RU2166948C1 - Method for treating gliomae aggravated with epileptic syndrome - Google Patents

Abstract

FIELD: medicine. SUBSTANCE: method involves per os administering riboxin to a patient at a dose of 0.2 g 3 times a day after removing tumor during 5-10 days. Radiation therapy is started at the same time with chemotherapy and brought to total dose of 42-54 Gr on the background of intravenous administration and later on per os administration of riboxin and proxiphein. Riboxin is intravenously injected at a dose of 10 ml during the first two weeks and then per os at a dose of 0.2 g three times a day up to 3 months long. Proxiphein is administered according to the following scheme. 2 days the dose is 0.25 g once a day, two days 0.25 g twice a day, and then, the dose is 0.25 g three times a day during 40-45 days. Chemotherapy course is repeated 4-5 weeks later. Benzonal is applied as anticonvulsive preparation at a dose of 0.1 g or finlepsin at a dose of 0.2 g 3 times a day during the first two weeks and then two times a day to the end of the chemotherapy course and later at a dose of 1 tablet before going to bed not less than 2-3 years long. EFFECT: enhanced effectiveness of treatment.

Description

 The invention relates to medicine, more specifically to oncology, and may find application in the treatment of malignant neoplasms.

 The treatment of brain tumors is one of the complex problems of neurosurgery. The most effective treatment for them is surgical, especially in cases where radical removal of the tumor focus is possible. As for gliomas with epileptic syndrome, in which the appearance of seizures is often the earliest and only manifestation of a neoplasm, this misleads the clinicians who treat patients with anticonvulsants for a long time about the alleged epilepsy of a traumatic or inflammatory etiology. In this regard, the tumor is diagnosed late, reaches large sizes and its radical removal most often becomes impossible. Therefore, in the postoperative period, combined treatment is carried out using antitumor drugs, radiation and immunostimulating therapy. Extremely important in the treatment of gliomas is the elimination of convulsive syndrome, which, according to various authors, persists in the postoperative period in 37.8 - 90% of cases and significantly disables patients. Mortality from brain tumors is very high. Life expectancy for malignant gliomas is on average 10 months, for benign - 2.6 years.

 Closest to the proposed is the "Method for the treatment of gliomas with epileptic syndrome" [Manual for doctors, Ministry of Health of the Russian Federation, Russian Research Institute of Neurosurgery named after A.L. Polenova, St. Petersburg, 1997], taken by us as a prototype. The method consists in the combined treatment of gliomas, including surgical removal of the tumor with internal decompression and subsequent chemo, radiation and anticonvulsant therapy.

 During the surgical intervention, as a rule, not only the clarification of the boundaries of the glioma, the possible maximum removal of the tumor tissue is carried out, but also the boundaries of the epileptic focus are determined, followed by subcial suction of the cortex or removal of the focus along with the tumor. A more complete, and in some cases a radical removal of the neoplasm is possible with its localization in the pole of the frontal or temporal, occipital lobe of the brain. In these cases, the epileptic zone of the indicated lobes is resected together with the tumor. When gliomas germinate in the cortex, only partial (25-75% of the volume) removal of the neoplasm is possible. In the postoperative period, patients undergo combination treatment. They begin it on the 4-12th day after the operation with the appointment of the antitumor drug proxyphein - a domestic highly effective cytostatic and radiosensitizing agent.

