title: Chemotherapy with BCNU in recurrent glioma: Analysis of clinical outcome and side effects in chemotherapy-naïve patients.
abstract: BACKGROUND
  To 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.
  
  
  METHODS
  Survival 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.
  
  
  RESULTS
  In 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.
  
  
  CONCLUSIONS
  In 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.
authors: Department of Neurosurgery, University Hospital Heidelberg, INF 400, 69120, Heidelberg, Germany. christine.jungk@med.uni-heidelberg.de.
authors: Christine
authors: C
authors: Jungk
authors: Department of Neurosurgery, University Hospital Heidelberg, INF 400, 69120, Heidelberg, Germany.
authors: Despina
authors: D
authors: Chatziaslanidou
authors: Department of Neurosurgery, University Hospital Heidelberg, INF 400, 69120, Heidelberg, Germany.
authors: Rezvan
authors: R
authors: Ahmadi
authors: Institute of Neuropathology, University of Heidelberg, INF 224, 69120, Heidelberg, Germany.
authors: David
authors: D
authors: Capper
authors: Institute of Medical Biometry & Informatics, University of Heidelberg, INF 305, 69120, Heidelberg, Germany.
authors: Justo Lorenzo
authors: JL
authors: Bermejo
authors: Department of Neurosurgery, University Hospital Heidelberg, INF 400, 69120, Heidelberg, Germany.
authors: Janina
authors: J
authors: Exner
authors: Institute of Neuropathology, University of Heidelberg, INF 224, 69120, Heidelberg, Germany.
authors: Andreas
authors: A
authors: von Deimling
authors: Department of Neurosurgery, University Hospital Heidelberg, INF 400, 69120, Heidelberg, Germany.
authors: Christel
authors: C
authors: Herold-Mende
authors: Department of Neurosurgery, University Hospital Heidelberg, INF 400, 69120, Heidelberg, Germany.
authors: Andreas
authors: A
authors: Unterberg
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002330:Carmustine / Q000008:administration & dosage* / Q000009:adverse effects; D003131:Combined Modality Therapy / Q000009:adverse effects; D018572:Disease-Free Survival; D005260:Female; D005910:Glioma / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000473:pathology; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000473:pathology*; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D002330:Carmustine