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ONCOLOGY AND RADIOLOGY
INVENTION
Patent of the Russian Federation RU2285531

METHOD OF TREATMENT OF UTERINE CERVICAL CANCER AND DEVICE FOR ITS IMPLEMENTATION

The name of the inventor: Nosovich Alexey Petrovich (RU); Rumyantseva Tatyana Viktorovna (RU); Sukhova Svetlana Nikolaevna (RU); Saveliev Vadim Yurievich (RU); Terentyev Igor Georgievich (RU)
The name of the patent holder: Federal State Unitary Enterprise "Research and Production Enterprise" Polet "(RU)
Address for correspondence: 603950, Nizhny Novgorod, GSP-462, pl. Komsomolskaya, 1, FSUE "NPP" Polet "
Date of commencement of the patent: 2004.09.13

The invention relates to medicine, namely to oncology, and can be used for the treatment of patients with cervical cancer. A method and a device are proposed. The method involves carrying out local high-frequency hyperthermia with a conductive fluid at a constant temperature control in the cervical canal immediately prior to intracavitary gamma-therapy sessions. Hyperthermia is carried out at a temperature of 45 ° C, and the conductive liquid contains 5-fluorouracil in a dose of 1000 mg. The device for carrying out the method comprises a hollow cylinder, provided with a rounded end piece fitted to one end of the cylinder, an electrode holder and monitoring devices mounted to the other end of the cylinder through a rubber gasket, the cylinder being encased in an elastic material cuff sealed at its ends by means of Rubber rings and has a thickened wall on the side of the holder in which longitudinal holes are provided communicating with the internal volume of the cylinder for placing the electrodes, and an opening communicating with the internal volume of the cylinder for placing the electrodes, and an opening communicating with the outer surface of the cylinder with the possibility Supplying air therethrough into the space between the outer surface of the cylinder and the cuff, and holes are provided in the holder coaxial to the cylinder openings. The use of the invention makes it possible to synchronize the mitotic cycle of tumor cells, increasing their sensitivity to heating and irradiation, while lowering the radiation doses, and allows controlling the adequacy of heating the tumor.

DESCRIPTION OF THE INVENTION

The invention relates to medicine, namely to oncology, and can be used for the treatment of patients with cervical cancer.

The use of hyperthermia in oncology as one of the methods of treating malignant neoplasms has been known for a long time. In the literature there are reports of the use of local hyperthermia as a radio modifier in many malignant tumors.

However, the use of hyperthermia as a radio modifier in malignant neoplasms of female genital organs was not widely used due to technical and methodological difficulties.

At present, generators of electromagnetic radiation in microwave, HF and UHF bands are used for local heating.

A method for conducting hyperthermia is known (Gusev LI et al, Hyperthermia in Combined Therapy of Endometrial Cancer, Clinical and Experimental Problems of Thermal Radiation Therapy, Obninsk, 1989, p.55-57) , which proposed the use of a local microwave (microwave) as a radio modifier, Hyperthermia in radiation treatment of endometrial cancer. Hyperthermic effects on the tumor were carried out on the Yakhta-3 apparatus using a mono- and dipole antenna with a diameter of 8-10 mm and a working part length of 80-130 mm with a circular heating zone. Heating to 42.5-43 ° C for 60 min was performed before 2, 4, 6, 8 and 10 sessions of intracavitary irradiation by the method of sequential automated administration of endostats and high-activity radiation sources. The choice of the temperature-exposure regime was substantiated in studies on radiobiology (Konoplyannikov AG et al., The Use of Hyperthermia to Suppress Reparative Processes in Tumor Cells and to Increase the Efficiency of Radiation Therapy.) Medical Radiology., 1977, no.2, p.23). Therefore, the authors considered it possible to reduce the total absorbed dose by the amount of the FID dose change factor.

In the process of microwave hyperthermia, thermal burns on the endometrial mucosa and cervix of the uterus have developed in this way in a number of cases. And not all patients managed to conduct hyperthermia sessions by the proposed method because of technical difficulties associated with obturation with tumor masses of the cervical canal.

A more optimal method is to conduct intracavitary high-frequency hyperthermia in patients with advanced cervical cancer (Kostromina KN et al., Medical Radiology 1989, pp. 50-54), in which intracavitary high-frequency (HF) hyperthermia was performed on a Plot apparatus Immediately before the sessions of intracavitary gamma therapy, which was carried out on the AGAT-B apparatus. The temperature was adjusted to 42-43 ° C and kept at this level for 90 minutes at a coolant temperature of 25-30 ° C. The temperature was measured directly on the surface of the uterine mucosa. According to the authors, hyperthermia in none of the cases led to an exacerbation of inflammatory processes in the small pelvis.

