RU2234318C2 - Method for treating rectal cancer - Google Patents

Abstract

FIELD: medicine, oncology.

SUBSTANCE: the present innovation deals with methods of combined therapy in oncological patients. The method deals with affecting a tumor with distance gamma-radiation, local UHF-hyperthermia and intra-intestinal injection of composite mixture followed by operative interference. On the 1^st d of 5-d-long course of radiation patients undergoes a seance of distance gamma-therapy ROD - 5 Gr. On the 2^nd and 4^th d one should intrarectally introduce a composite mixture containing metronidasol, sodium alginate and 2%-dimethylsulfoxide solution at the following ratios of ingredients, weight%: metronidasol 12-22, sodium alginate 4-6, dimethylsulfoxide 2, distilled water - up to 100. After 6-h-long exposure comes seance of distance gamma-therapy ROD - 5 Gr, moreover, on the 4^th d - with subsequent local UHF-hyperthermia at 42.5-43 C for 60 min. On the 3d and 5^th d it is necessary to conduct analogous seances of local UHF-hyperthermia followed by those of distance gamma-therapy ROD - 5 Gr. The method enables to enhance damaging action of preoperational irradiation upon a tumor by providing maximum radiosensitizing effect and decrease the frequency of locoregional relapses.

EFFECT: higher efficiency of therapy.

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Description

The invention relates to medicine, namely to methods of combination therapy for cancer patients, in particular, colorectal cancer.

In recent years, Russia has a tendency to increase the incidence of colorectal cancer. Colorectal cancer takes the 2nd place among tumors of the gastrointestinal tract and makes up 80% among colon cancers and 4-6% of malignant neoplasms of all localizations. The incidence of colorectal cancer in Russia averages 11.6 per 100,000 of the population. More than 600,000 people fall ill with colorectal cancer in Russia every year and 300,000 die from the same disease.

Until recently, the main method of treating colorectal cancer has remained surgical intervention - 72% (V.V. Starinsky et al. “Malignant tumors of the colon and rectum in Russia in 1980-1996.” Russian Oncology Journal, No. 6, 1998, p. 4-13). At the same time, its results remain unsatisfactory. According to various authors, 5-year survival is not more than 60%. In half of the patients, in the next 2-3 years after radical surgery, local relapses and distant metastases occur.

Currently, a combined method for the treatment of colorectal cancer, including radiation therapy (B. A. Berdov et al. “Diagnosis and combined treatment of colorectal cancer”, M .: Medicine, 1986) or a combination of microwave hyperthermia in as a radio modifier with preoperative radiation (Kulieva N. “The effectiveness of preoperative thermoradiotherapy in the treatment of patients with colorectal cancer”; Ibragimov E. “Results of surgical and combined treatment of patients with colorectal cancer.” Abstracts of the II Congress of Oncologists of the CIS, Kiev, 2000, 7 43, 734). The use of the combined treatment method allows to improve the long-term results of surgical intervention (Nadvikova EA et al. “Preoperative irradiation of malignant tumors of the rectum.” In the book Materials of the V All-Russian Congress of Oncologists “High Technologies in Oncology”, Kazan October 4-7, 2000 ., Volume 2, pp. 240-241; Tsyb A.F. et al. “Local UHF hyperthermia in increasing the efficiency of radiation therapy for malignant tumors of various localizations. Theses of the II Congress of Oncologists of the CIS, Kiev, 2000, 381).

Along with hyperthermia, a radiomodifying agent that increases the sensitivity of a tumor to ionizing radiation, there may be chemical compounds, in particular metronidazole (SP Yarmonenko in the book “Radiomodifiers in radiation therapy of tumors”, Obninsk, 1982, p. 126).

The closest in technical essence and the achieved result to the claimed proposal is “A method for the treatment of colorectal cancer” (authors A. I. Kozhushkov et al., AS 1540072, 1987), which consists in the fact that in the preoperative period the patient local microwave hyperthermia is performed while metronidazole is added to the tumor in a DMSO solution, followed by irradiation of the tumor and radical surgery.

