CC BY
11
34
Евразийский Союз Ученых (ЕСУ) #5 (50), 2018
CLINICAL ESTIMATION OF EFFICIENCY OF COHERENT IMMUNOPHARMACOTHERAPY IN COMPLEX TREATMENT OF UTERINE _CERVICAL CANCER_
Kamishov Sergey Viktorovich
MD, PhD, senior researcher, chemotherapeutist Republican Specialized Scientific and Practical Medical Center of Oncology and Radiology of the Ministry
of Health of the Republic of Uzbekistan, Tashkent, Uzbekistan
КЛИНИЧЕСКАЯ ОЦЕНКА ЭФФЕКТИВНОСТИ СОПРОВОДИТЕЛЬНОЙ
ИММУНОФАРМАКОТЕРАПИИ В КОМПЛЕКСНОМ ЛЕЧЕНИИ РАКА ШЕЙКИ МАТКИ
Камышов Сергей Викторович
кандидат медицинских наук, старший научный сотрудник отдела химиотерапии Республиканского специализированного научно-практического медицинского центра онкологии и радиологии Министерства Здравоохранения Республики Узбекистан, Ташкент
АННОТАЦИЯ
Целью исследования явилась оценка эффективности сопроводительной иммунотерапии в комплексном лечения больных раком шейки матки в стационарных условиях. Материал и методы. С этой целью были обследованы больных раком шейки матки (РШМ) T2-3N0-iM0 стадий (II-III клинические стадии). Результаты и обсуждения. В контрольной группе больных проведение химиотерапии приводило к выраженному проявлению признаков токсичности. Выраженность таких побочных проявлений химиотерапии, как анемия, лейкопения, ухудшение аппетита, тошнота и аллопеция, у части больных составляла третью степень токсичности, и у 13,3% пациенток - четвертую степень по аллопеции. Третья и четвертая степень токсичности уже не встречалась, за исключением такого специфического проявления, как аллопеция. Проведение ЭИФТ с плазмаферезом способствовало еще более выраженному снижению побочных проявлений цитостатического лечения на организм пациенток. У больных данной группы в половине случаев и более удалось купировать основные клинические проявления токсичности химиотерапии.
Вывод. Проведенные исследования показали, что наибольшей эффективностью в плане снижения побочных эффектов химиотерапии в комплексном лечении больных РШМ II-III стадий, а также в улучшении субъективного состояния больных и качества их жизни, обладает схема иммунотерапии, включающая прерывистый плазмаферез с последующей ЭИФТ, которая снижает основные клинические проявления токсичности химиотерапии, улучшает показатели субъективного состояния больных и качества их жизни.
Ключевые слова: рак шейки матки, иммунотерапия, полихимиотерапия, оценка эффективности лечения
ANNOTATION
The aim of the study was to evaluate the effectiveness of the accompanying immunotherapy in the complex treatment of patients with cervical cancer under stationary conditions. Material and methods. To this end, patients with cervical cancer (CC) T2-3N0-1M0 stages (II-III clinical stages) were examined. Results and discussion. In the control group of patients, chemotherapy led to pronounced signs of toxicity. The severity of such side effects of chemotherapy, like anemia, leukopenia, appetite impairment, nausea and allopecia, was a third degree of toxicity in some patients, and a fourth degree in allopecia in 13.3% of patients. The third and fourth degree of toxicity was not found, except for such a specific manifestation as allopecia. Carrying out EIPHT with plasmapheresis promoted an even more pronounced decrease in the side effects of cytostatic treatment on the patient's body. In the patients of this group, in half the cases and more, the main clinical manifestations of the toxicity of chemotherapy were suppressed. Conclusion. conducted studies showed that the greatest effectiveness in reducing side effects of chemotherapy in the integrated treatment of cervical cancer II-III stages, as well as in improving the subjective state of patients and their quality of life, has an immunotherapy scheme that includes intermittent plasmapheresis followed by EIPHT, which reduces the main clinical manifestations of toxicity of chemotherapy, improves the indicators of the subjective state of patients and the quality of their life.
