RU2238731C2 - Method for treating metastatic cerebral lesions - Google Patents

Abstract

FIELD: medicine, chemotherapy.

SUBSTANCE: the present innovation deals with intrathecal introduction of metotrexate at the quantity of 1.2-2.5 mg/kg patient's body weight along with cytozar at the quantity of 3-5 mg/kg and hydrocortisone at the quantity of 125 mg at preliminary cerebral dehydration and intravenous introduction of cerebrolysine. Since the second day of chemopreparations introduction it is necessary to conduct 1-2 plasmapheresis seances. Preparations should be introduced thrice at 7-d-long intervals, further - once monthly, thrice. The method decreases toxic complications of chemotherapy performed.

EFFECT: higher efficiency of therapy.

2 cl, 1 ex, 1 tbl

Description

The invention relates to medicine, in particular to chemotherapy of metastatic brain lesions.

A known method of chemotherapeutic effects on the body with intrathecal administration of methotrexate in an amount of 0.25 mg per kg of body weight (Methodological recommendations for chemotherapy of malignant brain tumors. Approved by the Bureau of the Presidium of the Scientific Medical Council of the Ministry of Health of the Ukrainian SSR October 27, 1975, 12-13 pp.).

The disadvantage of this method is its low efficiency.

A known method of chemotherapeutic effects with endolumbar (intrathecal) administration of methotrexate (A.P. Romodanov, Yu.A. Zozulya, Yu.D. Sosnov. Metastatic brain tumors. - Kiev: Health, 1973, 172 S.).

The disadvantage of this method is its low efficiency. A known method of treating neuroleukemia by intrathecal methotrexate at a dose of 12.5 mg / m ² (0.35 mg / kg body weight) (Edited by N.I. Perevodchikova Antitumor chemotherapy. Handbook, Moscow, 1996, 28 pp.).

A known method of treating damage to the meninges with leukemia by intrathecal cytosar at a dose of 30-50 mg / m ² (1.5 mg / kg weight) once, twice or three times a week (A.M. Garin, A.V. Khlebnov. Reference practical tumor chemotherapy, Moscow, 1995, 59 pp.).

It is known the treatment of cancer metastases and melanomas in the brain using corticosteroids (A.P. Romodanov, Yu.A. Zozulya, Yu.D. Sosnov. Metastatic brain tumors. - Kiev: Health, 1973, 172 pp.).

The disadvantage of this method is also their low efficiency.

The objective of the invention is to lengthen the remission of the tumor process in the brain and increase the duration and improve the quality of life of patients.

The problem is solved in that in a method of treating metastatic brain lesions, including chemotherapeutic effects on the body during intrathecal (endolumbar) administration, methotrexate is administered in megadoses of 1.2-2.5 mg / kg body weight in combination with cytosar 3-5 mg / kg body weight and hydrocortisone in an amount of 125 mg.

The problem is solved in that for the prevention of acute cerebral edema and, as a consequence, seizures with megadose administration of methotrexate and cytosar, drug dehydration of the brain with intravenous administration of cerebrolysin is performed before the procedure.

The problem is also solved by the fact that to reduce the general toxic effect from 2 days after the introduction of chemotherapy, 1-2 sessions of plasmapheresis are carried out.

The problem is also solved by the fact that the drugs are administered three times with an interval of 7 days, then once a month three times.

It has been established that in the method of treating metastatic brain lesions by administering chemotherapeutic drugs into the cerebrospinal fluid (intrathecal, endolumbar), the most complete utilization of the antiblastic agent is achieved, whereas with another systemic (intravenous, intramuscular, oral) administration, factors such as the biological blood-brain barrier and high dilution drug in plasma, binding to plasma proteins, deactivation in the liver and other tissues, prevent the penetration and creation of an effective concentration of repair in the brain. Increasing the doses of drugs during systemic exposure is limited to general toxic reactions. The presence of a biological blood-brain barrier allows avoiding the ingress of high doses of intrathecally administered chemotherapy drugs into the bloodstream and reducing the severity of general toxic complications. Thus, intrathecal administration is the most pathognomonic route in the treatment of brain metastases. The drug introduced by this method propagating through the cerebrospinal fluid to the resorption zone, both due to diffusion and due to respiratory vibrations of the cerebrospinal fluid, can penetrate into remote areas of the neoplasm, affecting the zone of its infiltrative growth. The most suitable and safe for intrathecal administration are methotrexate and cytosar (cytosine arabinoside). The restriction to the use of intrathecal methotrexate is an excess of the administered dose of more than 0.35 mg / kg due to the frequent development of acute cerebral edema and generalized seizures. A limitation to the use of intrathecal cytosar is the development of arachnoiditis in excess of a dose of 50 mg / m ² (1: 5 mg / kg body weight). The principle of limiting the use of such therapy is associated with adverse reactions and complications from the central nervous system (cerebral edema, convulsions, arachnoiditis) and general toxic reactions, which is explained by the penetration of sufficiently high doses of chemotherapy from the cerebrospinal fluid into the bloodstream due to the suppression of the protective functions of the cell system (cell depression) of the subarachnoid space - one of the components of the blood-brain barrier in the toxic and mechanical effects of the blastomatous process. But with methodologically correct preparation for the introduction of drugs, these complications can be reduced or avoided.

