A method of treatment of gliomas with epileptic syndrome

 

(57) Abstract:

The invention relates to medicine, namely to Oncology and neurosurgery. After removal of the tumor within 5-10 days the patient orally administered Riboxin 0.2 g 3 times a day. Radiation therapy is begun simultaneously with chemotherapy, carrying her to a total dose of 42-54 Gr on the background of intravenous and then oral administration of Riboxin and proxiphen. Riboxin intravenously injected 10 ml in the first 2 weeks, then oral administration of 0.2 g 3 times a day for up to three months. PROXIFIER impose on the scheme: 2 days 0.25 g 1 time 2 days - 0.25 g 2 times and then 0.25 g 3 times within 40-50 days. Chemotherapy repeated every 4-5 weeks. As anticonvulsants administered benzonal 0.1 g or Finlepsin 0.2 g 3 times a day during the first two weeks and then 2 times a day until the end of chemotherapy and then 1 tablet for the night at least 2-3 years. The method allows to increase the effectiveness of the treatment.

The invention relates to medicine, more specifically to Oncology, and can find application in the treatment of malignant tumors.

Treatment of brain tumors is one of the difficult problems of neurosurgery. The most effective method is chaga. As for gliomas with epileptic syndrome, in which the occurrence of seizures is often early and the only manifestation of tumors, it is misleading clinicians who have long used to cure anticonvulsants about the proposed epilepsy traumatic or inflammatory etiology. In this regard, the tumor is diagnosed late, attains a large size and radical removal it often becomes impossible. Therefore, in the postoperative period exercise combined treatment using anticancer drugs, radiation and immunostimulating therapy. Very important in the treatment of gliomas is the elimination of seizures, which, according to various authors, is stored in the postoperative period in 37.8 - 90% of cases and largely invaliditetom patients. Mortality from brain tumors is very high. The life expectancy in malignant gliomas average of 10 months, in benign - 2.6.

Closest to the proposed is a Method of treatment of gliomas with epileptic syndrome" [Handbook for physicians, Ministry of health of the Russian Federation, Russian research Arminianism the treatment of gliomas, includes surgical removal of the tumor with the internal decompression and subsequent realization of chemotherapy, radiation and anticonvulsant therapy.

During the surgical intervention is performed, as a rule, not only the delimitation of gliomas, the maximum possible destruction of tumor tissue, but also define the boundaries of the epileptic focus with subsequent Subtelny suction crust or remove a lesion along with the tumor. More complete, and in some cases, radical removal of the tumor is possible in the localization his pole in the frontal or temporal lobes, occipital lobes of the brain. In these cases, is resection of the epileptic zone of these shares, together with the tumor. During germination of gliomas in the bark may only partial (25-75% by volume) removal of the tumor. In postoperative patients is combined treatment. Start it on a 4-12 days after surgery with the purpose of anticancer drug proxiphen - domestic highly cytotoxic and radio-sensitizing tools.

PROXIFIER--dimethylaminopropylamine ether 8-oxycodeine [ed.St. N 209464 from 2.11.67, and N 1826184 from 20.07.90,] has a high selectivity of protiva the Ute with intravenous injection of 10 ml of 5% solution, divorced isotonic solution of sodium chloride at the rate of 1 g proxiphen to 1000 ml of fluid injected slowly, drip, within 2-3 hours of 1 times a day for 10 days under the scheme: in the first 2 days, the dose of proxiphen 0.5 g, then every 2 days, increase the dose by 0.25 g to 1.5 g per 9 and 10 days. From the third day from the start of treatment additionally assign PROXIFIER oral tablets according to the scheme: 1 to 5 days 0.25 g 4 times a day, from 6 th to 10-th day - to 0.5 g 4 times a day, from 11 th to 16-th day - 1 g 4 times a day. 16-day conduct radiation therapy to a total dose of 50-70 Gy treatment (depending on the condition of the patient a course of radiation therapy is often necessary to make a 2 stage), before the end of radiation treatment is given to proxiphen 0.5 g 3 times a day, for up to 40 days. Throughout the course of treatment is given 10 g of proxiphen in the form of injections and 100-120 g inside. During chemo - and radiation therapy, the patient prescribed drugs potassium (Panangin, asparkam, potassium orotate), sedative and immunostimulirutuyu therapy with levamisole. Given the fact that after removal of the tumor with an epileptic focus does not exclude the continuation of the paroxysms, conduct anticonvulsant therapy in optimal doses analogous to treating the epila is recorded seizures), cancel anticonvulsant treatment is carried out slowly, with gradual dose reduction during the month under the control of the EEG. Of anticonvulsants used benzonal, phenytoin, Finlepsin, etc.

