[01] Martina E. Becker-Schiebe, Department of Radiotherapy and Radio-Oncology, Klinikum Braunschweig, Hannover Medical School, Braunschweig, Germany; Radiation Oncology, Hannover Medical School, Hannover, Germany. [02] Martina Wetzel, Department of Geriatrics, Klinikum Braunschweig, Hannover Medical School, Braunschweig, Germany. [03] Fabian Wetzel, Department of Radiotherapy and Radio-Oncology, Klinikum Braunschweig, Hannover Medical School, Braunschweig, Germany. [04] Hans Christansen, Radiation Oncology, Hannover Medical School, Hannover, Germany. [05] Wolfgang Hoffmann, Department of Radiotherapy and Radio-Oncology, Klinikum Braunschweig, Hannover Medical School, Braunschweig, Germany.

Purpose: The aim of this analysis was to assess the hematological toxicity profile of glioblastoma patients undergoing radiation and temozolomide treatment (RCT). Methods: A total of 69 patients were evaluated retrospectively. A correlation analysis was undertaken to explore factors predisposing for acute hematological toxicity. Results: The overall incidence of any clinically acute hematologic toxicity was 42%. Severe anemia (i.e. grade 3/4), leucopenia and thromobocytopenia was diagnosed in 5.8%, 7.2% and 8.6% of the patients respectively. MGMT methylation was described in 23 (35%) cases. Female gender and MGMT methylation seemed to be risk factors for grade 4 toxicity (p< 0.05). The mean irradiated volume for patients with any degree of hematotoxicity was 238.4 ccm compared to 211.9 ccm for patients without any toxicity reactions. Conclusions: Our results confirmed that the female gender, radiation volume and MGMT methylation were factors associated with severe hematotoxicity. To our knowledge this is the first report suggesting the relevance of the MGMT methylation status of glioblastoma cells to treatment-related toxicity.