 Proxyphein-γ-dimethylaminopropyl ether of 8-hydroxycaffeine [auth. N 209464 from 2.11.67, and N 1826184 from 07.20.90] has a high selectivity of antitumor action, easily penetrates the blood-brain barrier, low toxicity. Its use begins with the intravenous administration of 10 ml of a 5% solution, diluted with an isotonic sodium chloride solution at the rate of 1 g of proxyfein per 1000 ml of liquid, administered slowly, dropwise, for 2-3 hours, 1 time per day for 10 days according to the scheme: the first 2 days, the dose of proxyphein 0.5 g, then every next 2 days the dose is increased by 0.25 g to 1.5 g on 9 and 10 days. From the third day from the start of treatment, proxyfein is additionally prescribed orally in tablets according to the scheme: from the 1st to the 5th days, 0.25 g 4 times a day, from the 6th to 10th days - 0.5 g 4 times a day, from the 11th to the 16th days - 1 g 4 times a day. From the 16th day, radiation therapy is carried out up to a total dose of 50-70 Gy per treatment course (depending on the patient’s condition, the course of radiation therapy often has to be carried out in 2 stages), before the end of radiation treatment, proxyfine 0.5 g 3 times a day is given, 40 days. In total, 10 g of proxyphein in the form of injections and 100-120 g orally are given for the course of treatment. During chemotherapy and radiation therapy, the patient is prescribed potassium preparations (panangin, aspartame, potassium orotate), sedative and immunostimulating therapy with levamisole. Given the fact that after the removal of a tumor with an epileptic focus, the continuation of paroxysms is not excluded, anticonvulsant therapy is carried out in optimal doses similar to the treatment of epilepsy of another etiology. Anticonvulsant therapy is carried out continuously and for a long time (at least 2-2.5 years after the cessation of seizures), anticonvulsant treatment is canceled slowly, with a gradual decrease in dose over a month under the control of EEG. Of the anticonvulsants, benzonal, diphenin, finlepsin, etc. are used.

 Such treatment, as the authors note, can increase the average life expectancy up to 1 year 6 months. in patients with glioblastomas and up to 3-4 years with astrocytomas, oligodendrogliomas, as well as eliminate epileptic syndrome in the postoperative period in 62% of patients, and in the rest - dramatically reduce the number of paroxysms.

 However, such chemoradiotherapy is difficult for patients to tolerate. This is primarily due to radiation edema of the brain and, accordingly, an increase in convulsive activity, which, despite an increase in the dose of anticonvulsants, often requires the separation of radiation therapy into 2 stages. In addition, in the prototype method, large single (up to 4 g) and course (110-130 g) doses of proxyphein are used, which, despite its relatively low toxicity, adversely 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 proxyphein, antiepileptic drugs and radiation exposure.

 This result is achieved by the fact that in the treatment of gliomas with epileptic syndrome, including surgical removal of the tumor, chemotherapy via intravenous and oral administration of proxyphein, as well as radiation and anticonvulsant therapy, 0.2 g of oral riboxin is administered to the patient for 5-10 days after removal of the tumor once a day, radiation therapy is started simultaneously with chemotherapy, carrying out it up to a total dose of 42-54 Gy on the background of intravenous and then oral administration of riboxin and proxyphein, with riboxin inside 10 ml are administered orally in the first 2 weeks, 0.2 g orally 3 times a day for up to 3 months, and when proxyfein is orally administered, 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 is repeated after 4-5 weeks, and anticonvulsant drugs are administered orally 1 tablet. 3 times during the first two weeks, then 1 table. 2 times before the end of the course of chemotherapy and then 1 table. 1 time at night for at least 2-3 years.

 Having been engaged in the treatment of malignant tumors for many years, we were constantly looking for means to alleviate the condition of patients during chemoradiotherapy, as well as preventing radiation complications.

 Considering that radiation exposure damages the genetic apparatus of the cell and reduces reparative processes, we previously used the drug riboxin, which is widely used in medical practice, especially in cardiology, during radiation therapy of lymphogranulomatosis and lung cancer. This natural compound is the precursor of ATP, takes an active part in the biosynthesis of a number of nucleotides and, due to this, modifies some biochemical and physiological processes. It is very likely that the ability of riboxin to interfere with the exchange of cyclic nucleotides explains the radioprotective effect of the drug, which we noted in the experiment with both fractionated and single exposure.

