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13«MEDICINE, SCIENCE AND EDUCATION», № 1, 2023
УДК: 616.006:615.7 DOI: 10.24412/1609-8692-2023-1-10-17
МРНТИ: 76.29.49
RETROSPECTIVE ANALYSIS OF TOXIC COMPLICATIONS OF METHOTREXATEAFTER HIGH-DOSE CHEMOTHERAPY IN PEDIATRIC ONCOLOGY
* Z. Tobylbayeva1,2, S. Zhaganova1, М. Baimuratova1, А. Ryskulova1
1. Kazakhstan's Medical University «KSPH» Almaty, Kazakhstan 2.Corporate fund «University Medical Center», Astana, Kazakhstan
Summary
Today, thanks to the President of Kazakhstan, pediatric oncology has high verification and timely treatment regardless of age and type of morbidity. Retrospective analysis of detected toxic complications after high-dose chemotherapy in children showed the severity of diseases in the regions of our country in the past years. Development and revision of treatment protocols and introduction of new methods in intensive therapy of toxic complications are the main directions in pediatric oncology.
Key words. Methotrexate, high-dose chemotherapy, hemoperfusion, toxic complications, pediatric oncology.
Relevance. A retrospective analysis of toxic complications after high-dose chemotherapy with methotrexate in children with cancer is presented for the 2019-2020 period. This analysis was prepared in the framework of the Grant project of the Ministry of Education and Science of the Republic of Kazakhstan "A new method for reducing the methotrexate toxicity after high-dose chemotherapy in children with cancer by hemoperfusion with HA 230, 330 absorbers", the premise of which was a progressive increase in the number of toxic complications of varying severity and damage after high-dose chemotherapy . On average, 20 % of the total number of patients with an oncological profile developed complications with the gastrointestinal tract, respiratory and urinary systems.
Introduction. The relevance of the topic is based on the recent increase of oncological diseases among children in the country. This is related not only to the current growth, but also to an increase in the alertness of district doctors and pediatricians, an improvement in the quality and availability of diagnostic tools.
According to World Health Organization 80% of children with cancer survive in high-income countries , compared to 30% in low-income countries with uncomfortable conditions. Each year, an estimated 400 000 children (aged 0-19 years) develop cancer globally [1]. Therefore, according to the Ministry of Health, the incidence of malignant neoplasms in 2021 was 52% ( in pediatric oncology), while in 2015 this figure used to be 29% ( informburo. kz 15.02.2022). statistically. Every year in Kazakhstan, on average, about 600 new cases of malignant neoplasms in children are detected. Among these cases, there are about 40% of leu-kemias and 60% of solid tumors.
High-dose chemotherapy with metho-trexate is one of the treatments for many types of cancer, including, acute lymphoblastic leukemia (ALL), non-Hodgkin's lymphoma, and osteosarcoma [1-4]. Methotrexate concentration monitoring is a generally accepted method for identifying patients with high risk of developing severe toxic effects of the drug usage [57] and preventing toxic effects by early administration modified dose in patients with signs
PUBLIC HEALTH
of impaired plasma clearance of methotrexate [4,8-10]. However, even with adherence to the treatment protocol and the use of the above-mentioned toxicity reducing methods, there is a delay in the elimination of methotrexate from the body. In these cases, side and toxic effects can be fatal, which in 80% of cases is associated with myelosuppression. [11-15] And then extracoporal methods of blood purification is regarded as the method of choice.
The main innovation of the study is the use of the hemosorption method with HA 230,330 adsorbers in cases where conservative therapy is unsuccessful, to eliminate methotrexate and, thus, reduce the toxic effect in children with cancer after high-dose chemotherapy.
For a number of reasons related to both the course and progression of the underlying disease and the action of methotrexate, the excretion of the latter can be impaired, which can lead to the development of a lethal outcome [4,15].
The aim of the study was to study the dynamic changes in the type and frequency of complications after high-dose chemotherapy with methotrexate in children with cancer over the 2019-2020 period.
Material and methods: A retrospective analysis of 529 medical case histories of patients with oncological profile was carried out for 2019-2020 period on the basis of the Corporate Fund "University Medical Center", Department of Pediatric Anesthesiology and Intensive Care (with a surgery unit). The ob-
tained data was recorded in the created registry in Microsoft Office Excel and was processed by the methods of variation statistics in the "Statistica 6.0" application package. Numerical data will be presented in absolute values and standard deviation, and categorical data as frequency and percentage. The normality of the data can be assessed using the asymmetry coefficient, and normally distributed variables will be analyzed using parametric tests (paired t test and analysis of variance), the Tukey weighted mean determination. P-values < 0.05 will be regarded as significant.