Malignant Glioma, Temozolomide, Myelosuppression

[01] Sengupta S, Marrinan J, Frishman C, Sampath P. Impact of temozolomide on immune response during malignant glioma chemotherapy. Clin Dev Immunol. 2012; R, Hegi ME, Mason WP, et al. 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: 459–66. [02] Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group. N Engl J Med 2005; 352(10): 987-96. [03] Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, et al. 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: 459–66. [04] Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Eng J Med 2005; 352(10): 997–1003. [05] Wick W, Weller M, van den Bent M, Sanson M, Weiler M, von Deimling A, et al. MGMT testing--the challenges for biomarker-based glioma treatment. Nat Rev Neurol 2014; 10(7): 372-85. [06] Bae SH, Park MJ, Lee MM, Kim TM, Lee SH, Cho SY, et al. Toxicity profile of temozolomide in the treatment of 300 malignant glioma patients in Korea. J Korean Med Sci 2014; 29(7): 980-84. [07] CommonToxicityCriteria.2014.[http://www.rtog.org/ResearchAssociates/ AdverseEventReporting/CooperativeGroupCommonToxicityCriteria.aspx]. [08] Chakrabarti I, Cockburn M, Cozen W, Wang YP, Preston-Martin S. A population based description of glioblastoma multiforme in Los Angeles County, 1974-1999. Cancer 1999; 104: 2798-2806. [09] Schiebe M, Ohneseit P, Hoffmann W, Meyermann R, Rodemann HP, Bamberg M. Loss of heterozygosity at 11p15 and p53 alterations in malignant gliomas. J Cancer Res Clin Oncol. 2001; 127(5): 325-328. [10] Schiebe M, Ohneseit P, Hoffmann W, Meyermann R, Rodemann HP, Bamberg M. Analysis of mdm2 and p53 gene alterations in glioblastomas and its correlation with clinical factors. J Neurooncol 2000; 49(3): 197-203. [11] Macdonald DR. Temozolomide for recurrent high grade glioma. Sem in Oncol 2001; 28: 3-12. [12] Wick W, Hartmann C, Engel C, Stoffels M, Felsberg J, Stockhammer F, et al. NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with procarbazine, lomustine, and vincristine or temozolomide. Clin Oncol 2009; 27(35): 5874-80. [13] Momota H, Narita Y, Miyakita Y, Shibui S. Secondary hematological malignancies associated with temozolomide in patients with glioma. Neuro Oncol 2013; 15: 1445-1450. [14] Kesari S, Schiff D, Henson JW, Muzikansky A, Gigas DC, Doherty L, et al. Phase II study of temozolomide, thalidomide, and celecoxib for newly diagnosed glioblastoma in adults. Neuro Oncol 2008;10(3): 300. [15] Bae SH, Park MJ, Lee MM, Kim TM, Lee SH, Cho SY, et al. Toxicity Profile of Temozolomide in the Treatment of 300 Malignant Glioma Patients in Korea. J Korean Med Sci 2014; 29: 980-984. [16] Ishikawa E, Yamamoto T, Sakamoto N, Nakai K, Akutsu H, Tsuboi K, et al. Low peripheral lymphocyte count before focal radiotherapy plus concomitant temozolomide predicts severe lymphopenia during malignant glioma treatment. Neurol Med Chir (Tokyo) 2010; 50(8):638-44. [17] Gupta T, Mohanty S, Moiyadi A, Jalali R. Factors predicting temozolomide induced clinically significant acute hematologic toxicity in patients with high-grade gliomas: a clinical audit. Clin Neurol Neurosurg 2013; 115(9): 1814-19. [18] Grossman SA, Ye X, Lesser G, Sloan A, Carraway H, Desideri S, Piantadosi S; NABTT CNS Consortium. Immunosuppression in patients with high-grade gliomas treated with radiation and temozolomide. Clin Cancer Res 2011; 17(16): 5473-80. [19] Nagane M, Nozue K, Shimizu S, Waha A, Miyazaki H, Kurita H, et al. Prolonged and severe thrombocytopenia with pancytopenia induced by radiation-combined temozolomide therapy in a patient with newly diagnosed glioblastoma--analysis of O6-methylguanine-DNA methyltransferase status. J Neurooncol 2009; 92(2): 227-32. [20] Anderson G. Gender differences in pharmacological response. Int Rev Neurobiol 2008; 83: 1-10. [21] Armstrong TS, Cao Y, Scheurer ME, Vera-Bolaños E, Manning R, Okcu MF, et al. Risk analysis of severe myelotoxicity with temozolomide: the effects of clinical and genetic factors. Neuro Oncol 2009; 11(6): 825-32. [22] Lombardi G, Rumiato E, Bertorelle R, Saggioro D, Farina P, Della Puppa A, et al. Clinical and Genetic Factors Associated With Severe Hematological Toxicity in Glioblastoma Patients During Radiation Plus Temozolomide Treatment: A Prospective Study. Am J Clin Oncol 2013 Sep 21. [Epub ahead of print] [23] Kleinberg L, Grossman SA, Piantadosi S, Zeltzman M, Wharam M. The effects of sequential versus concurrent chemotherapy and radiotherapy on survival and toxicity in patients with newly diagnosed high-grade astrocytoma. Int J Radiat Oncol Biol Phys 1999; 44(3): 535-43. [24] Sabharwal A, Waters R, Danson S, Clamp A, Lorigan P, Thatcher N, et al. Predicting the myelotoxicity of chemotherapy: the use of pretreatment O6-methylguanine-DNA methyltransferase determination in peripheral blood mononuclear cells. Melanoma Res 2011; 21(6): 502-8. [25] Schena M, Guarrera S, Buffoni L, Salvadori A, Voglino F, Allione A, et al. DNA repair gene expression level in peripheral blood and tumor tissue from non-small cell lung cancer and head and neck squamous cell cancer patients. DNA Repair (Amst) 2012; 11(4): 374-80.