Intravenous BCNU Research Articles

Ischemic stroke in patients with glioblastoma multiforme

Sirs: Tumor-related ischemic strokes are most unusual in patients with malignant gliomas [1–3]. We report here two adult patients with supratentorial glioblastoma who developed an ischemic stroke on the tumor side. Patient 1: In March 2000, a 60year-old man became confused. MRI revealed a right temporal tumor which was partially resected and found to be a glioblastoma. Focal radiotherapy was administered. Four months later, intravenous BCNU was started because of tumor progression. On 13 February, 2001, he developed acutely a left hemiplegia. CT showed an extensive infarct in the territory of the right middle cerebral artery (MCA) (Fig. 1). He became comatous and died on 22 February, 2001. Patient 2: In July 1994, a 41-yearold man developed intracranial hypertension. MRI disclosed a right temporal tumor which was partially resected and found to be a glioblastoma. A course of focal radiotherapy was administered. Three months later, he had a sudden left hemiplegia and MRI showed a right lenticulostriate infarct related to an occlusion of the right supraclinoid internal carotid artery (ICA) shown by angiography. The patient died on 5 April, 1995. Permission for autopsy was not granted for either patient. These two patients suffering from a right temporal glioblastoma presented an ischemic stroke in the right ICA-MCA territories. To explain these acute events three hypotheses were considered: 1) A fortuitous association between glioma and stroke in the same location. This hypothesis is unlikely since both patients had no cerebrovascular risk factors and the angiogram in patient 2 showed no atheroma in the cervical or cerebral vessels. 2) Radiation damage to the large intracranial cerebral vessels was also considered but the very short delay between the completion of RT (5 and 3 months) and the stroke makes this hypothesis unlikely. Indeed, radiation-induced damage to the large vessels always occurs many years after RT (mean 7 years [4–6]). 3) The third possibility is a primary role for the underlying gliomas in the development of stroke. Vasospasm with multifocal infarcts has been incriminated previously in one patient with leptomeningeal gliomatosis [7] but this hypothesis can be excluded, at least in our second patient who had a persistent ICA thrombosis three months after the stroke. A hypercoagulable state (procoagulant factors secreted by gliomas) is common and partly accounts for the high incidence of deep vein thromLETTER TO THE EDITORS

A randomized comparison of intra-arterial versus intravenous with or without intravenous 5-fluorouracil, for newly diagnosed patients with malignant glioma

This Phase III trial tested the efficacy and safety of intra-arterial 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) for the treatment of newly resected malignant glioma, comparing intra-arterial BCNU and intravenous BCNU (200 mg/sq m every 8 weeks), each regimen without or with intravenous 5-fluorouracil (1 gm/sq m three times daily given 2 weeks after BCNU). All patients also received radiation therapy. A total of 505 patients were randomly assigned within the study. Fifty-seven patients were excluded, primarily because of neuropathology error, and the remaining 448 patients constituted the Valid Study Group. Of the total 505 patients, 190 patients could not receive intra-arterial BCNU and 315 patients were randomly assigned to receive intra-arterial (167 patients) and intravenous (148 patients) BCNU. Actuarial analysis (log-rank) demonstrated reduced survival for the intra-arterial group (p = 0.03). Serious toxicity was observed in the intra-arterial group; 16 patients (9.5%) developed irreversible encephalopathy with computerized tomography evidence of cerebral edema, and 26 patients (15.5%) developed visual loss ipsilateral to the infused carotid artery. Administration of 5-fluorouracil did not influence survival. The survival rate between the intravenous and the intra-arterial BCNU patients with glioblastoma multiforme did not differ, but was worse for intra-arterial BCNU patients with anaplastic astrocytoma than for those receiving intravenous BCNU (p = 0.002). Neuropathologically, intra-arterial BCNU produced white matter necrosis. It is concluded that intra-arterial BCNU is neither safe nor effective in prolonging survival when administered by the methods used in this study of newly diagnosed patients with malignant glioma.

Early metabolic changes following chemotherapy of human gliomas in vivo demonstrated by phosphorus magnetic resonance spectroscopy.

The authors have used phosphorus magnetic resonance spectroscopy to monitor pH changes in malignant gliomas following treatment with intravenous and intra-arterial 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU). Image-guided, localized phosphorus spectra of human gliomas in situ were obtained using a 1.5-T whole body combined imaging and spectroscopy system. Initial intravenous BCNU treatment was followed by a transient decrease of tumor intracellular pH by 0.15 +/- 0.03 pH units (mean +/- SD). Superselective intra-arterial administration of the same drug was followed by an increase of tumor intracellular pH by 0.15 +/- 0.6 pH units (mean +/- SD). These changes occurred prior to any changes on x-ray, computed tomography (CT), or magnetic resonance imaging (MRI). In addition to enhancing our understanding of the metabolic effects of BCNU, such changes may correlate with drug efficacy or toxicity and may be useful in guiding therapy in the future.

Intravenous BCNU and AZQ in patients with recurrent malignant gliomas.

Twenty-four patients with recurrent malignant glioma were treated with intravenous BCNU (80 mg/m2/day X 3 days) alternating with AZQ (8 mg/m2/day X 5 days) every 6-8 weeks. Twenty patients received two or more courses of chemotherapy, ten anaplastic astrocytomas (AA), eight glioblastomas (GBM), and two malignant oligodendrogliomas (Oligo). All had prior surgery and irradiation; one had prior chemotherapy. Median age was 37.5 years. The median Zubrod performance status (PS) was 1. Three patients (15%) achieved response status, and 7 (35%) had stable disease with median times to tumor progression (MTP) of 56 wks and 35 wks. MTP for patients with progression was 11 weeks. No GBM was responsive to chemotherapy and none of the ten patients with stable or responsive disease were older than fifty years. Dose limiting toxicity was consisted of thrombocytopenia and leukopenia. Young patients with recurrent AA and good PS appear more likely to respond to alternating BCNU/AZQ chemotherapy. The overall response rate (response plus stable) of 50% was comparable to that of BCNU alone and the hematologic toxicity was cumulative.