The following disease inclusion criteria were established: early and late complications after high-dose chemotherapy with methotrex-ate for the 2019-2020 period.
Exclusion criteria: complications after chemotherapy with other cytostatics.
Results. 529 case histories were analyzed for the 2019-2020 period. The total number of patients under the age of 5 years who received high-dose chemotherapy with methotrexate during this two-year period was 182 people. An analysis of the data obtained confirms the relevance of oncological diseases in the pedi-atric population problems, namely (Table 1): admissions of patients to the hospital in 2020 increased by 32% compared to admissions in 2019 (in 2019-228; in 2020-301 patients); the frequency of hospitalizations in 2020 increased from 1 to 11 times, while the frequency of hos-pitalizations in 2019 upsurged from 1 to 9 times.
Table 1. Patients who received Methotrexate for the 2019-2020period:
2019 2020
Total number of patients 228 301
Boys 137 167
Girls 91 134
Children under 5 years 79 103
Initial admission 43 52
Readmission 1SS 249
Number of complications 169 141
As can be seen in Table 1, despite the admissions in 2020 increased significantly relatively stable number of initial admission (Table 2) compared to 2019 (85 and 96, re-(2019-43 and 2020-52), the number of re- spectively).
Table 2. Comparative number of hospitalizations for the analyzed period:
2019 2020
First admission 43 52
Second admission 85 96
Third admission 61 84
Forth admission 51 61
Fifth admission 22 44
Sixth admission 20 33
Seventh admission 12 18
Eighth admission 6 8
Ninth admission 1 2
Tenth admission 0 4
Eleventh admission 2 1
The frequency along with the primary ority of secondary and even tertiary hospital-admission of patients to the hospital can be izations is obvious, which undoubtedly proves judged from the data in Table 2, where the pri- the relevance of studied topic.
Table 3. Number of patients by nosology in years
2019 DISEASE 2020
172 Acute lymphoblastic leukemia 214
9 Burkitt's lymphoma 8
21 Osteogenic sarcoma 24
4 Non-Hotfgkin's lymphoma 6
15 Medulloblastoma 26
1 T-cell lymphoblastic lymphoma 4
2 Anaplastic large cell lymphoma 0
0 Malignant neoplasm 3
0 Embryonic tumor of CMS 9
0 Aplastic large cell lymphoma 7
2 Acute myeloid leukemia 0
1 & large-cell lymphoma 0
1 Histiocytosis 0
228 Overall 301
In addition, the interest was high on the data obtained by us in the context of each of the studied years (Table 3). The number of methotrexate complications depending on 13 disease forms, was observed in the direction of a dynamic increase in episodes with diagnoses: acute lymphoblastic leukemia, osteogenic sarcoma, non-Hodgkin's lymphoma, medulloblastoma, T-cell lym-phoblastic lymphoma, accounting for 38.5% (n -5). At the same time, as can be seen in Table 3, there was an increase from zero values in 2019 an increase and in the next year (2020), these are registered cases with a clinically established diagnosis, isolated cases: a malignant neoplasm, an embryonic tumor of the central nervous system, aplas-tic large cell lymphoma, composing 23.1% (n -3).
Thus, monitoring the registration of complications, depending on the type and frequency of diseases, after high-dose che-
motherapy with methotrexate in children with cancer over a 2-year period, made it possible to identify 61.5% (n -8) of cases.
We noted a 3.3 times increase in early complications registered in 2019 (58 cases) compared with cases detected in 2020 (192 cases). Similarly, comparative statistics for 2019-2020 shows an increase in the number of late complications in 2020 - 103 cases and in 2019 - 66 cases (Figure 1), where the tendency of intoxication uplifted significantly by 2 times. It should be noted that in 2020 emitogenic disorders prevailed substantially (22%), while in 2019, the above-mentioned disorders alongside with early complications accounted for only 3%. Perhaps this increase in complications is due to the ineffective administration of the methotrexate antidote (sodium folinate intravenously) at the early stages of treatment, which requires the introduction of combination therapy for toxic complications in children.
