RU2392983C1 - Method for treatment and prevention of cancer recurrence and metastasis - Google Patents

Abstract

FIELD: medicine. ^ SUBSTANCE: invention refers to medicine, particularly to oncology and concerns treatment and prevention of recurrence and metastasis of tumours containing sex hormone receptors. That is ensured by taking a biopsy material of the tumour to be analysed for androgen and oestrogen receptors to be found. Then the sex hormone level is determined to provide a basis to enable hyperandrogenism to develop by administering a hormonal preparation. Thereafter, the tumour is exposed to a gamma teletherapy in Basic Dose Mode 25 Gy or Basic Dose Mode 40 Gy. Further, if any oestrogen receptors are found in the taken biopsy material, permanent androgenisation is supposed to be achieved, and if observing androgen receptors in the biopsy material, oestrogenisation is required. ^ EFFECT: improved therapeutic effect while inhibiting tumour growth and metastasis up to regress, with reducing number of by-effects and contraindications for the therapy. ^ 3 cl, 1 ex, 1 tbl

Description

The invention relates to medicine, and more specifically to methods of combination therapy for malignant tumors, and can be used in the treatment and prevention of cancer.

A known method for the combined treatment of cancer, including local radiomodification of tumor cells, followed by radiation therapy and radical surgery, characterized in that local radiomodification is carried out by endovascular perfusion of its tissue with 5% solution of metronidazole through the upper rectal artery in the upper ampullar rectal cancer, upper rectal and one of the internal iliac arteries in the middle and lower ampullar rectal cancer with occlusion of these vessels by non-lysing tgenokontrastnymi emboli See. Patent RU № 2269341, cl. A61N 5/10, publ. 2006 02.10. The method allows to enhance the damaging effect of radiation exposure on radioresistant forms of cancer.

There is a method of treating cancer by treating a tumor in the preoperative period with remote gamma radiation, taking capecitabine orally, injecting metronidazole intrarectally into the rectum in the form of a composite mixture of metronidazole, sodium alginate and dimethyl sulfoxide, followed by surgery, while the patient is being treated with a remote gamma therapy ROD-5 Gy on the background of twice taking capecitabine, see patent RU, No. 2311909, class A61N 5/10, publ. 2007.12.10. The invention allows to reduce the frequency of locoregional relapses and metastases and prolongs the disease-free period.

The disadvantage of these known methods of treating cancer is their lack of effectiveness, associated with the risk of relapse and distant metastases, as well as technical difficulties encountered in the treatment of metronidazole.

A known method of treating colorectal cancer by treating a tumor in the preoperative period with remote gamma radiation, local microwave hyperthermia and metronidazole introduced into the intestine as a composite mixture, mainly with the following ratios of ingredients, wt.%: Metronidazole 12-22, sodium alginate 4 -6, dimethyl sulfoxide 2, distilled water to 100, when implementing the method, the patient is given a 5-day course of remote gamma-therapy sessions ROD - 5 Gy with the introduction of an intrarectal composite mixture and holding sessions of l microwave microwave hyperthermia, see patent RU, No. 2234318, class. A61N 5/10, publ. 2004 08 20. This method allows effective combined treatment of patients with primarily operable forms of colorectal cancer, to reduce the incidence of locoregional relapses, and to increase the average life expectancy and 5-year patient survival. The specified well-known object of the invention - the method adopted as a prototype as the closest in technical essence and the achieved result analogue.

The disadvantage of the prototype and all of the listed known methods for the treatment of colorectal cancer is the low degree of radiomodification of the tumor tissue achieved during its implementation, which is a consequence of the use of metronidazole as the main radio modifier, which has a low degree of selective accumulation in the tumor tissue. In addition, the method of treating colorectal cancer according to the prototype has pronounced side effects associated with organoleptic properties, the irritating effect of the chemical on the mucous membrane of the gastrointestinal tract and neurotoxicity.

Achievable in the proposed method, the technical result is:

- an increase in the therapeutic effect,

- suppression of tumor growth and metastasis of the tumor until its regression,

- reduction in the number of side effects and contraindications.

Thus, the proposed method allows to increase the effectiveness of the treatment and prevention of cancer, to expand the scope of the method. In the proposed method, all the positive properties of the prototype are maximally preserved, namely, an integrated approach, characteristic, for example, of a combined method for the treatment of colorectal cancer.

The invention is based on an original technical solution for the use of hyperandrogenemia (conditions of sustained increased androgen content) as a radio modifying agent that increases the sensitivity of the tumor to ionizing radiation, instead of a chemical compound, as well as monitoring and stimulating the patient's hormonal background in the preoperative period. The inventors have established a unique relationship between the tendency to relapse and metastasis of cancerous tumors and changes in the hormonal background of the patient.

The method is as follows.

At the first stage of treatment, biopsy material of the tumor is collected and the presence of androgen and estrogen receptors is determined. In addition, the level of sex hormones is determined, on the basis of which they achieve the development of hyperandrogenemia.