The intraarterial route of drug delivery in the chemotherapy of malignant brain tumours.

This review is based on literature data and own experiences in 79 patients with malignant brain tumours using intraarterial delivery of cytostatic agents as adjuvant therapy. A survey is given of the pharmacological rationale of this therapeutic approach, of the drugs which have been used and of the related experimental and clinical experiences. Advantages and limitations are discussed and clinical conclusion drawn. Experience so far suggests that in anaplastic astrocytomas and oligodendrogliomas intraarterial ACNU might be as effective as intravenous BCNU against the tumours but causes less systemic side-effects.

Recovery of blood and bone marrow stem cells following intense chemotherapy and autologous bone marrow transplantation.

Sixteen patients with advanced (stage III) malignant melanoma were treated with escalating doses of intravenous BCNU and melphalan starting at 400 and 35 mg/m2, respectively, and escalating to 1,000 and 110 mg/m2, respectively, combined with autologous marrow transplantation. The duration of granulocytopenia and time to granulocyte recovery was similar in all groups regardless of chemotherapy dose. Platelet recovery was delayed in patients receiving the highest doses of chemotherapy. This study showed that bone marrow colony-forming units in culture took as long as 6 months to recover. This was adequate to bring peripheral blood counts to normal but not to pretreatment levels. These studies indicate that autologous bone marrow transplantation is beneficial in enhancing short-term recovery, but may not be beneficial in the long-term hematopoietic recovery.

Intraarterial 1,3-bis(2-chloroethyl)-l-nitrosourea chemotherapy for the treatment of malignant gliomas of the brain: A preliminary report

In a clinical trial, 10 patients with malignant gliomas underwent partial resection of their tumors and were treated by intraarterial 1,3-bis(2-chloroethyl)-l-nitroso-urea (BCNU) chemotherapy. The drug was given at least 1 month after the completion of postoperative radiotherapy in total doses of 270–280 mg/m 2 in two sessions separated by a 48-hour interval (the two sessions with interval were equal to one course). This therapy was repeated every 8–10 weeks. Four patients had three courses and the other six patients had two courses of chemotherapy. This therapy was the only antitumor chemotherapy for this group of patients. Our preliminary results demonstrate the safety of this new procedure and suggest that intraarterial BCNU chemotherapy may be more effective, and has a better tolerance and less toxicity, than intravenous BCNU chemotherapy. Furthermore, it was demonstrated that, in the case of one patient, higher antitumor activity resulted from intraarterial BCNU chemotherapy as compared to intravenous BCNU therapy.

Multimodality therapy for medulloblastoma.

Eight patients with recurrent medulloblastoma were treated with a chemotherapy regimen consisting of vincristine, BCNU, dexamethasone and intrathecal and intermediate dose intravenous methotrexate (500 mg/m2). Five also received local low dose radiotherapy (RT). All 8 patients responded to treatment; 6 completely and 2 partially. These latter 2 were in their second and third recurrences. Three remain in remission. The median duration of response was 18.8 months, and median time from start of chemotherapy to death was 32 months using the Kaplan-Meier technique. In addition, 9 other patients with newly diagnosed medulloblastoma were treated with craniospinal radiation and the same adjuvant chemotherapy as above. The first 5 patients also received intraventricular methotrexate and/or intravenous BCNU during radiotherapy. The toxicity in the 5 patients was very severe. There were three toxic deaths, one death from cancer; one patient survives disease-free, but he is demented. With the discontinuance of intraventricular methotrexate and the postponement of myelo-suppressive chemotherapy until after the completion of radiotherapy, the regimen has been well tolerated. All 4 patients treated this way remain alive, well, and disease-free at intervals up to 36 months. We conclude that recurrent medulloblastomas are sensitive to multiagent chemotherapy and that prolonged remissions may occur. With primary adjuvant chemotherapy, extreme caution with myelo-suppressive drugs must be exercised during the period of craniospinal radiotherapy. We also do not recommend the use of intraventricular methotrexate. When these two criteria were followed, the preliminary results with adjuvant chemotherapy appear encouraging.

BCNU and Steroids in the Viral-Induced Dog Brain Tumor

Schmidt-Ruppin strain of Rous Sarcoma was inoculated intracerebrally into 27 newborn beagle dogs. Fourteen days after viral inoculation, 13 of the dogs were given intravenous BCNU (1 mg/kg). The other 14 were given the same volume of intravenous saline in a randomized, double-blinded fashion. Ninety percent of all dogs developed intracranial tumors. Radionuclide (mercury 197) brain scans were done on each dog at 2-week intervals. Median survival was 113 days in the BCNU group and 115 days in the placebo group (P > .99). Unequivocally positive radionuclide brain scans were detected in 5 dogs treated with BCNU and in 2 of the controls. There were no gross or microscopic differences at autopsy between treated and nontreated animals. BCNU, as given in this animal brain tumor model, did not demonstrate any oncolytic effect. An improvement in sequential brain scans was detected in 2 other dogs in response to Dexamethasone, which was given in a double-blinded, cross-over controlled fashion. Computerized tomography clearly demonstrated the tumor in two cases.