oncotomskСибирский онкологический журналSiberian journal of oncology1814-48612312-3168Tomsk National Research Medical Сепtеr of the Russian Academy of Sciences10.21294/1814-4861-2024-23-2-92-100oncotomsk-3046Research ArticleОБЗОРЫREVIEWSТерапия протонами в детской нейроонкологии. Потенциальные достоинства и соотношение между стоимостью и результатамиProton therapy in pediatric neuro-oncology. Potential advantages and the relationship between cost and resultshttps://orcid.org/0000-0002-0219-7260РегентоваО. С.RegentovaO. S.

Регентова Ольга Сергеевна - кандидат медицинских наук, заведующая отделением лучевой терапии детей с койками онкологии.

117997, Москва, ул. Профсоюзная, 86

Olga S. Regentova - MD, PhD, Head of the Children’s Oncology Department, Russian Scientific Center of Roentgenoradiology of the Ministry of Health of Russia.

86, Profsoyuznaya St., Moscow, 117997

https://orcid.org/0000-0003-0786-5448ЩербенкоО. И.ShcherbenkoO. I.

Щербенко Олег Ильич - доктор медицинских наук, профессор, главный научный сотрудник научно-организационного отдела.

117997, Москва, ул. Профсоюзная, 86

Oleg I. Shcherbenko - MD, Professor, Chief Researcher, Scientific and Organizational Department, Russian Scientific Center of Roentgenoradiology of the Ministry of Health of Russia.

86, Profsoyuznaya St., Moscow, 117997

sherbenko@mail.ruhttps://orcid.org/0000-0001-6125-2410КумироваЭ. В.KumirovaE. V.

Кумирова Элла Вячеславовна - доктор медицинских наук, профессор, главный научный сотрудник научно-исследовательского отдела комплексной диагностики заболеваний и радиотерапии, ФГБУ «РНЦР» Минздрава России; заместитель главного врача по онкологии, ГБУЗ «Морозовская ДГКБ ДЗМ»; научный консультант НИИ ДГиО, ФГБУ «НМИЦ онкологии им. Н.Н. Блохина» Минздрава России; заведующая кафедрой паллиативной педиатрии, ФГАОУ ВО «РНИМУ им. Н.И. Пирогова» Минздрава России.

117997, Москва, ул. Профсоюзная, 86; 119049, Москва, 4-й Добрынинский пер., 1/9; 115478, Москва, Каширское шоссе, 24; 117997, Москва, ул. Островитянова, 1

Researcher ID (WOS): ACC-2499-2022

Ella V. Kumirova - MD, Professor, Chief Researcher, Complex Diagnostics of Diseases and Radiotherapy, Russian Scientific Center of Roentgenoradiology of the Ministry of Health of Russia; Deputy Chief Physician for Oncology, Morozov Children’s City Clinical Hospital of the Moscow City, Healthcare Department; Scientific Consultant of Dmiytry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, N.N. Blokhin National Medical Research Center of Oncology of the Ministry of Health of Russia; Head of the Department of Palliative Pediatrics, N.I. Pirogov Russian National Research Medical University of the Ministry of Health of Russia.

86, Profsoyuznaya St., Moscow, 117997; 1/9, Chetverty Dobryninskiy Ln, Moscow, 119049; 24, Kashirskoye Shosse, Moscow, 115522; 1, Ostrovityanova St., Moscow, 117997

Researcher ID (WOS): ACC-2499-2022

https://orcid.org/0000-0001-5900-6755АнтоненкоФ. Ф.AntonenkoF. F.

Антоненко Федор Федорович - доктор медицинских наук, профессор, член-корреспондент РАН, заведующий лабораторией лучевой терапии и комплексных методов лечения онкологических заболеваний.

117997, Москва, ул. Профсоюзная, 86

Fedor F. Antonenko - MD, Professor, Corresponding Member of RAS, Head of the Laboratory of Radiation Therapy and complex methods of cancer treatment, Russian Scientific Center of Roentgenoradiology of the Ministry of Health of Russia.

86, Profsoyuznaya St., Moscow, 117997

https://orcid.org/0000-0002-1641-6452СолодкийВ. А.SolodkiyV. A.

Солодкий Владимир Алексеевич - доктор медицинских наук, профессор, академик РАН, директор.

117997, Москва, ул. Профсоюзная, 86

VladimirA. Solodkiy - MD, Professor, Academician of RAS, Director, Russian Scientific Center of Roentgenoradiology of the Ministry of Health of Russia.

86, Profsoyuznaya St., Moscow, 117997

ФГБУ «Российский научный центр рентгенорадиологии» Минздрава РоссииРоссияRussian Scientific Center of Roentgenoradiology of the Ministry of Health of RussiaRussian FederationФГБУ «Российский научный центр рентгенорадиологии» Минздрава России; ГБУЗ «Морозовская детская городская клиническая больница ДЗМ»; ФГБУ «Национальный медицинский исследовательский центр онкологии им. Н.Н. Блохина» Минздрава России; ФГАОУ ВО «Российский национальный исследовательский медицинский университет им. Н.И. Пирогова» Минздрава РоссииРоссияRussian Scientific Center of Roentgenoradiology of The Ministry of Health of Russia; Morozov Children’s City Clinical Hospital of The Moscow City, Healthcare Department; N.N. Blokhin National Medical Research Center of Oncology of The Ministry of Health of The Russia; N.I. Pirogov Russian National Research Medical University of The Ministry of Health of RussiaRussian Federation20241205202423292100Copyright © Регентова О.С., Щербенко О.И., Кумирова Э.В., Антоненко Ф.Ф., Солодкий В.А., 20242024Регентова О.С., Щербенко О.И., Кумирова Э.В., Антоненко Ф.Ф., Солодкий В.А.Regentova O.S., Shcherbenko O.I., Kumirova E.V., Antonenko F.F., Solodkiy V.A.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.siboncoj.ru/jour/article/view/3046