At the second stage of treatment, a steady increased content of androgens in the patient's body is created by the introduction of hormonal drugs. As a hormonal drug, sex hormones testosterone or synestrol are used. Testosterone is the main male sex hormone, which is secreted by the male sex glands - the testes, and in small quantities - by the adrenal cortex in both sexes. The biological effect of testosterone is most specifically manifested in target tissues, where its selective accumulation occurs, mainly cells of the organs of the reproductive system belong to such tissues. In medical practice, synthetic testosterone preparations are used - propionate, Sinestrol methyltestosterone, a synthetic analogue of female sex hormones, powder, odorless, white or white with a slightly yellowish tint, practically insoluble in water, easily soluble in alcohol, difficult - in peach oil, different in chemical structure from steroid estrogen hormones, but its biological and therapeutic properties are close to them. For accelerated penetration of drugs into the body, they are rubbed into the skin. In parallel, drugs are administered intramuscularly. Preparations at this stage are used in the form of a gel, mainly in oily solutions (synestrol is used as a 2% oil solution). Thus, drugs are administered daily in 3-4 ml. The total dose and duration of treatment depends on changes in the composition of the blood and lasts until a stable, elevated hormone content is achieved. The necessary and maximum concentration of the hormone in the blood is determined individually for each patient based on the parameters of his height, weight and initial concentration. The drugs are well tolerated, quickly absorbed and the desired effect, as a rule, is achieved in 7-10 sessions.

The increased content in the body of the level of sex hormone has an effective radiomodifying effect on tumor cells. Additionally, after the administration of androgenic or estrogenic drugs and before conducting remote gamma therapy, local microwave hyperthermia is performed at a temperature of 42.5-43 ° for 60 minutes.

In addition, after 6-8 hours after hormone therapy, a remote gamma-therapy session of ROD-25 Gy or ROD-40 Gy is performed. Based on the assessment of the results of the exposure, a decision is made on further treatment. If necessary, hormone therapy courses are repeated. 24-48 hours after completion of the course of preoperative radiation, if necessary, radical surgery is performed, the nature and volume of which is determined by the level of tumor localization and the degree of its local distribution.

At the final stage, if there are estrogen receptor tumors in the previously taken biopsy material, they achieve constant androgenization in the patient’s body, and if there are androgen receptor tumors in the biopsy material, estrogenization is achieved. At the same time, hormonal levels in the patient's blood are constantly monitored.

A study of the effect of the created hyperadrogenemia on the tumor sensitivity to remote gamma therapy with a previous session of local microwave hyperthermia was carried out in laboratory animals vaccinated with solid Ehrlich solid carcinoma of the ELD line. Animals - mice of the BALB / C line, males weighing 20-22 g. ELD Ehrlich carcinoma cells were grafted into the leg muscle of mice 7 days before irradiation. The day before irradiation, animals were given testosterone (Testosterone propionate 5%) or synestrol (Sinestrol, 0.1% oil solution). Local microwave hyperthermia was carried out by heating a limb with a growing tumor at a temperature of 43 ° C for 60 minutes. On the day of irradiation, the diameter of the lower leg with a growing tumor varied between 7–9 mm (the diameter of the lower leg of mice without an inoculated tumor was approximately 4 mm in the middle). Each experimental group consisted of 6-8 animals. Irradiation occurred on the AGAT-R cobalt gamma installation equipped with an additional device for increasing the dose rate difference between the irradiated tumor and the screened body of the animal. The radiation dose was 5 Gy.

Animals with vaccinated tumors on the day of exposure were divided into the following groups

- control group, no effects;

- Remote gamma therapy ROD-5 Gy (Region) of the tumor;

- Remote gamma therapy ROD-5 Gy (Region) of the tumor in combination with previous local microwave hyperthermia (HT) (Region + HT);

- Remote gamma therapy ROD-5 Gy (Region) of the tumor against the background of the introduction of the radio-modifying hormonal drug Testosterone (Testosterone + Region);

- Remote gamma-therapy ROD-5 Gy (Region) of the tumor in combination with previous local microwave hyperthermia (HT) against the background of the administration of the radio-modifying hormonal drug Testosterone (Testosterone + Region + GT);

- Remote gamma therapy ROD-5 Gy (Obl) of the tumor against the background of the introduction of the radio-modifying hormonal drug Sinestrol (Sinestrol + Obl);

- Remote gamma therapy ROD-5 Gy (Region) of the tumor in combination with previous local microwave hyperthermia (HT) with the introduction of the radio-modifying hormonal drug Sinestrol (Sinestrol + Region + HT).

The impact effect was evaluated by measuring the tumor volume, i.e. maximum tumor size in three perpendicular directions. The resulting numbers were multiplied. Data obtained on the day of irradiation was considered as the initial volume (Vo) of neoplasms, and data on the remaining days of measurements was designated as (Vt). The dynamics of regression and relapse of the tumor reflects the ratio of Vt and Vo. The determination of the Vt value was carried out three times a week for twenty-six days after exposure. The results of the dynamics of changes in the volume of tumors in the control group of animals, as well as animals whose tumors were subjected to remote gamma-therapy ROD-5 Gy (Region) in combination with local microwave hyperthermia (HT), as well as the effects of these agents on the background of testosterone administration ( T) or synestrol (C) are shown in Table 1.