Key words: cervical cancer, immunotherapy, polychemotherapy, evaluation of treatment effectiveness
Topicality. The history of cancer immunotherapy refers to 1891, when Dr. W. Coley of the Memorial Sloan-Kettering Cancer Center (USA, New York) first attempted to treat cancer patients with extracts from streptococcal cultures. As a result, in some patients tumor growth was inhibited, while others died from cachexia not associated with cancer. That's when the assumption arose about the harmful effect on the tumor of some factors that appear in response to the introduction of bacterial extracts [3, P.1419; 6, P.357;
7, P.1; 8 P.1597]. In 1962, O'Malley et al., In experiments in mice, showed that hemorrhagic necrosis in tumors after the introduction of bacterial lipopolysaccharide (LPS) is due to the action of not the LPS itself, but of some intermediate factor that appears in the blood serum in response to injection of LPS [ 1, P.330; 3, P.1419;4,P. 154; 6, P.357]. This serum had the ability to kill tumor cells when administered to other mice that did not receive LPS injections. Finally, in 1975, again at the Memorial Sloan-Kettering Cancer
Institute, E.Carswell et al. Discovered and described a mediator that has a cytotoxic effect on various tumor cells that appears in the blood of mice in response to the introduction of LPS from Bacillus Calmette-Guerin and named it "Tumor necrosis factor" - a factor of tumor necrosis [1, P.330; 8, P.1597]. During 10 years of work on this program, the scientists of the Institute developed a 3-step method for assessing the effectiveness of cancer biotherapy methods [3, P.1419; 5, P.1885]. For many years, cancer treatment has focused on surgery, chemotherapy and radiotherapy, but as knowledge about the immune system's capabilities in the fight against cancer deepens, treatment methods using the immune system against malignant tumors began to develop [8, P.1597]. Although immunotherapy of malignant tumors is a relatively new scientific trend, the results obtained over the last decade allow us to count on the important role of immunotherapeutic approaches in the treatment of cancer. Currently, immunotherapy is one of the most promising directions in the treatment of malignant neoplasms. It includes treatment of tumors with monoclonal antibodies, antitumor vaccines, cytokines, activated lymphocytes, etc. [8, P.1597]. Clear evidence and deciphering of the mechanism of oncogenesis, knowledge of the laws of this process and the "control system" at the molecular level of regulation allow one to speak about the effect on the various links of the pathogenetic process, not only from the point of application of suppressing the growth of neoplastic cells, but also from the positions of the immune response of the organism to the tumor process [6, P.357; 8, P.1597]. Thus, a new field of oncology - oncoimmunology, the formation of which began with the discovery of oncogenes and the development of methods for the formation of a specific immune response against them [5, P.1885; 7, P.1]. However, fundamental questions remain concerning the expression of specific antigens by human tumors, the immune response to this antigen, and the ability to influence this response in order to combat the tumor [2,4].
The most difficult question in the study of the effectiveness of the use of immunomodulators is a correct assessment of the appropriateness of the appointment of immunocorrective treatment and its effectiveness. It is clear that the progressing tumor causes serious changes in the immune response, with which the immune system alone cannot cope and the inclusion of immunomodulators in the complex of treatment of cancer patients is justified. In modern oncology, the role of immunology has significantly expanded, which provides new methods for diagnosis, monitoring and treatment of cancer, as well as correction of complications of traditional treatment. The new cancer treatment strategy is based on the principle of "complementary oncotherapy" [3, P.1419; 7, P.1; 8, P.1597], which implies the synergistic therapeutic effect of existing traditional and immunological methods of treatment, taking into account the etiopathogenetic significance of each method. Immunological methods of treatment, in this case, are present at all stages of antitumor treatment, but at each stage they perform various tasks.
Based on the foregoing, the aim of the study was to evaluate the effectiveness of accompanying immunotherapy in the complex treatment of patients with cervical cancer under stationary conditions.