 This fact prompted us to introduce riboxin into the treatment regimen for malignant brain tumors. As our experience in the treatment of patients with gliomas showed, the use of riboxin allowed us to reduce the dose of antiepileptic drugs (possibly due to a decrease in radiation edema) and carry out radiation therapy without interruption and simultaneously with chemotherapy, which increases the effectiveness of treatment.

 The use of lower doses of proxyphein (50 g per course versus 110-130 g with the traditional use of proxyphein) 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 radiation exposure (42-54 Gy versus 50-70 Gy) helps to prevent radiation complications.

 In this regard, we believe that the chemoradiotherapy regimen we developed is very gentle, easily tolerated by patients, and contributes to better tolerability of subsequent treatment.

 The essence of the method is illustrated by examples.

 Example 1

 Patient F., born in 1957 (and / b N 1243), was admitted to the Central Research Institute of Radiotherapy, 02.09.99, with a diagnosis of a brain tumor (right frontal and parietal lobe) with epileptic syndrome. From the anamnesis it is known that it has been sick since January 1999, when an epileptic seizure first developed. Clinical and radiological examination at the Neurosurgical Institute. prof. A.L. Polenova revealed a tumor in the right hemisphere of the brain.

 March 24, 1999 was performed osteoplastic trepanation of the skull with partial removal of the tumor. Histologically - anaplastic astrocytoma (3rd degree of malignancy). The postoperative period was uneventful. The frequency of epileptic seizures decreased to one in 4-5 days. The patient is recommended to take 3 tablets of benzonal daily. To continue treatment, the patient was sent to TsNIRRI.

 Upon admission to TsNIRRI 04/16/99 (and / b N 698): general condition is relatively satisfactory, Karnovsky index of 70 points, moderate left-side hemiparesis, self-serving himself with difficulty, needed the help of others. Epileptic syndrome persisted (short-term blackouts without a convulsive component). The patient received 3 benzonal tablets per day. According to the results of the survey (MRI of the brain dated 04/23/99), the diagnosis was established: the condition after partial removal of a brain tumor, the size of the formation was 4.1x3.5 cm with cysts and perifocal edema. According to the EEG from 04/22/99 the presence of a focus of convulsive readiness in the right frontoparietal region.

 In the period from April 26, 1999 to May 24, 1999, the patient was given chemotherapeutic treatment with proxyphein according to the traditional scheme: intravenous administration of 10 ml of a 5% solution of proxyphein diluted in isotonic sodium chloride solution (at the rate of 1 g of proxyphein per 1000 ml of liquid), slowly , drip, for 2-3 hours 1 time per day for 10 days, moreover, in the first 2 days the dose of proxyfein was 0.5 g, then every subsequent 2 days the dose was increased by 0.25 g to 1.5 g on the 9th and 10th day. From the third day from the start of treatment, in addition to intravenous administration, proxyfein was administered orally in tablets according to the scheme: from the 1st to the 5th days, 0.25 g 4 times a day, from the 6th to the 10th days - 0.5 g ( 2 tablets) 4 times a day, from the 11th to the 16th days - 1 g (4 tablets) 4 times a day. Subsequently, proxyfein was given 0.5 g 3 times a day.

 During treatment, a deterioration of the patient's condition was noted in the form of an increase in hypertension-hydrocephalic syndrome (increased headaches, nausea not associated with eating, vomiting, instability of blood pressure - rises to 150/100 mm Hg). Epipristes became more frequent - they were noted every 2 days, in connection with which the dose of benzonal was increased - up to 4 tablets per day, dehydration therapy was strengthened.

 On May 24, 1999, the patient was discharged in a relatively satisfactory condition under the supervision of a neurosurgeon, neurologist, and oncologist at the place of residence with a recommendation to continue taking proxyphein 0.5 g (2 tablets) 3 times a day until the total dose of 100 g.

