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The efficacy and safety of various dose-dense regimens of temozolomide for recurrent high-grade glioma: a systematic review with meta-analysis

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Abstract

The goal of this meta-analysis was to identify the temozolomide (TMZ) regimen with optimal efficacy and tolerance for treatment of recurrent high-grade glioma (HGG). The PubMed and EMBASE databases were searched from the earliest records to February 2015, which identified 33 studies with 1760 participants that met the inclusion criteria. The standard schedule and three most common dose-dense regimens of TMZ therapy for recurrent HGG were included in this meta-analysis. The schedule of 7 days on/7 days off for the treatment of grade IV gliomas was significantly superior to the standard regimen with respect to progression-free survival at 6 months (34.8 %; 95 % confidence interval (CI) 27.0–43.4 %) and 12 months (15.5 %; 95 % CI 10.7–21.8 %). For grade III gliomas, this regimen conveyed a significantly greater overall survival (OS) rate at 12 months (79.0 %; 95 % CI 56.2–91.7 %), as compared to the standard schedule. Also, the 21 days on/7 days off regimen had significantly longer OS rates at 6 months (73.6 %; 95 % CI 63.4–81.8 %) and 12 months (40.6 %; 95 % CI 32.6–48.6 %) than the standard regimen for grade IV gliomas. In addition, the standard schedule showed a significantly higher clinical benefit rate than the 7 days on/7 days off and 21 days on/7 days off regimens. However, the grade 3–4 toxicity rate of lymphopenia of the standard schedule was 76.5 % (95 % CI 45.5–92.7 %), which was the highest among the four regimens. Recurrent HGG patients receiving personalized treatment should be closely followed up, especially those with concurrent hematological diseases.

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References

  1. Kong DS, Lee JI, Kim WS et al (2006) A pilot study of metronomic temozolomide treatment in patients with recurrent temozolomide-refractory glioblastoma. Oncol Rep 16:1117–1121

    CAS  PubMed  Google Scholar 

  2. Louis DN, Ohgaki H, Wiestler OD et al (2007) The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114:97–109. doi:10.1007/s00401-007-0243-4

    Article  PubMed Central  PubMed  Google Scholar 

  3. Easaw JC, Mason WP, Perry J et al (2011) Canadian recommendations for the treatment of recurrent or progressive glioblastoma multiforme. Curr Oncol 18:e126–e136

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  6. Han SJ, Rolston JD, Molinaro AM et al (2014) Phase II trial of 7 days on/7 days off temozolmide for recurrent high-grade glioma. Neuro Oncol 16:1255–1262. doi:10.1093/neuonc/nou044

    Article  PubMed Central  PubMed  Google Scholar 

  7. Terasaki M, Tokutomi T, Shigemori M (2009) Salvage therapy with temozolomide for recurrent or progressive high-grade gliomas refractory to ACNU [1-(4-amino-2-methyl-5-pyrimidynyl) methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride]. Mol Med Rep 2:417–421. doi:10.3892/mmr_00000115

    CAS  PubMed  Google Scholar 

  8. Norden AD, Lesser GJ, Drappatz J et al (2013) Phase 2 study of dose-intense temozolomide in recurrent glioblastoma. Neuro Oncol 15:930–935. doi:10.1093/neuonc/not040

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Omuro A, Chan TA, Abrey LE et al (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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Yung WK, 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 83:588–593. doi:10.1054/bjoc.2000.1316

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Wick W, Platten M, Weller M (2009) New (alternative) temozolomide regimens for the treatment of glioma. Neuro Oncol 11:69–79. doi:10.1215/15228517-2008-078

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Newlands ES, Stevens MF, Wedge SR et al (1997) Temozolomide: a review of its discovery, chemical properties, pre-clinical development and clinical trials. Cancer Treat Rev 23:35–61

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  14. Gerson SL (2002) Clinical relevance of MGMT in the treatment of cancer. J Clin Oncol 20:2388–2399

