patients, those with grade I tumors (n = 8) and those with grade II or III tumors (n = 13) was 61.9, 87.5 and 46.2%, respectively. Patients with grade II or III tumors had poorer PFS and OS than those with grade I tumors, (P = 0.025 and P = 0.018) respectively. The only grade 3 or greater adverse event occurring in ≥10% of patients was anemia (10%). Imatinib plus hydroxyurea is well tolerated among patients with meningioma but has modest anti-tumor activity for this indication.


Meningioma Platelet-derived growth factor receptor Imatinib mesylate Hydroxyurea 



Overall survival


Progression-free survival




CYP3A enzyme inducing anti-epileptic drugs


Karnofsky performance status


Progressive disease


Stereotactic radiosurgery


External beam radiotherapy


Central nervous system


Platelet derived growth factor receptor


Subtotal resection


Stereotactic radiosurgery



This study was financially supported by grants P50 NS20023 and R37 CA011898 from NIH, Department of Health and Human Services, Bethesda, Maryland and a research grant from Novartis Pharmaceuticals. The investigators wish to thank Wendy Gentry for her assistance in the preparation of this manuscript.


  1. 1.
    CBTRUS (2004–2006) 2010 Statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2004–2006. Central Brain Tumor Registry of the United StatesGoogle Scholar
  2. 2.
    Mawrin C, Perry A (2010) Pathological classification and molecular genetics of meningiomas. J Neurooncol 99:379–391. doi: 10.1007/s11060-010-0342-2 PubMedCrossRefGoogle Scholar
  3. 3.
    Al-Mefty O, Kadri PA, Pravdenkova S, Sawyer JR, Stangeby C, Husain M (2004) Malignant progression in meningioma: documentation of a series and analysis of cytogenetic findings. J Neurosurg 101:210–218. doi: 10.3171/jns.2004.101.2.0210 PubMedCrossRefGoogle Scholar
  4. 4.
    Louis DN, Ohgaki H, Wiestler OD, Cavenee WK (2007) WHO Classification of Tumours of the Central Nervous System. International Agency for Research on Cancer (IARC), LyonGoogle Scholar
  5. 5.
    U.S. Department of Health and Human Services CfDE, and Research FaDa (2006) FDA project on cancer drug approval endpointGoogle Scholar
  6. 6.
    Rogers L, Gilbert M, Vogelbaum MA (2010) Intracranial meningiomas of atypical (WHO grade II) histology. J Neurooncol 99:393–405. doi: 10.1007/s11060-010-0343-1 PubMedCrossRefGoogle Scholar
  7. 7.
    Hanft S, Canoll P, Bruce JN (2010) A review of malignant meningiomas: diagnosis, characteristics, and treatment. J Neurooncol 99:433–443. doi: 10.1007/s11060-010-0348-9 PubMedCrossRefGoogle Scholar
  8. 8.
    Aghi MK, Carter BS, Cosgrove GR, Ojemann RG, Amin-Hanjani S, Martuza RL, Curry WT Jr, Barker FG 2nd (2009) Long-term recurrence rates of atypical meningiomas after gross total resection with or without postoperative adjuvant radiation. Neurosurgery 64:56–60. doi: 10.1227/01.NEU.0000330399.55586.63 discussion 60PubMedCrossRefGoogle Scholar
  9. 9.
    Chamberlain MC, Tsao-Wei DD, Groshen S (2004) Temozolomide for treatment-resistant recurrent meningioma. Neurology 62:1210–1212PubMedGoogle Scholar
  10. 10.
    Chamberlain MC, Tsao-Wei DD, Groshen S (2006) Salvage chemotherapy with CPT-11 for recurrent meningioma. J Neurooncol 78:271–276PubMedCrossRefGoogle Scholar
  11. 11.
    Johnson DR, Kimmel DW, Burch PA, Cascino TL, Giannini C, Wu W, Buckner JC (2011) Phase II study of subcutaneous octreotide in adults with recurrent or progressive meningioma and meningeal hemangiopericytoma. Neuro Oncol 13:530–535. doi: 10.1093/neuonc/nor044 PubMedCrossRefGoogle Scholar
  12. 12.
    Chamberlain MC, Glantz MJ, Chalmers L, Van Horn A, Sloan AE (2007) Early necrosis following concurrent temodar and radiotherapy in patients with glioblastoma. J Neurooncol 82:81–83PubMedCrossRefGoogle Scholar
  13. 13.