The disadvantage of this technique is that in the primary tumor site (with the localization of the process in the cervix) only a radiosensitizing effect is achieved.

Intracavitary hyperthermia is carried out only under intravenous anesthesia.

The possibility of conducting intracavitary hyperthermia in women who underwent an operation of supravaginal amputation of the uterus and having cancer of the cervix of the uterus is excluded.

This contingent of patients is particularly difficult, because due to the absence of the uterine body, early radiation reactions from the bladder and rectum occur, which limits the use of combined radiotherapy in a radical program.

There is also a method for treating cervical cancer (patent of the Russian Federation No. 99116336), which consists in conducting isolated, local microwave hyperthermia at a temperature of 42-44 ° C, daily, for a course of 10 to 15 sessions, and then contact dry-jet chemotherapy with antitumor agents Driving at a pressure of 1-1.5 atm, for 2-3 seconds with the removal of detritus, starting from the 5 treatment session in order to influence the deeper layers of the tumor. To perform dry jet chemotherapy, chemotherapy is used that causes coagulation-necrotic changes in contact with tissues that are unpredictable and can cause extensive necrosis and bleeding. Doxorubicin acts in all phases of the cell cycle and is unable to synchronize the phases of the cell cycle. At the same time, it is known that the antitumor effect of therapeutic factors depends on the phase of the cell cycle: the most effective radiation therapy is in the M phase (mitosis), the sensitivity of the cells to heating rises in phase S (DNA synthesis), the time of activity of the chemotherapy depends on its chemical formula (Cytostatics - phase S, mitotic poison - phase M (mitosis), methotrexate - S and G 1 (rest phase 1)).

This method has the following drawbacks. Suction to the vaults is possible only with the preserved vaults of the vagina. When the tumor spreads to the vaginal vaults, this method is impossible to use because of its traumatic nature (50% of cases of cervical cancer are started, and the tumor bleeds on contact). The uncontrollability of the reaction of the cervical and vaginal tissues to chemotherapy, and therefore the possibility of complications (extensive necrosis with the exposure of large vessels and embolization of necrotic and tumor masses). Inability to provide tightness, due to the looseness and bleeding of the tissue. This method can be used only in the early stages of the disease and was used by the authors as preoperative preparation. It is contraindicated in advanced forms of the tumor. The phases of the cell cycle of tumor cells are not taken into account.

As a prototype for the method, a method of treating patients with advanced cervical cancer has been selected (RF patent No. 2001125824).

In the latter, in order to increase the effectiveness of combined radiation treatment of cervical cancer, a method of local HF hyperthermia using electromagnetic HF radiation in a conductive liquid is proposed.

Patients undergo local RF hyperthermia at a temperature of 42.5-43 ° C, with constant monitoring on the surface of the endocervix, immediately before intracavitary gamma-therapy sessions, beforehand the cervix is ​​removed by means of a Cusco mirror and around it are placed electrodes in the form of T-shaped elements Cylindrical surface fixed by a spring-loaded lock, then 50-60 ml of a conductive liquid are introduced into the vagina and irradiation is performed by electromagnetic oscillations at a frequency of 13.56 MHz for 15-20 min until the temperature is reached and within 30 minutes after reaching it at a constant temperature control In the conductive fluid and in the cervical canal.

Constant temperature monitoring is preferably performed by means of flexible temperature sensors, one of which is introduced into the cervical canal up to the internal pharynx.

Local RF hyperthermia is performed immediately before intracavitary gamma therapy by the method of sequential manual insertion of endostats and sources of low activity (simple af terloading).

The disadvantages of this method include the following. A difficult problem is to maintain the level of the conductive fluid in the vagina to completely cover the electrodes. Heating the fluid in vivo (in the vagina) prolongs the period of heating of the tumor tissues to 20 minutes, which promotes the activation of the multiplication of tumor cells occurring at a temperature of 40-42 ° C, causing a greater risk of metastasis, dissemination and tumor progression. The need to place the patient in a fixed position on the gynecological chair for 45-50 minutes with raised legs and a lowered head end, which wears the patient and has contraindications from the cardiovascular and nervous systems. In addition, only two antitumor factors (temperature and radiation) are used and the phases of the cell cycle of tumor cells are not taken into account.

