Concurrent Treatment with BCNU and Gamma Knife Radiosurgery in the Rat Malignant Glioma Model

Abstract

Background Radiosurgery has been shown in a randomized trial not to provide any survival benefit for newly diagnosed glioblastoma multiforme (GBM). Nevertheless, several institutional retrospective series have supported the role of radiosurgery as an adjuvant therapy in GBM. The purpose of this study was to investigate the efficacy of concurrent therapy with 1,3 bis[2-chloroethyl]-1-nitrosourea (BCNU; carmustine) and Gamma Knife radiosurgery (GKRS; Gamma Knife^® Model C, Elekta AB, Stockholm, Sweden) in the C6 rat glioma model. Taken together, new therapeutic strategies other than the simple addition of radiosurgery deserve to be investigated in the interest of enhancing the effects of radiosurgery.

Material and Methods C6 glioma cells of 5 × 10⁵ were stereotactically implanted into Sprague-Dawley rats. Tumor volume was measured 2 weeks later using brain magnetic resonance (MR) imaging and rats were treated with BCNU (7 mg/kg, intraperitonial injection), GKRS (20 Gy at 50% isodose line), or BCNU followed by GKRS at a 1.5-hour interval. The six surviving rats in each group were sacrificed, 2 weeks after treatment. Tumor volume was measured in the tissue sections and compared with that measured via MR imaging. Percent volume growth was calculated and categorized into one of four groups: progressive disease, stable disease, partial response, or complete response.

Results Tumor volume significantly increased in all six rats in the control group and decreased in all six rats in the BCNU + GKRS group after treatment. Better tumor control was observed in the BCNU + GKRS group compared with the control, BCNU, and GKRS groups on linear-by-linear association analysis and Fischer's exact test.

Conclusions We suggest that concurrent treatment with BCNU and GKRS is more effective in local tumor control compared with GKRS or BCNU alone, in the C6 rat glioma model.

Keywords

glioblastoma multiforme - 1,3 bis[2-chloroethyl]-1-nitrosourea (BCNU) - C6 rat glioma model - gamma knife radiosurgery - local tumor control