Figure 1. Comparative assessment of early complications for the 2019-2020 period
Undoubtedly, the absence of methotrexate use related complications therapy (Table 4) has led to a high frequency of early and late complications in one patient simultaneously (2019-5 patients; 2020-146 patients).
It is worth noticing that the total number of patients who received sodium folinate was 463 children, namely:
In 2019 - 45.4% (n -210 patients)
In 2020 - 54.64% (n -253 patients) At the same time, the cost of 1 sodium folinate bottle is 18 000 tenge. The cost of this drug soared every year (in a ratio of 1:2) to the total number of children receiving methotrexate. The economic benefit proves the implementation of extracorporeal treatment methods, while without these methods, the amount of expenses per 1 patient during the analyzed period uplifted significantly (Table 5).
Table 4. Comparative characteristics of late complications for the 2019-2020period:
Late complications: 2019 2020
Hematopoietic aplasia 42 53
Neurological disorders 1 4
Methotrexate elimination delay 6 6
Toxic dermatitis 6 12
Toxic hepatitis 6 8
Acute renal failure 1 4
Acute liver failure 1 2
Pneumonitis 2 2
Hemorrhagic syndrome - 3
Epidermolysis - 1
Arterial hypertension - 1
Chemo resistant form - 1
Protein-energy malnutrition - 2
Toxic gastritis - 1
Allergic dermatitis - 1
Genital herpes 1 -
Hyperplastic syndrome - 2
Table 5. Comparative assessment of costs per patient with and without hemodiafiltration
for the 2019-2020period:
Patients without HDF Expenses Patients with HDF Expenses
2019 7 278 414,40 2019 1 582 844,3
2020 26 132 845,76 2020 3 471 635,84
Discussion. As a part of the scientific project implementation, some positive results have been achieved, especially: new criteria for the oncological profile patients' transfer to the anesthesiology and intensive care department (with a surgery unit) - pending approval; developed and approved criteria for hemoperfusion using HA 230,330 absorbers in chemotherapy complications treatment in children; developed and approved informed consents of parents/guardians for hemoperfusion using HA 230,330 absorbers; the introduction of early chemotherapy in case of suspected pneumotoxic reaction and fluid overload; laboratory monitoring of patients receiving high-dose chemotherapy with metho-trexate was introduced.
The method of choice, indications and contraindications for hemoperfusion using HA 230,330 absorbers, the duration and frequency of the session, the criteria for effectiveness in
the treatment of toxic complications were determined. Monitoring of all hemoperfusion side effects after high-dose methotrexate therapy was carried out.The advantages and disadvantages of hemoperfusion with HA230,330 were revealed. The total number of hemoperfusions accounted for 15 sessions; received sessions - 7 patients; discharged with remission of the underlying disease - 5 patients; 2 patients died due to the underlying disease progression.
The new method will allow discharged patients to receive the next stage of chemotherapy and achieve complete remission for the underlying oncological disease.Our hypothesis claims that, considering the molecular mass of methotrexate 454 Da, the HA 230 absorber is potentially more effective and safer in removing elevated methotrexate levels in children than other extra-corporeal detoxification methods. In addition, the HA330 absorber plays a key role in the intensive care of late complications, such as sepsis.
Currently, in the treatment of sepsis and toxic complications after chemotherapy in adults, methods of extracorporeal support (CVVHDF) are actively used. It should be noted that data emerging on the use of CVVHDF with HA330 in children have appeared recently in specific countries.
Other well-known methods of detoxification, such as peritoneal dialysis, are used only for chronic renal failure in adults and children. Over the past year, we have performed 15 sessions of CVVHDF with HA330 in children with sepsis on the background of acute lymphoblastic leukemia. There were no complications revealed. The CVVHDF session was carried out for 4 hours, the sepsis markers were reduced to normal within 12 hours from the start of the procedure. We
organized a scientific project to support the treatment of toxic complications in children with leukemia and we plan to report further annual results.
Conclusion: Retrospective monitoring for the 2019-2020 period of registered complications (early and late toxic complications), depending on the type and frequency of diseases, after high-dose chemotherapy with methotrexate in children with oncological diseases over a 2-year period revealed 61.5% (n -8) cases, which indicates the priority of this study. Urgency and relevance of using sorption methods after high-dose chemotherapy in children with oncological diseases by hemo-perfusion with HA 230, 330 absorbers have been proved, based on a comparative analysis of various detoxification methods.
