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Journal of Neuro-Oncology

, Volume 103, Issue 3, pp 595–602 | Cite as

Radiotherapy followed by adjuvant temozolomide with or without neoadjuvant ACNU-CDDP chemotherapy in newly diagnosed glioblastomas: a prospective randomized controlled multicenter phase III trial

  • Il Han Kim
  • Chul-Kee Park
  • Dae Seog Heo
  • Chae-Yong Kim
  • Chang Hun Rhee
  • Do-Hyun Nam
  • Seung Hoon Lee
  • Jung Ho Han
  • Se-Hoon Lee
  • Tae Min Kim
  • Dong-Wan Kim
  • Jeong Eun Kim
  • Sun Ha Paek
  • Dong Gyu Kim
  • In Ah Kim
  • Yu Jung Kim
  • Jee Hyun Kim
  • Byung-Joo Park
  • Hee-Won Jung
Clinical Study – Patient Study

Abstract

A prospective randomized controlled multicenter phase III trial was conducted to evaluate the effects of neoadjuvant chemotherapy with nimustine (ACNU)-cisplatin (CDDP) when used in conjunction with radiotherapy plus adjuvant temozolomide in patients with newly diagnosed glioblastoma. The study population was randomly assigned into one treatment and one control group. Both groups received radiotherapy followed by six cycles of adjuvant oral temozolomide (150–200 mg/m2) for 5 days every 28 days after surgery. Prior to radiotherapy, the treatment group also received two cycles, 6 weeks apart, of neoadjuvant chemotherapy with ACNU (40 mg/m2/day) and CDDP (40 mg/m2/day) infused continuously for 72 h. The primary end-point was median survival time. The study has closed after interim analysis with a total of 82 patients (48.8% of target number) due to unacceptable high frequency of toxicity profiles in spite of the promising actuarial survival outcome. Median survival time was 28.4 months [90% confidence interval (CI), 21.1 months to not available] in the treatment group and 18.9 months (90% CI, 17.1–27.4 months) in the control group (P = 0.2). The 2-year survival rate and progression-free survival time were 50.9% and 6.6 months (90% CI, 3.5–9.5 months) in the treatment group and 27.8% and 5.1 months (90% CI, 3.8–8.8 months) in the control group. Grade 3 or 4 toxicity was documented in 26 (68.4%) patients in the treatment group, including three neutropenic fever and one death from sepsis, while grade 3 or 4 toxicity occurred in 6 patients (15.8%) in the control group. The high frequency of serious hematological toxicity with ACNU-CDDP neoadjuvant chemotherapy followed by radiotherapy and adjuvant temozolomide limits its usage as primary treatment for glioblastoma. Future studies should aim to identify a subpopulation at reduced risk for ACNU-CDDP toxicity so that the potential of this protocol can be realized.

Keywords

Glioblastoma Neoadjuvant chemotherapy ACNU-CDDP Temozolomide Toxicity 

Notes

Acknowledgments

This study was partially supported by a grant of Korea Health 21 R&D Project, Ministry of Health, Welfare, and Family Affairs, Republic of Korea (grant code A06-0171-B51004-06N1-00040B) and by a grant (study number 03-2007-026-0) from the Seoul National University Hospital Research Fund.