    Article  CAS  PubMed  Google Scholar 

  15. Kurzen H, Schmitt S, Näher H et al (2003) Inhibition of angiogenesis by non-toxic doses of temozolomide. Anticancer Drugs 14:515–522

    Article  CAS  PubMed  Google Scholar 

  16. Kim JT, Kim J-S, Ko KW et al (2006) Metronomic treatment of temozolomide inhibits tumor cell growth through reduction of angiogenesis and augmentation of apoptosis in orthotopic models of gliomas. Oncol Rep 16:33–39

    PubMed  Google Scholar 

  17. Klement G, Huang P, Mayer B et al (2002) Differences in therapeutic indexes of combination metronomic chemotherapy and an anti-VEGFR-2 antibody in multidrug-resistant human breast cancer xenografts. Clin Cancer Res 8:221–232

    CAS  PubMed  Google Scholar 

  18. Plate KH, Risau W (1995) Angiogenesis in malignant gliomas. Glia 15:339–347

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Chen C, Xu T, Lu Y et al (2013) The efficacy of temozolomide for recurrent glioblastoma multiforme. Eur J Neurol 20:223–230. doi:10.1111/j.1468-1331.2012.03778.x

    Article  CAS  PubMed  Google Scholar 

  21. Galldiks N, Berhorn T, Blau T et al (2013) “One week on-one week off”: efficacy and side effects of dose-intensified temozolomide chemotherapy: experiences of a single center. J Neurooncol 112:209–215. doi:10.1007/s11060-013-1048-z

    Article  CAS  PubMed  Google Scholar 

  22. Moher D, Liberati A, Tetzlaff J et al (2010) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Int J Surg 8:336–341. doi:10.1016/j.ijsu.2010.02.007

    Article  PubMed  Google Scholar 

  23. 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

    CAS  PubMed  Google Scholar 

  24. Colditz GA, Burdick E, Mosteller F (1995) Heterogeneity in meta-analysis of data from epidemiologic studies: a commentary. Am J Epidemiol 142:371–382

    CAS  PubMed  Google Scholar 

  25. Higgins J, Thompson SG (2002) Quantifying heterogeneity in a meta-analysis. Stat Med 21:1539–1558

    Article  PubMed  Google Scholar 

  26. Harris R, Bradburn M, Deeks J et al (2008) Metan: fixed- and random-effects meta-analysis. Stata J 8:3–28

    Google Scholar 

  27. Hassler M, Micksche M, Stockhammer G et al (2006) Temozolomide for recurrent or progressive high-grade malignant glioma: results of an Austrian multicenter observational study. Wien Klin Wochenschr 118:230–238. doi:10.1007/s00508-006-0576-3

    Article  CAS  PubMed  Google Scholar 

  28. Chang SM, Theodosopoulos P, Lamborn K et al (2004) Temozolomide in the treatment of recurrent malignant glioma. Cancer 100:605–611. doi:10.1002/cncr.11949

    Article  CAS  PubMed  Google Scholar 

  29. Aoki T, Mizutani T, Ishikawa M et al (2003) A first feasibility study of temozolomide for Japanese patients with recurrent anaplastic astrocytoma and glioblastoma multiforme. Int J Clin Oncol 8:301–304. doi:10.1007/s10147-003-0339-3

    Article  CAS  PubMed  Google Scholar 

  30. Brandes AA, Ermani M, Basso U et al (2002) Temozolomide in patients with glioblastoma at second relapse after first line nitrosourea-procarbazine failure a phase II study. Oncology 63:38–41

    Article  CAS  PubMed  Google Scholar 

  31. Chinot OL, Honore S, Dufour H et al (2001) Safety and efficacy of temozolomide in patients with recurrent anaplastic oligodendrogliomas after standard radiotherapy and chemotherapy. J Clin Oncol 19:2449–2455

    CAS  PubMed  Google Scholar 

  32. Harris MT, Rosenthal MA, Ashley DL et al (2001) An Australian experience with temozolomide for the treatment of recurrent high grade gliomas. J Clin Neurosci 8:325–327. doi:10.1054/jocn.2000.0809

