Randomized phase II study evaluating a carbon ion boost applied after combined radiochemotherapy with temozolomide versus a proton boost after radiochemotherapy with temozolomide in patients with primary glioblastoma: the CLEOPATRA trial

Stephanie E Combs, Meinhard Kieser, Stefan Rieken, Daniel Habermehl, Oliver Jäkel, Thomas Haberer, Anna Nikoghosyan, Renate Haselmann, Andreas Unterberg, Wolfgang Wick, Jürgen Debus, Stephanie E Combs, Meinhard Kieser, Stefan Rieken, Daniel Habermehl, Oliver Jäkel, Thomas Haberer, Anna Nikoghosyan, Renate Haselmann, Andreas Unterberg, Wolfgang Wick, Jürgen Debus

Abstract

Background: Treatment standard for patients with primary glioblastoma (GBM) is combined radiochemotherapy with temozolomide (TMZ). Radiation is delivered up to a total dose of 60 Gy using photons. Using this treatment regimen, overall survival could be extended significantly however, median overall survival is still only about 15 months. Carbon ions offer physical and biological advantages. Due to their inverted dose profile and the high local dose deposition within the Bragg peak precise dose application and sparing of normal tissue is possible. Moreover, in comparison to photons, carbon ions offer an increase relative biological effectiveness (RBE), which can be calculated between 2 and 5 depending on the GBM cell line as well as the endpoint analyzed. Protons, however, offer an RBE which is comparable to photons. First Japanese Data on the evaluation of carbon ion radiation therapy showed promising results in a small and heterogeneous patient collective.

Methods/design: In the current Phase II-CLEOPATRA-Study a carbon ion boost will be compared to a proton boost applied to the macroscopic tumor after surgery at primary diagnosis in patients with GBM applied after standard radiochemotherapy with TMZ up to 50 Gy. In the experimental arm, a carbon ion boost will be applied to the macroscopic tumor up to a total dose of 18 Gy E in 6 fractions at a single dose of 3 Gy E. In the standard arm, a proton boost will be applied up to a total dose 10 Gy E in 5 single fractions of 2 Gy E. Primary endpoint is overall survival, secondary objectives are progression-free survival, toxicity and safety.

Discussion: The Cleopatra Trial is the first study to evaluate the effect of carbon ion radiotherapy within multimodality treatment of primary glioblastoma in a randomized trial comparing this innovative treatment of the treatment standard, consisitng of photon radiotherapy in combination with temozolomide.

Trial registration: ISRCTN37428883 and NCT01165671.

Figures

Figure 1
Figure 1
Workflow diagram of the Cleopatra Study evaluation the role of carbon ion radiotherapy for the treatment of patients with primary glioblastoma.