    Chamberlain MC, Glantz MJ (2008) Interferon-alpha for recurrent World Health Organization grade 1 intracranial meningiomas. Cancer 113:2146–2151PubMedCrossRefGoogle Scholar
  14. 14.
    Grunberg SM, Weiss MH, Russell CA, Spitz IM, Ahmadi J, Sadun A, Sitruk-Ware R (2006) Long-term administration of mifepristone (RU486): clinical tolerance during extended treatment of meningioma. Cancer Invest 24:727–733. doi: 10.1080/07357900601062339 PubMedCrossRefGoogle Scholar
  15. 15.
    Lamberts SW, Tanghe HL, Avezaat CJ, Braakman R, Wijngaarde R, Koper JW, De Jong H (1992) Mifepristone (RU 486) treatment of meningiomas. J Neurol Neurosurg Psychiatry 55:486–490PubMedCrossRefGoogle Scholar
  16. 16.
    Norden AD, Raizer J, Abrey L, Lamborn K, Lassman A, Chang SM, Yung WKA, Gilbert M, Fine HA, Mehta M, De Angelis L, Cloughesy T, Robins HI, Aldape K, Dancey J, Prodos M, Lieberman F, Wen PY (2009) Phase II Trials of erlotinb or gefitinib in patients with recurrent meningioma. J Neurooncol 96(2):211–217PubMedCrossRefGoogle Scholar
  17. 17.
    Newton HB (2007) Hydroxyurea chemotherapy in the treatment of meningiomas. Neurosurg Focus 23:E11PubMedCrossRefGoogle Scholar
  18. 18.
    Newton HB, Scott SR, Volpi C (2004) Hydroxyurea chemotherapy for meningiomas: enlarged cohort with extended follow-up. Br J Neurosurg 18:495–499PubMedCrossRefGoogle Scholar
  19. 19.
    Newton HB, Slivka MA, Stevens C (2000) Hydroxyurea chemotherapy for unresectable or residual meningioma. J Neurooncol 49:165–170PubMedCrossRefGoogle Scholar
  20. 20.
    Loven D, Hardoff R, Sever ZB, Steinmetz AP, Gornish M, Rappaport ZH, Fenig E, Ram Z, Sulkes A (2004) Non-resectable slow-growing meningiomas treated by hydroxyurea. J Neurooncol 67:221–226PubMedCrossRefGoogle Scholar
  21. 21.
    Mason WP, Gentili F, Macdonald DR, Hariharan S, Cruz CR, Abrey LE (2002) Stabilization of disease progression by hydroxyurea in patients with recurrent or unresectable meningioma. J Neurosurg 97:341–346. doi: 10.3171/jns.2002.97.2.0341 PubMedCrossRefGoogle Scholar
  22. 22.
    Rosenthal MA, Ashley DL, Cher L (2002) Treatment of high risk or recurrent meningiomas with hydroxyurea. J Clin Neurosci 9:156–158. doi: 10.1054/jocn.2001.1019 PubMedCrossRefGoogle Scholar
  23. 23.
    Schrell UM, Rittig MG, Anders M, Koch UH, Marschalek R, Kiesewetter F, Fahlbusch R (1997) Hydroxyurea for treatment of unresectable and recurrent meningiomas. II. decrease in the size of meningiomas in patients treated with hydroxyurea. J Neurosurg 86:840–844PubMedCrossRefGoogle Scholar
  24. 24.
    Hahn BM, Schrell UM, Sauer R, Fahlbusch R, Ganslandt O, Grabenbauer GG (2005) Prolonged oral hydroxyurea and concurrent 3d-conformal radiation in patients with progressive or recurrent meningioma: results of a pilot study. J Neurooncol 74:157–165. doi: 10.1007/s11060-004-2337-3 PubMedCrossRefGoogle Scholar
  25. 25.
    Ragel BT, Jensen RL (2010) Aberrant signaling pathways in meningiomas. J Neurooncol 99:315–324. doi: 10.1007/s11060-010-0381-8 PubMedCrossRefGoogle Scholar
  26. 26.
    Yang SY, Xu GM (2001) Expression of PDGF and its receptor as well as their relationship to proliferating activity and apoptosis of meningiomas in human meningiomas. J Clin Neurosci 8 Supplement 1:49–53. doi: 10.1054/jocn.2001.0877
  27. 27.
    Nagashima G, Asai J, Suzuki R, Fujimoto T (2001) Different distribution of c-myc and MIB-1 positive cells in malignant meningiomas with reference to TGFs, PDGF, and PgR expression. Brain Tumor Pathol 18:1–5PubMedCrossRefGoogle Scholar
  28. 28.
    Todo T, Adams EF, Fahlbusch R, Dingermann T, Werner H (1996) Autocrine growth stimulation of human meningioma cells by platelet-derived growth factor. J Neurosurg 84:852–858 discussion 858–859PubMedCrossRefGoogle Scholar
  29. 29.
    Mauro A, Di Sapio A, Mocellini C, Schiffer D (1995) Control of meningioma cell growth by platelet-derived growth factor (PDGF). J Neurol Sci 131:135–143PubMedCrossRefGoogle Scholar