Цель исследования – проанализировать накопленный опыт и попытаться определить те клинические ситуации, в которых применение протонов окажется экономически и клинически более эффективным, чем фотонное излучение. Материал и методы. Проведен поиск и анализ доступных литературных источников, посвященных изучению оценки и сравнению эффективности протонного и фотонного пучка излучения в лечении опухолей центральной нервной системы, найденных в Medline, Embase и Кохрановской библиотеке, опубликованных за последние 25 лет. Результаты. Проведенный анализ доступных публикаций показал, что ускоренные протоны не улучшают показатели выживаемости и безрецидивного течения при всех формах опухолей головного мозга по сравнению с фотонным излучением ускорителей. Однако протоны позволяют существенно повысить уровень конформности распределения дозы облучения и снизить дозу на критические структуры (гипофиз, улитку, хрусталики глаз, гипоталамус). Благодаря этому уменьшается риск отдаленных последствий в виде нарушения слуха и зрения, снижения вероятности гормональных и когнитивных расстройств. Все это критически важно для потенциально излечимых злокачественных опухолей, таких как медуллобластома и герминома, для опухолей низкой степени злокачественности, таких как глиома Gr 1–2, или обладающих низкой потенцией к метастазированию, поскольку использование протонов, по сравнению с фотонами, уменьшает риск развития отдаленных последствий, ухудшающих качество жизни излеченных детей. Заключение. Лучевая терапия признана важным терапевтическим компонентом лечения и часто используется в стратегиях мультимодальной терапии опухолей центральной нервной системы у детей. Протонная лучевая терапия является одним из привлекательных методов проведения радиотерапии с минимальным распределением дозы на непораженные ткани и снижением поглощенной дозы. Прецизионность протонов приводит к снижению риска возникновения долгосрочных побочных эффектов, связанных с проведением данного вида лечения, и индукции вторичных злокачественных новообразований, что имеет особое значение для качества жизни.

The aim of study: to analyze the accumulated experience and try to identify those clinical situations in which the use of protons will be economically and clinically more effective than photon radiation therapy. Material and methods. The articles devoted to the study of the evaluation and comparison of the effectiveness of proton and photon radiation beams in the treatment of tumors of the central nervous system and published over the past 25 years were searched in the Medline, Embase and the Cochrane Library databases. Results. the analysis of available publications has shown that accelerated protons do not improve survival rates and disease-free rates in all forms of brain tumors compared with photon therapy. However, protons can significantly increase the level of dose distribution conformity and reduce the dose to critical structures (pituitary gland, cochlea, eye lenses, hypothalamus), thus reducing the risk of hearing and visual impairment as well as hormonal and cognitive disorders. All this is critically important for potentially curable malignant tumors, such as medulloblastoma and germinoma, for low malignant potential tumors (grade 1–2 glioma) or tumors with decreased metastatic potential, since proton therapy compared to photon therapy reduces the risk of late side effects that worsen the quality of life of cured children. Conclusion. central nervous system tumors are one of the most common solid malignant neoplasms in children. Radiation therapy (RT) is recognized as an important therapeutic component of treatment and is often used in strategies for multimodal therapy of tumors of the central nervous system in children. Proton radiation therapy is one of the attractive methods of radiotherapy with minimal dose distribution to normal tissues and a decrease in the absorbed dose. The precision of protons reduces the risk of long-term side effects associated with this type of treatment and the induction of secondary malignancies, which is of particular importance for the quality of life.