Such treatment, as noted by the authors, allows to increase the average life expectancy of up to 1 year and 6 months. patients with glioblastomas and up to 3-4 years with astrocytomas, oligodendrogliomas), and to eliminate epileptic syndrome in the postoperative period in 62% of patients, and the rest - to reduce the number of seizures.

However, this chemo treatment is poorly tolerated by patients. This is due, primarily, with radial swelling of the brain and thus increases seizure activity that, despite increasing doses of anticonvulsants, often requires the division of radiation therapy in 2 stages. In addition, in the method prototype using large meals a day (up to 4 g) and exchange rate (110-130 g) dose of proxiphen that, despite its relatively low toxicity, affects the quality of life of patients.

The technical result of the present invention is to improve the quality of life of patients by reducing doses of proxiphen, protevoepilepticeski syndrome, includes surgical removal of the tumor, chemotherapy by intravenous and oral administration of proxiphen, as well as radiation and anticonvulsant therapy, within 5-10 days after removal of the tumor the patient orally administered Riboxin 0.2 g 3 times a day, radiation therapy is begun simultaneously with chemotherapy, carrying her to a total dose of 42-54 Gr on the background of intravenous and then oral administration of Riboxin and proxiphen, and Riboxin intravenously injected 10 ml in the first 2 weeks, orally 0.2 g 3 times a day up to 3 months., and by oral administration of proxiphen it is given according to the scheme: 2 days 0.25 g 1 time, 2 days - 0.25 g 2 times and then 0.25 g 3 times a day for 40-50 days, and such chemotherapy repeated every 4-5 weeks, and anticonvulsants administered orally 1 tab. 3 times within the first two weeks, then 1 tab. 2 times before the end of chemotherapy and then 1 tab. 1 time at night at least 2-3 years.

Doing for many years the treatment of malignant tumors, we were constantly looking for tools to help the condition of patients during chemotherapy and radiation warning complications.

Given that radiation damages the genetic characters of the and lung was used medication Riboxin, widely used in medical practice, especially in cardiology. This natural compound is a precursor of ATP, is actively involved in the biosynthesis of a number of nucleotides and modifies some biochemical and physiological processes. It is highly likely that the ability of Riboxin to interfere with the metabolism of cyclic nucleotides explains the radioprotective effect of the drug, we observed in the experiment when fractionated and single exposure.

This fact has motivated us to introduce Riboxin in the treatment of malignant brain tumors. As shown by our experience in the treatment of patients with gliomas, using Riboxin allowed to reduce the dose of antiepileptic drugs (possibly by reducing the radial swelling) and radiotherapy without interruption and at the same time with chemotherapy, which increases the effectiveness of the treatment.

The use of lower doses of proxiphen (50 g per course against 110-130 g at the traditional use of proxiphen) significantly reduces the overall toxic effect on the body, improving the quality of life of patients both during treatment and in remission.

The use of a lower total dose of radiology is m we consider what we have developed a scheme chemoradiation therapy is a very gentle, easily tolerated and contributes to a better tolerance of subsequent treatment.

The essence of the method is illustrated by examples.

Example 1.

Patient F. , 1957 R. (and/b N 1243), was admitted to the hospital, cnerry 02.09.99 was diagnosed with a brain tumor (right frontal and parietal lobes) with epileptic syndrome. From the anamnesis it is known that she has been ill since January 1999, when he first developed an epileptic fit. Conducted clinical and radiological examination in neurosurgical Institute. Professor A. L. Polenov revealed a tumor of the right hemisphere of the brain.

