Вопросы гематологии/онкологии и иммунопатологии в педиатрии. 2022; 21: 45-52
Нейробластома 1-й стадии с амплификацией гена MYCN: результаты ретроспективного мультицентрового исследования
https://doi.org/10.24287/1726-1708-2022-21-4-45-52Аннотация
Нейробластома (НБ) рассматривается в качестве модели для риск-адаптированной терапии злокачественных новообразований у детей. Использование комбинации прогностических факторов, таких как возраст, стадия опухолевого процесса, гистологический вариант и молекулярно-генетический профиль опухоли, позволяет выделить 3 группы риска, характеризующихся различными объемами терапии и прогнозом заболевания. Однако стратификация пациентов с 1-й стадией НБ и наличием амплификации гена MYCN в определенную группу риска и, следовательно, выбор терапевтической тактики для больных данной группы значительно варьируют в протоколах крупных исследовательских групп по изучению НБ. Данное исследование одобрено независимым этическим комитетом и утверждено решением ученого совета НМИЦ ДГОИ им. Дмитрия Рогачева. Был проведен сбор клинических данных о пациентах с НБ 1-й стадии по INSS и наличием амплификации гена MYCN, получавших лечение за период с 2013 по 2021 г., путем направления запросов и анкет в 77 специализированных (онкологических) медицинских учреждений Российской Федерации. Проводилась оценка объема терапии и статуса по заболеванию на момент сбора информации. Всего были зарегистрированы 7 пациентов: 3 мальчика и 4 девочки. Медиана возраста на момент постановки диагноза составила 4,8 (разброс 1,5–53,7) месяца. Первичная опухоль у всех больных локализовалась в области надпочечников. У 4/7 (57,2%) пациентов выявлена делеция 1р, у 6/7 (85,7%) детей, которым проводилась оценка статуса 11q, делеции выявлено не было. Терапия проводилась по модифицированному протоколу NB2004. Индукционную терапию, высокодозную химиотерапию и аутологичную трансплантацию гемопоэтических стволовых клеток (аутоТГСК) получили 6/7 (85,7%) человек. Иммунотерапия анти-GD2-моноклональными антителами проведена 1 (14,2%) больному. На момент написания статьи все пациенты оставались живы без событий. Один пациент с тяжелым врожденным пороком сердца (единственный желудочек, транспозиция магистральных сосудов) не получал системную терапию и жив без событий на момент написания статьи. Пациенты с локализованной 1-й стадией НБ, включенные в настоящее исследование и стратифицированные в группу высокого риска в рамках тактики протокола NB2004 за счет выявления амплификации гена MYCN, имели высокие показатели выживаемости без неблагоприятных событий на фоне проведения интенсивной мультимодальной терапии. Однако, учитывая литературные данные международных научных групп о снижении интенсивности терапии у этой когорты пациентов, например отказ от ауто-ТГСК, а также высокий риск развития отдаленных побочных эффектов лечения, в том числе вторичных злокачественных опухолей, у пациентов, получающих терапию по протоколам для группы высокого риска, возможен пересмотр ее концепции. Для этого необходимо проведение полной регистрации всех случаев НБ в России, внедрение диагностического алгоритма, включая выполнение сцинтиграфии с 123I-метайодбензилгуанидином, референса данных визуализационных методов исследования, гистологии и молекулярно-цитогенетического исследования в национальных/федеральных онкологических учреждениях. При накоплении более презентативных данных вероятен отказ от ауто-ТГСК у пациентов с 1-й стадией НБ по INSS и наличием амплификации гена MYCN, но при отсутствии других неблагоприятных маркеров заболевания.
Список литературы
1. Ward E., Desantis C., Robbins A., Kohler В., Jemal А. Childhood and adolescent cancer statistics, 2014. CA Cancer J Clin 2014; 64 (2): 83–103.
2. Liang W.H., Federico S.M., London W.B., Naranjo A., Irwin M.S., Volchenboum S.L., et al. Tailoring Therapy for Children With Neuroblastoma on the Basis of Risk Group Classification: Past, Present, and Future. JCO Clin Cancer Inform 2020; 4: 895–905.
3. Christiansen H., Sahin K., Berthold F., Hero B., Terpe H.J., Lampert F. Comparison of DNA aneuploidy, chromosome 1 abnormalities, MYCN amplification and CD44 expression as prognostic factors in neuroblastoma. Eur J Cancer 1995; 31A (4): 541–4.