References

    1. Walker MD, Strike TA, Sheline GE. An analysis of dose-effect relationship in the radiotherapy of malignant gliomas. Int J Radiat Oncol Biol Phys. 1979;5:1725–1731.
    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. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352:987–996. doi: 10.1056/NEJMoa043330.
    1. Schulz-Ertner D, Karger CP, Feuerhake A, Nikoghosyan A, Combs SE, Jakel O, Edler L, Scholz M, Debus J. Effectiveness of carbon ion radiotherapy in the treatment of skull-base chordomas. Int J Radiat Oncol Biol Phys. 2007;68:449–457.
    1. Schulz-Ertner D, Nikoghosyan A, Hof H, Didinger B, Combs SE, Jakel O, Karger CP, Edler L, Debus J. Carbon ion radiotherapy of skull base chondrosarcomas. Int J Radiat Oncol Biol Phys. 2007;67:171–177.
    1. Combs SE, Nikoghosyan A, Jaekel O, Karger CP, Haberer T, Munter MW, Huber PE, Debus J, Schulz-Ertner D. Carbon ion radiotherapy for pediatric patients and young adults treated for tumors of the skull base. Cancer. 2009;115:1348–1355. doi: 10.1002/cncr.24153.
    1. Combs SE, Hartmann C, Nikoghosyan A, Jakel O, Karger CP, Haberer T, von Deimling A, Munter MW, Huber PE, Debus J, Schulz-Ertner D. Carbon ion radiation therapy for high-risk meningiomas. Radiother Oncol. 2010;95:54–59. doi: 10.1016/j.radonc.2009.12.029.
    1. Fitzek MM, Thornton AF, Rabinov JD, Lev MH, Pardo FS, Munzenrider JE, Okunieff P, Bussiere M, Braun I, Hochberg FH, Hedley-Whyte ET, Liebsch NJ, Harsh GR. Accelerated fractionated proton/photon irradiation to 90 cobalt gray equivalent for glioblastoma multiforme: results of a phase II prospective trial. J Neurosurg. 1999;91:251–260. doi: 10.3171/jns.1999.91.2.0251.
    1. Iwadate Y, Mizoe J, Osaka Y, Yamaura A, Tsujii H. High linear energy transfer carbon radiation effectively kills cultured glioma cells with either mutant or wild-type p53. Int J Radiat Oncol Biol Phys. 2001;50:803–808.
    1. Combs SE, Bohl J, Elsaesser T, Weber KJ, Schulz-Ertner D, Debus J, Weyrather WK. Radiobiological evaluation and correlation with the local effect model (LEM) of carbon ion radiation therapy and temozolomide in glioblastoma cell lines. Int J Rad Biol. 2008. in press .
    1. Mizoe JE, Tsujii H, Hasegawa A, Yanagi T, Takagi R, Kamada T, Tsuji H, Takakura K. Phase I/II clinical trial of carbon ion radiotherapy for malignant gliomas: combined X-ray radiotherapy, chemotherapy, and carbon ion radiotherapy. Int J Radiat Oncol Biol Phys. 2007;69:390–396.
    1. Paganetti H, Niemierko A, Ancukiewicz M, Gerweck LE, Goitein M, Loeffler JS, Suit HD. Relative biological effectiveness (RBE) values for proton beam therapy. Int J Radiat Oncol Biol Phys. 2002;53:407–421.
    1. Suit H, Kooy H, Trofimov A, Farr J, Munzenrider J, DeLaney T, Loeffler J, Clasie B, Safai S, Paganetti H. Should positive phase III clinical trial data be required before proton beam therapy is more widely adopted? No. Radiother Oncol. 2008;86:148–153. doi: 10.1016/j.radonc.2007.12.024.
    1. Suit H, Kooy H, Trofimov A, Farr J, Munzenrider J, DeLaney T, Loeffler J, Clasie B, Safai S, Paganetti H. Should positive phase III clinical trial data be required before proton beam therapy is more widely adopted? No. Radiother Oncol. 2008;86:148–153. doi: 10.1016/j.radonc.2007.12.024.
    1. Emami B, Lyman J, Brown A, Coia L, Goitein M, Munzenrider JE, Shank B, Solin LJ, Wesson M. Tolerance of normal tissue to therapeutic irradiation. Int J Radiat Oncol Biol Phys. 1991;21:109–122.
    1. O'Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics. 1979;35:549–556. doi: 10.2307/2530245.
    1. Schoenfeld D. The asymptotic properties of nonparametric tests for comparing survival distributions. Biometrika. 1981;68:316–319. doi: 10.1093/biomet/68.1.316.
    1. Schoenfeld D. Sample size formula for the proportional-hazard regression model. Biometrika. 1983;39:499–503.
    1. ADDPLAN. Adaptive Designs - Plans and Analyses. Version 4.0. 20107.
    1. Kalbfleisch JD, Prentice RL. The Statistical Analysis of Failure Time Data. John Wiley. New York; 1980.
    1. Allison PD. Survival Analysis Using the SAS System - A Practical Guide. SAS Institute Inc. Cary, North Carolina; 1995.
    1. Mirimanoff RO, Gorlia T, Mason W, van den Bent MJ, Kortmann RD, Fisher B, Reni M, Brandes AA, Curschmann J, Villa S, Cairncross G, Allgeier A, Lacombe D, Stupp R. Radiotherapy and temozolomide for newly diagnosed glioblastoma: recursive partitioning analysis of the EORTC 26981/22981-NCIC CE3 phase III randomized trial. J Clin Oncol. 2006;24:2563–2569. doi: 10.1200/JCO.2005.04.5963.
    1. Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, Ludwin SK, Allgeier A, Fisher B, Belanger K, Hau P, Brandes AA, Gijtenbeek J, Marosi C, Vecht CJ, Mokhtari K, Wesseling P, Villa S, Eisenhauer E, Gorlia T, Weller M, Lacombe D, Cairncross JG, Mirimanoff RO. 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. 2009;10:459–466. doi: 10.1016/S1470-2045(09)70025-7.
    1. Chan JL, Lee SW, Fraass BA, Normolle DP, Greenberg HS, Junck LR, Gebarski SS, Sandler HM. Survival and failure patterns of high-grade gliomas after three-dimensional conformal radiotherapy. J Clin Oncol. 2002;20:1635–1642. doi: 10.1200/JCO.20.6.1635.
    1. Combs SE, Thilmann C, Edler L, Debus J, Schulz-Ertner D. Efficacy of fractionated stereotactic reirradiation in recurrent gliomas: long-term results in 172 patients treated in a single institution. J Clin Oncol. 2005;23:8863–8869. doi: 10.1200/JCO.2005.03.4157.
    1. Schulz-Ertner D, Karger CP, Feuerhake A, Nikoghosyan A, Combs SE, Jakel O, Edler L, Scholz M, Debus J. Effectiveness of carbon ion radiotherapy in the treatment of skull-base chordomas. Int J Radiat Oncol Biol Phys. 2007;68:449–457.
    1. Schulz-Ertner D, Nikoghosyan A, Hof H, Didinger B, Combs SE, Jakel O, Karger CP, Edler L, Debus J. Carbon ion radiotherapy of skull base chondrosarcomas. Int J Radiat Oncol Biol Phys. 2007;67:171–177.
    1. Schulz-Ertner D, Nikoghosyan A, Didinger B, Munter M, Jakel O, Karger CP, Debus J. Therapy strategies for locally advanced adenoid cystic carcinomas using modern radiation therapy techniques. Cancer. 2005;104:338–344. doi: 10.1002/cncr.21158.
    1. Schulz-Ertner D, Tsujii H. Particle radiation therapy using proton and heavier ion beams. J Clin Oncol. 2007;25:953–964. doi: 10.1200/JCO.2006.09.7816.
    1. Tsuboi K, Moritake T, Tsuchida Y, Tokuuye K, Matsumura A, Ando K. Cell cycle checkpoint and apoptosis induction in glioblastoma cells and fibroblasts irradiated with carbon beam. J Radiat Res (Tokyo) 2007;48:317–325. doi: 10.1269/jrr.06081.

Source: PubMed

赞助者和合作者

医疗条件

药物干预

3
订阅