опухоли мозгадетиускоренные протоныфотонное излучениекачество жизнинейроонкологиялучевая терапияbrain tumorschildrenaccelerated protonsphoton radiationquality of lifeneurooncologyradiation therapyReferencesЗлокачественные новообразования в России в 2020 году (заболеваемость и смертность). Под ред. А.Д. Каприна, В.В. Старинского, А.О. Шахзадовой. М., 2021. 239 с.Malignant tumors in Russia in 2020 (morbidity and mortality). Ed. by A.D. Kaprin, V.V. Starinsky, A.O. Shakhzadova. Moscow, 2021. 239 p. (in Russian).Geyer J.R., Sposto R., Jennings M., Boyett J.M., Axtell R.A., Breiger D., Broxson E., Donahue B., Finlay J.L., Goldwein J.W., Heier L.A., Johnson D., Mazewski C., Miller D.C., Packer R., Puccetti D., Radcliffe J., Tao M.L., Shiminski-Maher T. Children’s Cancer Group. Multiagent chemotherapy and deferred radiotherapy in infants with malignant brain tumors: a report from the Children’s Cancer Group. J Clin Oncol. 2005; 23(30): 7621–31. doi: 10.1200/JCO.2005.09.095.Geyer J.R., Sposto R., Jennings M., Boyett J.M., Axtell R.A., Breiger D., Broxson E., Donahue B., Finlay J.L., Goldwein J.W., Heier L.A., Johnson D., Mazewski C., Miller D.C., Packer R., Puccetti D., Radcliffe J., Tao M.L., Shiminski-Maher T. Children’s Cancer Group. Multiagent chemotherapy and deferred radiotherapy in infants with malignant brain tumors: a report from the Children’s Cancer Group. J Clin Oncol. 2005; 23(30): 7621–31. doi: 10.1200/JCO.2005.09.095.Oeffinger K.C., Mertens A.C., Sklar C.A., Kawashima T., Hudson M.M., Meadows A.T., Friedman D.L., Marina N., Hobbie W., Kadan-Lottick N.S., Schwartz C.L., Leisenring W., Robison L.L.; Childhood Cancer Survivor Study. Chronic health conditions in adult survivors of childhood cancer. N Engl J Med. 2006; 355(15): 1572–82. doi: 10.1056/NEJMsa060185.Oeffinger K.C., Mertens A.C., Sklar C.A., Kawashima T., Hudson M.M., Meadows A.T., Friedman D.L., Marina N., Hobbie W., Kadan-Lottick N.S., Schwartz C.L., Leisenring W., Robison L.L.; Childhood Cancer Survivor Study. Chronic health conditions in adult survivors of childhood cancer. N Engl J Med. 2006; 355(15): 1572–82. doi: 10.1056/NEJMsa060185.Armstrong G.T., Liu Q., Yasui Y., Neglia J.P., Leisenring W., Robison L.L., Mertens A.C. Late mortality among 5-year survivors of childhood cancer: a summary from the Childhood Cancer Survivor Study. J Clin Oncol. 2009; 27(14): 2328–38. doi: 10.1200/JCO.2008.21.1425.Armstrong G.T., Liu Q., Yasui Y., Neglia J.P., Leisenring W., Robison L.L., Mertens A.C. Late mortality among 5-year survivors of childhood cancer: a summary from the Childhood Cancer Survivor Study. J Clin Oncol. 2009; 27(14): 2328–38. doi: 10.1200/JCO.2008.21.1425.Paganetti H., Niemierko A., Ancukiewicz M., Gerweck L.E., Goitein M., Loeffler J.S., Suit H.D. Relative biological effectiveness (RBE) values for proton beam therapy. Int J Radiat Oncol Biol Phys. 2002; 53(2):407–21. doi: 10.1016/s0360-3016(02)02754-2.Paganetti H., Niemierko A., Ancukiewicz M., Gerweck L.E., Goitein M., Loeffler J.S., Suit H.D. Relative biological effectiveness (RBE) values for proton beam therapy. Int J Radiat Oncol Biol Phys. 2002; 53(2):407–21. doi: 10.1016/s0360-3016(02)02754-2.Щербенко О.И. Ускоренные протоны в лечении опухолей ЦНС у детей. Практическая онкология. 2017; 18(3): 298–306.Shcherbenko O.I. Accelerated protons in the treatment of cns tumors in children: a review of the literature. Practical Oncology. 2017; 18(3): 298–306. (in Russian).Забелин М.В., Климанов В.А., Галяутдинова Ж.Ж., Самойлов А.С., Лебедев А.О., Шелухина Е.В. Протонная лучевая терапия: возможности клинического применения и перспективы исследования. Исследования и практика в медицине. 2018; 5(1): 82–95. doi: 10.17709/2409-2231-2018-5-1-10.Zabelin M.V., Klimanov V.A., Galyautdinova J.J., Samoilov A.S., Lebedev A.O., Shelyhina E.V. Proton radiation therapy: clinical application opportunities and research prospects. Research and Practical Medicine Journal. 2018; 5(1): 82–95. (in Russian). doi: 10.17709/2409-2231-2018-5-1-10.Солодкий В.А., Измайлов Т.Р., Полушкин П.В. Сравнение эффективности протонной и фотонной терапии у пациентов с глиомами головного мозга. Сибирский онкологический журнал. 2021; 20(2):127–35. doi: 10.21294/1814-4861-2021-20-2-127-135.Solodky V.A., Izmailov T.R., Polushkin P.V. Comparison of the effectiveness of proton and photon therapy in patients with brain tumors. Siberian Journal of Oncology. 