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Efficacy of protracted dose-dense temozolomide in patients with recurrent high-grade glioma

  • Clinical Study – Patient Study
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Abstract

The current standard therapy for newly diagnosed glioblastoma is multimodal, comprising surgical resection plus radiotherapy and concurrent temozolomide, then adjuvant temozolomide for 6 months. This has been shown to provide survival benefits; however, the prognosis for these patients remains poor, and most relapse. The objective of this prospective Phase II study was to evaluate the efficacy and tolerability of protracted, dose-dense temozolomide therapy (100 mg/m2 for 21 consecutive days of a 28-day cycle) in patients with recurrent glioblastoma or grade 3 gliomas who had previously received standard therapy. Of the 25 patients included (median age 50 years), 20 were evaluable for radiologic response. Two patients had partial responses and 10 had stable disease (60% overall clinical benefit); 8 patients (40%) progressed after the first treatment cycle. Five patients were not assessed for radiologic response due to early clinical progression but were included in the progression-free survival (PFS) and overall survival (OS) analyses. The median follow-up time was 7 months (range, 1–14 months). The median PFS was 3 months (95% confidence interval, CI, 1.8–4.2) and the median OS was 7 months (95% CI 5.1–8.9). The 6-month PFS rate (primary endpoint) was 17.3% (95% CI 1.7–32.2) and the 1-year OS rate was 12% (95% CI −1–25). This regimen was well tolerated. The most frequent adverse event was lymphopenia (grade 3–4 in 20 patients); no opportunistic infections were reported. Treatment was discontinued due to toxicity in 2 patients (grade 4 hepatic toxicity and thrombocytopenia). These data suggest that protracted, dose-dense temozolomide had modest activity with manageable toxicity in patients with recurrent high-grade glioma previously treated with temozolomide.

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References

  1. Newlands ES, Blackledge GR, Slack JA et al (1992) Phase I trial of temozolomide (CCRG 81045: M&B 39831: NSC 362856). Br J Cancer 65(2):287–291

    Article  PubMed  CAS  Google Scholar 

  2. Yung WKA, Albright RE, Olson J et al (2000) A phase II study of temozolomide vs. procarbazine in patients with glioblastoma multiforme at first relapse. Br J Cancer 83(5):588–593

    Article  PubMed  CAS  Google Scholar 

  3. Yung WK, Prados MD, Yaya-Tur R et al (1999) Multicenter phase II trial of temozolomide in patients with anaplastic astrocytoma or anaplastic oligoastrocytoma at first relapse. J Clin Oncol 17(9):2762–2771

    PubMed  CAS  Google Scholar 

  4. Stevens MFG, Hickman JA, Langdon SP et al (1987) Antitumor activity and pharmacokinetics in mice of 8-carbamoyl-3-methyl-imidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one (CCRG 81045; M&B 39831), a novel drug with potential as an alternative to dacarbazine. Cancer Res 47(22):5846–5852

    PubMed  CAS  Google Scholar 

  5. Newlands ES, Stevens MFG, Wedge SR, Wheelhouse RT, Brock C (1997) Temozolomide: a review of its discovery, chemical properties, preclinical development and clinical trials. Cancer Treat Rev 23(1):35–61

    Article  PubMed  CAS  Google Scholar 

  6. Stupp R, Mason WP, Van den Bent MJ et al (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352(10):987–996

    Article  PubMed  CAS  Google Scholar 

  7. Stupp R, Hegi ME, Mason WP et al (2009) Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 10(5):459–466

    Article  PubMed  CAS  Google Scholar 

  8. 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(8):2572–2578

    PubMed  CAS  Google Scholar 

  9. Butowski NA, Sneed P, Chang SM (2006) Diagnosis and treatment of recurrent high-grade astrocytoma. J Clin Oncol 24(8):1273–1280

    Article  PubMed  CAS  Google Scholar 

  10. Hegi M, Diserens A-C, Gorlia T et al (2005) MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352(10):997–1003

    Article  PubMed  CAS  Google Scholar 

  11. Gorlia T, Van den Bent M, Hegi M et al (2008) Nomograms for predicting survival of patients with newly diagnosed glioblastoma: prognostic factor analysis of EORTC and NCIC trial 26981-22981/CE.3. Lancet Oncol 9(1):29–38

    Article  PubMed  Google Scholar 

  12. Wick W, Steinbach JP, Kuker WM, Dichgans J, Bamberg M, Weller M (2004) One week on/one week off: a novel active regimen of temozolomide for recurrent glioblastoma. Neurology 62(11):2113–2115

    PubMed  CAS  Google Scholar 

  13. Khan RB, Raizer JJ, Malkin MG, Bazylewicz KA, Abrey LE (2002) A phase II study of extended low-dose temozolomide in recurrent malignant gliomas. Neurooncology 4(1):39–43

    CAS  Google Scholar 

  14. Balmaceda C, Peereboom D, Pannullo S et al (2008) Multi-institutional phase II study of temozolomide administered twice daily in the treatment of recurrent high-grade gliomas. Cancer 112(5):1139–1146