An apparatus for treating cervical cancer (patent of the Russian Federation No. 99116336) is known, including a cylinder with an annular slotted space at its edge connected through a vacuum suction tube. Two tubes are inserted into the bottom of the cylinder, one end connected to its cavity, and the other, the outer end, one tube connected to a source of dry jet chemotherapy and detritus lead, and the other tube is connected to the source of local hyperthermia by the outer end.

The main disadvantage of this device is that it can be used only in the early stages of the disease, when it is possible to provide suction of vaginal arches along the circumference of the cylinder, free finding of the cervix in the cylinder space for carrying out isolated dry jet chemotherapy and cervical hyperthermia. With advanced cervical cancer, the use of this device is impossible, because The suction ring should have a close contact with the vaginal vaults, and the spread of the tumor on them will not allow creating the necessary sealing. It should be noted and the possibility of contact bleeding, especially dangerous in this group of patients with anemia, due to previous bleeding and cancer intoxication.

METHOD OF TREATMENT OF UTERINE CERVICAL CANCER AND DEVICE FOR ITS IMPLEMENTATION

The main technical task, to which the group of claimed inventions is directed, is to increase the efficiency of treatment of inoperable cervical cancer and to reduce traumatism during hyperthermia procedures.

This technical result is achieved by the fact that in a method for treating cervical cancer involving local high-frequency hyperthermia with constant temperature control in the cervical canal immediately before intracavitary gamma-therapy sessions, hyperthermia is carried out at a temperature of 45 ° C and the conductive liquid contains 5-fluorouracil in a dose 1000 mg.

This technical result is achieved by the fact that the device for treatment of cervical cancer containing a hollow cylinder for carrying out the method according to the invention is provided with a tip with rounded edges installed on one end of the cylinder and an electrode holder and monitoring devices mounted to the other end of the cylinder through a rubber gasket, Wherein the cylinder is encased in an elastic material cuff sealed at its ends by means of rubber rings and has, on the holder side, a thickened wall in which longitudinal openings communicating with the internal volume of the cylinder for accommodating the electrodes are made, and an opening communicating with the outer surface of the cylinder With the possibility of supplying air through it to the space between the outer surface of the cylinder and the collar, and in the holder holes are provided coaxial to the cylinder holes.

The figure shows a version of the design of the device described, where the following designations are used: 1 - hollow cylinder, 2 - cuff of elastic material, eg latex, 3 - rubber rings, 4 - tip, 5 - electrode holder and monitoring devices, eg endoscope, 6 - a rubber gasket, 7 - longitudinal holes communicating with the internal volume of the cylinder for placing the electrodes, 8 - an opening communicating with the outer surface of the cylinder, adapted to supply air therethrough into the space between the outer surface of the cylinder 1 and the collar 2 of the elastic material. The opening 8 through the union 9 by means of the medical tube 10 is connected to the device for injecting air into the space between the outer surface of the cylinder 1 and the cuff 2.

METHOD WITH THE USE OF THE PROPOSED DEVICE EXISTS AS FOLLOWS:

The procedure is performed on the operating table or couch. According to the gynecological examination, the appropriate size of the gynecological attachment is selected. The nozzle is treated with sterile vaseline and injected into the vagina, taking into account the spread of the tumor. In the nozzle until it is completely filled, 20-40 ml of pre-heated to 45 ° C physiological solution containing chemotherapy is injected. Air is injected into the space between the outer surface of the cylinder 1 and the cuff 2, thereby fixing the device in the desired position with the necessary tightness for carrying out the procedure. In the holder, the electrodes and the temperature sensor are fixed, connected to the corresponding connectors of the RF hyperthermia device. The temperature sensor measures the temperature in the cervical channel. If necessary, you can monitor the placement of the device as a whole, and, the electrodes and the thermal sensor, examining the vagina through an endoscope through a special hole in the nozzle. The second temperature sensor is located in the rectum. The temperature of the liquid after administration drops from 45 to 42 ° C. For its rapid heating up to 45 ° C, an electromagnetic field of 13.56 MHz is used in a continuous mode. Thus, a rapid warming up of the tumor (after 30-40 seconds) is ensured to a temperature of 45 ° C, at which the tumor cells are devitalized. After reaching the temperature plateau of 45 ° C, the pulse mode of heating is used, which does not give burns and pain sensations with an exposure of 45 minutes.