• References

• 1 Barth RF. Rat brain tumor models in experimental neuro-oncology: the 9L, C6, T9, F98, RG2 (D74), RT-2 and CNS-1 gliomas. J Neurooncol 1998; 36 (1) 91-102
• 2 Bjerkvig R, Oredsson SM, Marton LJ, Linden M, Deen DF. Cell cycle age response of 9L cells to 1,3-bis(2-chloroethyl)-1-nitrosourea and modification by alpha-difluoromethylornithine. Cancer Res 1983; 43 (4) 1497-1500
• 3 Chung HT, Chung YS, Kim DG, Paek SH, Cho KT. Development of a stereotactic device for gamma knife irradiation of small animals. J Korean Neurosurg Soc 2008; 43 (1) 26-30
• 4 Combs SE, Widmer V, Thilmann C, Hof H, Debus J, Schulz-Ertner D. Stereotactic radiosurgery (SRS): treatment option for recurrent glioblastoma multiforme (GBM). Cancer 2005; 104 (10) 2168-2173
• 5 Crowley RW, Pouratian N, Sheehan JP. Gamma knife surgery for glioblastoma multiforme. Neurosurg Focus 2006; 20 (4) E17
• 6 Deutsch M, Green SB, Strike TA , et al. Results of a randomized trial comparing BCNU plus radiotherapy, streptozotocin plus radiotherapy, BCNU plus hyperfractionated radiotherapy, and BCNU following misonidazole plus radiotherapy in the postoperative treatment of malignant glioma. Int J Radiat Oncol Biol Phys 1989; 16 (6) 1389-1396
• 7 Diserbo M, Agin A, Lamproglou I , et al. Blood-brain barrier permeability after gamma whole-body irradiation: an in vivo microdialysis study. Can J Physiol Pharmacol 2002; 80 (7) 670-678
• 8 Flowers A, Levin VA. Chemotherapy for brain tumors. In: Kaye AH, ed. Brain Tumors. New York: Churchill Livingstone; 1995: 351-356
• 9 Fornace Jr AJ, Kohn KW, Kann Jr HE. Inhibition of the ligase step of excision repair by 2-chloroethyl isocyanate, a decomposition product of 1,3-bis(2-chloroethyl)-1-nitrosourea. Cancer Res 1978; 38 (4) 1064-1069
• 10 Green SB, Byar DP, Walker MD , et al. Comparisons of carmustine, procarbazine, and high-dose methylprednisolone as additions to surgery and radiotherapy for the treatment of malignant glioma. Cancer Treat Rep 1983; 67 (2) 121-132
• 11 Griffin TW, Rasey JS, Bleyer WA. The effect of photon irradiation on blood-brain barrier permeability to methotrexate in mice. Cancer 1977; 40 (3) 1109-1111
• 12 Hou LC, Veeravagu A, Hsu AR, Tse VC. Recurrent glioblastoma multiforme: a review of natural history and management options. Neurosurg Focus 2006; 20 (4) E5
• 13 Hsieh PC, Chandler JP, Bhangoo S , et al. Adjuvant gamma knife stereotactic radiosurgery at the time of tumor progression potentially improves survival for patients with glioblastoma multiforme. Neurosurgery 2005; 57 (4) 684-692 , discussion 684–692
• 14 Kann Jr HE, Blumenstein BA, Petkas A, Schott MA. Radiation synergism by repair-inhibiting nitrosoureas in L1210 cells. Cancer Res 1980; 40 (3) 771-775
• 15 Khil MS, Kolozsvary A, Apple M, Kim JH. Increased tumor cures using combined radiosurgery and BCNU in the treatment of 9l glioma in the rat brain. Int J Radiat Oncol Biol Phys 2000; 47 (2) 511-516
• 16 Kim B, Chenevert TL, Ross BD. Growth kinetics and treatment response of the intracerebral rat 9L brain tumor model: a quantitative in vivo study using magnetic resonance imaging. Clin Cancer Res 1995; 1 (6) 643-650
• 17 Kim JE, Paek SH, Chung HT, Kim DG, Jung HW. In vitro biological response of malignant glioma cell lines to gamma knife irradiation. J Korean Neurosurg Soc 2004; 35: 599-604
• 18 Kondziolka D, Flickinger JC, Bissonette DJ, Bozik M, Lunsford LD. Survival benefit of stereotactic radiosurgery for patients with malignant glial neoplasms. Neurosurgery 1997; 41 (4) 776-783 , discussion 783–785
• 19 Kondziolka D, Lunsford LD, Claassen D, Pandalai S, Maitz AH, Flickinger JC. Radiobiology of radiosurgery: Part II. The rat C6 glioma model. Neurosurgery 1992; 31 (2) 280-287 , discussion 287–288
• 20 Kong DS, Lee JI, Park K, Kim JH, Lim DH, Nam DH. Efficacy of stereotactic radiosurgery as a salvage treatment for recurrent malignant gliomas. Cancer 2008; 112 (9) 2046-2051
• 21 Loeffler JS, Alexander III E, Shea WM , et al. Radiosurgery as part of the initial management of patients with malignant gliomas. J Clin Oncol 1992; 10 (9) 1379-1385
• 22 Mehta MP. Fractionated radiotherapy for malignant brain tumors. In: Winn HR, ed. Youmans Neurological Surgery. 5th ed. Philadelphia: Saunders; 2004: 4019-4020
• 23 Nair V, Mackie JD. Modification of the central nervous system syndrome in head-irradiated rabbits with pharmacologic agents. Radiat Res 1974; 58 (3) 373-383
• 24 Nakata H, Yoshimine T, Murasawa A , et al. Early blood-brain barrier disruption after high-dose single-fraction irradiation in rats. Acta Neurochir (Wien) 1995; 136 (1-2) 82-86
