Вопросы гематологии/онкологии и иммунопатологии в педиатрии. 2024; 23: 59-67
Вторичные злокачественные опухоли у пациентов после терапии нейробластомы: опыт одного Центра
https://doi.org/10.24287/1726-1708-2024-23-3-59-67Аннотация
Интенсификация терапии у пациентов с нейробластомой (НБ) группы промежуточного/высокого риска привела к улучшению выживаемости, но в то же время в группе выживших отмечается высокая частота встречаемости отдаленных побочных эффектов (ОПЭ) терапии. Самым серьезным ОПЭ является развитие вторичных злокачественных опухолей (ВЗО) с частотой встречаемости 1,2%. В исследование включены 176 выживших пациентов с НБ группы промежуточного/высокого риска, которые получили лечение на базе ФГБУ «НМИЦ ДГОИ им. Дмитрия Рогачева» Минздрава России. Исследование одобрено независимым этическим комитетом и утверждено решением ученого совета Центра им. Дмитрия Рогачева. Специфическое лечение проводилось по модифицированному протоколу GPOH NB-2004 с января 2012 г. по декабрь 2019 г. Режимы высокодозной химиотерапии включали карбоплатин/этопозид/мелфалан (CEM) (до июля 2013 г.) и треосульфан/мелфалан (Treo/Mel) (с июля 2013 г. по настоящее время). С июля 2014 г. пациентам с НБ группы высокого риска с сохранением метаболически активнои опухоли после этапа индукции проводилась терапия 131I-метайодбензилгуанидином (131I-МЙБГ-терапия). Тридцать шесть (20%) пациентов, включенных в исследование, развили рецидив заболевания. Терапия рецидива проводилась в зависимости от инициальной группы риска, объема предшествующей терапии и характера рецидива. Медиана времени наблюдения от даты постановки диагноза НБ до даты последнего наблюдения за пациентами, включенными в исследование, составила 76 мес (разброс 37–152 мес). Дата проведения анализа – 31.12.2023. Всем пациентам при выявлении ВЗО проводилось молекулярно-генетическое исследование для поиска герминальных и соматических вариантов в генах в лаборатории молекулярной биологии и лаборатории молекулярной онкологии ФГБУ «НМИЦ ДГОИ им. Дмитрия Рогачева» Минздрава России. Использовались метод высокопроизводительного секвенирования ДНК, выделенной из ткани опухоли, для поиска соматических вариантов (панель «Генетическая характеристика детских солидных опухолей (Pediatric oncopanel v.4.2)») и полногеномное секвенирование ДНК, выделенной из периферической крови пациента, в целях поиска герминальных мутаций в генах, ассоциированных с синдромами предрасположенности к опухолям. В ходе исследования выявлено 3 (1,7%) случая ВЗО: папиллярная карцинома щитовидной железы (n = 2), вторичный острый миелоидный лейкоз (n = 1). Возраст пациентов на момент постановки диагноза НБ, которые развили ВЗО, составил 39, 52 и 55 месяцев. В 2 случаях пациенты инициально были из группы высокого риска и в 1 – с комбинированным рецидивом из группы промежуточного риска. Высокодозная химиотерапия проведена 2 пациентам группы высокого риска в первой линии и 1 пациенту группы промежуточного риска в рецидиве. 131I-МЙБГ-терапия в первой линии и лучевая терапия на область головы в рецидиве проводились в 1 случае. Время развития ВЗО от даты диагноза НБ составило 66,5, 76,5 и 56,6 мес. Кумулятивная частота развития ВЗО у пациентов с НБ промежуточного/высокого риска через 5, 6 и 7 лет составила 0,73% (95% доверительный интервал (ДИ) 0,01–5,07), 1,64% (95% ДИ 0,41–6,44) и 2,75% (95% ДИ 0,88–8,42) соответственно. В ходе молекулярно-генетического анализа в образцах ткани опухоли были выявлены соматические генетические варианты, в то время как герминальных мутаций в генах, составляющих регион интереса, обнаружено не было. ВЗО являются редким, но грозным осложнением терапии пациентов с НБ. Важное значение имеет тщательное динамическое наблюдение за больными с НБ, завершившими лечение, с формированием алгоритма обследования на основе объема проведенной терапии.