The chemotherapy used is 5-fluorouracil in a dose of 1000 mg. Under its influence, cells in different phases of the cycle are inhibited in phase S, during which the sensitivity of cells to heating increases, and together they reach the phase of mitosis, when they are most susceptible to irradiation. In addition, it is known that tumor cells in the phase of DNA synthesis, resistant to irradiation, show sensitivity to 5-fluorouracil.

Exposition - 45 minutes. The temperature determined by the thermal sensor (when the generator is temporarily turned off) from the surface of the endocervix is ​​45-47 ° C. The temperature value measured on the rectal epithelium reaches 43 ° C in 30-40 minutes from the beginning of the procedure and serves as an indicator of the adequacy of heating. At the end of the procedure, the device is removed from the vagina after sucking out the heated liquid from it.

After the procedure of local HF hyperthermia, the patient undergoes intracavitary gamma therapy (GHD = 5 Gy) on the apparatus "AGAT-VU". No enhancement of radiation complications was noted. Strengthened the degree of therapeutic pathomorphosis in the complex use of local HF hyperthermia and chemoradiotherapy. The phenomenon of "synchronization of the mitotic cycle", obtained by combining deep heating of the tumor with radiation therapy and chemotherapy, raises the level of therapeutic pathomorphosis, gives hope for increased patient cure and lower required effective doses of radiation.

The proposed method (in combination with remote gamma therapy) is used in common forms of cervical cancer, low-grade radioresistant cervical tumors, cervical cancer, cervical canal obturation by tumor masses.

The control of the effectiveness of treatment is carried out on the basis of regression rates of the primary tumor focus during palpation and visual examination, as well as histological examination data (assessment of the degree of therapeutic pathomorphosis).

Taking into account the possibility of achieving the cytodegressive temperature regime in the region of the tumor focus with the proposed method, it is possible to increase the efficiency of combined radiation treatment in cases where this is impossible with the use of the prototype method.

Examples

1. Patient S., 42 g. Was hospitalized with the diagnosis: Cervical cancer T2bN × Mo, utero-parametrically-vaginal variant, infiltrative-ulcerative form (histologically squamous cell carcinoma without keratinization). 3 sessions of local HF hyperthermia with a conductive fluid and chemotherapy, combined radiotherapy with a radical program were conducted.

2. Patient B., 62. Was in hospital treatment with the diagnosis: Cervical cancer T3bN × Mo, parametrically-vaginal variant, infiltrative-ulcerative form (histologically squamous nonkeratinized cancer). 3 sessions of local HF hyperthermia with a conductive fluid and chemotherapy, combined radiotherapy with a radical program were conducted.

In the process of RF hyperthermia with a conductive fluid containing chemotherapy, patients did not experience any painful sensations. Objectively, the general condition remained satisfactory. Locally on the mucous membrane of the cervix after HF hyperthermia, signs of inflammation and whitish plaque appeared. In the cytomorphological study, no malignant cells were detected. The period of observation of patients is from 6 to 12 months. Signs of progression of malignant neoplasm have not been noted.

CLAIM

1. A method of treating cervical cancer comprising performing local high-frequency hyperthermia with a conductive fluid at a constant temperature control in the cervical channel immediately prior to intracavitary gamma-therapy sessions, characterized in that the hyperthermia is carried out at a temperature of 45 ° C. and the conductive liquid contains 5-fluorouracil In a dose of 1000 mg.

2. The method of claim 1, wherein the conductive liquid is heated in-vitro to a temperature of 45 ° C.

3. The method of claim 1, further comprising monitoring the heating temperature of the rectal epithelium.

4. The method of claim 1, wherein a visual inspection of the heating zone through the endoscope is performed.

5. The apparatus for carrying out the method of claim 1, comprising a hollow cylinder provided with a round-end tip mounted to one end of the cylinder and an electrode holder and monitoring devices mounted to the other end of the cylinder through a rubber gasket, the cylinder being encased in a cuff of Elastic material, hermetically sealed at the ends by means of rubber rings, and has, on the side of the holder, a thickened wall in which longitudinal openings are provided communicating with the internal volume of the cylinder for positioning the electrodes, and an opening communicating with the outer surface of the cylinder, Space between the outer surface of the cylinder and the cuff, and in the holder are made holes coaxial with the holes of the cylinder.

print version
Date of publication 06.01.2007gg