The disadvantages of the prototype method is the complexity of the method of summing up metronidazole (the need to create special antennas emitters for microwave hyperthermia), the time limit for the exposure of metronidazole in a DMSO solution to the tumor is 60 minutes (the maximum allowable time for microwave hyperthermia), the lack of the ability to accurately dose the drug (dissolution of metronidazole in DMSO is carried out until a saturated solution is obtained), pronounced general and neurotoxic side effects of the action of metronidazole p If the treatment efficiency is not high enough, due to the lack of achieving the necessary concentration of the drug in the tumor tissue.

The objective of the present invention is to provide a new, more effective method for the combined treatment of patients with primary operable forms of colorectal cancer, which allows to reduce the incidence of locoregional relapses, increase the average life expectancy and 5-year survival, among patients subjected to such treatment. The problem is solved in that a method for the treatment of colorectal cancer exposure of a tumor to radiation, local microwave hyperthermia and metronidazole in the form of a composite mixture with subsequent radical surgery is proposed. At the same time, on the 1st day of the 5-day course of irradiation, the patient is given a session of remote gamma-therapy ROD - 5 Gray; in the 2nd and 4th, intrarectal administration of a composite mixture containing metronidazole, sodium alginate and a 2% solution of dimethyl sulfoxide (DMSO) is carried out, and after a 6-hour exposure, a gamma-ray therapy of ROD - 5 Gray is performed, and in the 4th day - with subsequent intrarectal local microwave hyperthermia at a temperature of 42.5-43 ° C for 60 minutes; on the 3rd and 5th days, similar sessions of local microwave hyperthermia are carried out followed by remote gamma-therapy ROD - 5 Gray (scheme).

Scheme

Polyradiomodification technique in the treatment of colorectal cancer

RT - radiation therapy

M - metronidazole

Microwave - local microwave hyperthermia

Intrarectally injected composite mixture contains metronidazole, sodium alginate and dimethyl sulfoxide in the following ratios of ingredients in the composition in wt.%:

Metronidazole 12-22

Alginate Na 4-6

Dimethyl sulfoxide 2

Distilled water Up to 100

Example 1

Metronidazole 12

Alginate Na 4

Dimethyl sulfoxide 2

Distilled water 82

Example 2

Metronidazole 17

Alginate Na 5

Dimethyl sulfoxide 2

Distilled water 76

Example 3

Metronidazole 22

Alginate Na 6

Dimethyl sulfoxide 2

Distilled water 70

The quantitative composition of the composite mixture is calculated individually for each patient, based on the parameters of his height and weight. When using individually calculated doses of metronidazole in a composite mixture at a 6-hour intrarectal exposure, the concentration of the drug in the tumor tissue reaches 180-200 μg / g, which was established by pharmacokinetic analysis of pieces of tumor tissue removed during surgery, and is a necessary condition for effective action metronidazole to tumor cells as a radio modifier. The composite mixture is prepared ex tempore by mixing the calculated dose of metronidazole, DMSO and sodium alginate, followed by bringing the amount of the mixture to 200 g with distilled water. At the end of the 6-hour exposure, the mixture is removed from the rectum with a cleansing enema.

24-48 hours after the completion of the 5-day course of preoperative radiation, radical surgery is performed, the nature and volume of which is determined by the level of tumor localization in the rectum and the degree of its local distribution.

Examples of specific performance of the described method for the treatment of patients with colorectal cancer.

Example 1

Patient Blagov A.I., and / b No. 02/8815, 67 years old.

Clinical diagnosis: Cancer of the lower ampullar rectum (histologically - adenocarcinoma).

Height - 189 cm.

Weight 92 kg.

The required estimated amount of metronidazole in the composite mixture is 22 g. The total weight of the composite mixture is 200 g.

Treatment Methodology:

1st day - a session of remote gamma-therapy ROD - 5 Gray.

2nd day - intrarectal administration of a composite mixture with individually calculated amount of metronidazole 22 g individually for a given patient; after 6 hours holding a session of remote gamma-therapy ROD - 5 Gray.

Day 3 - a session of local intrarectal microwave hyperthermia at a temperature of 42.5-43 ° C for 60 minutes, followed by remote gamma-therapy ROD - 5 Gray.