 At the outpatient appointment on July 12, 1999, the patient's condition remained relatively satisfactory, mild left-side hemiparesis, as well as epileptic seizures, continued up to 1 time in 6-7 days despite daily benzonal administration. According to brain MRI (from 13.07.99), the size of the tumor lesion was 3.5 x 2.5 cm, EEG (from 12.07.99) was the focus of convulsive activity in the right frontoparietal region. The patient was offered to continue treatment at TsNIRRI in September 1999.

 Upon admission to the clinic TsNIRRI 02.09.99, the patient's condition is relatively satisfactory; left-side hemiparesis with preservation of epipristi up to 1 time in 5-6 days. Anticonvulsants (benzonal) take regularly up to 3 tablets per day.

 Considering the brain MRI (from 07/13/99) about the presence of a tumor site 3.5 × 2.5 cm in size, the EEG (from 07/12/99) of a site of convulsive activity, as well as on the basis of a neurological examination, it was decided to conduct further treatment with a combination of chemotherapy and radiation therapy.

 From September 2, 1999 to September 7, 1999, the patient received riboxin in the form of tablets of 0.2 g (1 tablet) 3 times a day and benzonal 0.3 g per day (3 tablets). From September 8, 1999, riboxin was administered intravenously in a dose of 10 ml daily for 10 days, and at the same time proxyphein according to the scheme: September 8–9, 10 ml dropwise of a 5% solution of proxyphein diluted with physiological saline to 500 ml, September 10–11 15 ml of a 5% solution of proxyphein diluted with saline to 750 ml, intravenously and 0.25 g once daily, orally, September 13-14 - 20 ml of a 5% solution of proxyphein in 1000 ml of saline intravenously and 0.25 g 2 times per day orally, September 15-16 - 25 ml each; and September 17-18 - 30 ml 5% proxyphein solution in 2000 ml of saline intravenously and from September 15 to September 18, additionally 0.25 mg of proxyphein 3 times a day orally, and then throughout the course of treatment daily 0.25 mg of proxyphein 3 times a day.

 From September 08, 1999 to October 6, 1999, radiation therapy was simultaneously carried out on the Rocus-M apparatus from a single field of 5x6 cm in a single dose of 2 Gy to a total dose of 42 Gy, that is, it was carried out against the background of the administration of proxyphein and riboxin, which from September 20, 1999 was administered orally at 0.2 g 3 times a day, then continuing such oral administration for up to 3 months.

 During chemoradiotherapy, the patient additionally received lasix (diuretic) every other day, daily panangin (1 tablet 3 times) and benzonal.

 The patient's condition during treatment remained satisfactory, the number of epiprises did not increase, which under the control of EEG allowed to reduce benzonal administration from 09/22/99 to 2 tablets per day.

 When the patient is discharged from the clinic on 08.10.99: the condition is satisfactory, a blood test, ECG, ultrasound of the abdominal cavity - without features. According to the EEG results, the convulsive focus is out of activity. The patient was prescribed oral administration: 3 months riboxin 0.2 g 3 times a day and 1.5 months. - proxyphein 0.25 g 3 times a day (up to a total dose of 40 g) and benzonal 1 table. 2 times a day, and then take benzonal constantly 1 tablet. for the night. Contact the institute in early December for a follow-up examination.

At the reception in the clinic TsNIRRI 06.12.99:
The condition is satisfactory, light left-side hemiparesis, self-serving, Karnovsky index of 90 points. There were no epiprots. Take 1 tablet of benzonal at night. Brain MRI (from 02.12.99) - the size of the tumor lesion 1.5x1.0 cm (volume reduction), EEG (from 06.12.99) - diffuse changes that prevail in the right frontoparietal regions, a convulsive focus out of activity. Analyzes of blood, urine, ECG, ultrasound of the abdominal cavity - without features. Inspection of an ophthalmologist, ENT doctor, general practitioner - no pathology was detected.

 Conclusion: stabilization of the tumor process. Turn up at TsNIRRI in a month to continue chemotherapy treatment.

