A method for the treatment of metastatic brain lesions

 

(57) Abstract:

The invention relates to medicine, in particular to chemotherapy of metastatic brain lesions. The method includes intrathecal injection of methotrexate in the amount of 1.2-2.5 mg / kg of body weight of the patient in combination with Cytosar in the amount of 3-5 mg per kg of body weight and hydrocortisone in the amount of 125 mg with preliminary dehydration of the brain and intravenous administration of Cerebrolysin. From the second day after drug administration spend 1-2 sessions of plasmapheresis. Drugs injected three times with an interval of 7 days, a further 1 per month three times. The method allows to increase the effectiveness of the treatment by reducing toxic complications of chemotherapy. 2 C.p. f-crystals, 1 table.

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

The known method chemotherapeutic effects on the body when intrathecal administration of methotrexate in the amount of 0.25 mg per kg of body weight (Methodical recommendations on chemotherapy of malignant brain tumors. Approved by the Bureau of the Presidium of the scientific Medical Council of the Ministry of healthcare of the USSR on 27 October 1975, 12-13 C.).

The disadvantage of this method auseinet (intrathecal) injection of methotrexate (A. P. Romodanov, Y. A. Zozulya, Y. D. Sosnov. Metastatic brain tumors. - Kiev: Health, 1973, 172 S.).

The disadvantage of this method is its low efficiency. There is a method of treatment of neuroleukemia the intrathecal injection of methotrexate in a dose of 12.5 mg/m2(0.35 mg/kg of body weight) (Ed. by N. And.Perevozchikova Anticancer chemotherapy. Handbook, Moscow, 1996, 28 S.).

There is a method of treatment of lesions of the meninges with leukemia, intrathecal Cytosar in a dose of 30-50 mg/m2(1.5 mg/kg of body weight) one, two or three times a week (A. M. Garin, A. C. Chlenov. The practical Handbook of cancer chemotherapy, Moscow, 1995, 59 S.).

Known treatment of cancer metastasis and melanoma to the brain by the use of corticosteroid (A. P. Romodanov, Y. A. Zozulya, Y. D. Sosnov. Metastatic brain tumors. - Kiev: Health, 1973, 172 S.).

The disadvantage is their low efficiency.

Object of the invention is the expansion of a remission of tumor in the brain and increase longevity and improve the quality of life of patients.

The task is solved in that in the method of treatment of metastatic brain lesions, including chemotherapeutic effects osah of 1.2-2.5 mg/kg body weight in combination with Cytosar 3-5 mg/kg body weight and hydrocortisone in the amount of 125 mg.

The task is solved in that for the prevention of acute swelling of the brain and, as a consequence, convulsing with megadoses the introduction of methotrexate and Cytosar before the procedure is performed medicinal dehydration of brain with intravenous administration of Cerebrolysin.

The problem is solved also by the fact that to reduce General toxic effect from the 2nd day after drug administration spend 1-2 sessions of plasmapheresis.

The problem is solved also by the fact that drugs injected three times with an interval of 7 days, in the future, once a month three times.

Found that in the treatment of metastatic brain lesions introduction of chemotherapy in liquoroso direction (intrathecal, endolyumbalno) is the most complete utilization of antibioticheskih agent, while another systemic (intravenous, intramuscular, oral) introduction factors such as biological blood-brain barrier, high dilution of the drug in plasma, plasma protein binding, deactivation in the liver and other tissues, prevent the penetration and establishment of effective drug concentrations in the brain. Increasing doses of drugs for systemic exposure is limited to General toxic Rea is alcalino injected chemicals into the blood stream and reduce the severity of General toxic complications. Thus, intrathecal is most pathognomonic by treatment of metastases in the brain. The drug is introduced in this way spreading the cerebral spinal fluid to the zone of resorption as effective diffusion and through the respiratory fluctuations of the cerebrospinal fluid can penetrate into remote areas of the tumor, affecting the area of infiltrative growth. The most suitable and safe for intrathecal injection are medications methotrexate and Cytosar (cytosine arabinoside). A limitation to the use of intrathecal methotrexate is the excess of the injected dose of 0.35 mg/kg in connection with the frequent development of acute brain swelling and generalized seizures. A limitation to the use of intrathecal Cytosar is the development of arachnoiditis when the dose of 50 mg/m2(1:5 mg/kg of body weight). The principle limitations to the use of such therapy is associated with adverse reactions and complications as with Central nervous system (brain swelling, seizures, arachnoiditis), and General toxic reactions, which is explained by the penetration of sufficiently high doses of chemotherapeutic drugs from the CSF into the blood stream due to suppression of the protective functions of the system of cells (depression mesh) subarachnoidal the m exposure blastomycosis process. But at methodically the correct preparations for the introduction of drugs can reduce or avoid these complications.

