Randomized phase III trials have shown significant improvement of survival 1, 2, and 3 years after implantation of 1,3-bis (2-chloroethyl)-1-nitrosourea (
BCNU) wafers for patients with newly diagnosed
malignant glioma. But these studies and subsequent non-phase III studies have also shown risks associated with local
chemotherapy within the central nervous system. The introduction of
concomitant radiochemotherapy with
temozolomide (TMZ) has later demonstrated a survival benefit in a phase III trial and has become the current treatment standard for newly diagnosed
malignant glioma patients. Lately, this has resulted in clinical protocols combining local
chemotherapy with
BCNU wafers and
concomitant radiochemotherapy with TMZ although this may carry the risk of increased toxicity. We have compiled the treatment experience of seven neurosurgical centers using implantation of
carmustine wafers at primary surgery followed by 6 weeks of
radiation therapy (59-60 Gy) and 75 mg/m(2)/day TMZ in patients with newly diagnosed
glioblastoma followed by TMZ monochemotherapy. We have retrospectively analyzed the postoperative
clinical course, occurrence and severity of adverse events, progression-free interval, and overall survival in 44 patients with newly diagnosed
glioblastoma multiforme. All patients received
multimodal treatment including
tumor resection,
BCNU wafer implantation, and
concomitant radiochemotherapy. Of 44 patients (mean age 59 ± 10.8 years) with
glioblastoma who received
Gliadel wafer at primary surgery, 28 patients (64%) had died, 16 patients (36%) were alive, and 15 patients showed no evidence of clinical or radiographic progression after a median follow-up of 15.6 months. At time of analysis of adverse events in this patient population, the median overall survival was 12.7 months and median progression-free survival was 7.0 months. Surgical, neurological, and medical adverse events were analyzed. Twenty-three patients (52%) experienced adverse events of any kind including complications that did not require treatment. Nineteen patients (43%) experienced grade 3 or grade 4 adverse events. Surgical complications included
cerebral edema, healing abnormalities, cerebral spinal fluid leakage,
meningitis, intracranial
abscess, and
hydrocephalus. Neurological adverse events included newly diagnosed
seizures, alteration of mental status, and new neurological deficits. Medical complications were thromboembolic events (
thrombosis,
pulmonary embolism) and hematotoxicity. Combination of both treatment strategies, local
chemotherapy with
BCNU wafer and
concomitant radiochemotherapy, appears attractive in aggressive
multimodal treatment schedules and may utilize the sensitizing effect of TMZ and
carmustine on MGMT and AGT on their respective drug resistance genes. Our data demonstrate that combination of local
chemotherapy and
concomitant radiochemotherapy carries a significant risk of toxicity that currently appears underestimated. Adverse events observed in this study appear similar to complication rates published in the phase III trials for
BCNU wafer implantation followed by
radiation therapy alone, but further add the toxicity of
concomitant radiochemotherapy with systemic TMZ. Save use of a combined approach will require specific prevention strategies for
multimodal treatments.