24.03.99 was done osteoplastic craniotomy with partial removal of the tumor. Histologically - anaplastic astrocytoma (3rd grade). The postoperative period was uneventful. The frequency of epileptic seizures decreased to one in 4-5 days. Patient recommended taking 3 tablets of benzonal per day. For further treatment the patient is sent to cnerry.

When entering cnerry 16.04.99 (and/b N 698): overall state is relatively satisfactory, the Karnofsky index of 70 points in renalka epileptic syndrome (short-term shutdown of consciousness without convulsions component). The patient received 3 tablets of benzonal per day. According to the results of the survey (brain MRI from 23.04.99) diagnosed with the condition after partial removal of a brain tumor, the size of the formation 4.1x3.5 cm with cysts and perifocal edema. According to EEG from 22.04.99 the presence of a hearth convulsive readiness in the right fronto-parietal region.

In the period from 26.04.99 on 24.05.99 the patient was conducted chemotherapeutic treatment PROXIFIER under the traditional scheme: intravenous administration of 10 ml of a 5% solution of proxiphen diluted in isotonic sodium chloride (1 g proxiphen to 1000 ml of fluid), slow drip, within 2-3 hours of 1 times a day for 10 days, with the first 2 days, the dose of proxiphen was 0.5 g, then every 2 days, the dose was increased by 0.25 g to 1.5 g of the 9-th and 10-th day. From the third day from the beginning of treatment, in addition to intravenous, PROXIFIER is administered orally in tablets according to the scheme: 1 to 5 days 0.25 g 4 times a day, from 6 th to 10 th days, 0.5 g (2 PL.) 4 times a day, from 11 th to 16-th day - 1 g (4 PL. ) 4 times a day. Further PROXIFIER were given 0.5 g 3 times a day.

During treatment there was a marked deterioration bolnore meal vomiting, unstable blood pressure rises up to 150/100 mm RT.cent.). Frequent epileptic seizures was recorded every 2 days, and therefore was increased dose of benzonal - up to 4 tablets per day, strengthened dehydration therapy.

24.05.99 patient was discharged in satisfactory condition under the supervision of a neurosurgeon, neurologist, oncologist at the place of residence with the recommendation to continue taking proxiphen 0.5 g (2 PL.) 3 times a day to a total dose of 100 g

On outpatient reception 12.07.99 the patient's condition remained relatively satisfactory, remained mild left hemiparesis and seizures to 1 times in 6-7 days despite a daily intake of benzonal. According to brain MRI (13.07.99) the size of the lesion was 3.5 x 2.5 cm, EEG (from 12.07.99) - center of seizure activity in the right fronto-parietal region. The patient offered continued treatment in cnerry in September 1999

When entering the clinic cnerry 02.09.99, the patient's condition is satisfactory; left-sided hemiparesis with preservation of epileptic seizures to 1 times in 5-6 days. Anticonvulsants (benzonal) regularly takes up to 3 tablets per day.

With 02.09.99 on 07.09.99 patient received Riboxin in tablets 0,2 g (table 1). 3 times a day and benzonal 0.3 g per day (3 PL.). With 08.09.99 Riboxin was injected intravenously 10 ml introduction daily for 10 days and simultaneously PROXIFIER scheme: 8-9 September drip 10 ml of a 5% solution of proxiphen, diluted with saline, 500 ml, 10-11 September 15 ml of 5% solution of proxiphen, diluted with saline to 750 ml, intravenous drip and 0.25 g of 1 times a day, orally, 13-14 September 20 ml of 5% solution of proxiphen in 1000 ml of saline intravenously and 0.25 g 2 times a day orally, 15-16 September 25 ml and 17-18 September 30 ml of 5% solution of proxiphen in 2000 ml of saline intravenously and from 15 to 18 September additional 0.25 mg proxiphen 3 times a day orally, and then during the entire course of treatment daily 0.25 mg proxiphen 3 times a day.

With 08.09.99 on 06.10.99 simultaneously radiotherapy was performed on the device "Rocus-M" with one field 5x6 cm in a dose of 2 Gy to a total dose of 42 Gy, i.e., exercised against the background of the introduction of proxiphen, and the rib is up to 3 months.

