Intraarterial Chemotherapy of Brain Tumors under Conditions of Temporary Breaking of Blood-Brain Barrier

G.L. Kobyakov, A.Yu. Lubnin, S.B. Yakovlev, E.Yu. Bukharin, L.A. Israelyan

Burdenko Research Institute of Neurosurgery, Moscow, Russia

 

Today chemotherapy is the third and less developed trend among surgery and radiation therapy, used for treatment of patients with brain tumors. It is caused by relative impermeability of the blood-brain barrier (BBB) for chemotherapeutic drugs, as all cytostatic preparations are high-molecular compounds, having a charge in a dissolved state. Possibility of its temporary opening under conditions of an osmotic blow seems to be prospective.

The goal of the present study was to analyze clinical experience of temporary breaking of the blood-brain barrier in patients with brain tumors (primary lymphomas of the CNS) for carrying out subsequent chemotherapy and to estimate its efficacy.

Materials and Methods. Intraarterial chemotherapy against a background of BBB temporary breaking (15 procedures) was carried out in 10 patients with primary cerebral lymphomas, verified histologically. A number of procedures was as follows: 3 - 1 patient, 2 - 3 cases and 1 - 6 cases. Osmotic breaking of BBB was achieved by quick intraarterial infusion of warm solution of an osmotic diuretic (400 ml of 15% solution of mannitol), lasting 3.5 minutes. The procedures were carried out under conditions of general anesthesia, trachea intubation and artificial respiration with an oxygen-air mixture and normal ventilation. Monitoring of the following parameters was carried out: EEG in three leads, blood pressure (a catheter in the radial artery), indices of pulse oximetry, CO2 level, esophageal temperature. Chemotherapy started with I/V infusion of cyclophosphan in a dose of 200 mg/m2 of a body surface; it was done 30-40 minutes before BBB breaking.

A hyperosmotic blow, caused by mannitol, was followed by administration of methotrexat in a dose of 1 g/m2 (1-2 g on the average) during 10 minutes. It was done with the help of a catheter, inserted above a place of branching of the ophthalmic artery from the carotid artery. We did not observe any hemodynamic changes during this process. CT with enhancing was used before the procedure and 20 minutes after completion of intraarterial chemotherapy with BBB breaking in one patient. The purpose was revealing signs of increased BBB permeability. It was demonstrated, that a mannitol blow resulted in some increase of a zone of contrast accumulation. It confirmed a change of the BBB state.

Treatment with leucovorin started in 36 hours and continued during 2 days. Control CT-examination with enhancing was carried out on the 8 day after administration with the purpose of estimating an effect of treatment.

Preliminary results. There were 23 procedures, performed in 14 patients (1- 3 cases, 2 - 8 cases and 3 in 2 cases). Control CT demonstrated considerable reduction of a tumor size a week after the procedure in all the cases. It was confirmed by improvement of a neurologic status as well.

According to our data, chemotherapy toxicity was not high. Hematological toxicity of grade 3-4 was watched only in one female patient. However, it should be noted, that she underwent a course of I/V chemotherapy with other drugs before our procedure. Severe hematological toxicity with sepsis, caused by staphylococcus, was observed in one male patient after the second course of treatment with methotrexat, which was administered intravenously due to technical difficulties There were no hematological toxicity in the rest patients. It allowed to reduce an interval between manipulations up to 2-3 weeks. At present the maximum relapse-free period is 36 months.

Conclusion. We have developed an original method of superselective intraarterial therapy under conditions of breaking the blood-brain barrier. The results are characterized by high efficacy of chemotherapy of primary intracranial lymphoma and rather small hematological toxicity. The next step in this direction is studying use of this method in combination with intravenous chemotherapy and radiation therapy for determination of an optimum mode of treatment.