Список литературы
1. Spix C., Pastore G., Sankila R., Stiller C.A., Steliarova-Foucher E. Neuroblastoma incidence and survival in European children (1978–1997): report from the Automated Childhood Cancer Information System project. Eur J Cancer 2006; 42 (13): 2081–91.
2. Hero B., Simon T., Spitz R., Ernestus K., Gnekow A.K., Scheel-Walter H.-G., et al. Localized infant neuroblastomas often show spontaneous regression: results of the prospective trials NB95-S and NB97. J Clin Oncol 2008; 26 (9): 1504–10.
3. Irwin M.S., Park J.R. Neuroblastoma: paradigm for precision medicine. Pediatr. Clin North Am 2015; 62 (1): 225–56.
4. Applebaum M.A., Vaksman Z., Lee S.M., Hungate E.A., Henderson T.O., London W.B., et al. Neuroblastoma survivors are at increased risk for second malignancies: A report from the International Neuroblastoma Risk Group Project. Eur J Cancer 2017; 72: 177–85.
5. Kushner B.H., Kramer K., Modak S., Qin L.-X., Yataghena K., Jhanwar S.C., et al. Reduced risk of secondary leukemia with fewer cycles of dose-intensive induction chemotherapy in patients with neuroblastoma. Pediatr Blood Cancer 2009; 53 (1): 17–22.
6. Haghiri S., Fayech C., Mansouri I., Dufour C., Pasqualini C., Bolle S., et al. Long-term follow-up of high-risk neuroblastoma survivors treated with high-dose chemotherapy and stem cell transplantation rescue. Bone Marrow Transplant 2021; 56 (8): 1984–97.
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9. Berthold F., Hömberg M., Proleskovskaya I., Mazanek P., Belogurova M., Ernst A., et al. Metronomic therapy has low toxicity and is as effective as current standard treatment for recurrent high-risk neuroblastoma. Pediatr Hematol Oncol 2017; 34 (5): 308–19.
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12. Laverdière C., Liu Q., Yasui Y., Nathan P.C., Gurney J.G., Stovall M., et al. Long-term Outcomes in Survivors of Neuroblastoma: A Report From the Childhood Cancer Survivor Study. J Natl Cancer Inst 2009; 101 (16): 1131–40.
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14. Martin A., Schneiderman J., Helenowski I.B., Morgan E., Dilley K., Danner-Koptik K., et al. Secondary malignant neoplasms after high-dose chemotherapy Second Neoplasms After Neuroblastoma. Pediatr Blood Cancer 2014; 61 (8): 1350–6.
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16. Rubino C., Adjadj E., Guérin S., Guibout C., Shamsaldin A., Dondon M.-G., et al. Long-term risk of second malignant neoplasms after neuroblastoma in childhood: role of treatment. Int J Cancer 2003; 107 (5): 791–6.
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21. Lebbink C.A., Waguespack S.G., van Santen H.M. Thyroid Dysfunction and Thyroid Cancer in Childhood Cancer Survivors: Prevalence, Surveillance and Management. Front Horm Res 2021: 54: 140–53.
22. Clement S.C., van Eck-Smit B.L. F., van Trotsenburg A.S.P., Kremer L.C.M., Tytgat G.A.M., van Santen H.M. Long-term follow-up of the thyroid gland after treatment with 131I-Metaiodobenzylguanidine in children with neuroblastoma: importance of continuous surveillance. Pediatr Blood Cancer 2013; 60 (11): 1833–8.