 At the patient’s admission on 12/20/99 (4 weeks after the end of proxyphein administration): satisfactory condition, no epipristia after the last treatment.

 To prevent further tumor growth, the patient was prescribed a course of chemotherapy with proxyphein according to the scheme of the previous treatment, i.e. holding it against the background of riboxin and benzonal, the dose of which in the first two weeks was 3 tablets. and was gradually reduced to 2 tablets. per day under the control of EEG.

 On January 10, 2000, the patient was discharged in satisfactory condition from the clinic with a recommendation to take proxyphein 0.25 g 3 times a day to a total dose of 50 g against riboxin (0.2 g 3 times a day) and benzonal (1 table. 2 times a day) . In total, the patient took 60 g of proxyphein for this course of treatment (10 g intravenously and 50 g orally).

At the control examination in March 2000:
Brain MRI data from 10.03.00, there were no signs of continued tumor growth, EEG is a convulsive focus out of activity. The patient's condition is stabilized, his health is good, which allows us to hope for a stable remission.

 Example 2

 Patient T, born in 1955 (medical history N 356), was admitted to the TsNIRRI clinic on 16.02.99 with a diagnosis of a brain tumor (right frontal lobe) with epileptic syndrome. Condition after osteoplastic trepanation of the skull. From the anamnesis it is known that she is sick for a year. Notes a deterioration in general condition, an increase in headaches, and in November 1998 the first local cramps appeared in the left hand. In January 1999, a generalized epileptic seizure with loss of consciousness, the patient was hospitalized in the neurological department of hospital No. 2, where during a clinical and radiological examination (CT of the brain, EEG, cerebral angiography, consultation of a neurologist, ophthalmologist, neurosurgeon) a volumetric process of the frontal frontal was revealed share. 01/25/99, performed osteoplastic trepanation of the skull in the right frontal region with partial removal of the tumor. Histologically - glioblastoma (4 degrees of malignancy). To stop epileptic seizures, the patient was prescribed finlepsin.

 To continue treatment, the patient was sent to TsNIRRI.

Upon admission to the clinic TsNIRRI 02.16.99:
The state of moderate severity, epileptic seizures in the form of convulsive contractions in the left arm and leg without loss of consciousness up to 1 time in 3-4 days. The patient was prescribed finlepsin orally in 2 tablets. per day (1/2 - in the morning and afternoon and 1 - at night) - the frequency of seizures decreased, their nature changed to light muscle contractions in the arm and leg. According to the results of brain MRI, there are signs of subtotal removal of the tumor, the accumulation zone of the contrast medium was 2.5 x 3.0 x 1.6 cm. EEG - pronounced diffuse changes localized in the right frontal lobe, the focus of epileptic activity in this area, amplified by functional loads.

 From 02.17.99, the patient received finlepsin in 2 tablets. per day, oral riboxin 0.2 g 3 times a day, then intravenously riboxin and proxyphein with a gradual transition to their further oral administration according to the scheme similar to example 1. At the same time, radiation therapy sessions were conducted on the Rocus-M apparatus. A single focal dose was 2 Gy, the total - 54 Gy.

 The patient underwent a satisfactory course of treatment, there was no increase in neurological symptoms, and there were no epiprises. Under the control of EEG, the dose of finlepsin was first reduced to 1.5 tablets (1/2 in the morning and 1 in the night) per day.

 04/05/99, the patient was discharged from the hospital in satisfactory condition with pronounced positive dynamics. It is recommended to continue taking proxyphein to a total dose of 40 g against a background of riboxin (0.2 g 3 times a day). Take finlepsin in the same doses until the end of proxyphein, then gradually reduce to 1 table. for the night.

