gms | German Medical Science

48th Meeting of the Particle Therapy Co-Operative Group

Particle Therapy Co-Operative Group (PTCOG)

28.09. - 03.10.2009, Heidelberg

Radiobiological evaluation and correlation with the local effect model (LEM) of carbon ion radiation therapy and temozolomide in glioblastoma cell lines: Radiobiological Basis for a Phase II Clinical Study Protocol (CLEOPATRA)

Meeting Abstract

  • S. Combs - Departments of Radiation Oncology, Neurooncology and Neurosurgery, University Hospital of Heidelberg, Heidelberg
  • M. Kieser - Heidelberg
  • W. Wick - Department of Biostatistics, University Heidelberg, Heidelberg
  • A. Unterberg - Gesellschaft für Schwerionenforschung (GSI), Darmstadt
  • J. Bohl - Gesellschaft für Schwerionenforschung (GSI), Darmstadt
  • T. Elsässer - Gesellschaft für Schwerionenforschung (GSI), Darmstadt
  • K.-J. Weber - Departments of Radiation Oncology, Neurooncology and Neurosurgery, University Hospital of Heidelberg, Heidelberg
  • D. Schulz-Ertner - Departments of Radiation Oncology, Neurooncology and Neurosurgery, University Hospital of Heidelberg, Heidelberg
  • W. K. Weyrather - Gesellschaft für Schwerionenforschung (GSI), Darmstadt
  • J. Debus - Departments of Radiation Oncology, Neurooncology and Neurosurgery, University Hospital of Heidelberg, Heidelberg

PTCOG 48. Meeting of the Particle Therapy Co-Operative Group. Heidelberg, 28.09.-03.10.2009. Düsseldorf: German Medical Science GMS Publishing House; 2009. Doc09ptcog044

DOI: 10.3205/09ptcog044, URN: urn:nbn:de:0183-09ptcog0445

Published: September 24, 2009

© 2009 Combs et al.
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Outline

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Purpose: To investigate the cytotoxic effect of high linear-energy transfer (LET) carbon irradiation on glioblastoma cells lines in combination with temozolomide (TMZ) and to generate a radiobiological basis for subsequent clinical trials.

Methods and materials: The cell lines U87-MG expressing wild-type p53 and LN229 expressing both mutant and wild-type p53 were irradiated with monoenergetic carbon ion beams (LET 172 keV/µm) or an extended Bragg peak (LET 103 keV/µm) after treatment with 10 µM or 20 µM TMZ. Cytotoxicity was measured by a clonogenic survival assay, and cell growth as well as cell cycle progression were examined.

Results: The p53 mutant was more sensitive to x-ray irradiation than the p53 wild type cell line, which was also expressed in a shorter G2 block. High LET carbon ions show an increased biological effectiveness in both cell lines, which is consistent with the predictive calculations by the Local Effect Model (LEM) introduced by Scholz. et al. The cell line LN229 was more sensitive to TMZ treatment than the U87MG cell line expressing wild-type p53 only. The combination of TMZ and irradiation showed an additive effect in both cell lines.

Based on these preclinical data, we developed a Phase II study protocol (CLEOPATRA-Study) for the treatment of patients with primary glioblastoma after subtotal resection or biopsy. Additionally to combined chemoradiation with TMZ, which is considered standard treatment, the experimental treatment consists of photon irradiation in combination with TMZ up to 50 Gy, and adds a carbon ion boost of 6x3 GyE to the macroscopic tumor. Primary endpoint of the study is overall survival secondary endpoints are progression-free survival as well as toxicity. A planned number of 50 patients per treatment arm will be recruited.

Conclusion: High LET carbon ion irradiation is significantly more effective for glioblastoma cell lines compared to photon irradiation. An additional treatment with TMZ may offer a great chance especially for several tumor types. This treatment concepts will be evaluated in a Phase II randomized clinical study protocol (CLEOPATRA-Study).