References

  1. 1.
    Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996. doi: 10.1056/NEJMoa043330 PubMedCrossRefGoogle Scholar
  2. 2.
    Wolff JE, Berrak S, Koontz Webb SE, Zhang M (2008) Nitrosourea efficacy in high-grade glioma: a survival gain analysis summarizing 504 cohorts with 24193 patients. J Neurooncol 88:57–63. doi: 10.1007/s11060-008-9533-5 PubMedCrossRefGoogle Scholar
  3. 3.
    Reardon DA, Rich JN, Friedman HS, Bigner DD (2006) Recent advances in the treatment of malignant astrocytoma. J Clin Oncol 24:1253–1265. doi: 10.1200/JCO.2005.04.5302 PubMedCrossRefGoogle Scholar
  4. 4.
    Grossman SA, Wharam M, Sheidler V, Kleinberg L, Zeltzman M, Yue N, Piantadosi S (1997) Phase II study of continuous infusion carmustine and cisplatin followed by cranial irradiation in adults with newly diagnosed high-grade astrocytoma. J Clin Oncol 15:2596–2603PubMedGoogle Scholar
  5. 5.
    Choi IS, Lee SH, Kim TY, Bang JS, Paek SH, Kim S, Kim IH, Heo DS, Bang YJ, Kim DG, Jung HW, Kim NK (2002) Phase II study of chemotherapy with ACNU plus cisplatin followed by cranial irradiation in patients with newly diagnosed glioblastoma multiforme. J Neurooncol 60:171–176PubMedCrossRefGoogle Scholar
  6. 6.
    Gwak HS, Youn SM, Kwon AH, Lee SH, Kim JH, Rhee CH (2005) ACNU-cisplatin continuous infusion chemotherapy as salvage therapy for recurrent glioblastomas: phase II study. J Neurooncol 75:173–180. doi: 10.1007/s11060-005-1858-8 PubMedCrossRefGoogle Scholar
  7. 7.
    Han JH, Park CK, Lee SH, Kim CY, Kim DW, Paek SH, Kim DG, Heo DS, Kim IH, Jung HW (2009) Preradiation chemotherapy with ACNU-CDDP in patients with newly diagnosed glioblastoma: a retrospective analysis. Chemotherapy 55:145–154. doi: 10.1159/000214142 PubMedCrossRefGoogle Scholar
  8. 8.
    Lachin JM, Foulkes MA (1986) Evaluation of sample size and power for analyses of survival with allowance for nonuniform patient entry, losses to follow-up, noncompliance, and stratification. Biometrics 42:507–519PubMedCrossRefGoogle Scholar
  9. 9.
    DeAngelis LM, Burger PC, Green SB, Cairncross JG (1998) Malignant glioma: who benefits from adjuvant chemotherapy? Ann Neurol 44:691–695. doi: 10.1002/ana.410440418 PubMedCrossRefGoogle Scholar
  10. 10.
    Stewart LA (2002) Chemotherapy in adult high-grade glioma: a systematic review and meta-analysis of individual patient data from 12 randomised trials. Lancet 359:1011–1018. doi: S0140673602080911 PubMedCrossRefGoogle Scholar
  11. 11.
    Quinn JA, Jiang SX, Reardon DA, Desjardins A, Vredenburgh JJ, Friedman AH, Sampson JH, McLendon RE, Herndon JE, 2nd, Friedman HS (2009) Phase II trial of temozolomide (TMZ) plus irinotecan (CPT-11) in adults with newly diagnosed glioblastoma multiforme before radiotherapy. J Neurooncol doi: 10.1007/s11060-009-9937-x [doi]
  12. 12.
    Prados MD, Yung WK, Wen PY, Junck L, Cloughesy T, Fink K, Chang S, Robins HI, Dancey J, Kuhn J (2008) Phase-1 trial of gefitinib and temozolomide in patients with malignant glioma: a North American brain tumor consortium study. Cancer Chemother Pharmacol 61:1059–1067. doi: 10.1007/s00280-007-0556-y PubMedCrossRefGoogle Scholar
  13. 13.
    Prados MD, Yung WK, Fine HA, Greenberg HS, Junck L, Chang SM, Nicholas MK, Robins HI, Mehta MP, Fink KL, Jaeckle KA, Kuhn J, Hess KR, Schold SC Jr (2004) Phase 2 study of BCNU and temozolomide for recurrent glioblastoma multiforme: North American brain tumor consortium study. Neuro Oncol 6:33–37. doi: 10.1215/S1152851703000309 PubMedCrossRefGoogle Scholar
  14. 14.
    Prados MD, Chang SM, Butowski N, DeBoer R, Parvataneni R, Carliner H, Kabuubi P, Ayers-Ringler J, Rabbitt J, Page M, Fedoroff A, Sneed PK, Berger MS, McDermott MW, Parsa AT, Vandenberg S, James CD, Lamborn KR, Stokoe D, Haas-Kogan DA (2009) Phase II study of erlotinib plus temozolomide during and after radiation therapy in patients with newly diagnosed glioblastoma multiforme or gliosarcoma. J Clin Oncol 27:579–584. doi: 10.1200/JCO.2008.18.9639 PubMedCrossRefGoogle Scholar
  15. 15.
    Grossman SA, O’Neill A, Grunnet M, Mehta M, Pearlman JL, Wagner H, Gilbert M, Newton HB, Hellman R (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
  16. 16.
    Weller M, Muller B, Koch R, Bamberg M, Krauseneck P (2003) Neuro-Oncology Working Group 01 trial of nimustine plus teniposide versus nimustine plus cytarabine chemotherapy in addition to involved-field radiotherapy in the first-line treatment of malignant glioma. J Clin Oncol 21:3276–3284. doi: 10.1200/JCO.2003.03.509 PubMedCrossRefGoogle Scholar
  17. 17.
    Valk PE, Dillon WP (1991) Radiation injury of the brain. AJNR Am J Neuroradiol 12:45–62PubMedGoogle Scholar
  18. 18.
    Gilbert M, O’Neill A, Grossman S, Grunnet M, Mehta M, Jubelirer S, Hellman R (2000) A phase II study of preradiation chemotherapy followed by external beam radiotherapy for the treatment of patients with newly diagnosed glioblastoma multiforme: an Eastern cooperative oncology group study (E2393). J Neurooncol 47:145–152PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2010

Authors and Affiliations

  • Il Han Kim
    • 1
  • Chul-Kee Park
    • 2
  • Dae Seog Heo
    • 3
  • Chae-Yong Kim
    • 4
  • Chang Hun Rhee
    • 5
  • Do-Hyun Nam
    • 6
  • Seung Hoon Lee
    • 7
  • Jung Ho Han
    • 4
  • Se-Hoon Lee
    • 3
  • Tae Min Kim
    • 3
  • Dong-Wan Kim
    • 3
  • Jeong Eun Kim
    • 2
  • Sun Ha Paek
    • 2
  • Dong Gyu Kim
    • 2
  • In Ah Kim
    • 8
  • Yu Jung Kim
    • 9
  • Jee Hyun Kim
    • 9
  • Byung-Joo Park
    • 10
  • Hee-Won Jung
    • 2
  1. 1.Department of Radiation Oncology, Cancer Research InstituteSeoul National University HospitalSeoulKorea
  2. 2.Department of NeurosurgerySeoul National University HospitalSeoulKorea
  3. 3.Department of Internal Medicine, Cancer Research InstituteSeoul National University HospitalSeoulKorea
  4. 4.Department of NeurosurgerySeoul National University Bundang HospitalSeoulKorea
  5. 5.Department of NeurosurgeryKorea Cancer Center HospitalSeoulKorea
  6. 6.Department of Neurosurgery, Samsung Medical Center Sungkyunkwan University School of MedicineSeoulKorea
  7. 7.Neuro-Oncology ClinicNational Cancer CenterSeoulKorea
  8. 8.Department of Radiation OncologySeoul National University Bundang HospitalSeoulKorea
  9. 9.Department of Internal MedicineSeoul National University Bundang HospitalSeoulKorea
  10. 10.Department of Preventive MedicineSeoul National University College of MedicineSeoulKorea

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