4. Bagatell R., Beck-Popovic M., London W.B., Zhang Y., Pearson A.D.J., Matthay K.K., et al. International Neuroblastoma Risk Group. Clin Oncol 2009; 27 (3): 365–70.
5. NB2004 Trial Protocol for Risk Adaptet Treatment of Children with Neuroblastoma, Köln; 2004.
6. Шаманская Т.В., Бургол М.М., Качанов Д.Ю., Рыбалко Н.А., Панкратьева Л.Л., Сугак А.Б., и соавт. Ассоциация врожденных пороков сердца и нейробластомы у детей. Вопросы гематологии/онкологии и иммунопатологии в педиатрии 2018; 17 (3): 28–34.
7. Matthay K.K., Maris J.M., Schleiermacher G., Nakagawara A., Mackall C.L., Diller L., et al. Neuroblastoma. Nat Rev Dis Primers 2016; 2: 16078.
8. Evans A.E., D'Angio G.J., Sather H.N., de Lorimier A.A., Dalton A., Ungerleider R.S., et al. A comparison of four staging systems for localized and regional neuroblastoma: a report from the Children’s Cancer Study Group. J Clin Oncol 1990; 8 (4): 678–88.
9. Brodeur G.M., Pritchard J., Berthold F., Carlsen N.L., Castel V., Castelberry R.P., et al. Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment. J Clin Oncol 1993; 11 (8): 1466–77.
10. Schwab M., Alitalo K., Klempnauer K.H., Varmus H.E., Bishop J.M., Gilbert F., et al. Amplified DNA with limited homology to myc cellular oncogene is shared by human neuroblastoma cell lines and a neuroblastoma tumour. Nature 1983; 305 (5931): 245–8.
11. Park J.R., Kreissman S.G., London W.B., Naranjo A., Cohn S.L., Hogarty M.D., et al. Effect of Tandem Autologous Stem Cell Transplant vs Single Transplant on Event-Free Survival in Patients with High-Risk Neuroblastoma: A Randomized Clinical Trial. JAMA 2019; 322 (8): 7
12. Ladenstein R., Pötschger U., Valteau-Couanet D., Luksch R., Castel V., Yaniv I., et al. Interleukin 2 with anti-GD2 antibody ch14.18/CHO (dinutuximab beta) in patients with high-risk neuroblastoma (HR-NBL1/ SIOPEN): a multicentre, randomised, phase 3 trial. Lancet Oncol 2018; 19 (12): 1617–29.
13. Simon T., Hero B., Schulte J.H., Deubzer H., Hundsdoerfer P., von Schweinitz D., et al. 2017 GPOH Guidelines for Diagnosis and Treatment of Patients with Neuroblastic Tumors. Klin Padiatr 2017; 229 (3): 147–67.
14. Cohn S.L., Look A.T., Joshi V.V., Holbrook T., Salwen H., Chagnovich D., et al. Lack of correlation of N-myc gene amplification with prognosis in localized neuroblastoma: a Pediatric Oncology Group study. Cancer Res 1995; 55 (4): 721–6.
15. Perez C.A., Matthay K.K., Atkinson J.B., Seeger R.C., Shimada H., Haase G.M., et al. Biologic variables in the outcome of stages I and II neuroblastoma treated with surgery as primary therapy: a children's cancer group study. J Clin Oncol 2000; 18 (1): 18–26.
16. Schneiderman J., London W.B., Brodeur G.M., Castleberry R.P., Look A.T., Cohn S.L. Clinical significance of MYCN amplification and ploidy in favorable-stage neuroblastoma: a report from the Children's Oncology Group. J Clin Oncol 2008; 26 (6): 913–8.
17. De Bernardi B., Mosseri V., Rubie H., Castel V., Foot A., Ladenstein R., et al. Treatment of localised resectable neuroblastoma. Results of the LNESG1 study by the SIOP Europe Neuroblastoma Group. Br J Cancer 2008; 99 (7): 1027–33.
18. Monclair T., Brodeur G.M., Ambros P.F., Brisse H.J., Cecchetto G., Holmes K., et al. The International Neuroblastoma Risk Group (INRG) staging system: an INRG Task Force report. J Clin Oncol 2009; 27 (2): 298–303.