Pediatric Hematology/Oncology and Immunopathology. 2024; 23: 59-67
Second malignant neoplasms after neuroblastoma treatment: a single center experience
https://doi.org/10.24287/1726-1708-2024-23-3-59-67Abstract
Treatment intensification in patients with intermediateand high-risk neuroblastoma (NB) has led to improved survival rates. However, NB survivors face a high risk of long-term side effects associated with intensified therapy, with second malignant neoplasms (SMN) being the most serious and occurring in 1.2% of cases. Our study included 176 cancer survivors who had been treated for intermediateand high-risk NB at the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Ministry of Healthcare of the Russian Federation. The study was approved by the Independent Ethics Committee and the Scientific Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Ministry of Healthcare of the Russian Federation. Specific treatment was carried out according to the modified GPOH NB-2004 protocol from January 2012 to December 2019. High-dose preparative chemotherapy regimens included carboplatin/etoposide/melphalan (CEM) (until June 2013) and treosulfan/melphalan (TreoMel) (from July 2013). Starting from July 2014, high-risk NB patients with metabolically active residual tumors received 131I-metaiodobenzylguanidine (131I-MIBG) therapy after induction chemotherapy. Thirty-six (20%) patients enrolled in our study developed disease relapse. Treatment for relapsed NB depended on the initial risk group, the extent of previous therapy and the type of relapse. The median follow-up time from the date of diagnosis of NB to the date of last follow-up for the patients included in the study was 76 months (range 37–152 months). The final analysis was performed on 31 December 2023. All the patients diagnosed with a second malignancy underwent molecular genetic testing for germline and somatic gene variants at the Laboratory of Molecular Biology and the Laboratory of Molecular Oncology of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Ministry of Healthcare of the Russian Federation. High-throughput sequencing of DNA isolated from tumor tissues was used for the detection of somatic variants (Genetic Characteristics of Pediatric Solid Tumors panel (Pediatric Oncopanel v.4.2)) and whole-genome sequencing of DNA isolated from the patients’ peripheral blood was utilized for the detection of germline mutations in genes associated with tumor predisposition syndromes. Three (1.7%) out of 176 patients developed SMNs: papillary thyroid carcinoma (n = 2) and secondary acute myeloid leukemia (n = 1). At the diagnosis of NB, they had been aged 39, 52, and 55 months. Two of them had been initially stratified to the high-risk group, and one case had been allocated to the intermediate-risk group (and subsequently developed a combined relapse). The two patients from the high-risk group received high-dose chemotherapy as a part of frontline treatment, while the patient with intermediate-risk NB was given high-dose chemotherapy at the time of relapse. 131I-MIBG-therapy as a component of frontline therapy and cranial radiotherapy at relapse were performed in one case. The time from the date of NB diagnosis to the development of second malignancy was 66.5, 76.5, and 56.6 months. The cumulative incidence of SMN in the patients diagnosed with intermediateand high-risk NB after 5, 6, and 7 years was 0.73% (95% confidence interval (CI) 0.01–5.07), 1.64% (95% CI 0.41–6.44), and 2.75% (95% CI 0.88–8.42), respectively. Our molecular genetic analysis revealed the presence of somatic genetic variants in the tumor tissue samples, however, no germline mutations were found in the regions of interest. Second malignancies are rare but serious complications of NB treatment. It is important to closely follow-up surviving patients after treatment for NB, and a follow-up care program should be based on the extent of the prior treatment.
References
1. Spix C., Pastore G., Sankila R., Stiller C.A., Steliarova-Foucher E. Neuroblastoma incidence and survival in European children (1978–1997): report from the Automated Childhood Cancer Information System project. Eur J Cancer 2006; 42 (13): 2081–91.
2. Hero B., Simon T., Spitz R., Ernestus K., Gnekow A.K., Scheel-Walter H.-G., et al. Localized infant neuroblastomas often show spontaneous regression: results of the prospective trials NB95-S and NB97. J Clin Oncol 2008; 26 (9): 1504–10.
3. Irwin M.S., Park J.R. Neuroblastoma: paradigm for precision medicine. Pediatr. Clin North Am 2015; 62 (1): 225–56.
4. Applebaum M.A., Vaksman Z., Lee S.M., Hungate E.A., Henderson T.O., London W.B., et al. Neuroblastoma survivors are at increased risk for second malignancies: A report from the International Neuroblastoma Risk Group Project. Eur J Cancer 2017; 72: 177–85.
5. Kushner B.H., Kramer K., Modak S., Qin L.-X., Yataghena K., Jhanwar S.C., et al. Reduced risk of secondary leukemia with fewer cycles of dose-intensive induction chemotherapy in patients with neuroblastoma. Pediatr Blood Cancer 2009; 53 (1): 17–22.
6. Haghiri S., Fayech C., Mansouri I., Dufour C., Pasqualini C., Bolle S., et al. Long-term follow-up of high-risk neuroblastoma survivors treated with high-dose chemotherapy and stem cell transplantation rescue. Bone Marrow Transplant 2021; 56 (8): 1984–97.
7. Zhang J., Walsh M.F., Wu G., Edmonson M.N., Gruber T.A., Easton J., et al. Germline Mutations in Predisposition Genes in Pediatric Cancer. N Engl J Med 2015; 373 (24): 2336–46.