2021; 20(2): 127–35. (in Russian). doi: 10.21294/1814-4861-2021-20-2-127-135.Гордон К.Б., Смык Д.И., Гулидов И.А. Протонная терапия в лечении опухолей области головы и шеи: состояние проблемы и перспективы развития (обзор). Современные технологии в медицине. 2021; 13(4): 70–81.Gordon K.B., Smyk D.I., Gulidov I.A. Proton therapy in the treatment of tumors of the head and neck: the state of the problem and prospects for development (review). Modern Technologies in Medicine. 2021; 13(4): 70–81. (in Russian).Oshiro Y., Mizumoto M., Okumura T., Sugahara S., Fukushima T., Ishikawa H., Nakao T., Hashimoto T., Tsuboi K., Ohkawa H., Kaneko M., Sakurai H. Clinical results of proton beam therapy for advanced neuroblastoma. Radiat Oncol. 2013; 8: 142. doi: 10.1186/1748-717X-8-142.Oshiro Y., Mizumoto M., Okumura T., Sugahara S., Fukushima T., Ishikawa H., Nakao T., Hashimoto T., Tsuboi K., Ohkawa H., Kaneko M., Sakurai H. Clinical results of proton beam therapy for advanced neuroblastoma. Radiat Oncol. 2013; 8: 142. doi: 10.1186/1748-717X-8-142.Oshiro Y., Sugahara S., Fukushima T., Okumura T., Nakao T., Mizumoto M., Hashimoto T., Tsuboi K., Kaneko M., Sakurai H. Pediatric nasopharyngeal carcinoma treated with proton beam therapy. Two case reports. Acta Oncol. 2011; 50(3): 470–3. doi: 10.3109/0284186X.2010.509106.Oshiro Y., Sugahara S., Fukushima T., Okumura T., Nakao T., Mizumoto M., Hashimoto T., Tsuboi K., Kaneko M., Sakurai H. Pediatric nasopharyngeal carcinoma treated with proton beam therapy. Two case reports. Acta Oncol. 2011; 50(3): 470–3. doi: 10.3109/0284186X.2010.509106.MacDonald T.J., Arenson E.B., Ater J., Sposto R., Bevan H.E., Bruner J., Deutsch M., Kurczynski E., Luerssen T., McGuire-Cullen P., O’Brien R., Shah N., Steinbok P., Strain J., Thomson J., Holmes E., Vezina G., Yates A., Phillips P., Packer R. Phase II study of high-dose chemotherapy before radiation in children with newly diagnosed high-grade astrocytoma: final analysis of Children’s Cancer Group Study 9933. Cancer. 2005;104(12): 2862–71. doi: 10.1002/cncr.21593.MacDonald T.J., Arenson E.B., Ater J., Sposto R., Bevan H.E., Bruner J., Deutsch M., Kurczynski E., Luerssen T., McGuire-Cullen P., O’Brien R., Shah N., Steinbok P., Strain J., Thomson J., Holmes E., Vezina G., Yates A., Phillips P., Packer R. Phase II study of high-dose chemotherapy before radiation in children with newly diagnosed high-grade astrocytoma: final analysis of Children’s Cancer Group Study 9933. Cancer. 2005;104(12): 2862–71. doi: 10.1002/cncr.21593.Muroi A., Mizumoto M., Ishikawa E., Ihara S., Fukushima H., Tsurubuchi T., Sakurai H., Matsumura A. Proton therapy for newly diagnosed pediatric diffuse intrinsic pontine glioma. Childs Nerv Syst. 2020;36(3): 507–12. doi: 10.1007/s00381-019-04420-9.Muroi A., Mizumoto M., Ishikawa E., Ihara S., Fukushima H., Tsurubuchi T., Sakurai H., Matsumura A. Proton therapy for newly diagnosed pediatric diffuse intrinsic pontine glioma. Childs Nerv Syst. 2020;36(3): 507–12. doi: 10.1007/s00381-019-04420-9.Vern-Gross T.Z., Schreiber J.E., Broniscer A., Wu S., Xiong X., Merchant T.E. Prospective evaluation of local control and late effects of conformal radiation therapy in children, adolescents, and young adults with high-grade glioma. Neuro Oncol. 2014; 16(12): 1652–60. doi: 10.1093/neuonc/nou101.Vern-Gross T.Z., Schreiber J.E., Broniscer A., Wu S., Xiong X., Merchant T.E. Prospective evaluation of local control and late effects of conformal radiation therapy in children, adolescents, and young adults with high-grade glioma. Neuro Oncol. 2014; 16(12): 1652–60. doi: 10.1093/neuonc/nou101.Merchant T.E., Kun L.E., Wu S., Xiong X., Sanford R.A., Boop F.A. Phase II trial of conformal radiation therapy for pediatric low-grade glioma. J Clin Oncol. 2009; 27(22): 3598–604. doi: 10.1200/JCO.2008.20.9494.Merchant T.E., Kun L.E., Wu S., Xiong X., Sanford R.A., Boop F.A. Phase II trial of conformal radiation therapy for pediatric low-grade glioma. J Clin Oncol. 2009; 27(22): 3598–604. doi: 10.1200/JCO.2008.20.9494.Hug E.B., Muenter M.W., Archambeau J.O., DeVries A., Liwnicz B., Loredo L.N., Grove R.I., Slater J.D. Conformal proton radiation therapy for pediatric low-grade astrocytomas. Strahlenther Onkol. 