    Article  CAS  PubMed  Google Scholar 

  33. Brandes AA, Ermani M, Basso U et al (2001) Temozolomide as a second-line systemic regimen in recurrent high-grade glioma, a phase II study. Ann Oncol 12:255–257

    Article  CAS  PubMed  Google Scholar 

  34. Brada M, Hoang-Xuan K, Rampling R et al (2001) Multicenter phase II trial of temozolomide in patients with glioblastoma. Ann Oncol 12:259–266

    Article  CAS  PubMed  Google Scholar 

  35. Paulsen F, Hoffmann W, Becker G et al (1999) Chemotherapy in the treatment of recurrent glioblastoma multiforme: ifosfamide versus temozolomide. J Cancer Res Clin Oncol 125:411–418

    Article  CAS  PubMed  Google Scholar 

  36. 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 40:484–488

    Article  CAS  PubMed  Google Scholar 

  37. Yang SH, Kim MK, Lee TK et al (2006) Temozolomide chemotherapy in patients with recurrent malignant gliomas. J Korean Med Sci 21:739–744

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. Teixeira MM, Garcia I, Portela I et al (2002) Temozolomide in second-line treatment after prior nitrosurea-based chemotherapy in glioblastoma multiforme: experience from a Portuguese institution. Int J Clin Pharmacol Res 22:19–22

    CAS  PubMed  Google Scholar 

  39. Perry JR, Belanger K, Mason WP et al (2010) Phase II trial of continuous dose-intense temozolomide in recurrent malignant glioma: RESCUE study. J Clin Oncol 28:2051–2057. doi:10.1200/jco.2009.26.5520

    Article  CAS  PubMed  Google Scholar 

  40. 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 113:2152–2157. doi:10.1002/cncr.23813

    Article  CAS  PubMed  Google Scholar 

  41. Kong DS, Lee JI, Kim JH et al (2010) Phase II trial of low-dose continuous (metronomic) treatment of temozolomide for recurrent glioblastoma. Neuro Oncol 12:289–296. doi:10.1093/neuonc/nop030

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  42. Strik HM, Buhk JH, Wrede A et al (2008) Rechallenge with temozolomide with different scheduling is effective in recurrent malignant gliomas. Mol Med Rep 1:863–867. doi:10.3892/mmr_00000042

    CAS  PubMed  Google Scholar 

  43. Brandes AA, Tosoni A, Cavallo G et al (2006) Temozolomide 3 weeks on 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 95:1155–1160. doi:10.1038/sj.bjc.6603376

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  44. Berrocal A, Perez Segura P, Gil M et al (2010) Extended-schedule dose-dense temozolomide in refractory gliomas. J Neurooncol 96:417–422. doi:10.1007/s11060-009-9980-7

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  45. 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 Invest 26:269–277. doi:10.1080/07357900701708393

    Article  CAS  PubMed  Google Scholar 

  46. Santoni M, Paccapelo A, Burattini L et al (2012) Protracted low doses of temozolomide for the treatment of patients with recurrent glioblastoma: a phase II study. Oncol Lett 4:799–801. doi:10.3892/ol.2012.788

    PubMed Central  CAS  PubMed  Google Scholar 

  47. Taal W, Segers-van Rijn JM, Kros JM et al (2012) Dose dense 1 week on/1 week off temozolomide in recurrent glioma: a retrospective study. J Neurooncol 108:195–200. doi:10.1007/s11060-012-0832-5

    Article  PubMed Central  PubMed  Google Scholar 

  48. Wick A, Felsberg J, Steinbach JP et al (2007) Efficacy and tolerability of temozolomide in an alternating weekly regimen in patients with recurrent glioma. J Clin Oncol 25:3357–3361. doi:10.1200/jco.2007.10.7722

    Article  CAS  PubMed  Google Scholar 

  49. Wong S, Rosenthal MA, Dowling A et al (2006) Phase II study of two-weekly temozolomide in patients with high-grade gliomas. J Clin Neurosci 13:18–22. doi:10.1016/j.jocn.2004.10.018

