RU2567836C1 - Method for thermochemoradiation therapy of malignant cerebral glioma - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: postoperative period involves a remote radiation therapy and a chemotherapy. That is combined with a local hyperthermia (LH) beginning simultaneously with the chemoradiation therapy. The sessions are performed at temperature 42-44°C for 60 min with a 15-20-minute break between a session of the radiation therapy and the local hyperthermia, 3 times a week, 10 sessions in total. The LH exposure area is supposed to cover a postoperative area and perifocal oedema areas.

EFFECT: improved survival rate in the patients with malignant cerebral gliomas by reducing a rate of recurrences with no impairment of the quality of life, and prolonging the survival rate up to 20 months.

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Description

The invention relates to medicine, specifically to methods for thermo-chemoradiation treatment of malignant gliomas of the brain.

Despite the improvement in diagnosis, the mortality rate of patients with intracerebral tumors remains high, and the treatment results are unsatisfactory. The average life expectancy of patients with malignant glioma (MH) when applying the modern standard of care is on average 14 months after diagnosis, despite aggressive surgical intervention, radiation treatment and chemotherapy (XT) [1, 2].

There is a method of treating malignant neoplasms of various localizations using local microwave hyperthermia, when at least 5 units of oxytocin are injected into the tissues surrounding the tumor before each session of LH [3]. The disadvantage of this method is the limited scope of its application in relation to deep-lying tumors, since direct access to them is limited.

A known method for the treatment of volumetric formations of the brain by exposing the tumor to a microwave field using a probe of the microwave apparatus, introduced intraoperatively through a milling hole in the skull. The microwave field causes thermal coagulation of the tumor tissue and its necrosis [4]. The method allows to reduce the duration and invasiveness of the operation.

The disadvantages of this method is that the effect on the tumor is limited to one local factor, and there is also no comprehensive approach to the treatment of brain tumors - chemotherapy, radiation therapy.

Closest to the proposed is a method of treating patients with MH using radiation therapy and the chemotherapeutic drug Temodal. The method consists in the fact that a month after the operation, patients undergo a course of radiation therapy on the "bed" of the tumor according to the standard method, ROD 2 Gy, SOD 56-60 Gy. From the first day of RT, Temodal chemotherapy is started at a dose of 200 mg / m ² for 5 days, the course is repeated every 23 days [5]. The disadvantages of this method is that due to the high resistance of MH to radiation and chemotherapy, the average life expectancy of patients remains low for an average of 16 months in patients with anaplastic astrocytoma and 13 months in patients with glioblastoma multiforme.

A new technical result is an improvement in the survival rates of patients with malignant gliomas by reducing the frequency of local relapses without compromising the quality of life.

To achieve a technical result in the method of treating malignant gliomas of the brain in the postoperative period, remote radiation therapy and chemotherapy are carried out, local hyperthermia is additionally carried out, and at the same time they are started with chemoradiotherapy, the sessions are carried out at a temperature of 42-44 ° C for 60 minutes, with an interval between a radiation therapy session and local hyperthermia 15-20 minutes, 3 times a week, a total of 10 sessions, while the postoperative area and zones of perifocal edema are included in the area of exposure to LH.

The proposed method meets the criterion of "novelty," because, unlike the prototype, it has the following significant distinguishing features:

- the inclusion of local hyperthermia in the treatment plan has an additional radiosensitizing as well as chemosensitizing effect.

Through the use of these treatment methods in this method, as well as their use in the aggregate and a certain sequence and mode, we can conclude that the proposed method is “inventive step”.

The invention meets the criterion of "industrial applicability", as it has been tested in clinical practice for the treatment of patients with malignant gliomas of the brain.

The method is as follows: in the postoperative period (after a month) in patients with malignant gliomas G III-IV, treatment is carried out:

- local hyperthermia on a Celsius TCS device (Germany) from the first day of chemoradiation therapy 3 times a week (10 sessions in total) 15-20 minutes after a radiation therapy session for 60 minutes at a temperature of 42-44 ° C;

- Temodal is taken in a single dose of 200 mg / m ² / day for five days, the courses are repeated every 23 days;

- radiation therapy is carried out on a Theratron Equinox 1.25 MeV device (Canada) in a standard dose fractionation regimen, ROD 2 Gy for 6 weeks to a total focal dose of 60 Gy, a break between the radiation therapy session and LH for 15-20 minutes.

The rationale for the method. Malignant gliomas are a class of infiltrative, aggressive tumors that are sufficiently resistant to ongoing therapy. A combination of surgical removal of the tumor and adjuvant radiation therapy is considered the standard treatment method, but it has comparatively low efficacy. High mortality is due to several factors:

- relapses (continued growth) develop in more than half of patients;

- the relatively low sensitivity of MH to standard chemo- and radiation therapy.

So, when using adjuvant radiation therapy, the median survival is 6-10 months, and the combination of radiation therapy with Temodal can increase the average life expectancy up to 14 months [6, 7].

Due to the relatively low efficiency of radiation and chemotherapy for MH, currently the prospects for improving treatment outcomes are associated with the search for optimal radio and chemosensitizers. One of the most common radio modifiers is local hyperthermia, i.e. heating the tumor zone in a certain temperature-exposure mode. A number of studies have shown the direct damaging effect of high temperatures of 42-43 ° C on tumor cells [8].

