Pathology of high-dose intraarterial BCNU.

Current radiotherapy and chemotherapy for high-grade and/or recurrent astrocytomas result in only moderate increases in survival time. In an attempt to improve this, high-dose intraarterial 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU) was utilized on 41 patients with these neoplasms over a 4-year period at our institution. Eight of the 41 patients came to biopsy or autopsy at times sufficiently following intraarterial BCNU infusion and with adequate tissue samples to evaluate the histological changes induced by the drug. Two of the eight patients received no additional radiotherapy or chemotherapy. The other five received conventional whole brain irradiation, and one additionally received 50 mg of intravenous 2-deoxy-5-fluorouridine (FUdR). The eight patients showed mild to severe amounts of bland coagulative necrosis, vascular hyalinization, perithelial fibroblastic proliferation, and endothelial atypia. One of these patients had a recognized severe clinical leukoencephalopathy, and the pathological changes were maximal in this individual. Six patients had radiological evidence of increased necrosis and clinical deterioration prebiopsy or preautopsy, but, within this group, there were no distinguishing clinical features. Microscopic changes were severe in two of these patients. A final patient died of unrelated septic shock 5 days after a single infusion of intraarterial BCNU, and the microscopic changes were least extensive in her. This study suggests that high-dose intraarterial BCNU can cause a leukoencephalopathy, sometimes severe, either alone or in synergistic fashion with cranial irradiation. Occurrence of such leukoencephalopathy is not always predictable based on BCNU dosage and cannot always be reliably distinguished from tumor regrowth or tumor necrosis by radiological and clinical evaluation. Hence, caution most be exercised in continuation of high-dose intraarterial BCNU protocols.

Phase I clinical trial of intracarotid bis-chloroethylnitrosourea (BCNU) and 2' dioxy-5-fluorouridine (FUDR) in malignant astrocytomas.

Systemic chemotherapy has been of limited benefit in the treatment of intracranial neoplasms, due, in part, to the inability to deliver effective drug doses to the neoplasm without systemic toxicity. We have completed a clinical trial of intracarotid BCNU and FUDR using an implantable pump in patients with unilateral malignant astrocytomas (Grade III and IV) in the hope of obtaining better tumor control with less systemic toxicity. Six patients had in-dwelling catheters placed in the internal carotid artery attached to a percutaneous refillable pump (Infusaid 400). The treatment program consisted of bolus BCNU 400 mg every 6 weeks and FUDR by continuous infusion at dosages ranging from 0.5 mg/24 h to 2.5 mg/24 h. The maximum tolerable dose of FUDR was 1 mg/24 h with ipsilateral mucositis and conjunctivitis being dose limiting factors. Flow studies demonstrated significant perfusion of the ipsilateral eye and surrounding face secondary to ophthalmic artery collaterals. No patient had systemic toxicity and the lowest WBC encountered was 2 400 with normal differential and platelets.

Topographic electroencephalographic study with power ratio index mapping in patients with malignant brain tumors.

A variant of electroencephalogram (EEG) power spectral mapping called power ratio index (PRI) mapping was used to monitor 15 patients with malignant brain tumors. This index is generated by dividing the low frequency (delta, theta) power by the high frequency (alpha, beta) power. Because the nonparoxysmal effect of a brain tumor on the EEG is reflected as a relative loss of high frequency power and a gain in low frequency power, utilization of the PRI has the effect of placing the epicenter of the "power dysfunction" coincident with the epicenter of the tumor.