    Article  CAS  PubMed  Google Scholar 

  50. Wick W, Weller M (2005) How lymphotoxic is dose-intensified temozolomide? The glioblastoma experience. J Clin Oncol 23:4235–4236. doi:10.1200/JCO.2004.00.8417

    Article  PubMed  Google Scholar 

  51. Wick W, Steinbach JP, Kuker WM et al (2004) One week on/one week off: a novel active regimen of temozolomide for recurrent glioblastoma. Neurology 62:2113–2115

    Article  CAS  PubMed  Google Scholar 

  52. Weller M, Tabatabai G, Kästner B et al (2015) MGMT promoter methylation is a strong prognostic biomarker for benefit from dose-intensified temozolomide rechallenge in progressive glioblastoma: the DIRECTOR Trial. Clin Cancer Res 21:2057–2064

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  54. Esteller M, Garcia-Foncillas J, Andion E et al (2000) Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. N Engl J Med 343:1350–1354

    Article  CAS  PubMed  Google Scholar 

  55. Krex D, Klink B, Hartmann C et al (2007) Long-term survival with glioblastoma multiforme. Brain 130:2596–2606

    Article  PubMed  Google Scholar 

  56. Dong X, Liu RY, Chen WD (2014) Correlation of promoter methylation in the MGMT gene with glioma Risk and prognosis: a meta-analysis. Mol Neurobiol. doi:10.1007/s12035-014-8760-3

    Google Scholar 

  57. Weiler M, Hartmann C, Wiewrodt D et al (2010) Chemoradiotherapy of newly diagnosed glioblastoma with intensified temozolomide. Int J Radiat Oncol Biol Phys 77:670–676

    Article  CAS  PubMed  Google Scholar 

  58. Chinot OL, Barrié M, Fuentes S et al (2007) Correlation between O6-methylguanine-DNA methyltransferase and survival in inoperable newly diagnosed glioblastoma patients treated with neoadjuvant temozolomide. J Clin Oncol 25:1470–1475

    Article  CAS  PubMed  Google Scholar 

  59. Kerbel RS, Kamen BA (2004) The anti-angiogenic basis of metronomic chemotherapy. Nat Rev Cancer 4:423–436

    Article  CAS  PubMed  Google Scholar 

  60. Bertolini F, Paul S, Mancuso P et al (2003) Maximum tolerable dose and low-dose metronomic chemotherapy have opposite effects on the mobilization and viability of circulating endothelial progenitor cells. Cancer Res 63:4342–4346

    CAS  PubMed  Google Scholar 

  61. Emmenegger U, Man S, Shaked Y et al (2004) A comparative analysis of low-dose metronomic cyclophosphamide reveals absent or low-grade toxicity on tissues highly sensitive to the toxic effects of maximum tolerated dose regimens. Cancer Res 64:3994–4000

    Article  CAS  PubMed  Google Scholar 

  62. Bocci G, Francia G, Man S et al (2003) Thrombospondin 1, a mediator of the antiangiogenic effects of low-dose metronomic chemotherapy. Proc Natl Acad Sci USA 100:12917–12922

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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We thank all the participants in this work.

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Authors and Affiliations

  1. Department of Neurosurgery, The First Hospital of China Medical University, No. 155 Nanjing Bei Street, Heping District, Shenyang, 110001, Liaoning, China

    Wei Wei, Ximeng Ma, Dawei Wang & Zongze Guo

  2. Department of Clinical Epidemiology, and Center of Evidence Based Medicine, The First Affiliated Hospital of China Medical University, Shenyang, China

    Xin Chen

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  1. Wei Wei
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Wei, W., Chen, X., Ma, X. et al. The efficacy and safety of various dose-dense regimens of temozolomide for recurrent high-grade glioma: a systematic review with meta-analysis. J Neurooncol 125, 339–349 (2015). https://doi.org/10.1007/s11060-015-1920-0

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