• 25 Namba H, Irie T, Fukushi K, Iyo M, Hashimoto T, Ando K. Time courses of changes in cerebral blood flow and blood-brain barrier integrity by focal proton radiation in the rat. Neurol Res 1996; 18 (1) 83-86
• 26 Nwokedi EC, DiBiase SJ, Jabbour S, Herman J, Amin P, Chin LS. Gamma knife stereotactic radiosurgery for patients with glioblastoma multiforme. Neurosurgery 2002; 50 (1) 41-46 , discussion 46–47
• 27 Pan HC, Cheng FC, Sun MH, Chen CC, Sheehan J. Prediction of volumetric data errors in patients treated with gamma knife radiosurgery. Stereotact Funct Neurosurg 2007; 85 (4) 184-191
• 28 Parney IF, Chang SM. Current chemotherapy for glioblastoma. Cancer J 2003; 9 (3) 149-156
• 29 Parsa AT, Chakrabarti I, Hurley PT , et al. Limitations of the C6/Wistar rat intracerebral glioma model: implications for evaluating immunotherapy. Neurosurgery 2000; 47 (4) 993-999 , discussion 999–1000
• 30 Remsen LG, McCormick CI, Sexton G , et al. Long-term toxicity and neuropathology associated with the sequencing of cranial irradiation and enhanced chemotherapy delivery. Neurosurgery 1997; 40 (5) 1034-1040 , discussion 1040–1042
• 31 Rosenblum ML, Knebel KD, Vasquez DA, Wilson CB. In vivo clonogenic tumor cell kinetics following 1,3-bis(2-chloroethyl)-1-nitrosourea brain tumor therapy. Cancer Res 1976; 36 (10) 3718-3725
• 32 Rubin P, Gash DM, Hansen JT, Nelson DF, Williams JP. Disruption of the blood-brain barrier as the primary effect of CNS irradiation. Radiother Oncol 1994; 31 (1) 51-60
• 33 San-Galli F, Vrignaud P, Robert J, Coindre JM, Cohadon F. Assessment of the experimental model of transplanted C6 glioblastoma in Wistar rats. J Neurooncol 1989; 7 (3) 299-304
• 34 Sano Y, Hoshino T, Barker M, Deen DF. Response of 9L rat brain tumor multicellular spheroids to single and fractionated doses of 1,3-bis(2-chloroethyl)-1-nitrosourea. Cancer Res 1984; 44 (2) 571-576
• 35 Souhami L, Seiferheld W, Brachman D , et al. Randomized comparison of stereotactic radiosurgery followed by conventional radiotherapy with carmustine to conventional radiotherapy with carmustine for patients with glioblastoma multiforme: report of Radiation Therapy Oncology Group 93-05 protocol. Int J Radiat Oncol Biol Phys 2004; 60 (3) 853-860
• 36 Stewart LA. Chemotherapy in adult high-grade glioma: a systematic review and meta-analysis of individual patient data from 12 randomised trials. Lancet 2002; 359 (9311) 1011-1018
• 37 Stupp R, Mason WP, van den Bent MJ , et al; European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005; 352 (10) 987-996
• 38 Taphoorn MJ, Stupp R, Coens C , et al; European Organisation for Research and Treatment of Cancer Brain Tumour Group; EORTC Radiotherapy Group; National Cancer Institute of Canada Clinical Trials Group. Health-related quality of life in patients with glioblastoma: a randomised controlled trial. Lancet Oncol 2005; 6 (12) 937-944
• 39 Ueda-Kawamitsu H, Lawson TA, Gwilt PR. In vitro pharmacokinetics and pharmacodynamics of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). Biochem Pharmacol 2002; 63 (7) 1209-1218
• 40 Vince GH, Bendszus M, Schweitzer T , et al. Spontaneous regression of experimental gliomas—an immunohistochemical and MRI study of the C6 glioma spheroid implantation model. Exp Neurol 2004; 190 (2) 478-485
• 41 Walker MD, Alexander Jr E, Hunt WE , et al. Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas. A cooperative clinical trial. J Neurosurg 1978; 49 (3) 333-343
• 42 Wallner KE, Galicich JH, Krol G, Arbit E, Malkin MG. Patterns of failure following treatment for glioblastoma multiforme and anaplastic astrocytoma. Int J Radiat Oncol Biol Phys 1989; 16 (6) 1405-1409
• 43 Watanabe K, Sakamoto M, Somiya M, Amin MR, Kamitani H, Watanabe T. Feasibility and limitations of the rat model by C6 gliomas implanted at the subcutaneous region. Neurol Res 2002; 24 (5) 485-490
• 44 Wheeler GP, Alexander JA, Adamson DJ. Effects of N,N'-bis(2-chloroethyl)-N-nitrosourea and 2-[3-(2-chloroethyl)-3-nitrosoureido]-2-deoxy-D-glucopyranose upon the proliferation, DNA synthesis, and viability of cultured sensitive and resistant L1210 cells. Cancer Res 1980; 40 (10) 3723-3727
• 45 Yuan H, Gaber MW, Boyd K, Wilson CM, Kiani MF, Merchant TE. Effects of fractionated radiation on the brain vasculature in a murine model: blood-brain barrier permeability, astrocyte proliferation, and ultrastructural changes. Int J Radiat Oncol Biol Phys 2006; 66 (3) 860-866
• 46 Zhang M, Chakravarti A. Novel radiation-enhancing agents in malignant gliomas. Semin Radiat Oncol 2006; 16 (1) 29-37