2002;178(1): 10–7. doi: 10.1007/s00066-002-0874-2.Hug E.B., Muenter M.W., Archambeau J.O., DeVries A., Liwnicz B., Loredo L.N., Grove R.I., Slater J.D. Conformal proton radiation therapy for pediatric low-grade astrocytomas. Strahlenther Onkol. 2002;178(1): 10–7. doi: 10.1007/s00066-002-0874-2.Greenberger B.A., Pulsifer M.B., Ebb D.H., MacDonald S.M., Jones R.M., Butler W.E., Huang M.S., Marcus K.J., Oberg J.A., Tarbell N.J., Yock T.I. Clinical outcomes and late endocrine, neurocognitive, and visual profiles of proton radiation for pediatric low-grade gliomas. Int J Radiat Oncol Biol Phys. 2014; 89(5): 1060–8. doi: 10.1016/j.ijrobp.2014.04.053.Greenberger B.A., Pulsifer M.B., Ebb D.H., MacDonald S.M., Jones R.M., Butler W.E., Huang M.S., Marcus K.J., Oberg J.A., Tarbell N.J., Yock T.I. Clinical outcomes and late endocrine, neurocognitive, and visual profiles of proton radiation for pediatric low-grade gliomas. Int J Radiat Oncol Biol Phys. 2014; 89(5): 1060–8. doi: 10.1016/j.ijrobp.2014.04.053.Grill J., Sainte-Rose C., Jouvet A., Gentet J.C., Lejars O., Frappaz D., Doz F., Rialland X., Pichon F., Bertozzi A.I., Chastagner P., Couanet D., Habrand J.L., Raquin M.A., Le Deley M.C., Kalifa C.; French Society of Paediatric Oncology. Treatment of medulloblastoma with postoperative chemotherapy alone: an SFOP prospective trial in young children. Lancet Oncol. 2005; 6(8): 573–80. doi: 10.1016/S1470-2045(05)70252-7.Grill J., Sainte-Rose C., Jouvet A., Gentet J.C., Lejars O., Frappaz D., Doz F., Rialland X., Pichon F., Bertozzi A.I., Chastagner P., Couanet D., Habrand J.L., Raquin M.A., Le Deley M.C., Kalifa C.; French Society of Paediatric Oncology. Treatment of medulloblastoma with postoperative chemotherapy alone: an SFOP prospective trial in young children. Lancet Oncol. 2005; 6(8): 573–80. doi: 10.1016/S1470-2045(05)70252-7.Eaton B.R., Esiashvili N., Kim S., Patterson B., Weyman E.A., Thornton L.T., Mazewski C., MacDonald T.J., Ebb D., MacDonald S.M., Tarbell N.J., Yock T.I. Endocrine outcomes with proton and photon radiotherapy for standard risk medulloblastoma. Neuro Oncol. 2016; 18(6):881–7. doi: 10.1093/neuonc/nov302.Eaton B.R., Esiashvili N., Kim S., Patterson B., Weyman E.A., Thornton L.T., Mazewski C., MacDonald T.J., Ebb D., MacDonald S.M., Tarbell N.J., Yock T.I. Endocrine outcomes with proton and photon radiotherapy for standard risk medulloblastoma. Neuro Oncol. 2016; 18(6):881–7. doi: 10.1093/neuonc/nov302.Ruggi A., Melchionda F., Sardi I., Pavone R., Meneghello L., Kitanovski L., Zaletel L.Z., Farace P., Zucchelli M., Scagnet M., Toni F., Righetto R., Cianchetti M., Prete A., Greto D., Cammelli S., Morganti A.G., Rombi B. Toxicity and Clinical Results after Proton Therapy for Pediatric Medulloblastoma: A Multi-Centric Retrospective Study. Cancers (Basel). 2022; 14(11): 2747. doi: 10.3390/cancers14112747.Ruggi A., Melchionda F., Sardi I., Pavone R., Meneghello L., Kitanovski L., Zaletel L.Z., Farace P., Zucchelli M., Scagnet M., Toni F., Righetto R., Cianchetti M., Prete A., Greto D., Cammelli S., Morganti A.G., Rombi B. Toxicity and Clinical Results after Proton Therapy for Pediatric Medulloblastoma: A Multi-Centric Retrospective Study. Cancers (Basel). 2022; 14(11): 2747. doi: 10.3390/cancers14112747.Trybula S.J., Youngblood M.W., Kemeny H.R., Clark J.R., Karras C.L., Hartsell W.F., Tomita T. Radiation Induced Cavernomas in the Treatment of Pediatric Medulloblastoma: Comparative Study Between Proton and Photon Radiation Therapy. Front Oncol. 2021; 11. doi: 10.3389/fonc.2021.760691.Trybula S.J., Youngblood M.W., Kemeny H.R., Clark J.R., Karras C.L., Hartsell W.F., Tomita T. Radiation Induced Cavernomas in the Treatment of Pediatric Medulloblastoma: Comparative Study Between Proton and Photon Radiation Therapy. Front Oncol. 2021; 11. doi: 10.3389/fonc.2021.760691.Merchant T.E., Li C., Xiong X., Kun L.E., Boop F.A., Sanford R.A. Conformal radiotherapy after surgery for paediatric ependymoma: a prospective study. Lancet Oncol. 2009; 10(3): 258–66. doi: 10.1016/s1470-2045(08)70342-5.Merchant T.E., Li C., Xiong X., Kun L.E., Boop F.A., Sanford R.A. Conformal radiotherapy after surgery for paediatric ependymoma: a prospective study. Lancet Oncol. 