  30. 30.
    Schrell UM, Gauer S, Kiesewetter F, Bickel A, Hren J, Adams EF, Fahlbusch R (1995) Inhibition of proliferation of human cerebral meningioma cells by suramin: effects on cell growth, cell cycle phases, extracellular growth factors, and PDGF-BB autocrine growth loop. J Neurosurg 82:600–607. doi: 10.3171/jns.1995.82.4.0600 PubMedCrossRefGoogle Scholar
  31. 31.
    Kuratsu JI, Seto H, Kochi M, Ushio Y (1994) Expression of PDGF, PDGF-receptor, EGF-receptor and sex hormone receptors on meningioma. Acta Neurochir (Wien) 131:289–293CrossRefGoogle Scholar
  32. 32.
    Figarella-Branger D, Vagner-Capodano AM, Bouillot P, Graziani N, Gambarelli D, Devictor B, Zattara-Cannoni H, Bianco N, Grisoli F, Pellissier JF (1994) Platelet-derived growth factor (PDGF) and receptor (PDGFR) expression in human meningiomas: correlations with clinicopathological features and cytogenetic analysis. Neuropathol Appl Neurobiol 20:439–447PubMedCrossRefGoogle Scholar
  33. 33.
    Black PM, Carroll R, Glowacka D, Riley K, Dashner K (1994) Platelet-derived growth factor expression and stimulation in human meningiomas. J Neurosurg 81:388–393. doi: 10.3171/jns.1994.81.3.0388 PubMedCrossRefGoogle Scholar
  34. 34.
    Maxwell M, Galanopoulos T, Hedley-Whyte ET, Black PM, Antoniades HN (1990) Human meningiomas co-express platelet-derived growth factor (PDGF) and PDGF-receptor genes and their protein products. Int J Cancer 46:16–21PubMedCrossRefGoogle Scholar
  35. 35.
    Johnson MD, Okedli E, Woodard A, Toms SA, Allen GS (2002) Evidence for phosphatidylinositol 3-kinase-Akt-p7S6K pathway activation and transduction of mitogenic signals by platelet-derived growth factor in meningioma cells. J Neurosurg 97:668–675. doi: 10.3171/jns.2002.97.3.0668 PubMedCrossRefGoogle Scholar
  36. 36.
    Johnson MD, Woodard A, Kim P, Frexes-Steed M (2001) Evidence for mitogen-associated protein kinase activation and transduction of mitogenic signals by platelet-derived growth factor in human meningioma cells. J Neurosurg 94:293–300. doi: 10.3171/jns.2001.94.2.0293 PubMedCrossRefGoogle Scholar
  37. 37.
    Reardon DA, Egorin MJ, Quinn JA, Rich JN Sr, Gururangan I, Vredenburgh JJ, Desjardins A, Sathornsumetee S, Provenzale JM, Herndon JE 2nd, Dowell JM, Badruddoja MA, McLendon RE, Lagattuta TF, Kicielinski KP, Dresemann G, Sampson JH, Friedman AH, Salvado AJ, Friedman HS (2005) Phase II study of imatinib mesylate plus hydroxyurea in adults with recurrent glioblastoma multiforme. J Clin Oncol 23:9359–9368PubMedCrossRefGoogle Scholar
  38. 38.
    Wen PY, Yung WK, Lamborn KR, Dahia PL, Wang Y, Peng B, Abrey LE, Raizer J, Cloughesy TF, Fink K, Gilbert M, Chang S, Junck L, Schiff D, Lieberman F, Fine HA, Mehta M, Robins HI, De Angelis LM, Groves MD, Puduvalli VK, Levin V, Conrad C, Maher EA, Aldape K, Hayes M, Letvak L, Egorin MJ, Capdeville R, Kaplan R, Murgo AJ, Stiles C, Prados MD (2006) Phase I/II study of imatinib mesylate for recurrent malignant gliomas: North American Brain Tumor Consortium Study 99–08. Clin Cancer Res 12:4899–4907PubMedCrossRefGoogle Scholar
  39. 39.
    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
  40. 40.
    Chamberlain MC, Johnston SK (2011) Hydroxyurea for recurrent surgery and radiation refractory meningioma: a retrospective case series. J Neurooncol 104(3):765–771Google Scholar
  41. 41.
    Wen PY, Yung WK, Lamborn KR, Norden AD, Cloughesy TF, Abrey LE, Fine HA, Chang SM, Robins HI, Fink K, De Angelis LM, Mehta M, Di Tomaso E, Drappatz J, Kesari S, Ligon KL, Aldape K, Jain RK, Stiles CD, Egorin MJ, Prados MD (2009) Phase II study of imatinib mesylate for recurrent meningiomas (North American Brain Tumor Consortium study 01–08). Neuro Oncol 11:853–860. doi: 10.1215/15228517-2009-010 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2011