The sensitizing effect of hyperthermia is expressed in enhancing the cytostatic effect of radiation therapy and chemotherapy. Hyperthermia causes the depletion of ATP reserves and energy potential of the cell, as a result of which the processes of DNA recovery after exposure to ionizing radiation are disrupted. Under the influence of hyperthermia, both the inherent chemical activity of chemotherapy drugs and the degree of their penetration into cells increase due to the activation of membrane transport. In addition, the effect of hyperthermia is much higher in hypoxic tissues, in which radiation therapy and chemotherapy are just less effective. All these parameters make it possible to achieve a significant therapeutic gain without increasing the radiation load on the surrounding healthy tissues.

In the proposed method of treatment in patients with malignant gliomas in the adjuvant mode, simultaneous thermo-chemoradiotherapy is carried out.

Clinical example

Patient G., 21 years old. Diagnosis: Glioblastoma (GIV) of the left frontal lobe. Condition after surgical treatment 08/30/13, continued growth. Condition after surgical treatment 02.10.13, With a control MRI of the brain after repeated surgery, the volume of surgery is regarded as partial resection (Fig. 1). In terms of combination treatment, chemoradiotherapy is recommended. The treatment was carried out in the claimed way: from the first day of radiation therapy - 10 sessions of hyperthermia (3 times a week 42-44 ° C for 60 min), Temodal at a dose of 360 mg, radiation therapy in standard mode - ROD 2 Gy, SOD 60 Gy. Thermo-chemo-radiation treatment was carried out against the background of decongestant therapy (diacarb, glycerin, dexamethasone 16 mg / day). The treatment carried out in full, the patient suffered satisfactorily. In a control MRI of the brain with contrast 1 month after completion of treatment, the effect is regarded as partial regression (according to RANO criteria). After completing the full course of combined treatment (another 4 sessions of chemotherapy with temozolomide) with a control brain MRI, complete tumor regression (Fig. 2). With dynamic observation, there is no relapse for 20 months.

Using the proposed method, 9 patients with malignant gliomas of the brain of 21-70 years were treated. According to the histological type, the distribution was as follows: anaplastic astrocytoma (G III) was detected in 4 cases, glioblastoma (G IV) - in 5 cases. Despite multicomponent treatment, all patients underwent treatment in full. When assessing the objective effect, stabilization of the process was detected in all patients.

During thermo-chemoradiotherapy, the complications were unexpressed - development of nausea / vomiting of the first degree was noted, which did not require interruption of treatment and stopped fairly well by the appointment of symptomatic therapy. Patient observation time from 7 to 20 months.

Thus, the proposed method of treatment is selected experimentally and clinically. As a clinical study showed, the use of this method of treatment allows to achieve a new technical result, namely, to improve the survival rates of patients with malignant gliomas of the brain by reducing the frequency of relapses without compromising the quality of life.

Information sources

1. Martynov B.V. The method of stereotactic cryodestruction in the treatment of patients with brain gliomas // Issues of Neurosurgery named after N.N. Burdenko. 2011.V. 75.S. 17-24.

2. Svistov D.V., Martynov B.V., Kholyavin A.I. et al. Surgical resection in combination with stereotactic cryodestruction in patients with supratentorial gliomas in functionally significant areas of the brain: the possibility of using combined surgical treatment and its results // Bulletin of Surgery. I.I. Grekov. 2012.V. 171. No. 4. S. 11-16.

3. Svetitsky P.V., Poroshenko A.B., Solovyova M.A. and others. A method of treating malignant neoplasms // Patent for the invention of the Russian Federation No. 2211714 from 09/10/2003.

4. Konevsky M.A. A method for the treatment of volumetric formations of the brain // Patent for the invention of the Russian Federation No. 2504342 from 01.20.2014.

5. Osinov I.K., Musabaeva L.I., Nechitailo M.N., Choynzonov E.L. Chemoradiation treatment of malignant gliomas of the brain with the use of Temodal // Siberian Oncological Journal. 2009. No.6. S. 5-11.

6. Smolin A.V. Combined chemoradiotherapy for multiforme glioblastomas Burdenko // Modern problems of neurooncology: Proceedings. M.: Publishing House of the Russian Academy of Medical Sciences. 2007.S. 25-31.

7. Naskhletashvili D.R., Bekyashev A.Kh., Karakhan VB et al. Role of temozolomide in the treatment of glioblastomas of the brain // Tumors of the head and neck. 2011. No2. S. 34-35.

8. Yarmonenko S.P., Vinson A.A. Radiobiology of humans and animals. M .: Nauka, 2004.549 s.

Claims (1)

A method for the treatment of malignant gliomas of the brain, where remote radiation therapy and chemotherapy are performed in the postoperative period, characterized in that they additionally carry out local hyperthermia (LH), whereby they begin simultaneously with chemoradiotherapy, the sessions are carried out at a temperature of 42-44 ° C for 60 minutes , with an interval between a radiation therapy session and local hyperthermia of 15-20 minutes, 3 times a week, a total of 10 sessions, while the postoperative area and zones of perifocal edema are included in the area of exposure to LH.

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