2009; 10(3): 258–66. doi: 10.1016/s1470-2045(08)70342-5.Ares C., Albertini F., Frei-Welte M., Bolsi A., Grotzer M.A., Goitein G., Weber D.C. Pencil beam scanning proton therapy for pediatric intracranial ependymoma. J Neurooncol. 2016; 128(1): 137–45. doi: 10.1007/s11060-016-2090-4.Ares C., Albertini F., Frei-Welte M., Bolsi A., Grotzer M.A., Goitein G., Weber D.C. Pencil beam scanning proton therapy for pediatric intracranial ependymoma. J Neurooncol. 2016; 128(1): 137–45. doi: 10.1007/s11060-016-2090-4.MacDonald S.M., Safai S., Trofimov A., Wolfgang J., Fullerton B., Yeap B.Y., Bortfeld T., Tarbell N.J., Yock T. Proton radiotherapy for childhood ependymoma: initial clinical outcomes and dose comparisons. Int J Radiat Oncol Biol Phys. 2008; 71(4): 979–86. doi: 10.1016/j.ijrobp.2007.11.065.MacDonald S.M., Safai S., Trofimov A., Wolfgang J., Fullerton B., Yeap B.Y., Bortfeld T., Tarbell N.J., Yock T. Proton radiotherapy for childhood ependymoma: initial clinical outcomes and dose comparisons. Int J Radiat Oncol Biol Phys. 2008; 71(4): 979–86. doi: 10.1016/j.ijrobp.2007.11.065.Macdonald S.M., Sethi R., Lavally B., Yeap B.Y., Marcus K.J., Caruso P., Pulsifer M., Huang M., Ebb D., Tarbell N.J., Yock T.I. Proton radiotherapy for pediatric central nervous system ependymoma: clinical outcomes for 70 patients. Neuro Oncol. 2013; 15(11): 1552–9. doi: 10.1093/neuonc/not121.Macdonald S.M., Sethi R., Lavally B., Yeap B.Y., Marcus K.J., Caruso P., Pulsifer M., Huang M., Ebb D., Tarbell N.J., Yock T.I. Proton radiotherapy for pediatric central nervous system ependymoma: clinical outcomes for 70 patients. Neuro Oncol. 2013; 15(11): 1552–9. doi: 10.1093/neuonc/not121.Eaton B.R., Chowdhry V., Weaver K., Liu L., Ebb D., Mac-Donald S.M., Tarbell N.J., Yock T.I. Use of proton therapy for re-irradiation in pediatric intracranial ependymoma. Radiother Oncol. 2015; 116(2):301–8. doi: 10.1016/j.radonc.2015.07.023.Eaton B.R., Chowdhry V., Weaver K., Liu L., Ebb D., Mac-Donald S.M., Tarbell N.J., Yock T.I. Use of proton therapy for re-irradiation in pediatric intracranial ependymoma. Radiother Oncol. 2015; 116(2):301–8. doi: 10.1016/j.radonc.2015.07.023.Gunther J.R., Sato M., Chintagumpala M., Ketonen L., Jones J.Y., Allen P.K., Paulino A.C., Okcu M.F., Su J.M., Wein-berg J., Boehling N.S., Khatua S., Adesina A., Dauser R., Whitehead W.E., Mahajan A. Imaging Changes in Pediatric Intracranial Ependymoma Patients Treated With Proton Beam Radiation Therapy Compared to Intensity Modulated Radiation Therapy. Int J Radiat Oncol Biol Phys. 2015; 93(1): 54–63. doi: 10.1016/j.ijrobp.2015.05.018.Gunther J.R., Sato M., Chintagumpala M., Ketonen L., Jones J.Y., Allen P.K., Paulino A.C., Okcu M.F., Su J.M., Wein-berg J., Boehling N.S., Khatua S., Adesina A., Dauser R., Whitehead W.E., Mahajan A. Imaging Changes in Pediatric Intracranial Ependymoma Patients Treated With Proton Beam Radiation Therapy Compared to Intensity Modulated Radiation Therapy. Int J Radiat Oncol Biol Phys. 2015; 93(1): 54–63. doi: 10.1016/j.ijrobp.2015.05.018.Calaminus G., Kortmann R., Worch J., Nicholson J.C., Alapetite C., Garrè M.L., Patte C., Ricardi U., Saran F., Frappaz D. SIOP CNS GCT 96: final report of outcome of a prospective, multinational nonrandomized trial for children and adults with intracranial germinoma, comparing craniospinal irradiation alone with chemotherapy followed by focal primary site irradiation for patients with localized disease. Neuro Oncol. 2013; 15(6):788–96. doi: 10.1093/neuonc/not019.Calaminus G., Kortmann R., Worch J., Nicholson J.C., Alapetite C., Garrè M.L., Patte C., Ricardi U., Saran F., Frappaz D. SIOP CNS GCT 96: final report of outcome of a prospective, multinational nonrandomized trial for children and adults with intracranial germinoma, comparing craniospinal irradiation alone with chemotherapy followed by focal primary site irradiation for patients with localized disease. Neuro Oncol. 2013; 15(6):788–96. doi: 10.1093/neuonc/not019.Acharya S., DeWees T., Shinohara E.T., Perkins S.M. Long-term outcomes and late effects for childhood and young adulthood intracranial germinomas. Neuro Oncol. 2015; 17(5): 741–6. doi: 10.1093/neuonc/nou311.Acharya S., DeWees T., Shinohara E.T., Perkins S.M. Long-term outcomes and late effects for childhood and young adulthood intracranial germinomas. Neuro Oncol. 