Material and methods of investigation. For this purpose, patients with cervical cancer (cervical cancer) T2-3N0-1M0 stages (II-III clinical stages) who were in the oncological clinic in the departments of oncogynecology and chemotherapy were examined. All patients received comprehensive treatment of cervical cancer, comprising a two-stage combined chemoradiotherapy:chemotherapy cisplatine75mg/m2+ Ftoruracil 1000 mg/m2 1-5 days +telegammatherapy 50 Gy and brachytherapy 30-35 Gy. Extracorporeal immunopharmacotherapy was performed by exfusion of 500-1000 ml of autoblood in sterile "Gemakon" or "Terumo" containers and its centrifugation at 3000 rpm for 30 minutes. 50-80 ml of the supernatant of blood plasma, containing antibodies, circulating immune complexes, cytokines, products of cellular metabolism were removed. Then the obtained leukotrombomass and erythrocytic mass were incubated with thymalin in a total dose of 30 mg (for 3 procedures) at 37 ° C for 60-100 min, with the subsequent return of the conjugate to the circulatory system of patients. This method was carried out in a hospital, at the time when patients were admitted to chemotherapy and radiation therapy. In total, patients received 2 sessions of extracorporeal therapy at the beginning of admission to hospital and before discharge from the hospital. Depending on the type of extracorporeal therapy being performed, 4 groups of patients with cervical cancer were identified. The 1st group included patients of the control group, those patients with cervical cancer who did not receive immunotherapy. In the 2 nd (52 patients), cervical cancer patients underwent immunotherapy in the form of subcutaneous injections with thymomimetics (thymalin) in standard doses for 10-14 days. The third group consisted of 62 patients with cervical cancer who underwent extracorporeal immunotherapy (EIPHT) by exfusion 200-250 ml of autologous blood in sterile containers "blood bags" or "Terumo" immunomodulator thymalin incubation with a total dose of 30 mg (3 treatments) with 37 ° C for 60-100 min followed by reinfusion of the resulting conjugate and group 4 consisted of 54 patients with cervical cancer who were treated with EIPHT in combination with plasmapheresis. It should be noted that patients who received any type of immunotherapy, were subjected to it every time during the receipt of chemo-and radiotherapy. The overall cumulative five-year survival was assessed by Kaplan E.L. et Meier R. in patients with cervical cancer, depending on the different options of immunotherapy in complex treatment.
The results obtained and their discussion.
Initially, the degree of toxicity of polychemotherapy was studied, which showed that the degree of toxicity of chemotherapy in patients with cervical cancer was set on the CTC-NCIC scale. In the control group of patients, chemotherapy led to pronounced signs of toxicity. The severity of such side effects of chemotherapy, like anemia, leukopenia, appetite
impairment, nausea and allopecia, was a third degree of toxicity in some patients, and a fourth degree in allopecia in 13.3% of patients. The data presented show a decrease in the toxicity of chemotherapeutic treatment in this category of patients after EIPHT. The third and fourth degree of toxicity was not found, except for such a specific manifestation as allopecia. Carrying out EIPHT with plasmapheresis contributed to an even more pronounced decrease in the side effects of cytostatic treatment on the patient's body. In the patients of this group, in half the cases and more, the main clinical manifestations of the toxicity of chemotherapy were suppressed.
The evaluation of the effect of extracorporeal immunopharmacotherapy on the quality of life of patients showed that immediate changes in the subjective state of cervical cancer patients after the treatment were determined by the WHO ECOG scale. Parameters of the subjective condition of patients with cervical cancer were studied when patients were admitted to the autohemotherapy department before the course of immunotherapy and immediately before discharge from the hospital. In the control groups of patients where immunotherapy was not performed, the subjective state indicators are presented when patients enter the hospital and immediately before their discharge from the hospital. Conducting immunocorrection methods led to a reduction in the severity of the general condition of patients. In this case, a more pronounced effect on the reduction in the severity of the general condition of the patients was noted after the EIPT with plasmapheresis. Treatment of radiation damage is a rather difficult task. This is due to the fact that, as a rule, they are characterized by irreversible changes, although compensatory mechanisms can often be developed. According to data of different authors, a temporary cure is achieved only in 35-65% of patients, and relapses are observed in 3080% of