UA120904C2 - METHOD OF COMPLEX TREATMENT OF PATIENTS WITH UTERINE SARCOMA OF I-II STAGES - Google Patents

Abstract

The invention relates to a method of complex treatment of patients with stage I-II uterine sarcoma, including adjuvant chemotherapy - AHT, and remote radiation therapy - DPT, which after surgery is performed immunohistological examination of the tumor to determine the degree of expression of markers PD-L1 and MMP -9 and in the absence of expression in any of the markers, the tactics of adjuvant treatment consists of intracavitary gamma therapy with a single focal dose of 3.5 Gy to SOD 40 Gy and three cycles of ACT every three weeks according to the scheme: intravenous doxorubicin 60 mg / m2 and endoxan 600 mg / m2; and in the presence of expression of any degree in both markers first conduct three cycles of AHT with an interval of three weeks according to the scheme: gemcitabine 900 mg / m2 intravenously on the first and eighth day and docetaxel 75 mg / m2 intravenously on the eighth day from the beginning of AHT, then DPT to an average focal dose of 50 Gy and then three cycles of AHT every three weeks according to the scheme: intravenous doxorubicin 60 mg / m2 and endoxan 600 mg / m2.

Description

The method belongs to medicine, in particular to oncology and radiology, and can be used for complex therapy of patients with stage I-II uterine sarcoma.

Uterine sarcoma (US) is one of the most aggressive and rare tumors affecting the female genital tract. The frequency of its occurrence is from 3 to 9 95 of all uterine tumors. It has always been difficult to study the features of uterine sarcoma, because it is a rare tumor with different histological features, an aggressive course and an unfavorable prognosis. The achievements of recent years in oncology suggest that the unsatisfactory results of SM treatment may be associated with an underestimation of the role of heterogeneity of molecular genetic characteristics of the tumor, which require an individual approach to treatment.

Currently, the standard method of treating patients with uterine sarcoma is surgical intervention in the volume of hysterectomy with bilateral adnexectomy with a thorough examination of the contents of the abdominal and pelvic cavity with cytological control and biopsy of the omentum (11.

However, the surgical method of sarcoma treatment is not capable of significantly improving the effectiveness of treatment, in particular reducing the frequency of local and remote recurrence.

The use of chemotherapy (HT) after surgical intervention can increase the effectiveness of SM treatment. So, there is a known method of treating SM, in which CT is performed after surgery using the drugs gemcitabine and docetaxel, which allows to reduce the frequency of distant relapses (2). But the use of modern chemotherapy drugs without taking into account the molecular and genetic features of the tumor does not solve the problem of local recurrence, increases the toxicity of the treatment and leads to the occurrence of severe complications. Overall survival rates are also not satisfactory.

The method closest to the claimed method is a method of complex treatment of SM, which includes surgery, traditional remote radiation therapy and three cycles of monochemotherapy using doxorubicin at a dose of 60 mg/m 3). But the method does not reduce the frequency of occurrence of distant metastases and does not increase the duration of recurrence, which is 3.8 months on average. The reason for the negative performance indicators of the known method lies in the lack of an individual approach to a specific type of tumor without taking into account its molecular genetic features.

In this regard, the use of tumor markers in the treatment of cancer becomes especially important

The biological features of a sarcoma with an aggressive course and an unfavorable prognosis are taken into account for the selection of tactics and a comprehensive treatment program.

The invention is based on the task of creating a method of comprehensive treatment of patients with

SM stage I-II, in which determination of the degree of expression of RO-Y1 and MMP-9 markers and selection of the scheme of adjuvant chemotherapy (AKT) and radiation therapy (PT) in case of absence of expression in any of the markers or its presence in both markers, will allow choosing an individual scheme of AHT and PT, which will ensure an increase in the effectiveness of therapy due to a decrease in the frequency of occurrence of distant metastases and local recurrences and an increase in the recurrence-free period in patients.

The task is solved as follows: in the known method of complex treatment of patients with stage I-II uterine sarcoma, which includes adjuvant chemotherapy and remote radiation therapy (DPT), according to the invention, after surgery, an immunohistological examination of the tumor is performed using RO-I1 markers and MMP-9, determine the degree of expression of each of them, and in the absence of expression of any of the markers, the tactics of adjuvant treatment consists of intracavitary gamma therapy with a single focal dose of 3.5 Gy to SOD of 40 Gy and three cycles of AHT every three weeks according to the scheme: intravenous doxorubicin 60 mg/m2 and endoxan 600 mg/m2; and in case of any degree of expression in both markers, three cycles of AHT are first performed with an interval of three weeks according to the scheme: gemcitabine 900 mg/m? intravenously on the first and eighth day and docetaxel 75 mg/m? intravenously on the eighth day from the start of AHT, then DPT to an average focal dose of 50 Gy and then three cycles of AHT every three weeks according to the scheme: intravenous doxorubicin 60 mg/m: and endoxan 600 mg/m.