In the proposed method of treatment was applied to the above drugs in megadose (methotrexate 1,2-2.5 mg/kg of body weight and Cytosar 3-5 mg/kg of body weight). For the prevention of acute swelling of the brain used dehydration drug therapy in combination with intravenous administration of Cerebrolysin for at least 7 days before intrathecal injection. Cerebrolysin improves 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 products of lipid peroxidation, increases berievement and prevent the death of neurons during hypoxia and ischemia, reduces the damaging neurotoxic effects of excitatory amino acids (glutamate). For the same purpose the chemicals were introduced in liquoroso direction in combination with hydrocortisone - 125 mg. Hydrocortisone prevents or weakens vasogenic brain swelling due to a stabilizing effect on membranes of endothelial cells of blood vessels of the brain and the protective function of cells and, as a consequence, the s chemicals and water in the extracellular space. In addition, hydrocortisone, with a pronounced anti-inflammatory effect, prevents the development of reactive arachnoiditis on the introduction of chemotherapy.

To reduce the General toxic effect of the ongoing megadoses chemotherapy along with traditional methods of drug detox used plasmapheresis using plasma filter-800 ("Plasmofilter", s-Petersburg) with the conduct of 1 or 2 sessions with an interval of 3 days, starting 2 days after drug administration. When conducting each session was removed and 800 ml of plasma. The advantage of using a plasma filter in front of discrete methods plasmapheresis was better portability of this invasive method in this category is seriously ill in connection with minimal hemodynamic changes during a single-step intake and plasma substitution adequate dose of plasma substitute. The use of plasmapheresis significantly reduce the frequency and severity of General toxic reactions. The percentage of complications was as follows: grade I-II degree - 40%, severe leukopenia and thrombocytopenia were not nablyudalis, stomatitis - 20%, liver and kidney were not significantly affected.

The proposed method megadoses hee is Olga at different stages of the neoplastic process.

Example. The proposed method was treated 24 patients with malignant disease with metastases to the brain (table).

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

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

The efficiency of the method was evaluated clinically (General condition of patients, regression of neurological symptoms, disappearance of tumor cells in the cerebrospinal fluid) and the instrumental investigations: CT scan, MRI brain (table). The research was carried out before and after one, three and six months after the start of treatment.

The drugs were intrathecally (into the spinal canal) in the following dirofilaria with 125 mg of hydrocortisone. The drugs were injected three times with an interval of 7 days, and thereafter once a month three times. 7-10 days prior to drug administration were appointed dehydration therapy (mannitol, low molecular weight dextrans, 40% glucose solution, diuretics, aminophylline, and others),/drip infusions of Cerebrolysin 10 ml, when recorded on EEG convulsive readiness - Finlepsin or other anti-convulsants. Premedication on the day of introduction - dexamethasone 8 mg/m, antihistamines, according to testimony - Relanium intravenously. The evacuation of the liquor adequately injected intrathecally volume of drugs (5-15 ml with significant (>10 ml) volume - partial). The intake of liquor for clinical and cytological study. Introduction the calculation of drug doses in a dilution of 1:1 with water for injection.

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

a) stomatitis II-III severity was observed in 50% of patients. His warning was administered leucovorin for 6 mg/m every 6 hours for 2-3 days.

b) leukopenia - 70% of the patients, normalization to an average of 40 days.

C) thrombocytopenia Ill-IV degree - 30% of patients, normalnym transfusion of leukotrienes.

Thus, this method intrathecal drug administration quite satisfactorily tolerated, short-and long-term complications are avoided on General principles with appropriate symptomatic treatment.

1. A method for the treatment of metastatic brain lesions, including chemotherapeutic effects following intrathecal administration of methotrexate and Cytosar, characterized in that the spinal canal is injected methotrexate in the amount of 1.2-2.5 mg per 1 kg of patient's weight in combination with Cytosar in the amount of 3-5 mg per 1 kg of weight and hydrocortisone in the amount of 125 mg with preliminary dehydration of the brain and intravenous administration of Cerebrolysin.

2. The method according to p. 1, characterized in that from the second day after drug administration spend 1-2 sessions of plasmapheresis.

3. The method according to p. 1, characterized in that the drugs injected three times with an interval of 7 days, a further 1 per month three times.

 

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