2015; 17(5): 741–6. doi: 10.1093/neuonc/nou311.Yang J.C., Terezakis S.A., Dunkel I.J., Gilheeney S.W., Wolden S.L. Intensity-Modulated Radiation Therapy With Dose Painting: A Brain-Sparing Technique for Intracranial Germ Cell Tumors. Pediatr Blood Cancer. 2016; 63(4): 646–51. doi: 10.1002/pbc.25867.Yang J.C., Terezakis S.A., Dunkel I.J., Gilheeney S.W., Wolden S.L. Intensity-Modulated Radiation Therapy With Dose Painting: A Brain-Sparing Technique for Intracranial Germ Cell Tumors. Pediatr Blood Cancer. 2016; 63(4): 646–51. doi: 10.1002/pbc.25867.Park J., Park Y., Lee S.U., Kim T., Choi Y.K., Kim J.Y. Differential dosimetric benefit of proton beam therapy over intensity modulated radio-therapy for a variety of targets in patients with intracranial germ cell tumors. Radiat Oncol. 2015; 10: 135. doi: 10.1186/s13014-015-0441-5.Park J., Park Y., Lee S.U., Kim T., Choi Y.K., Kim J.Y. Differential dosimetric benefit of proton beam therapy over intensity modulated radio-therapy for a variety of targets in patients with intracranial germ cell tumors. Radiat Oncol. 2015; 10: 135. doi: 10.1186/s13014-015-0441-5.Minniti G., Saran F., Traish D., Soomal R., Sardell S., Gonsalves A., Ashley S., Warrington J., Burke K., Mosleh-Shirazi A., Brada M. Fractionated stereotactic conformal radiotherapy following conservative surgery in the control of craniopharyngiomas. Radiother Oncol. 2007; 82(1): 90–5. doi: 10.1016/j.radonc.2006.11.005.Minniti G., Saran F., Traish D., Soomal R., Sardell S., Gonsalves A., Ashley S., Warrington J., Burke K., Mosleh-Shirazi A., Brada M. Fractionated stereotactic conformal radiotherapy following conservative surgery in the control of craniopharyngiomas. Radiother Oncol. 2007; 82(1): 90–5. doi: 10.1016/j.radonc.2006.11.005.Klimo P., Venable G.T., Boop F.A., Merchant T.E. Recurrent craniopharyngioma after conformal radiation in children and the burden of treatment. J Neurosurg Pediatr. 2015; 15(5): 499–505. doi: 10.3171/2014.10.PEDS14384.Klimo P., Venable G.T., Boop F.A., Merchant T.E. Recurrent craniopharyngioma after conformal radiation in children and the burden of treatment. J Neurosurg Pediatr. 2015; 15(5): 499–505. doi: 10.3171/2014.10.PEDS14384.Bishop A.J., Greenfield B., Mahajan A., Paulino A.C., Okcu M.F., Allen P.K., Chintagumpala M., Kahalley L.S., McAleer M.F., McGovern S.L., Whitehead W.E., Grosshans D.R. Proton beam therapy versus conformal photon radiation therapy for childhood craniopharyngioma: multi-institutional analysis of outcomes, cyst dynamics, and toxicity. Int J Radiat Oncol Biol Phys. 2014; 90(2): 354–61. doi: 10.1016/j.ijrobp.2014.05.051.Bishop A.J., Greenfield B., Mahajan A., Paulino A.C., Okcu M.F., Allen P.K., Chintagumpala M., Kahalley L.S., McAleer M.F., McGovern S.L., Whitehead W.E., Grosshans D.R. Proton beam therapy versus conformal photon radiation therapy for childhood craniopharyngioma: multi-institutional analysis of outcomes, cyst dynamics, and toxicity. Int J Radiat Oncol Biol Phys. 2014; 90(2): 354–61. doi: 10.1016/j.ijrobp.2014.05.051.Merchant T.E., Hua C.H., Shukla H., Ying X., Nill S., Oelfke U. Proton versus photon radiotherapy for common pediatric brain tumors: comparison of models of dose characteristics and their relationship to cognitive function. Pediatr Blood Cancer. 2008; 51(1): 110–7. doi:10.1002/pbc.21530.Merchant T.E., Hua C.H., Shukla H., Ying X., Nill S., Oelfke U. Proton versus photon radiotherapy for common pediatric brain tumors: comparison of models of dose characteristics and their relationship to cognitive function. Pediatr Blood Cancer. 2008; 51(1): 110–7. doi:10.1002/pbc.21530.Pearce M.S., Salotti J.A., Little M.P., McHugh K., Lee C., Kim K.P., Howe N.L., Ronckers C.M., Rajaraman P., Sir Craft A.W., Parker L., Berrington de González A. Radiation exposure from CT scans in child-hood and subsequent risk of leukaemia and brain tumours: a retrospective cohort study. Lancet. 2012; 380(9840): 499–505. doi: 10.1016/S0140-6736(12)60815-0.Pearce M.S., Salotti J.A., Little M.P., McHugh K., Lee C., Kim K.P., Howe N.L., Ronckers C.M., Rajaraman P., Sir Craft A.W., Parker L., Berrington de González A. Radiation exposure from CT scans in child-hood and subsequent risk of leukaemia and brain tumours: a retrospective cohort study. Lancet. 