8. German Society for Pediatric Oncology and Hematology GPOH gGmbH. NB2004 Trial Protocol for Risk Adapted Treatment of Children With Neuroblastoma.: Clinical trial registration NCT00410631 2013, clinicaltrials. gov.
9. Berthold F., Hömberg M., Proleskovskaya I., Mazanek P., Belogurova M., Ernst A., et al. Metronomic therapy has low toxicity and is as effective as current standard treatment for recurrent high-risk neuroblastoma. Pediatr Hematol Oncol 2017; 34 (5): 308–19.
10. Utalieva D.T., Kalinina I.I., Kachanov D.Yu., Evseev D.A., Shcherbakov A.P., Dubrovina M.E. i dr. Sluchai razvitiya v torichnog o mieloidnog o leikoza u patsienta s immunopatologii i v pediatrii 2020; 19 (3): 105–13. DOI: 10.24287/1726-1708-2020-19-3-105-113
11. Pinto N.R., Applebaum M.A., Volchenboum S.L., Matthay K.K., London W.B., Ambros P.F., et al. Advances in Risk Classification and Treatment Strategies for Neuroblastoma. J Clin Oncol 2015; 33 (27): 3008–17.
12. Laverdière C., Liu Q., Yasui Y., Nathan P.C., Gurney J.G., Stovall M., et al. Long-term Outcomes in Survivors of Neuroblastoma: A Report From the Childhood Cancer Survivor Study. J Natl Cancer Inst 2009; 101 (16): 1131–40.
13. Godley L.A., Larson R.A. Therapy-related myeloid leukemia. Semin Oncol 2008; 35 (4): 418–29.
14. Martin A., Schneiderman J., Helenowski I.B., Morgan E., Dilley K., Danner-Koptik K., et al. Secondary malignant neoplasms after high-dose chemotherapy Second Neoplasms After Neuroblastoma. Pediatr Blood Cancer 2014; 61 (8): 1350–6.
15. Le Deley M.-C., Leblanc T., Shamsaldin A., Raquin M.-A., Lacour B., Sommelet D., et al. Risk of secondary leukemia after a solid tumor in childhood according to the dose of epipodophyllotoxins and anthracyclines: a case-control study by the Société Française d’Oncologie Pédiatrique. J Clin Oncol 2003; 21 (6): 1074–81.
16. Rubino C., Adjadj E., Guérin S., Guibout C., Shamsaldin A., Dondon M.-G., et al. Long-term risk of second malignant neoplasms after neuroblastoma in childhood: role of treatment. Int J Cancer 2003; 107 (5): 791–6.
17. Veiga L.H.S., Holmberg E., Anderson H., Pottern L., Sadetzki S., Adams M.J., et al. Thyroid Cancer after Childhood Exposure to External Radiation: An Updated Pooled Analysis of 12 Studies. Radiat Res 2016; 185 (5): 473–84.
18. Veiga L.H.S., Bhatti P., Ronckers C.M., Sigurdson A.J., Stovall M., Smith S.A., et al. Chemotherapy and thyroid cancer risk: a report from the childhood cancer survivor study. Cancer Epidemiol. Biomarkers Prev 2012; 21 (1): 92–101.
19. Veiga L.H.S., Lubin J.H., Anderson H., de Vathaire F., Tucker M., Bhatti P., et al. A pooled analysis of thyroid cancer incidence following radiotherapy for childhood cancer. Radiat Res 2012; 178 (4): 365–76.
20. Clement S.C., van Rijn R.R., van Eck-Smit B.L.F., van Trotsenburg A.S.P., Caron H.N., Tytgat G.A.M., et al. Longterm efficacy of current thyroid prophylaxis and future perspectives on thyroid protection during 131I-metaiodobenzylguanidine treatment in children with neuroblastoma. Eur J Nucl Med Mol Imaging 2015; 42 (5): 706–15.
21. Lebbink C.A., Waguespack S.G., van Santen H.M. Thyroid Dysfunction and Thyroid Cancer in Childhood Cancer Survivors: Prevalence, Surveillance and Management. Front Horm Res 2021: 54: 140–53.
22. Clement S.C., van Eck-Smit B.L. F., van Trotsenburg A.S.P., Kremer L.C.M., Tytgat G.A.M., van Santen H.M. Long-term follow-up of the thyroid gland after treatment with 131I-Metaiodobenzylguanidine in children with neuroblastoma: importance of continuous surveillance. Pediatr Blood Cancer 2013; 60 (11): 1833–8.