Authors and Affiliations

  • David A. Reardon
    • 1
    • 2
    • 3
    Email author
  • Andrew D. Norden
    • 7
  • Annick Desjardins
    • 2
    • 4
  • James J. Vredenburgh
    • 2
    • 4
  • James E. HerndonII
    • 5
  • April Coan
    • 5
  • John H. Sampson
    • 2
  • Sridharan Gururangan
    • 2
    • 3
  • Katherine B. Peters
    • 2
    • 4
  • Roger E. McLendon
    • 6
  • Julie A. Norfleet
    • 2
  • Eric S. Lipp
    • 2
  • Jan Drappatz
    • 7
  • Patrick Y. Wen
    • 7
  • Henry S. Friedman
    • 2
    • 3
  1. 1.Duke University Medical CenterDurhamUSA
  2. 2.Department of Surgery, The Preston Robert Tisch Brain Tumor CenterDuke University Medical CenterDurhamUSA
  3. 3.Department of Pediatrics, The Preston Robert Tisch Brain Tumor CenterDuke University Medical CenterDurhamUSA
  4. 4.Department of Medicine, The Preston Robert Tisch Brain Tumor CenterDuke University Medical CenterDurhamUSA
  5. 5.Department of Biostatistics, The Preston Robert Tisch Brain Tumor CenterDuke University Medical CenterDurhamUSA
  6. 6.Departments of Neurobiology and Pathology, The Preston Robert Tisch Brain Tumor CenterDuke University Medical CenterDurhamUSA
  7. 7.The Center for Neuro-OncologyDana Farber Cancer InstituteBostonUSA

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