oncotomskСибирский онкологический журналSiberian journal of oncology1814-48612312-3168Tomsk National Research Medical Сепtеr of the Russian Academy of Sciences10.21294/1814-4861-2020-19-5-121-130oncotomsk-1587Research ArticleОБЗОРЫREVIEWSГЕМАТОЛОГИЧЕСКИЕ НЕЖЕЛАТЕЛЬНЫЕ ЛЕКАРСТВЕННЫЕ РЕАКЦИИ ПРИ ИСПОЛЬЗОВАНИИ ИНГИБИТОРОВ ФАКТОРА РОСТА ЭНДОТЕЛИЯ СОСУДОВ И ЦИТОСТАТИЧЕСКИХ ПРЕПАРАТОВ В ЛЕЧЕНИИ ГЛИОБЛАСТОМЫ: СИСТЕМАТИЧЕСКИЙ ОБЗОРHEMATOTOXIC ADVERSE DRUG REACTIONS ASSOCIATED WITH VASCULAR ENDOTHELIAL GROWTH FACTOR INHIBITORS AND CYTOTOXIC DRUGS IN THE TREATMENT OF GLIOBLASTOMA: A SYSTEMATIC REVIEWhttps://orcid.org/0000-0001-9039-9147СтепановИ. А.StepanovI. A.

аспирант кафедры нейрохирургии и инновационной медицины,

г. Иркутск, 664022, ул. 3 июля, 8

MD, Postgraduate, Department of Neurosurgery and Innovative Medicine,

8, July 3 Street, 664022, Irkutsk

https://orcid.org/0000-0002-3085-2998ШамееваМ. А.ShameevaM. A.

клинический ординатор кафедры нейрохирургии и инновационной медицины,

г. Иркутск, 664022, ул. 3 июля, 8

MD, Clinical Resident, Department of Neurosurgery and Innovative Medicine,

8, July 3 Street, 664022, Irkutsk

КручининД. Б.KruchininD. B.

клинический ординатор кафедры нейрохирургии и инновационной медицины, 

г. Иркутск, 664022, ул. 3 июля, 8

MD, Clinical Resident, Department of Neurosurgery and Innovative Medicine,

8, July 3 Street, 664022, Irkutsk

https://orcid.org/0000-0003-4349-7101БывальцевВ. А.ByvaltsevV. A.

заведующий кафедрой нейрохирургии и инновационной медицины, г. Иркутск, 664022, ул. 3 июля, 8;

руководитель Центра нейрохирургии, г. Иркутск, 664005, ул. Боткина, 102;

заместитель директора по инновационной и международной деятельности Иркутского научного центра хирургии и травматологии, 664003, г. Иркутск, ул. Борцов Революции, 13;

профессор кафедры травматологии, ортопедии и нейрохирургии, 664049, г. Иркутск, м/р Юбилейный, 100; 

доктор медицинских наук, профессор, главный нейрохирург Дирекции здравоохранения ОАО «РЖД»

 

Head of the Department of Neurosurgery and Innovative Medicine, 8, July 3 Street, 664022, Irkutsk;

Head of the Neurosurgery Center, 10, Botkin Street, 664005, Irkutsk;

Deputy Director for Innovation and International Activities, 1, Fighters of the Revolution Street, 664003, Irkutsk; 

Professor, Department of Traumatology, Orthopedics and Neurosurgery, 100, Yubileiny district, 664049, Irkutsk;

MD, PhD, Chief neurosurgeon of the Health Directorate of JSC «Russian Railways»

vadimabyvaltsev@gmail.comШагдуроваИ. А.ShagdurovaI. A.

клинический ординатор кафедры нейрохирургии и инновационной медицины,

г. Иркутск, 664022, ул. 3 июля, 8

MD, Clinical Resident, Department of Neurosurgery and Innovative Medicine, I

8, July 3 Street, 664022, Irkutsk

ФГБОУ ВО «Иркутский государственный медицинский университет» Министерства здравоохраненияРоссияIrkutsk State Medical UniversityRussian FederationФГБОУ ВО «Иркутский государственный медицинский университет» Министерства здравоохранения; НУЗ «Дорожная клиническая больница на ст. Иркутск-Пассажирский» ОАО «РЖД-Медицина»; ФГБНУ «Иркутский научный центр хирургии и травматологии»; ФГБОУ ДПО «Иркутская государственная медицинская академия последипломного образования» – филиал ФГБОУ ДПО РМАНПО Министерства здравоохранения РФРоссияIrkutsk State Medical University; Road Clinical Hospital at st. Irkutsk-Passenger; Irkutsk Scientific Center of Surgery and Traumatology; Irkutsk State Medical Academy of Postgraduate EducationRussian Federation202029102020195121130Copyright © Степанов И.А., Шамеева М.А., Кручинин Д.Б., Бывальцев В.А., Шагдурова И.А., 20202020Степанов И.А., Шамеева М.А., Кручинин Д.Б., Бывальцев В.А., Шагдурова И.А.Stepanov I.A., Shameeva M.A., Kruchinin D.B., Byvaltsev V.A., Shagdurova I.A.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.siboncoj.ru/jour/article/view/1587

Эффективность использования ингибиторов фактора роста эндотелия сосудов (Vascular Endothelial Gowth Factor, VEGF) в терапии глиобластомы за счет достоверного увеличения показателя выживаемости без прогрессирования наглядно продемонстрирована в ряде исследований. Применение анти-VEGF агентов ассоциировано с развитием ряда нежелательных лекарственных реакций (НЛР), среди которых наибольшую распространенность имеют гематологические.

