Chemotherapy in malignant brain tumors Frank Zimmermann Institut für Radioonkologie Universitätsspital Basel Petersgraben 4 CH 4031 Basel zimmermannf@uhbs.ch
Tumor types Neuro-epithelial tumors - Glioblastoma - Astrocytoma Oligodendroglioma Ependymal tumors Embryonal tumors - Medulloepithelioma - Neuroblastoma - Medulloblastoma Meningeoma a.o.
Neuroepithelial tumors
Temozolomide-based trial Overall median survival (16 months, n.s.) and quality of life (s.) (German trial: 65 pts., 11 centers) Kocher et al. Strahlenther Onkol 2008
Glioblastoma Overall median survival (14.6 vs. 12.1 months, s.) > 30000 CHF more than RT alone (s.) 56.041 CHF more per gained year (European and Canadian trial: 573 pts., 85 centers) Stupp et al. N Engl J Med 2005 Lamers et al. Cancer 2008
Temozolomide-based treatment Overall median survival (13.4 vs. 7.7 months, s.) (Greek trial: 110/130 pts., in 36 months, 5 centers) Athanassiou et al. J Clin Oncol 2005
Temozolamide treatment Wolf et al. J Neurooncol 2008
MGMT - Resistance to alkylating agents O 6 -methylguanine methyltransferase (MGMT) is a cellular DNA repair protein that rapidly reverses alkylation (including methylation) at the O 6 position of guanine, thereby neutralizing the cytotoxic effects of alkylating agents such as temozolomide or nitrosoureas. Guanine Gerson et al., J Clin Oncol 2002 Hegi et al. J Clin Oncol 2008
MGMT - Resistance to alkylating agents Methylation of the MGMT promoter has been observed in a variety of tumor types and results in a decreased MGMT expression in tumor cells thus leading to reduced resistance to alkylating agents. At present not used to exclude initiation of chemotherapy! acc. to Hegi et al. J Clin Oncol 2008
MGMT-Methylation and outcome Hegi et al. J Clin Oncol 2008
ACNU-based treatment Overall median survival (17.3 vs. 15.7 months, n.s.) 3000 CHF more than RT alone (s.) (German trial: 375 pts., 16 centers) Weller et al. J Clin Oncol 2003
Nitrosoureas-based treatment Based on 24.193 patients Wolf et al. J Neurooncol 2008
Neuro-epithelial tumors NOA-1 EORTC Pats. 362 / 375 557 / 573 Glioblastoma 83.1 % 92.5 % Median OS in Glioblastoma Toxicity > II Conclusion 17.3 / 15.7 months 14.6 / 12.1 months 20 % leukopenia 13 % thrombopenia 2 % anemia RT + ACNU + VM26 (teniposide) 14 % leukopenia 12 % thrombopenia 1 % anemia RT + Temozolomide
Concepts and costs Concepts in Glioblastoma in Astrocytoma? Temozolomide: 5 x 75 mg/sqm weekly during RT 5 x 150-200 mg/sqm weekly every 4 weeks for 6 cycles (30.000,00 CHF) ACNU / tenoposide: 1 x 90 mg/qm and 3 x 60 mg/sqm every 6 weeks (3.000,00 CHF) Anti-angiogenesis (bevacizumab, sorafinib) in studies (in recurrent tumors)
Oligodendroglioma and -astrocytoma Treatment with PCV (procarbazine, lomustine, vincristin) Progression-free survival (23.0 vs. 13.2 months, s) 65 % toxicity III-IV Van den Bent et al. J Clin Oncol 2006
Systemic treatment Treatment with PCV (procarbazine, lomustine, vincristin) or temozolamide (response rate about 75 %) Taliansky-Aronov et al. J Neurooncol 2006 Mohile et al. J Neurooncol 2008
Brain metastases Concepts Small cell lung cancer: Response rates 30-80 % chemotherapy when no neurol. symptoms Breast cancer: Response rates 30-50 % Non-small cell lung cancer: Response rates 10-30 % No survival benefit for simultaneous application of radioand chemotherapy (topotecan? targeted therapies?) Soffietti et al. Curr Opin Oncol 2008
Conclusion Chemotherapy in glioblastoma is an individual decision driven by There is not 1 standard Chemotherapy in astrocytoma and oligodendroglioma is open In low-grade gliomas chemotherapy should not be offered Children should be treated within protocols only