In the drawing, the results of Table 1 are presented in graphical form, while: a smooth curve displays the dynamics of changes in the volume of tumors in the control group of animals; the curve marked with black squares is a group of animals subjected to remote gamma-therapy ROD-5 Gy (Region); the curve marked with white squares is the group of animals subjected to remote gamma-therapy ROD-5 Gy of the tumor in combination with previous local microwave hyperthermia (Region + HT); the curve marked with plus signs (+) is the group of animals subjected to remote gamma-therapy ROD-5 Gy of the tumor against the background of the introduction of the radio-modifying hormonal drug testosterone (Testosterone + Obl); the curve marked by black rhombs is the group of animals subjected to remote gamma-therapy ROD-5 Gy of the tumor in combination with previous local microwave hyperthermia (HT) against the background of the administration of the radio-modifying hormonal drug testosterone (Testosterone + Obl + HT); the curve marked with crosses is a group of animals subjected to remote gamma-therapy ROD-5 Gy of the tumor against the background of the introduction of the radio-modifying hormonal drug synestrol (Sinestrol + Obl); the curve marked by black triangles is a group of animals subjected to remote gamma-therapy ROD-5 Gy of the tumor in combination with previous local microwave hyperthermia with the introduction of the radio-modifying hormonal drug synestrol (Sinestrol + Obl + GT).

Table 2 presents the results of measurements of the time (in days) of growth to the initial volume of tumors of all groups, as well as the time of doubling the volume of tumors.

From the materials presented in tables 1, 2 and in the graphs (see drawing), it can be seen that remote gamma-therapy ROD-5 Gy leads to significant inhibition of tumor growth, and when exposed to local microwave hyperthermia, this effect is somewhat enhanced. Both hormonal drugs and testosterone and synestrol increase the depth of tumor regression both after remote gamma-therapy ROD-5 Gy and after remote gamma-therapy ROD-5 Gy in combination with previous local microwave hyperthermia. The depth of regression is most pronounced on the sixth day after remote gamma-therapy, with testosterone increasing the depth of regression more than synestrol. The effect of modification of tumor damage by hormonal preparations in the presented experiments is quite definite. At the same time, the modifying effect of testosterone and synestrol is approximately the same for ROD-5 Gy gamma-ray therapy and ROD-5 Gy gamma-ray remote therapy in combination with previous local microwave hyperthermia, which implies that the effect is enhanced by hormonal drugs due to the modification of the action of the radiation component.

Example 1

Patient 3. Age 60 years. The diagnosis is rectal cancer of the fourth century, the presence of distant metastases. Hormonal status assessment results: Testosterone 5.4 nmol / L (normal 7.0-30 nmol / L).

The patient was treated with the claimed method.

Tumor biopsy material was collected. Examination of the material revealed the presence of estrogen receptors. Based on the detected testosterone level, hormonal preparations were introduced into the patient's body, which allowed the development of hyperandrogenemia. Against the background of developed hyperandrogenemia, an effect on the tumor was carried out by means of remote gamma-therapy ROD-25 Gy. Due to the fact that estrogen receptors were detected in the biopsy material taken, after exposure, measures were taken to achieve constant androgenization in the patient's body.

As a result of the treatment, tumor regression was noted, which allowed the patient to undergo radical surgical treatment (abdominal-perineal extirpation of the rectum).

The patient was under observation for 2 years. No recurrence and metastasis were detected during this period.

Currently, we have obtained the results of a 2-year observation of 12 patients (with receptor-containing tumors) in whom the proposed method was applied. In all patients, no recurrence or metastasis was observed during this period.

Claims (3)

1. A method for the treatment and prevention of recurrence and metastasis of tumors containing sex hormone receptors by exposing the tumor to remote gamma therapy, characterized in that the biopsy material of the tumor is preliminarily taken and the presence of androgenic and estrogen receptors is determined, then the level of sex hormones is determined by on the basis of which they achieve the development of hyperandrogenism by introducing a hormonal drug into the body, after which they influence on op the ear by means of remote gamma-therapy ROD-25 Gy or ROD-40 Gy, then, if there are estrogen receptor tumors in the pre-taken biopsy material, the patient will achieve constant androgenization in the patient’s body, and if there is an androgen receptor tumor in the biopsy material, estrogenization. 2. The method according to claim 1, characterized in that in addition to 24-48 hours after conducting remote gamma-therapy, radical surgery is performed. 3. The method according to claim 1, characterized in that additionally after the administration of androgenic or estrogenic drugs and before conducting remote gamma therapy, local microwave hyperthermia is performed at a temperature of 42.5-43 ° for 60 minutes

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