Intra-arterial BCNU Research Articles

Treatment of recurrent glioblastoma with intra-arterial BCNU [1, 3-bis (2-chloroethyl)-1-nitrosourea

Contemporary therapies for patients with glioblastomas remain marginally efficient, and recurrence following surgery, radiation therapy and adjuvant chemotherapy is practically universal. The major obstacles to the successful use of chemotherapy for CNS tumors are the drug delivery to the tumor site and the infusion of chemotherapeutic agents directly into the arterial supply of a tumor. The latter could provide a pharmacokinetic advantage by enhancing drug delivery to the tumor. Sixteen patients with recurrent unilateral glioblastomas treated with intra-arterial BCNU were evaluated retrospectively. During the infusion, eleven patients referred pain in the ipsilateral eye, five patients were nauseated, three reported headache, one patient presented mental confusion, while two presented focal signs. There were two deaths during the course of therapy. Four patients achieved temporary clinical improvement, seven showed disease stability, and three presented clinical deterioration. The median total survival time was 87.9 weeks. Unilateral vision loss and focal signs were observed as delayed complications of this treatment. This study has confirmed previous reports indicating that arterial chemotherapy is clearly not curative, and presents serious toxicity. Only through a randomized prospective study performed in a large series of patients can the questions concerning survival period increment be answered properly.

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.

Selective intra-arterial chemotherapy with BCNU in recurrent malignant gliomas.

Study of intra-arterial BCNU in 12 patients with recurrent glioblastoma multiforme and 5 patients with recurrent anaplastic astrocytoma already treated by surgery and radiotherapy indicates that the risk of BCNU toxicity can be reduced by the use of relatively low doses (160-180 mg/m2) of BCNU, the use of dextrose as solvent, selective injections of BCNU, and fast "bolus" injections of drug. No certain toxic effects of BCNU were observed in the 17 patients treated this way. Anaplastic astrocytomas, particularly in young patients, seem to respond relatively well to this treatment.

Intra-arterial BCNU in the treatment of recurrent medulloblastoma

Two patients with recurrent medulloblastomas were treated with combined oral and intravenous chemotherapy followed by intra-arterial BCNU. The 7 days course of oral and intra-venous chemotherapy consisted of CCNU and Procarbazin orally and Vincristine intravenously (PCV), repeated after 6 weeks. Intra-arterial chemotherapy consisted of 4 cycles of BCNU. Both patients responded well to treatment, evaluated by CT scans. One of the patients died of a new local recurrence 6 months after initiation of chemotherapy, whereas the other patient remains well, without CT evidence of tumour 36 months after the start of the treatment. No serious adverse side-effects related to the treatment were seen.

Fatal necrotizing encephalopathy complicating treatment of malignant gliomas with intra-arterial BCNU and irradiation: a pathological study.

We describe the neuropathologic findings at autopsy in six patients who developed a progressive encephalopathy complicating the treatment of malignant gliomas with combined intra-arterial 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and cerebral irradiation. Four brains were free of tumor and one contained a microscopic focus of residual glioma. In only one case was there evidence of tumor progression. A disseminated process characterized by miliary foci of necrosis with mineralizing axonopathy was present in all cases, restricted to the internal carotid distribution of the perfused hemisphere and involving primarily though not exclusively the white matter, which was diffusely and severely edematous. This was combined in 3 cases with a histologically dissimilar, massive necrotizing leukoencephalopathy indistinguishable from pure radionecrosis. Much of the toxicity of this therapy is mediated by vascular injury, but the disseminated necrotizing lesion probably reflects, at least in part, direct neural damage.

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)-l-nitrosurea (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 leukoen-cephalopathy 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.

Combined Intraarterial and Systemic Chemotherapy for Intracerebral Tumors

Twenty-six patients with intracerebral tumors (predominantly gliomas) were treated with intraarterial BCNU, VM-26, and cisplatin combined with the systemic administration of VM-26, methotrexate, vincristine, bleomycin, and procarbazine. Oral glycerol was given before i.v. VM-26. Twelve patients responded (46% of all patients and 63% of the fully evaluable patients). The response rate for gliomas was 50% if all patients were considered and 71% if only fully evaluable patients were considered. The response rate did not seem to be affected by glioma grade, prior chemotherapy, or pretreatment performance status. Median time to tumor progression for responders was 19 weeks. Median survival from initiation of treatment was 21 weeks for evaluable patients and 17 weeks for all patients. Median survival from initial diagnosis was 55 weeks. Myelosuppression was dose-limiting for the systemic chemotherapy. Reversible neurological toxicity was common, but tolerable. One patient developed ipsilateral blindness, and two patients developed prolonged neurological toxicity. Pulmonary toxicity was also seen. Vertebral artery infusions proved feasible, although difficult and more toxic than carotid infusions. Overall, this regimen was not more active than the intraarterial combination of BCNU, VM-26, and cisplatin without the systemic chemotherapy. Further studies of more intensive intracarotid therapy combined with different systemic drugs are being initiated.