Hyperexpression of the RO-I/1 marker in tumor cells correlates with an unfavorable disease prognosis and promotes tumor metastasis by releasing matrix metalloproteinases (MMPs). Assessment of the degree of co-expression of the molecule PO-Y1 and MMP-9 is a potential biomarker of the aggressiveness of the course of CM, which is characterized by the frequency of relapses (Table 1).

Table 1

The relationship between the coexpression of RO-I 1 and MMP-9 and the frequency of recurrence for the main histotypes of uterine sarcoma

Number Presence Absence of markers, points o; UT o; LMS", p | ESSYA p | VAT" p

SRO HER MMR-Z patients, n relapse, 7o relapse, 7o 0 10 1 2 1 sh 0 - ! 0 10 o 71 101 16 | 1875 | 83 | 1 | 1 | 1 1 12 1 2 1 l00 | - | 0 | about | 2 72 | 1 1 4 1 700 | - | 0 | 0 | 4 3 | 0 1 2 1 0 HER - ! 01 0 o

Note. "LMSO - leiomyosarcoma; "ESS - endometrial stromal sarcoma; "VAT is an undifferentiated sarcoma.

The data shown in the table confirm the presence of relapses in 100 95 patients with co-expression

RO-I1 and MMP-9 of any degree and the absence of relapses or their presence only in 18.75 95 (in 3 out of 16) patients with zero expression of any of the markers. On the basis of experimental data, the authors established for the first time the dependence of the frequency of recurrence on the degree of co-expression of markers RO-Y/1 and MMP-9, and, based on its level, to prescribe appropriate individualized treatment. The presented set of features of the invention is optimal for choosing adequate AHT regimens and PT dose regimens, which leads to an increase in the susceptibility of tumor cells, which results in a decrease in the frequency of distant metastases and local recurrences.

In the open sources of information of Ukraine, the CIS countries, and abroad, no methods of complex treatment of patients with SM were found, in which the choice of personal AHT schemes and dosage regimen

PT was carried out depending on the degree of co-expression of RO-I1 and MMP-9 markers.

The invention is industrially suitable because it can be reproduced and repeated many times in health care facilities.

The claimed method is carried out as follows.

In the tissue of the tumor, obtained after surgical intervention, an immunohistological study was carried out using the markers RO-Y7 and MMP-9 and the degree of expression of each of the markers |4)Y1 was determined by known immunohistochemical methods. After that, the degree of expression of each marker was evaluated in points according to the scale of intensity (or reaction) of cytoplasmic staining of tumor cells (4). For RO-I1 and MMP-9 markers, the scale looks like this: 0 points - no reaction, 1 point - weak cytoplasmic staining (up to 30.0 95 tumor cells), 2 points - moderate reaction (from 30.0 to 60.0 95 stained cells), Z points - a strong cytoplasmic reaction (60.0-100.0 95 tumor cells). In the absence of expression of any of the markers, intracavitary gamma therapy was performed with a single focal dose of 3.5 Gy to a SOD of 40 Gy. After 2 weeks, AHT was started and three cycles were performed with an interval of 21 days. Scheme of each cycle: intravenous doxorubicin 60 mg/m: and endoxan 600 mg/m-. In the case of any degree of expression in both markers, three cycles of AHT were first performed according to the scheme of each of them: gencitabine 900 mg/m intravenously in

From the first and eighth day and docetaxel 75 mg/m? intravenously on the eighth day from the start of AHT.

After 2 weeks, remote radiation therapy (PT) was performed to an average focal dose of 50

Gr. Three weeks after PT, three cycles of AHT were performed according to the scheme of each of them: intravenous doxorubicin 60 mg/m: and endoxan 600 mg/m.

Below are examples of the use of the claimed method.

Example 1

Patient G., 60 years old, ist. min. Mo. 12282, was treated at the clinic of the "S.P. Grigoriev Institute of Medical Radiology of the National Medical University of Ukraine" in the department of combined radiation and complex therapy from 11/16/2016 to 02/10/2017 with a primary diagnosis of uterine fibroids. The patient underwent radical surgery and a pathohistological diagnosis of uterine leiomyosarcoma was established

1st stage (TIM x MO). In the tumor tissue, in accordance with the proposed method, the degree of expression of markers RO-Y1Y7 and MMP-9 was determined, with further evaluation of their value. It was established that there was no expression of the MMP-9-0 marker, and a weak degree of expression of the PO- (1-1) marker. The scheme of adjuvant treatment of the patient in this case began with intracavitary gamma therapy with a single focal dose of 3.5 Gy up to SOD 40 Gy. After 2 weeks, three cycles of AHT were performed with an interval of 21 days. The scheme of each cycle: intravenous doxorubicin 60 mg/me and endoxan 600 mg/me. During further observation, the patient remained in remission for 13 months after treatment. Relapses and distant metastases in was not detected during the observation process.