Control examination at TsNIRRI 05.10.99:
MRI of the brain with a contrast agent - signs of subtotal removal of a tumor of the right frontal lobe, cerebrospinal cyst 1.5x1.2x1.0 cm, accumulation of a contrast agent along its periphery (significant decrease in tumor size). The displacement of the middle structures is not observed. EEG - marked diffuse changes in the right frontal lobe, the epileptic focus is determined with functional load, at rest outside of activity. Analyzes of blood, urine, ECG, ultrasound of the abdominal cavity - no pathology was detected. The patient's condition is satisfactory, contact, oriented in the environment and time, mild pyramidal insufficiency on the left is determined neurologically. Epileptic seizures were not observed, constantly taking finlepsin 1 tablet. for the night. The patient works as a homeworker (knitting), copes with the work. Given the data of clinical and radiological examinations, she was assigned to repeat the course of proxyphein from 05.31.99

 Upon repeated hospitalization of the patient on May 31, 1999, a chemotherapy course was carried out (5 weeks after the first administration of proxyphein) according to the same scheme against the background of riboxin and finlepsin.

 06/18/99, was discharged from the hospital in satisfactory condition with the recommendation to continue taking proxyfein to a total dose of 40 g against a background of riboxin and finlepsin.

Control examination in a hospital on September 6, 1999:
Brain MRI - tumor size 1.0x0.7x0.5 cm, EEG - convulsive focus out of activity (takes 1 tablet of finlepsin per night), other data - ultrasound, blood tests, specialist examinations - showed that the patient has a stabilization process . The patient was discharged from the clinic with a recommendation to conduct a similar course of proxyphein on an outpatient basis under the supervision of a neurosurgeon and oncologist at the place of residence.

 On March 14, 2000, according to the results of the control examination at the Central Research Institute of Radiology, the patient was in satisfactory condition, according to MRI, the size of the tumor was 0.7x0.5x0.5 cm, and the EEG showed a convulsive focus out of activity. The patient is in remission for more than 1 year.

 To date, the proposed method has been the treatment of 16 patients with brain tumors (anaplastic astrocytomas of 2-3 degrees, glioblastoma - 4 degrees of malignancy) with epileptic syndrome. All patients satisfactorily underwent treatment, all are currently in remission. Since the proposed method has been used only since February 1999, it is premature to talk about its duration. We can only say that the stabilization of the process was noted in patients, which gives hope that it will be sufficiently stable.

 Compared with the known, the proposed method of treatment has several advantages.

 1. A decrease in the overall toxic effect due to a significant decrease in the total dose of proxyfein (per treatment course 50 g), while in the prototype method it is 110-130 g. This improves the quality of life of patients both during treatment and in remission .

 2. The reduction in radiation exposure to 42 - 54 Gy compared with the total dose in the prototype, comprising 56-70 Gy, along with a decrease in the total dose of proxyphein favorably affects the condition of patients and contributes to better tolerability of subsequent treatment.

 3. Reducing the duration of inpatient treatment of patients up to 40 days with chemoradiotherapy, while in the prototype it takes about 2 months.

 The method was developed in the department of radiation treatment of oncological diseases TsNIRRI Ministry of Health of the Russian Federation and so far has passed clinical testing in 16 patients with a positive result.

Claims (1)

 A method for the treatment of gliomas with epileptic syndrome, including surgical removal of the tumor, chemotherapy via intravenous and oral administration of proxyfein, as well as radiation and anticonvulsant therapy, characterized in that within the period of 5 to 10 days after removal of the tumor, 0.2 g of riboxin is administered to the patient orally once a day, radiation therapy is started simultaneously with chemotherapy, carrying out it up to a total dose of 42 - 54 Gy on the background of intravenous and then oral administration of riboxin and proxyphein, and riboxin is administered intravenously 10 ml each in the first 2 weeks, 0.2 g orally 3 times a day for up to 3 months, and when proxyphein is orally administered, it is given as follows: 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 to 50 days, and such chemotherapy is carried out after 4 to 5 weeks, anticonvulsants are administered in a constantly decreasing dose until the end of the chemotherapy course and then for 2 to 3 years at night 1 tablet, for example benzene or finlepsin.