In the proposed method of treatment, the above preparations were used in megadoses (methotrexate 1.2-2.5 mg / kg body weight and cytosar 3-5 mg / kg body weight). For the prevention of acute cerebral edema, dehydration drug therapy was used in combination with intravenous administration of cerebrolysin for at least 7 days before intrathecal administration of drugs. Cerebrolysin increases the efficiency of aerobic energy metabolism of the brain, protects neurons from the damaging effects of lactic acidosis, prevents the formation of free radicals and reduces the concentration of lipid peroxidation products, increases survivability and prevents the death of neurons under conditions of hypoxia and ischemia, and reduces the damaging neurotoxic effect of excitatory amino acids (glutamate). For the same purpose, chemotherapy drugs were injected into the cerebrospinal bed in combination with hydrocortisone - 125 mg per administration. Hydrocortisone prevents or weakens vasogenic cerebral edema due to the stabilizing effect on the membranes of the endothelial cells of the cerebral vessels and the protective function of the cell system and, as a result, normalizes the permeability of the blood-brain barrier and prevents the penetration of osmotically active substances and water into the extracellular space. In addition, hydrocortisone, having a pronounced anti-inflammatory effect, prevents the development of reactive arachnoiditis on the introduction of chemotherapy.

To reduce the general toxic effect of megadose chemotherapy, along with traditional methods of drug detoxification, plasmapheresis was used using the PFM-800 plasma filter (Plazmofiltr CJSC, St. Petersburg) with 1-2 sessions with a break of 3 days, starting from 2 days after the administration of chemotherapy . During each session, up to 800 ml of plasma was removed. The advantage of using a plasma filter over discrete plasmapheresis methods was the better tolerance of this invasive method in this category of seriously ill patients due to minimal hemodynamic disturbances during simultaneous plasma sampling and replacement with an adequate dose of a plasma substitute. The use of plasmapheresis significantly reduced the frequency and severity of general toxic reactions. The percentage of complications was distributed as follows: I-II degree leukopenia - 40%, severe leukopenia and thrombocytopenia were not observed, stomatitis - 20%, liver and kidney function did not significantly suffer.

The proposed method of megadose chemotherapy is effective in most patients with brain metastases with various histiostructures of tumors at various stages of the tumor process.

Example. According to the proposed method, 24 patients with malignant diseases with brain metastases were treated (table).

The effect of treatment on the metastatic process is significant. A positive effect according to computed tomography (CT) or nuclear magnetic resonance imaging (NMR) of the brain was observed in 42% of patients. The stabilization of the process occurred in 42% of patients. Regression of neurological symptoms was observed in all patients with a positive effect and stabilization of the process. Lack of effect in 16% of patients (progression of symptoms and death).

The average survival rate reached 33 weeks in patients with a positive effect, 23 weeks with stabilization of the process, 5 weeks in patients who did not respond to treatment.

The effectiveness of the method was evaluated clinically (general condition of patients, regression of neurological symptoms, disappearance of tumor cells in the cerebrospinal fluid) and according to instrumental research methods: CT, brain MRI (table). Studies were performed before, one, three, and six months after the start of treatment.

The drugs were administered intrathecally (into the spinal canal) in the following dosages: cytosar from 3 to 5 mg / kg of the patient’s body weight, methotrexate from 1.2 to 2.5 mg / kg of the patient’s body weight for administration in combination with 125 mg of hydrocortisone. The drugs were administered three times with an interval of 7 days, and then once a month three times. Dehydration therapy (mannitol, low molecular weight dextrans, 40% glucose solution, diuretics, aminophylline, etc.) was prescribed 7-10 days before the administration of chemotherapy, intravenous drip infusion of cerebrolysin 10 ml, with convulsive readiness recorded on the EEG - finlepsin or other anticonvulsants. Premedication on the day of administration - dexamethasone 8 mg IM, antihistamines, according to indications - relanium intravenously. Evacuation of cerebrospinal fluid adequately administered intrathecal volume of drugs (5-15 ml with a significant (more than 10 ml) volume - in part). CSF intake for clinical and cytological studies. The introduction of estimated doses of drugs in a dilution of 1: 1 with water for injection.

The percentage of complications was calculated in a group of patients with stabilization of the process and a positive result of treatment:

a) stomatitis II-III severity was observed in 50% of patients. To prevent it, leucovorin was prescribed at 6 mg / m every 6 hours for 2-3 days.

b) leukopenia - in 70% of patients, normalization by an average of 40 days.

c) thrombocytopenia of Ill-IV degree - in 30% of patients, normalization by day 36.

These complications were stopped by the use of colony-stimulating factors and replacement transfusion of leukotrombomass.

Thus, this method of intrathecal administration of chemotherapy is quite satisfactorily tolerated by patients, immediate and long-term complications are stopped according to general principles by the appointment of appropriate symptomatic treatment.

Claims (3)

1. A method of treating metastatic brain lesions, including a chemotherapeutic effect with intrathecal administration of methotrexate and cytosar, characterized in that methotrexate is administered in the amount of 1.2-2.5 mg per 1 kg of the patient’s weight in combination with cytosar in the amount of 3 -5 mg per 1 kg of weight and hydrocortisone in an amount of 125 mg with preliminary brain dehydration and intravenous administration of cerebrolysin. 2. The method according to claim 1, characterized in that from the second day after the introduction of chemotherapy, 1-2 sessions of plasmapheresis are carried out. 3. The method according to claim 1, characterized in that the drugs are administered three times with an interval of 7 days, then 1 time per month three times.