19. Cohn S.L., Pearson A.D., London W.B., Monclair T., Ambros P.F., Brodeur G.M., et al. The International Neuroblastoma Risk Group (INRG) classification system: an INRG Task Force report. J Clin Oncol 2009; 27 (2): 289–97.
20. Strother D.R., London W.B., Schmidt M.L., Brodeur G.M., Shimada H., Thorner P., et al. Outcome after surgery alone or with restricted use of chemotherapy for patients with low-risk neuroblastoma: results of Children's Oncology Group study P9641. J Clin Oncol 2012; 30 (15): 1842–8.
21. ANBL1232. Response and Biology-Based Risk Factor-Guided Therapy in Treating Younger Patients With Non-high Risk Neuroblastoma. NCT02176967.
22. ANBL00B1. Biomarkers in Tumor Tissue Samples From Patients With Newly Diagnosed Neuroblastoma or Ganglioneuroblastoma. NCT00904241.
23. Irwin M.S., Naranjo A., Zhang F.F., Cohn S.L., London W.B., Gastier-Foster J.M., et al. Revised Neuroblastoma Risk Classification System: A Report From the Children's Oncology Group. J Clin Oncol 2021; 39 (29): 3229–41.
24. European Low and Intermediate Risk Neuroblastoma Protocol. Clinical trial identifier. NCT01728155.
25. Berthold F., Faldum A., Ernst A., Boos J., Dilloo D., Eggert A., et al. Extended induction chemotherapy does not improve the outcome for high-risk neuroblastoma patients: results of the randomized open-label GPOH trial NB2004-HR. Ann Oncol 2020; 31 (3): 422–9.
Pediatric Hematology/Oncology and Immunopathology. 2022; 21: 45-52
MYCN-amplified stage 1 neuroblastoma: results of a retrospective multicenter study
https://doi.org/10.24287/1726-1708-2022-21-4-45-52Abstract
Neuroblastoma (NB) is considered as a model of risk-adapted therapy for malignant neoplasms in children. The use of a combination of prognostic factors, such as age, stage of the tumor process, histological variant, and molecular genetic profile of a tumor, makes it possible to identify three risk groups characterized by different intensity of therapy and prognosis. However, the stratification of patients with MYCN-amplified stage 1 NB into a certain risk group and, consequently, the choice of therapeutic tactics for patients in this group vary significantly in the protocols of large cooperative NB study groups. 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 of Ministry of Healthcare of the Russian Federation. Clinical data were collected on patients with stage 1 NB according to the INSS system and the presence of the MYCN gene amplification, who received treatment in the period from 2013 to 2021, by sending requests and questionnaires to 77 specialized (oncological) medical institutions in the Russian Federation. At the time of information collection, we made an assessement of the extent of therapy and the status of the disease. A total of 7 patients were registered: 3 boys and 4 girls. The median age at diagnosis was 4.8 months (range 1.5–53.7 months). The primary tumor in all patients was located in the adrenal gland. In 4/7 (57.2%) patients, the 1p deletion was detected, in 6/7 (85.7%) patients who underwent an assessment of the 11q status, no deletion was detected. The therapy was carried out according to the modified NB2004 protocol. Induction therapy, high-dose chemotherapy and autologous hematopoietic stem cell transplantation (auto-HSCT) were received by 6/7 (85.7%) patients. Immunotherapy with anti-GD2 monoclonal antibodies was performed in 1 patient (14.2%). At the time of the manuscript preparation, all patients remained alive without events. One patient with severe congenital heart disease (single ventricle, transposition of the great vessels) has not received systemic therapy and is alive without events at the time of the analysis. Patients with MYCN-amplified stage 1 NB included in this study and stratified into the high-risk group according to the NB2004 protocol, had high survival rates without any adverse events during intensive multimodal therapy. However, given the literature data of international cooperative groups on a decrease in the intensity of therapy in this cohort of patients, for example, refusal of auto-HSCT, as well as a high risk of developing long-term side effects of therapy, including secondary malignant tumors, in patients receiving therapy according to protocols for high-risk groups, it is possible to revise the concept of therapy in this category of patients. This requires a complete registration of all cases of NB in the Russian Federation, the implementation of a diagnostic algorithm, including scintigraphy with 123I-metaiodobenzylguanidine, review of imaging data, histology and molecular cytogenetic studies in national/federal oncological institutions. With the accumulation of more representative data, auto-HSCT is likely to be omitted in patients with MYCN-amplified stage 1 NB with the absence of other unfavorable biological markers of the disease.
