Phase II study of neoadjuvant 1, 3-bis (2-chloroethyl)-1-nitrosourea and temozolomide for newly diagnosed anaplastic glioma: a North American Brain Tumor Consortium Trial.
BACKGROUND
Temozolomide (TMZ) and 1, 3-bis (2-chloroethyl)-1-nitrosourea (BCNU) are reported to be active agents in anaplastic glioma (AG). TMZ has also been shown to deplete alkyltransferase, a DNA repair enzyme that contributes to nitrosourea resistance. The objective of the current study was to determine the efficacy and toxicity profile of a combination of these agents before radiotherapy in newly diagnosed AG.


METHODS
Eligibility criteria included histologically confirmed newly diagnosed AG with measurable enhancing disease, a Karnofsky performance score (KPS) > or = 60, normal pulmonary function, and normal laboratory parameters. In addition, informed consent was obtained from all patients. BCNU given at a dose of 150 mg/m(2) intravenously was followed after 2 hours by TMZ given at a dose of 550 mg/m(2) orally on Day 1 of a 42-day cycle to a maximum of 4 cycles, unless there was tumor progression or unacceptable toxicity.


RESULTS
Forty-one eligible patients were accrued. Their median age was 40 years. Seventy-six percent of patients had a KPS of 90-100. The histology was 81% anaplastic astrocytoma, 12% anaplastic oligodendroglioma, and 7% mixed tumors. Twenty-two percent of patients did not complete 4 cycles because of toxicity, mainly hematologic. Forty-six percent of patients experienced Grade 3 or 4 (according to National Cancer Institute Common Toxicity Criteria) thrombocytopenia. Twenty percent had Grade 4 granulocytopenia. Two patients died while receiving therapy, 1 of progressive disease and the other of Pneumocystis carinii pneumonia. The complete and partial response rates were 2% and 27% respectively. An additional 54% of patients had stable disease. Seventeen percent developed progressive disease (10% after the first cycle and 7% after the second cycle).


CONCLUSIONS
This neoadjuvant strategy was associated with significant myelosuppression and a modest response rate in patients with newly diagnosed AG.
Chang
Susan M
SM
Department of Neurological Surgery, Neuro-Oncology Service, University of California at San Francisco, San Francisco, California 94143, USA. changs@neurosurg.ucsf.edu
Prados
Michael D
MD
Yung
W K Alfred
WK
Fine
Howard
H
Junck
Larry
L
Greenberg
Harry
H
Robins
H Ian
HI
Mehta
Minesh
M
Fink
Karen L
KL
Jaeckle
Kurt A
KA
Kuhn
John
J
Hess
Kenneth
K
Schold
Clifford
C
D000293:Adolescent; D000328:Adult; D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002330:Carmustine / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D003606:Dacarbazine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D005260:Female; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D018714:Radiotherapy, Adjuvant; D016019:Survival Analysis; D000077204:Temozolomide
D018906:Antineoplastic Agents, Alkylating; D003606:Dacarbazine; D002330:Carmustine; D000077204:Temozolomide