2012; 380(9840): 499–505. doi: 10.1016/S0140-6736(12)60815-0.Fuss M., Hug E.B., Schaefer R.A., Nevinny-Stickel M., Miller D.W., Slater J.M., Slater J.D. Proton radiation therapy (PRT) for pediatric optic pathway gliomas: comparison with 3D planned conventional photons and a standard photon technique. Int J Radiat Oncol Biol Phys. 1999; 45(5):1117–26. doi: 10.1016/s0360-3016(99)00337-5.Fuss M., Hug E.B., Schaefer R.A., Nevinny-Stickel M., Miller D.W., Slater J.M., Slater J.D. Proton radiation therapy (PRT) for pediatric optic pathway gliomas: comparison with 3D planned conventional photons and a standard photon technique. Int J Radiat Oncol Biol Phys. 1999; 45(5):1117–26. doi: 10.1016/s0360-3016(99)00337-5.Pulsifer M.B., Sethi R.V., Kuhlthau K.A., MacDonald S.M., Tarbell N.J., Yock T.I. Early Cognitive Outcomes Following Proton Radiation in Pediatric Patients With Brain and Central Nervous System Tumors. Int J Radiat Oncol Biol Phys. 2015; 93(2): 400–7. doi: 10.1016/j.ijrobp.2015.06.012.Pulsifer M.B., Sethi R.V., Kuhlthau K.A., MacDonald S.M., Tarbell N.J., Yock T.I. Early Cognitive Outcomes Following Proton Radiation in Pediatric Patients With Brain and Central Nervous System Tumors. Int J Radiat Oncol Biol Phys. 2015; 93(2): 400–7. doi: 10.1016/j.ijrobp.2015.06.012.Yahya N., Manan H.A. Neurocognitive impairment following proton therapy for paediatric brain tumour: a systematic review of post-therapy assessments. Support Care Cancer. 2021; 29(6): 3035–47. doi: 10.1007/s00520-020-05808-z.Yahya N., Manan H.A. Neurocognitive impairment following proton therapy for paediatric brain tumour: a systematic review of post-therapy assessments. Support Care Cancer. 2021; 29(6): 3035–47. doi: 10.1007/s00520-020-05808-z.Mizumoto M., Murayama S., Akimoto T., Demizu Y., Fukushima T., Ishida Y., Oshiro Y., Numajiri H., Fuji H., Okumura T., Shirato H., Sakurai H. Long-term follow-up after proton beam therapy for pediatric tumors: a Japanese national survey. Cancer Sci. 2017; 108(3):444–7. doi: 10.1111/cas.13140.Mizumoto M., Murayama S., Akimoto T., Demizu Y., Fukushima T., Ishida Y., Oshiro Y., Numajiri H., Fuji H., Okumura T., Shirato H., Sakurai H. Long-term follow-up after proton beam therapy for pediatric tumors: a Japanese national survey. Cancer Sci. 2017; 108(3):444–7. doi: 10.1111/cas.13140.Jimenez R.B., Ahmed S., Johnson A., Thomas T., Depauw N., Horick N., Tansky J., Casey L., Evans C.L., Pulsifer M., Ebb D., Butler W.E., Fullerton B., Nancy J., Tarbell N.J., Torunn I., Yock T.I., MacDonald S.M. Proton Radiation Therapy for Pediatric Craniopharyngioma Int J Radiat Oncol Biol Phys . 2021; 110(5): 1480–7. doi: 10.1016/j.ijrobp.2021.02.045.Jimenez R.B., Ahmed S., Johnson A., Thomas T., Depauw N., Horick N., Tansky J., Casey L., Evans C.L., Pulsifer M., Ebb D., Butler W.E., Fullerton B., Nancy J., Tarbell N.J., Torunn I., Yock T.I., MacDonald S.M. Proton Radiation Therapy for Pediatric Craniopharyngioma Int J Radiat Oncol Biol Phys . 2021; 110(5): 1480–7. doi: 10.1016/j.ijrobp.2021.02.045.Verma V., Mishra M.V., Mehta M.P. A systematic review of the cost and cost-effectiveness studies of proton radiotherapy. Cancer. 2016;122(10): 1483–501. doi: 10.1002/cncr.29882.Verma V., Mishra M.V., Mehta M.P. A systematic review of the cost and cost-effectiveness studies of proton radiotherapy. Cancer. 2016;122(10): 1483–501. doi: 10.1002/cncr.29882.Mailhot Vega R.B., Kim J., Bussière M., Hattangadi J., HollanderA., Michalski J., Tarbell N.J., Yock T., MacDonald S.M. Cost effectiveness of proton therapy compared with photon therapy in the management of pediatric medulloblastoma. Cancer. 2013; 119(24): 4299–307. doi: 10.1002/cncr.28322.Mailhot Vega R.B., Kim J., Bussière M., Hattangadi J., HollanderA., Michalski J., Tarbell N.J., Yock T., MacDonald S.M. Cost effectiveness of proton therapy compared with photon therapy in the management of pediatric medulloblastoma. Cancer. 2013; 119(24): 4299–307. doi: 10.1002/cncr.28322.Ontario Health (Quality). Proton Beam Therapy for Cancer in Children and Adults: A Health Technology Assessment. Ont Health Technol Assess Ser. 2021; 21(1): 1–142.Ontario Health (Quality). Proton Beam Therapy for Cancer in Children and Adults: A Health Technology Assessment. Ont Health Technol Assess Ser. 2021; 21(1): 1–142.

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