During chemoradiation treatment the patient additionally had gotten through the day lasix (diuretic), daily Panangin (on 1 tab. 3 times) and benzonal.

The patient's condition during treatment remained satisfactory, the number of epileptic seizures has not increased under the control of EEG is possible to reduce the reception of benzonal with 22.09.99 up to 2 pills a day.

At discharge the patient from the clinic 08.10.99,: satisfactory condition, blood tests, ECG, ultrasound of the abdomen - without features. According to the results of EEG, seizure focus outside activity. Patient assigned to oral intake: 3 months Riboxin 0.2 g 3 times a day and 1.5 months. - PROXIFIER 0.25 g 3 times a day (up to a total dose of 40 g) and benzonal 1 tab. 2 times a day, and then benzonal to constantly take 1 tab. on the night. Contact the Institute at the beginning of December for a follow-up visit.

On admission to the clinic, cnerry 06.12.99:

The condition is satisfactory, easy left-side hemiparesis, serving themselves, the Karnofsky index 90 points. The epileptic seizures were observed. Take 1 tablet of benzonal at night. Brain MRI (02.12.99) - the size of the lesion 1.5x1.0 cm (volume reduction), EEG (from 06.12.99) - diffuse change is, The ZI abdomen - without features. The ophthalmologist, ENT doctor, therapist revealed no pathology.

Conclusion: stabilization of the tumor process. The turnout in cnerry a month to continue chemotherapy treatment.

On admission the patient 20.12.99 (4 weeks after receiving proxiphen): satisfactory condition, epileptic seizures after the last treatment were observed.

To prevent further growth of the tumor, the patient was prescribed a course of chemotherapy through proxiphen scheme of the previous treatment, i.e., holding it against Riboxin and benzonal dose for the first two weeks were 3 tables. and was gradually reduced to 2 PL. a day under the control of the EEG.

10.01.2000, the patient is in satisfactory condition he was discharged with the recommendation to take PROXIFIER 0.25 g 3 times a day up to a total dose of 50 g on the background Riboxin (0.2 g 3 times a day) and benzonal (1 tab. 2 times a day). During this treatment the patient received 60 g proxiphen (10 g intravenously and 50 g oral).

At the control examination in March 2000:

Data brain MRI from 10.03.00, - signs of continued growth of the tumor is not identified, EEG - the ship is taken on persistent remission.

Example 2.

Patient T., 1955 R. (history N 356), was admitted to the hospital, cnerry 16.02.99 was diagnosed with a brain tumor (right frontal lobe) with epileptic syndrome. Condition after osteoplastic craniotomy. From the anamnesis it is known that he was sick during the year. Notes the deterioration of the General condition, frequent headaches, in November 1998, the first local cramps in his left hand. In January 1999, generalized epileptic seizure with loss of consciousness, the patient admitted to the neurology Department of the hospital N 2, where clinical and radiological examination (CT scan brain, EEG, cerebral angiography, neurologist, ophthalmologist, neurosurgeon) showed a mass process right frontal lobe. 25.01.99 was done osteoplastic craniotomy in the right frontal region with partial removal of the tumor. Histologically - glioblastoma (4 grade). For relief of epileptic seizures the patient is assigned Finlepsin.

For further treatment the patient sent to cnerry.

When entering the clinic cnerry 16.02.99 was:

A state of moderate severity, epileptic seizures in the form of convulsive sacramenti (1/2 - morning and afternoon and 1 at night) - the frequency of attacks decreased, changed the nature of their prior lung muscle contractions in the hand and leg. According to the results of brain MRI signs Subtotal removal of the tumor, the zone of accumulation of contrast medium was 2.5 x 3.0 x 1.6 see EEG - denominated diffuse changes, localized in the right frontal lobe, the focus of epileptic activity in this area, increasing the functional loads.

With 17.02.99 the patient received Finlepsin in table 2. on the day, Riboxin oral 0.2 g 3 times a day, then intravenous Riboxin and PROXIFIER with gradual transition to further oral administration of their scheme analogously to example 1. There was a radiation therapy apparatus Rocus-M". Single focal dose was 2 Gy total - 54 Gr.

