Abstract
BackgroundTo date, standardized strategies for the treatment of recurrent glioma are lacking. Chemotherapy with the alkylating agent BCNU (1,3-bis (2-chloroethyl)-1-nitroso-urea) is a therapeutic option even though its efficacy and safety, particularly the risk of pulmonary fibrosis, remains controversial. To address these issues, we performed a retrospective analysis on clinical outcome and side effects of BCNU-based chemotherapy in recurrent glioma.MethodsSurvival data of 34 mostly chemotherapy-naïve glioblastoma patients treated with BCNU at 1st relapse were compared to 29 untreated control patients, employing a multiple Cox regression model which considered known prognostic factors including MGMT promoter hypermethylation. Additionally, medical records of 163 patients treated with BCNU for recurrent glioma WHO grade II to IV were retrospectively evaluated for BCNU-related side effects classified according to the National Cancer Institute Common Toxicity Criteria for Adverse Events (CTCAE) version 2.0.ResultsIn recurrent glioblastoma, multiple regression survival analysis revealed a significant benefit of BCNU-based chemotherapy on survival after relapse (p = 0.02; HR = 0.48; 95 % CI = 0.26–0.89) independent of known clinical and molecular prognostic factors. Exploratory analyses suggested that survival benefit was most pronounced in MGMT-hypermethylated, BCNU-treated patients. Moreover, BCNU was well tolerated by 46 % of the 163 patients analyzed for side effects; otherwise, predominantly mild side effects occurred (CTCAE I/II; 45 %). Severe side effects CTCAE III/IV were observed in 9 % of patients including severe hematotoxicity, thromboembolism, intracranial hemorrhage and injection site reaction requiring surgical intervention. One patient presented with a clinically apparent pulmonary fibrosis CTCAE IV requiring temporary mechanical ventilation.ConclusionIn this study, BCNU was rarely associated with severe side effects, particularly pulmonary toxicity, and, in case of recurrent glioblastoma, even conferred a favorable outcome. Therefore BCNU appears to be an appropriate alternative to other nitrosoureas although the efficacy against newer drugs needs further evaluation.
Highlights
IntroductionChemotherapy with the alkylating agent BCNU (1,3-bis (2-chloroethyl)-1-nitroso-urea) is a therapeutic option even though its efficacy and safety, the risk of pulmonary fibrosis, remains controversial
To date, standardized strategies for the treatment of recurrent glioma are lacking
Recent data demonstrated that the nitrosourea derivative ACNU alone failed to stabilize the disease in recurrent GBM [18] whereas ACNU in combination with teniposide (VM26) has been shown to be moderately effective in these patients but at the expense of an increased high-grade hematotoxicity [19]
Summary
Chemotherapy with the alkylating agent BCNU (1,3-bis (2-chloroethyl)-1-nitroso-urea) is a therapeutic option even though its efficacy and safety, the risk of pulmonary fibrosis, remains controversial. To address these issues, we performed a retrospective analysis on clinical outcome and side effects of BCNU-based chemotherapy in recurrent glioma. The interest in well-tolerated treatment regimens has grown due to a rising number of glioma patients pretreated with TMZ, resulting in a reduced bone marrow reserve that may influence the efficacy and tolerance of additional chemotherapy Nitrosourea derivatives, another class of alkylating agents, are widely applied in recurrent glioma even though their value remains controversial. Since data on BCNU-related side effects and its impact on patient outcome are still sparse and interpretation of study results is often hindered by a heterogeneously pre-treated patient sample, further evaluation of safety and efficacy in a large and homogeneously pre-treated cohort is warranted in order to consider BCNU as an appropriate treatment alternative
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