patients. Carrying out of immunotherapeutic measures has allowed to considerably reduce the degree of radiation complications of radiation reactions from the side of pelvic organs. The most important criterion for the success of ongoing treatment for cancer patients in recent years is the quality of their life. The quality of life is understood as an integral evaluation of a person's physical, mental and social functioning, based on his subjective perception. The quality of life of patients with cervical cancer after the treatment was assessed by the SF-36 questionnaire. The quality of life of patients with cervical cancer after performing immunoregulatory measures was significantly higher than in the control group of patients without immunotherapy, which was expressed in an increase in both the physical and mental components of health. The score of the physical component of health in the 3rd control group of patients with cervical cancer upon admission to the hospital was 141.4 ± 44.2 and 139.7 ± 46.5, and at discharge 163.5 ± 37.3 and 159.8 ± 40.4, respectively (P <0.01). In the 1st group of cervical cancer, where EIPHT was performed without plasmapheresis, this indicator at the beginning of treatment was 142.2 ± 41.0 and 139.1 ± 35.3, after immunotherapy - 254.6 ± 48.1 and 248, 7 ± 39.4,
respectively (P <0.01). The highest indicators of the physical component of health were noted in the 2 nd group of cervical cancer, in which EIPHT with plasmapheresis was used. Before the treatment, this indicator was 137.8 ± 45.5 and 140.2 ± 32.6, after the immunotherapy - 264.4 ± 41.9 and 261.6 ± 33.7, respectively (P <0.01). The sum of the points of the mental health component in the 3rd control group of patients with cervical cancer and in the 6th control group of patients with RY when admitted to the hospital was 174.5 ± 50.3 and 167.8 ± 48.8, and at discharge -187.9 ± 43.2 and 182.4 ± 47.7, respectively (P <0.01). In the 1st group of cervical cancer, where EIPHT was performed without plasmapheresis, this index at the beginning of treatment was 172.3 ± 54.6 and 164.8 ± 42.2, after carrying out immunotherapy - 232.0 ± 56.1 and 223, 6 ± 44.2, respectively (P <0.01). Just as with the indicator of the physical component of health in assessing the quality of life of oncogynecologic patients, the highest indices of the mental component of health were noted in the 2 nd group of cervical cancer, in which EIPHT with plasmapheresis was used. Before treatment, this indicator was 173.2 ± 51.1 and 170.0 ± 37.9, after immunotherapy - 251.1 ± 48.8 and 246.4 ± 37.4, respectively (P <0.01). Thus, the conducted studies made it possible to conclude that the most effective in the combined treatment of patients with cervical cancer II-III has stages of immunocorrection, including intermittent plasmapheresis followed by EIPHT, which reduces the main clinical manifestations of toxicity of chemotherapy, the severity of radiation complications and leads to improve the quality of their lives. Thus, the conducted studies showed that the most effective in reducing the side effects of chemotherapy in the complex treatment of cervical cancer II-III stages, as well as in improving the subjective state of patients and their quality of life, has an immunotherapy scheme that includes intermittent plasmapheresis followed by EIPHT, which reduces the main clinical manifestations of toxicity of chemotherapy, improves the indicators of the subjective state of patients and their quality of life.
REFERENCES
1. Allarez R. (DDR) and etoposide ( VP 16) for the treatment of recurrent or advanced M.,Munger K. Hemzar and zisplatin malignancies//! Clin. Oncol.-2005.-V. 16.-P.330-337.
2. Begley J., Ribas A. Targeted therapies to improve tumor immunotherapy // Clinical cancer research. -2008. -V.14. -P.4385-4391.
3. Bookman M.A., Brady M.F., McGuire W.P. et al. Evaluation of new platinum-based treatment of regimens in advanced-stage ovarian cancer: a phase III trial of the Gynecologic Cancer Intergroup // J. Clin. Oncol. -2009. -27 (9). -P.1419-1425.
4. Boyce J., Fruchter R., Nicastri A. Prognostic factors in stage I carcinoma of the cervix. // GynecolOncol. — 2011. — 12. — 154-165.
5. Charoentong P., Angelova M., Efremova M., Gallasch R., Hackl H., Galon J., Trajanoski Z. Bioinformatics for cancer immunology
Евразийский Союз Ученых (ЕСУ) # 5 (50), 2018
37
and immunotherapy // Cancer Immunol. Immunother. -2012. -V.61. -N11. -P.1885-1903.
6. Cheever M.A. Twelve immunotherapy drugs that could cure cancers // Immunol Rev. -2008. -V.222. -P.357-368.
7. De Felice F., Marchetti C., Palaia I., Musio D., Muzii L., Tombolini V., Panici P.B.
Immunotherapy of Ovarian Cancer: The Role of Checkpoint Inhibitors // Journal of Immunology Research. -2015. -P.1-7.
8. Emens L.A. Breast cancer immunobiology driving immunotherapy: vaccines and immune checkpoint blockade // Expert Rev. Anticancer Ther. -2012. -V.12. -N12. -P.1597-1611.