Цель исследования – выполнить систематический обзор, основанный на результатах рандомизированных контролируемых клинических исследований, которые изучают виды и частоту встречаемости гематологических НЛР при использовании анти-VEGF и химиотерапевтических агентов в терапии глиобластомы.

Материал и методы

Материал и методы. Выполнен поиск рандомизированных контролируемых клинических исследований в базах данных Pubmed, EMBASE, Cohrane Library и eLibrary, опубликованных в период с января 2008 г. по август 2019 г., касающихся безопасности применения анти-VEGF лекарственных средств в качестве основного/вспомогательного способа лечения пациентов с глиобластомой. Сформированы основные критерии соответствия включения исследований в настоящий систематический обзор.

Результаты

Результаты. В объединенный анализ данных включены 13 рандомизированных контролируемых клинических исследований. Средняя частота гематологических НЛР при использовании анти-VEGF агентов в качестве монотерапии глиобластомы составила 27,7 %, основными видами НЛР являлись нейтропения и тромбоцитопения. Средняя частота гематологических НЛР при применении цитотостатиков равнялась 48,1 %, при этом чаще всего наблюдались лимфопения и тромбоцитопения. Средняя частота гематологических НЛР при комбинированном использовании анти-VEGF и химиотерапевтических препаратов составила 46,2 %, в основном возникали тромбоцитопения, нейтропения и анемия. При сочетанном применении анти-VEGF, химиотерапевтических препаратов и лучевой терапии гематологических НЛР в среднем возникали в 12,3 % случаев, чаще всего наблюдалась тромбоцитопения тяжелой степени.

Заключение

Заключение. Применение анти-VEGF препаратов в виде монотерапии глиобластомы ассоциировано с меньшей частотой гематологических НЛР. При этом наиболее безопасным анти-VEGF агентом является бевацизумаб. Наибольшая частота гематологических НЛР характерна для комбинации анти-VEGF и цитостатических препаратов, таких как цедираниб с ломустином и бевацизумаб с карбоплатином. 

Several studies have shown that the use of inhibitors of vascular endothelial growth factor (Vascular Endothelial Gowth Factor, VEGF) in the treatment of glioblastoma results in a significant increase in the rate of progression-free survival. However, administration of anti-VEGF agents is associated with the development of a wide range of adverse drug reactions (ADR), among which, hematotoxic ADR is the most common.

The purpose of this study was to conduct a systematic review based on the results of randomized controlled clinical studies on the type and frequency of hematotoxic ADRs associated with anti-VEGF and chemotherapeutic agents in the treatment of glioblastoma.

Material and Methods

Material and Methods. Pubmed, EMBASE, Cohrane Library and eLibrary databases were used to identify reports from randomized controlled clinical studies on the safety of anti-VEGF drugs as the main/auxiliary treatment for patients with glioblastoma, and published from January 2008 to August 2019. The main criteria for inclusion of studies in the systematic review were determined.

Results

Results. The combined data analysis included 13 randomized controlled clinical trials. The average incidence of hematotoxic ADRs associated with anti-VEGF agents in monotherapy for glioblastoma was 27.7 %. Neutropenia and thrombocytopenia were the most common types of ADR. The average incidence of hematotoxic ADRs associated with cytotoxic drugs in monotherapy for glioblastoma was 48.1 %, and lymphopenia and thrombocytopenia were the main types of hematotoxic ADRs. The average incidence of hematotoxic ADRs associated with the combined use of anti-VEGF and chemotherapeutic drugs was 46.2 %. In this case, the most common ADRs were thrombocytopenia, neutropenia, and anemia. The use of a combination of anti-VEGF, chemotherapeutic drugs and radiation therapy was associated with the development of hematotoxic ADRs with an average incidence of 12.3 %. The most common ADR was severe thrombocytopenia.

Conclusion

Conclusion. The use of anti-VEGF drugs as monotherapy for glioblastoma was associated with a lower incidence of hematotoxic ADRs. In this case, bevacizumab was the safest anti-VEGF agent in relation to hematotoxicity. The highest incidence of hematotoxic ADRs is observed for a combination of antiVEGF and cytotoxic drugs, such as cediranib with lomustine and bevacizumab with carboplatin. 

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The authors declare that there are no conflicts of interest present.