The course of treatment the patient satisfactorily, increasing neurological symptoms were observed, epileptic seizures was not. Under the control of the EEG dose finlepsina was first reduced to 1.5 tablets (1/2 in the morning and 1 at night) in the night.

05.04.99, the patient was discharged in satisfactory condition with pronounced positive dynamics. Recommended to continue taking proxiphen the mA proxiphen, then gradually reduce to 1 table. on the night.

Control tests at cnerry 10.05.99 was:

MRI brain with contrast substance - signs Subtotal removal of the tumor from the right frontal lobe, liquor cyst 1,5x1,2x1,0 cm, the accumulation of contrast agent along the periphery (in a significant reduction in tumor size). The shift of median structures is not observed. EEG expressed diffuse changes in the right frontal lobe epileptic focus is determined at functional load, alone outside activity. Analyses of blood, urine, ECG, abdominal ultrasound revealed no pathology. The patient's condition is satisfactory, contact, oriented environment and time, neurologically determined light pyramidal insufficiency on the left. Epileptic seizures were observed, takes Finlepsin 1 tab. on the night. The patient works as najomnica (knitting), work very well. Given these clinical and radiological examination, assigned to repeat the course of proxiphen with 31.05.99,

When re-hospitalization patient 31.05.99) underwent chemotherapy (5 weeks after the first dose of proxiphen) according to the same scheme on the background Riboxin and finlepsina.

Control tests in the hospital 06.09.99 was:

MRI brain - tumor size 1.H.7x0.5 cm, EEG seizure focus outside activity (take 1 table. finlepsina at night), other data - ultrasound, blood tests, inspections specialists showed that patients show a stabilization process. The patient was discharged with the recommendation to conduct a similar course of proxiphen outpatient setting under the supervision of a neurosurgeon and a radiation oncologist at the place of residence.

14.03.2000, the follow-up inspection in cnerry health of the patient is satisfactory, according to MRI tumor formation 0.7x0.H.5 cm for EEG seizure focus outside activity. The patient is in remission for more than 1 year.

To date, the proposed method, the treatment of 16 patients with brain tumors (anaplastic astrocytomas and grade 2-3, glioblastoma - 4 grade) with epileptic syndrome. All patients had satisfactorily undergone the course of treatment, all are currently in remission. Since the proposed method uses only since February 1999, about how long it is premature. Can only say that patients Otechestvennye the proposed method of treatment has several advantages.

1. The decrease in the total toxic effect due to a significant reduction in total dose of proxiphen (for treatment 50 g), while in fashion prototype she is 110 - 130, It improves the quality of life of patients both during treatment and in remission.

2. The radiation dose should be decreased to 42 - 54 Gy in comparison with the total dose in the prototype, component 56-70 Gr, as well as reducing the total dose of proxiphen favorably affects patients and contributes to a better tolerance of subsequent treatment.

3. Reduction of term inpatient treatment for up to 40 days during chemo treatment, while in the prototype it takes about 2 months.

The method developed in the Department of radiation treatment of cancer of cnerry health Ministry and to the present time was clinically tested in 16 patients with a positive result.

A method of treatment of gliomas with epileptic syndrome, including surgical removal of the tumor, chemotherapy by intravenous and oral administration of proxiphen, as well as radiation and anticonvulsant therapy, characterized in that within 5 to 10 days after removal of the tumor the patient oral wodarski dose 42 - 54 Gy in the background of intravenous and then oral administration of Riboxin and proxiphen, and Riboxin intravenously injected 10 ml in the first 2 weeks, oral 0.2 g 3 times a day for up to 3 months, and oral introduction of proxiphen it is given according to the scheme: 2 days 0.25 g for 1 time, 2 days 0.25 g 2 times and then 0.25 g 3 times a day for 40 to 50 days and such chemotherapy performed after 4 to 5 weeks anticonvulsant medications administered in an ever-decreasing the dose until the end of chemotherapy and continuing for 2 to 3 years on night 1 tablet, for example benzene or finlepsina.

 

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