Central neurotoxicity following intracarotid BCNU chemotherapy for malignant gliomas.

Central neurotoxicity is reported in 5 of 16 patients with recently diagnosed anaplastic gliomas, who received intra-arterial BCNU (200 mg/M2/course) and also 2 in a series of 26 patients with recurrent gliomas similarly treated. Neurotoxicity was usually delayed, commencing several weeks following the second or third course. CT scans during central neurotoxicity represented 1 or more of 3 patterns: no change; increased low density area(s); and/or ipsilateral gyral enhancement and punctate calcification in the middle cerebral artery territory. In one clinicopathological correlation, coagulative necrosis of the white matter was observed, identical histologically to those changes recognized as delayed vascular events following radiotherapy. Cautious exploration of the various clinical factors that may contribute to this toxicity seems appropriate, as exploration of the potential benefits of regional chemotherapeutic infusions is undertaken.

The rationale and methodology for intra-arterial chemotherapy with BCNU as treatment for glioblastoma.

The rationale for, methodology of, and experience with intra-arterial BCNU infusion therapy of malignant glioma are described. This approach achieves tumor levels of drug four times greater than equal doses infused intravenously, and has been used to treat 79 patients over the course of 4 years. The drug was given in 192 infraophthalmic and 66 supraophthalmic carotid artery infusions. Patients who were treated via infraophthalmic carotid artery infusion following tumor recurrence (after both operation and irradiation) survived 54 additional weeks (92 weeks after initial diagnosis). Patients who were treated with BCNU immediately after initial irradiation therapy survived 64 weeks (infraophthalmic carotid artery infusion) and 49.5 weeks (supraophthalmic carotid artery infusion). The major ocular complications (pain and diminished visual acuity) associated with infraophthalmic carotid artery infusion are avoided by selective balloon-guided supraophthalmic carotid artery administration. However, both approaches were associated with white-matter changes, seen as diminished absorption on computerized tomography scans, in 20% of patients treated following irradiation therapy. This toxicity appears to preclude intra-arterial BCNU treatment in the immediate postirradiation period. Better results are being achieved with our current therapy, which involves four infusions of BCNU (400 mg every 4 weeks) into the infraophthalmic or supraophthalmic carotid artery in advance of irradiation. Cisplatin infusions (60 to 90 mg/sq m every 5 weeks) are offered for recurrent glioblastoma.

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.

Complications associated with intra-arterial BCNU administered in combination with vincristine and procarbazine for the treatment of malignant brain tumors.

We have used intra-arterial (i.a.) 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) either alone or as part of adjuvant chemotherapy in patients with malignant brain tumors over a 3 year period (1979-1982). The i.a. BCNU technique was used 111 times to infuse 134 arteries in 37 patients. These patients, 28 cases with glial tumor and 9 cases with brain metastasis, received i.a. BCNU in combination with Vincristine and Procarbazine every 6 weeks. Complications encountered were transient and included: periorbital erythralgia or occipital-nuchal pain in 23 (62%), mild confusion and disorientation in 14 (38%), and ipsilateral conjunctival edema in 10 (27%). Reversible myelosuppression was not found. Our findings suggest that BCNU (100 mg/M2) may be given by i.a. infusion in combination chemotherapy without persistent severe untoward effects with a cumulative dose of 700 mg/M2.

Intra-arterial BCNU in the treatment of metastatic brain tumors.

Thirty-one patients with metastatic brain tumors that either failed to respond or recurred after conventional therapy were treated by intra-arterial infusion of 100 mg/m2 of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) into either a carotid or vertebral artery. Five patients (three with lung cancer, one with breast cancer and one with melanoma) had a partial response of the tumor(s) in the distribution of the injected artery. In two patients, brain metastases not in the distribution of the injected artery enlarged, while the tumors perfused by the injected artery responded. In one of these patients, subsequent infusion of BCNU to the enlarging tumor resulted in a partial response. Among responders, the median survival following onset of BCNU was 17 weeks. One patient remains alive and well at 30 weeks. No permanent neurological, retinal or systemic toxicity was observed.

Intra-arterial BCNU therapy in the treatment of metastatic brain tumor from lung carcinoma: a preliminary report.

Nine patients with intracerebral metastasis from lung carcinoma were treated with intracarotid and intravertebral artery infusion of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). Four of these patients considered definite responders showed unequivocal clinical improvement and definite decreases in the size of tumors evaluated by neurologic examination, computerized tomographic (CT) scan and radionuclide brain scan (RBS). One patient's clinical condition stabilized with doubtful improvement of diagnostic tests (probable responder). The remaining four patients had further unfavorable progression of the clinical and scan findings and were clearly nonresponders. Complications were transient and included: local pain in the eye, orbit, and occipital-nuchal area during infusion in 7 patients, focal seizure in 3 patients, mild confusion with disorientation in 2 patients, and nausea in 2 patients. Our findings suggest that intra-arterial BCNU therapy may be effective and may be used as an adjuvant to surgery and/or radiotherapy for the treatment of metastatic brain tumor from lung carcinoma.