    Article  PubMed  CAS  Google Scholar 

  15. Brock CS, Newlands ES, Wedge SR et al (1998) Phase I trial of temozolomide using an extended continuous oral schedule. Cancer Res 58(19):4363–4367

    PubMed  CAS  Google Scholar 

  16. Bower M, Newlands ES, Bleehen NM et al (1997) Multicentre CRC phase II trial of temozolomide in recurrent or progressive high-grade glioma. Cancer Chemother Pharmacol 40(6):484–488

    Article  PubMed  CAS  Google Scholar 

  17. Denis L, Tolcher A, Figueroa J et al. (2000) Protracted daily administration of temozolomide is feasible: a phase I and pharmacokinetic–pharmacodynamic study. Proc Am Soc Clin Oncol 19:202a (abstr. no. 786)

    Google Scholar 

  18. Tolcher AW, Gerson SL, Denis L et al (2003) Marked inactivation of O6-alkylguanine-DNA alkyltransferase activity with protracted temozolomide schedules. Br J Cancer 88(7):1004–1011

    Article  PubMed  CAS  Google Scholar 

  19. Macdonald DR, Cascino TL, Schold SC Jr et al (1990) Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol 8(7):1277–1280

    PubMed  CAS  Google Scholar 

  20. Common Terminology Criteria for Adverse Events v3.0 (CTCAE) (2006) http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf. Accessed 17 Feb 2010

  21. Chamberlain MC, Tsao-Wei DD (2004) Salvage chemotherapy with cyclophosphamide for recurrent, temozolomide-refractory glioblastoma multiforme. Cancer 100(6):1213–1220

    Article  PubMed  CAS  Google Scholar 

  22. Soffietti R, Costanza A, Laguzzi E, Nobile M, Rudà R (2004) A phase II study of first-line temozolomide and second-line PCV in recurrent/progressive malignant gliomas. J Clin Oncol, 2004 ASCO annual meeting proceedings 22(14S):1574

  23. Gilbert MR (2006) Advances in the treatment of primary brain tumors: dawn of a new era? Curr Oncol Rep 8(1):45–49

    Article  PubMed  Google Scholar 

  24. Tisdale MJ (1987) Antitumor imidazotetrazines-XV. Role of guanine O6 alkylation in the mechanism of cytotoxicity of imidazotetrazinones. Biochem Pharmacol 36(4):457–462

    Article  PubMed  CAS  Google Scholar 

  25. Pegg AE (2000) Repair of O(6)-alkylguanine by alkyltransferases. Mutat Res 462(2–3):83–100

    PubMed  CAS  Google Scholar 

  26. Bobola MS, Tseng SH, Blank A, Berger MS, Silber JR (1996) Role of O6-methylguanine-DNA methyltransferase in resistance of human brain tumor cell lines to the clinically relevant methylating agents temozolomide and streptozotocin. Clin Cancer Res 2(4):735–741

    PubMed  CAS  Google Scholar 

  27. Lee SM, Thatcher N, Crowther D, Margison GP (1994) Inactivation of O6-alkylguanine-DNA alkyltransferase in human peripheral blood mononuclear cells by temozolomide. Br J Cancer 69(3):452–456

    Article  PubMed  CAS  Google Scholar 

  28. Brandsma D, Stalpers L, Taal W, Sminia P, van den Bent MJ (2008) Clinical features, mechanisms, and management of pseudoprogression in malignant gliomas. Lancet Oncol 9(5):453–461

    Article  PubMed  Google Scholar 

  29. Brandes AA, Franceschi E, Tosoni A et al (2008) MGMT promoter methylation status can predict the incidence and outcome of pseudoprogression after concomitant radiochemotherapy in newly diagnosed glioblastoma patients. J Clin Oncol 26(13):2192–2197

    Article  PubMed  Google Scholar 

  30. 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(1):81–83

    Article  PubMed  Google Scholar 

  31. Brandes AA, Tosoni A, Cavallo G et al (2006) Temozolomide 3 weeks and 1 week off as first-line therapy for recurrent glioblastoma: phase II study from Gruppo Italiano Cooperativo di Neuro-oncologia (GICNO). Br J Cancer 95(9):1155–1160

    Article  PubMed  CAS  Google Scholar 

  32. Caroli M, Locatelli M, Campanella R et al (2007) Temozolomide in glioblastoma: results of administration at first relapse and in newly diagnosed cases. Is still proposable an alternative schedule to concomitant protocol? J Neurooncol 84(1):71–77

    Article  PubMed  CAS  Google Scholar 

  33. Berrocal A, Perez Segura P, Gil M et al (2010) Extended-schedule dose-dense temozolomide in refractory gliomas. J Neurooncol 96(3):417–422

    Article  PubMed  CAS  Google Scholar 

  34. Neyns B, Chaskis C, Joosens E et al (2008) A multicenter cohort study of dose-dense temozolomide (21 of 28 days) for the treatment of recurrent anaplastic astrocytoma or oligoastrocytoma. Cancer Investig 26(3):269–277