Example 2

Patient G., 70 years old, ist. min. Mo. 04724, was treated at the clinic of the "S.P. Grigoriev Institute of Medical Radiology of the National Academy of Medical Sciences of Ukraine" in the department of combined radiation and complex therapy from 06.07.2014 to 04.12.2015 with a primary diagnosis of uterine fibroids. The patient underwent a radical operation and a pathohistological diagnosis of undifferentiated sarcoma of the uterus of the HER stage (T2MHMO) was established. In the tumor tissue, in accordance with the proposed method, the degree of expression of markers PO-I1 and MMP-9 was determined, with further evaluation of their value.

A high degree of expression of the MMP-9-3 marker and a moderate degree of expression of the RO-I 1-2 marker were established. Due to the presence of expression in both markers, the patient was first given three cycles of AHT according to the scheme of each of them: Gencitabine 900 mg/m? intravenously on the first and eighth day and docetaxel 75 mg/m? intravenously on the eighth day from the start of AHT. After 2 weeks, remote radiation therapy was performed to an average focal dose of 50 Gy. Three weeks after PT, three cycles of AHT were performed according to the scheme of each of them: intravenous doxorubicin 60 mg/m and endoxan 600 mg/m7. The patient remained in remission for 25 months. after treatment.

Recurrences and distant metastases were not detected during observation.

18 patients were treated using this method. The results of the treatment are summarized in the table.

Table 2

Characterization of the results of treatment of patients with SM

The indicator of the effectiveness of the treatment according to the claimed method, Sh

The frequency of occurrence of remote relapses, 90 observations up to 3 years, months.

So, the data presented in the table testify to the effectiveness of complex treatment of uterine sarcoma according to the claimed method, and confirm the decrease in the frequency of distant metastases and local recurrences, as well as an increase in the recurrence-free period to 32.2 months. when observed up to 3 years.

Thus, the use of the claimed method allows: to provide individual AHT schemes and an adequate dose regimen of PT for the treatment of sarcoma; reduce the frequency of local relapses to 5.3 9o; reduce the frequency of distant metastases to 16.7 95.

This will contribute to increasing the effectiveness of the complex treatment of SM, thanks to the prevention of relapses and metastases, which ensures the saving of medicines per patient in the amount of UAH 16,000.

Sources of information: 1. Veyid M.5. Tne Mapadetepi oi Shegipe Zagsotav: yeehirookK oi Supayesoiodisa! Opsoiodu / M.5.

Weead. - EBOO, 2013. - R. 399-404. 2. Fedenko A.A. Treatment of leiomyosarcoma! mothers / A.A. Fedenko, A.A. Konev, V.A. Gorbunova // Sarcomas of bones, soft tissues and skin tumors. - 2014. - Volume 1. - P. 56-63. 3. Sukhyn V.S. Features of the clinical course of undifferentiated sarcomas of the uterus /

V.S. Sukhyn // A7egba|tsap u. Opsoi - 2018. - Mo 1. - b. 31-34. 4. Babichenko I.I. New method of immunohistochemical diagnosis of tumor growth: учеб. manual / I.I. Babichenko, V.A. Kovyazin - M.: RUDN, 2008. - 109 p.

Claims (1)

FORMULA OF THE INVENTION The method of complex treatment of patients with stage I-II uterine sarcoma, which includes adjuvant chemotherapy - AHT, and remote radiation therapy - DPT, which is distinguished by the fact that after surgery, an immunohistological examination of the tumor is performed to determine the degree of expression of RO-1 and MMP markers -9 and in the absence of expression of any of the markers, the tactics of adjuvant treatment consists of intracavity gamma- therapy with a single focal dose of 3.5 Gy to SOD 40 Gy and three cycles of AHT every three weeks according to the scheme: intravenous doxorubicin 60 mg/m2 and endoxan 600 mg/m-; and in case of any degree of expression in both markers, three cycles of AHT are first performed with an interval of three weeks according to the scheme: gemcitabine 900 mg/m? intravenously on the first and eighth day and docetaxel 75 mg/m intravenously on the eighth day from the start of AHT, then DPT to an average focal dose of 50 Gy and then three cycles of AHT every three weeks according to the scheme: intravenous doxorubicin 60 mg/m: and endoxan 600 mg / m.