4th day - intrarectal administration of a composite mixture with individually calculated individual metronidazole amount of 22 g for a given patient; after 6 hours, conducting a session of remote gamma therapy ROD - 5 Gray with subsequent local intrarectal microwave hyperthermia at a temperature of 42.5-43 ° C for 60 minutes.

Day 5 - a session of local microwave hyperthermia at a temperature of 42.5-43 ° C for 60 minutes, followed by remote gamma-therapy ROD - 5 Gray.

The total total focal dose of preoperative exposure was 25 Gray.

One day after the completion of the irradiation course, an operation was performed in the amount of abdominal-anal rectal resection.

The postoperative course is smooth, no complications were noted. The patient was discharged from the hospital 15 days after the operation.

Example 2

Patient Khomyakov A.M., and / b No. 02/8439, 66 years old.

Clinical diagnosis: Colorectal cancer (histologically-adenocarcinoma).

Height - 167 cm.

Weight - 66 kg.

The required estimated amount of metronidazole in the composite mixture is 18 g. The total weight of the composite mixture is 200 g.

Treatment Methodology:

1st day - a session of remote gamma-therapy ROD - 5 Gray

2nd day - intrarectal administration of a composite mixture with the amount of metronidazole 18 g individually calculated for a given patient; after 6 hours holding a session of remote gamma-therapy ROD - 5 Gray.

Day 3 - a session of local intrarectal microwave hyperthermia at a temperature of 42.5-43 ° C for 60 minutes, followed by remote gamma-therapy ROD - 5 Gray.

4th day - intrarectal administration of the composite mixture with the amount of metronidazole 18 g calculated individually for a given patient; after 6 hours, conducting a session of remote gamma therapy ROD - 5 Gray with subsequent local intrarectal microwave hyperthermia at a temperature of 42.5-43 ° C for 60 minutes.

Day 5 - a session of local microwave hyperthermia at a temperature of 42.5-43 ° C for 60 minutes, followed by remote gamma-therapy ROD - 5 Gray.

The total total focal dose of preoperative exposure was 25 Gray.

A day after the completion of the irradiation course, an operation was performed in the amount of abdominal-perineal extirpation of the rectum.

The postoperative course is smooth, without complications. The patient was discharged in satisfactory condition 20 days after surgery.

Treatment by this technique was carried out in 10 patients. All patients were discharged from the hospital in satisfactory condition. During the year of observation after surgery, relapses and distant metastases were not detected.

The technical result.

The proposed method for the treatment of colorectal cancer can improve treatment results by enhancing the damaging effect of preoperative radiation on the tumor, due to its combination with local microwave hyperthermia and the parallel use of metronidazole in the form of a composite mixture in individually calculated concentrations for each patient. This allows you to achieve a standard therapeutic concentration of 180-200 μg / g in the tumor tissue with a standard 6-hour exposure and provides the maximum radiosensitizing effect. Along with this, the use of a composite mixture containing metronidazole and sodium alginate also reduces pain and local inflammatory manifestations of the rectal mucosa. The claimed method allows to reduce the incidence of locoregional relapses and, thus, improve long-term treatment results.

Claims (2)

1. A 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 with subsequent surgical intervention, characterized in that metronidazole is used in the form of a composite mixture, while in the 1st the day of a 5-day course of exposure to the patient, a remote gamma-therapy session of ROD - 5 Gy; on the 2nd and 4th days, a composite mixture containing metronidazole, sodium alginate and a 2% solution of dimethyl sulfoxide is injected intrarectally, and after a 6-hour exposure, a gamma-ray therapy of ROD is performed - 5 Gy, and on the 4th day - followed by local microwave hyperthermia at a temperature of 42.5-43 ° C for 60 minutes; on the 3rd and 5th days, similar sessions of local microwave hyperthermia are conducted with subsequent sessions of remote gamma-therapy ROD-5 Gy. 2. The method according to claim 1, characterized in that the injected intrectally composite mixture contains metronidazole, sodium alginate and dimethyl sulfoxide in the following ratios of ingredients, wt.%: Metronidazole 12-22, sodium alginate 4-6, dimethyl sulfoxide 2, distilled water to 100 .