NALYSIS OF EFFICIENCY OF IMMUNOPHARMACOTHERAPY IN COMPLEX TREATMENT OF OVARIAN CANCER AND CERVICAL CANCER
Kamishov Sergey Viktorovich
MD, PhD, senior researcher, chemotherapeutist
Republican Specialized Scientific and Practical Medical Center of Oncology and Radiology of the Ministry
of Health of the Republic of Uzbekistan, Tashkent, Uzbekistan
АНАЛИЗ ЭФФЕКТИВНОСТИ ИММУНОФАРМАКОТЕРАПИИ В КОМПЛЕКСНОМ ЛЕЧЕНИИ РАКА ЯИЧНИКОВ И РАКОМ ШЕЙКИ МАТКИ
Камышов Сергей Викторович,
кандидат медицинских наук, старший научный сотрудник отдела химиотерапии Республиканского специализированного научно-практического медицинского центра онкологии и радиологии Министерства Здравоохранения Республики Узбекистан, Ташкент
АННОТАЦИЯ
Цель исследования. оценка эффективности сопроводительной иммунотерапии в комплексном лечения больных раком шейки матки и раком яичников в стационарных условиях. Материалы и методы. С этой целью были обследованы больных раком шейки матки (РШМ) и раком шейки матки (РШМ) T2-3N0-iM0 стадий (II-III клинические стадии), которые находились в онкологической клинике в отделениях онкоги-некологии и химиотерапии. Результаты. Проведения ЭИФТ с плазмаферезом способствовало еще более выраженному снижению побочных проявлений цитостатического лечения на организм пациенток. Вывод. Проведенные исследования позволили сделать заключение о том, что наибольшей эффективностью в плане снижения побочных эффектов химиотерапии в комплексном лечении больных РШМ и РЯ II-III стадий, а также в улучшении субъективного состояния больных и качества их жизни, обладает схема иммунотерапии, включающая прерывистый плазмаферез с последующей ЭИФТ, которая снижает основные клинические проявления токсичности химиотерапии, улучшает показатели субъективного состояния больных и качества их жизни. Кроме того, использование методик ЭИФТ в комплексной терапии онкогинеко-логических заболеваний позволило повысить показатели пятилетней выживаемости пациенток.
Ключевые слова: рак яичников, рак шейки матки, иммунотерапия, полихимиотерапия, оценка эффективности лечения, безрецидивное течение
ANNOTATION
The aim of the study was to evaluate the effectiveness of accompanying immunotherapy in the complex treatment of cervical cancer and ovarian cancer in stationary conditions. Materials and methods. For this purpose, patients with cervical cancer (cervical cancer) and cervical cancer (cervical cancer) T2-3N0-1M0 stages (II-III clinical stages) were examined at oncology clinics in oncogynecology and chemotherapy departments. Results. Carrying out EIPHT with plasmapheresis contributed to an even more pronounced decrease in the side effects of cytostatic treatment on the patient's body. Conclusion. The conducted researches made it possible to draw a conclusion that the greatest effectiveness in reducing side effects of chemotherapy in the complex treatment of patients with cervical cancer and stage II-III stage II, as well as in improving the subjective state of patients and their quality of life, has an immunotherapy regimen including intermittent plasmapheresis followed by EIPHT, which reduces the main clinical manifestations of toxicity of chemotherapy, improves the indicators of the subjective state of patients and their quality of life. In addition, the use of EIPHT techniques in the complex therapy of oncogynecologic diseases made it possible to increase the five-year survival rates of patients.
Key words: ovarian cancer, cervical cancer, immunotherapy, polychemotherapy, evaluation of treatment efficacy, relapse-free current.
Topicality. The most difficult question in the study of the effectiveness of the use of immunomodulators is a correct assessment of the appropriateness of the appointment of immunocorrective treatment and its effectiveness. It is clear that the progressing tumor causes serious changes in the immune response, with which the immune system alone cannot cope and the inclusion of
immunomodulators in the complex of treatment of cancer patients is justified. In modern oncology, the role of immunology has significantly expanded, which provides new methods for diagnosis, monitoring and treatment of cancer, as well as correction of complications of traditional treatment. The new cancer treatment strategy is based on the principle of "complementary oncotherapy" [3, P.242; 7, P. 153;8,