БАЛАЛАР ОНКОЛОГИЯСЫНДАГЫ ЖОГАРЫ ДОЗАЛЫ ХИМИОТЕРАПИЯДАН КЕЙ1НГ1 МЕТОТРЕКСАТТЬЩ УЫТТЫ АСЦЫНУЛАРЫН РЕТРОСПЕКТИВТ1 ТАЛДАУ
*З. Тобылбаева1'2, С. ЖаFанова1, М. Баймуратова1, А. Рыскулова1
1. «^ДСЖМ» Казакстандык Медициналык Университет ЖШС Алматы к., ^азакстан 2. «University Medical Center» Корпоративтш ^оры Астана к., ^азакстан
Тушндеме
БYгiнгi тацда ^азакстан Президентшщ аркасында балалар онкологиясы жасына жэне сыркаттанушылык тYрiне карамастан жогары верификацияга жэне уактылы емделуге ие. Балалардагы жогары дозалы химиотерапиядан кешн аныкталган уытты аскынулардыц ретроспектива талдауы еткен жылдардагы елiмiздщ аймактарындагы аурулардыц ауырлыгын керсеттi. Емдеу хаттамаларын эзiрлеу мен кайта карау жэне уытты аскынулардыц каркынды терапиясына жаца эдiстердi енгiзу балалар онкологиясыныц непзп багыттары болып табылады.
Tyrnndi свздер: Метотрексат, жогары дозалы химиотерапия, гемоперфузия, уытты асцынулар, балалар онкологиясы.
РЕТРОСПЕКТИВНЫЙ АНАЛИЗ ТОКСИЧЕСКИХ ОСЛОЖНЕНИЙ У ДЕТЕЙ ПОСЛЕ ВЫСОКОДОЗНОЙ ХИМИОТЕРАПИИ МЕТОТРЕСАТОМ
*З. Тобылбаева1,2, С. ЖаFанова1, М. Баймуратова1, А. Рыскулова1
1.ТОО Казахстанский медицинский университет «ВШОЗ», г. Алматы, Казахстан 2.Корпоративный фонд «University Medical Center» г. Астана, Казахстан
Аннотация
На сегодняшний день, благодаря Президенту Казахстана, детская онкология имеет высокую верификацию и своевременное лечение независимо от возраста и вида заболеваемости. Ретроспективный анализ выявленных токсических осложнений после высокодозной химиотерапии у детей показал тяжесть заболеваний в регионах нашей страны за прошлые годы. Разработка и пересмотр протоколов лечения и внедрение новых методов в интенсивную терапию токсических осложнений являются основными направлениями в детской онкологии.
Ключевые слова: Метотрексат, высокодозная химиотерапия, гемоперфузия, токсические осложнения, детская онкология.
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Conflict of interest. All authors declare that there is no potential conflict of interest requiring disclosure in this article.
Contribution of the authors. All authors have made an equal contribution to the development of the concept, implementation,processing of results and writing of the article. We declare that this material has not been published before and is not under consideration by other publishers.
Financing. Absent.
Information about the authors
Corresponding author. Zaure Sakanovna Tobylbayeva, anesthesiologist-resuscitator, Corporate fund «University Medical Center»», 2nd year master's student in the specialty» Public Health»», Kazakhstan's Medical University «Kazakhstan's School of Public Health», Almaty, Kazakhstan, E-mail: zs.tobylbayeva@gmail.com, ORCID https://orcid.org/0000-0002-9047-8598.
Sabina Altynbekkyzy Zhaganova - 2nd year master's student in the specialty «Public Health», Kazakhstan's Medical University «Kazakhstan's School of Public Health», Almaty, Kazakhstan, E-mail: cherry.s.a@mail.ru, ORCID https://orcid.org/0000-0003-1164-3821.
Baimuratova Mayrash Aushatovna - candidate of Medical Sciences, Associate Professor of the Department of «Public Health and Social Sciences», Kazakhstan's Medical University «Kazakhstan's School of Public Health», Almaty, Kazakhstan, E-mail: mairash@list.ru , ORCID https://orcid.org/0000-0003-0219-7874.
Ryskulova Alma-Gul Rakhimovna - candidate of Medical Sciences, Associate Professor.
Head of Department of Population Health and Social Sciences, Kazakhstan's Medical University «Kazakhstan's School of Public Health», Almaty, Kazakhstan, E-mail: r.alma@bk.ru, ORCID https://orcid.org/0000-0003-4768-4799.
Article submitted: 05.01.2023
Accepted for publication: 27.03.2023.