    Article  CAS  Google Scholar 

  35. Perry JR, Rizek P, Cashman R et al (2008) Temozolomide rechallenge in recurrent malignant glioma by using a continuous temozolomide schedule, the “rescue” approach. Cancer 113(8):2152–2157

    Article  PubMed  CAS  Google Scholar 

  36. Perry JR, Bélanger K, Mason WP et al (2010) Phase II trial of continuous dose-intense temozolomide in recurrent malignant glioma: RESCUE study. J Clin Oncol 28(12):2051–2057

    Article  PubMed  CAS  Google Scholar 

  37. Brandes AA, Tosoni A, Basso U et al (2004) Second-line chemotherapy with irinotecan plus carmustine in glioblastoma recurrent or progressive after first-line temozolomide chemotherapy: a phase II study of the Gruppo Italiano Cooperativo di Neuro-Oncologia (GICNO). J Clin Oncol 22(23):4779–4786

    Article  PubMed  CAS  Google Scholar 

  38. Brandes AA, Tosoni A, Amistà P et al (2004) How effective is BCNU in recurrent glioblastoma in the modern era? A phase II trial. Neurology 63(7):1281–1284

    PubMed  CAS  Google Scholar 

  39. Franceschi E, Cavallo G, Scopece L et al (2004) Phase II trial of carboplatin and etoposide for patients with recurrent high-grade glioma. Br J Cancer 91(6):1038–1044

    PubMed  CAS  Google Scholar 

  40. Rosenthal MA, Ashley DL, Cher L (2004) BCNU as second line therapy for recurrent high-grade glioma previously treated with temozolomide. J Clin Neurosci 11(4):374–375

    Article  PubMed  CAS  Google Scholar 

  41. Vredenburgh JJ, Desjardins A, Reardon DA, Friedman HS (2009) Experience with irinotecan for the treatment of malignant glioma. Neurooncology 11(1):80–91

    CAS  Google Scholar 

  42. Chamberlain MC (2008) Bevacizumab plus irinotecan in recurrent glioblastoma. J Clin Oncol 26(6):1012–1013

    Article  PubMed  Google Scholar 

  43. Friedman HS, Prados MD, Wen PY et al (2009) Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol 27(28):4733–4740

    Article  PubMed  CAS  Google Scholar 

  44. Kreisl TN, Kim L, Moore K et al (2009) Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol 27(5):740–745

    Article  PubMed  CAS  Google Scholar 

  45. Vredenburgh JJ, Desjardins A, Herndon JE II et al (2007) Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol 25(30):4722–4729

    Article  PubMed  CAS  Google Scholar 

  46. Vredenburgh JJ, Desjardins A, Herndon JE II et al (2007) Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma. Clin Cancer Res 13(4):1253–1259

    Article  PubMed  CAS  Google Scholar 

  47. Reardon DA, Desjardins A, Vredenburgh JJ et al (2009) Metronomic chemotherapy with daily, oral etoposide plus bevacizumab for recurrent malignant glioma: a phase II study. Br J Cancer 101(12):1986–1994

    Article  PubMed  CAS  Google Scholar 

  48. Verhoeff JJ, Lavini C, van Linde ME et al (2010) Bevacizumab and dose-intense temozolomide in recurrent high-grade glioma. Ann Oncol 21(8):1723–1727

    Article  PubMed  CAS  Google Scholar 

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Acknowledgment

Presented in part at the 45th American Society of Clinical Oncology Annual Meeting, May 29–June 2, 2009, Orlando, FL. The study was supported by Merck and Co. Inc. (formerly Schering Corp). Editorial support was provided by Helen Varley, Evidence Scientific Solutions, Horsham, UK, and supported by Merck and Co. Inc. (formerly Schering Corp).

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Authors and Affiliations

  1. Radiation Oncology Department, Marmara University Hospital, Tophanelioglu Cad. 13/15 Altunizade, 34660, Istanbul, Turkey

    Ufuk Abacioglu, Hale B. Caglar, Zuleyha Akgun & Beste M. Atasoy

  2. Medical Oncology Division, Marmara University Hospital, Istanbul, Turkey

    Perran F. Yumuk

  3. Radiation Oncology Department, Acibadem Kozyatagi Hospital, Istanbul, Turkey

    Meric Sengoz

Authors
  1. Ufuk Abacioglu
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  2. Hale B. Caglar
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  3. Perran F. Yumuk
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  4. Zuleyha Akgun
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  6. Meric Sengoz
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Correspondence to Ufuk Abacioglu.

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ClinicalTrials.gov Identifier: NCT00575887.

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Abacioglu, U., Caglar, H.B., Yumuk, P.F. et al. Efficacy of protracted dose-dense temozolomide in patients with recurrent high-grade glioma. J Neurooncol 103, 585–593 (2011). https://doi.org/10.1007/s11060-010-0423-2

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  • DOI: https://doi.org/10.1007/s11060-010-0423-2

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