References
1. Ward E., Desantis C., Robbins A., Kohler V., Jemal A. Childhood and adolescent cancer statistics, 2014. CA Cancer J Clin 2014; 64 (2): 83–103.
2. Liang W.H., Federico S.M., London W.B., Naranjo A., Irwin M.S., Volchenboum S.L., et al. Tailoring Therapy for Children With Neuroblastoma on the Basis of Risk Group Classification: Past, Present, and Future. JCO Clin Cancer Inform 2020; 4: 895–905.
3. Christiansen H., Sahin K., Berthold F., Hero B., Terpe H.J., Lampert F. Comparison of DNA aneuploidy, chromosome 1 abnormalities, MYCN amplification and CD44 expression as prognostic factors in neuroblastoma. Eur J Cancer 1995; 31A (4): 541–4.
4. Bagatell R., Beck-Popovic M., London W.B., Zhang Y., Pearson A.D.J., Matthay K.K., et al. International Neuroblastoma Risk Group. Clin Oncol 2009; 27 (3): 365–70.
5. NB2004 Trial Protocol for Risk Adaptet Treatment of Children with Neuroblastoma, Köln; 2004.
6. Shamanskaya T.V., Burgol M.M., Kachanov D.Yu., Rybalko N.A., Pankrat'eva L.L., Sugak A.B., i soavt. Assotsiatsiya vrozhdennykh porokov serdtsa i neiroblastomy u detei. Voprosy gematologii/onkologii i immunopatologii v pediatrii 2018; 17 (3): 28–34.
7. Matthay K.K., Maris J.M., Schleiermacher G., Nakagawara A., Mackall C.L., Diller L., et al. Neuroblastoma. Nat Rev Dis Primers 2016; 2: 16078.
8. Evans A.E., D'Angio G.J., Sather H.N., de Lorimier A.A., Dalton A., Ungerleider R.S., et al. A comparison of four staging systems for localized and regional neuroblastoma: a report from the Children’s Cancer Study Group. J Clin Oncol 1990; 8 (4): 678–88.
9. Brodeur G.M., Pritchard J., Berthold F., Carlsen N.L., Castel V., Castelberry R.P., et al. Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment. J Clin Oncol 1993; 11 (8): 1466–77.
10. Schwab M., Alitalo K., Klempnauer K.H., Varmus H.E., Bishop J.M., Gilbert F., et al. Amplified DNA with limited homology to myc cellular oncogene is shared by human neuroblastoma cell lines and a neuroblastoma tumour. Nature 1983; 305 (5931): 245–8.
11. Park J.R., Kreissman S.G., London W.B., Naranjo A., Cohn S.L., Hogarty M.D., et al. Effect of Tandem Autologous Stem Cell Transplant vs Single Transplant on Event-Free Survival in Patients with High-Risk Neuroblastoma: A Randomized Clinical Trial. JAMA 2019; 322 (8): 7
12. Ladenstein R., Pötschger U., Valteau-Couanet D., Luksch R., Castel V., Yaniv I., et al. Interleukin 2 with anti-GD2 antibody ch14.18/CHO (dinutuximab beta) in patients with high-risk neuroblastoma (HR-NBL1/ SIOPEN): a multicentre, randomised, phase 3 trial. Lancet Oncol 2018; 19 (12): 1617–29.
13. Simon T., Hero B., Schulte J.H., Deubzer H., Hundsdoerfer P., von Schweinitz D., et al. 2017 GPOH Guidelines for Diagnosis and Treatment of Patients with Neuroblastic Tumors. Klin Padiatr 2017; 229 (3): 147–67.
14. Cohn S.L., Look A.T., Joshi V.V., Holbrook T., Salwen H., Chagnovich D., et al. Lack of correlation of N-myc gene amplification with prognosis in localized neuroblastoma: a Pediatric Oncology Group study. Cancer Res 1995; 55 (4): 721–6.
15. Perez C.A., Matthay K.K., Atkinson J.B., Seeger R.C., Shimada H., Haase G.M., et al. Biologic variables in the outcome of stages I and II neuroblastoma treated with surgery as primary therapy: a children's cancer group study. J Clin Oncol 2000; 18 (1): 18–26.
16. Schneiderman J., London W.B., Brodeur G.M., Castleberry R.P., Look A.T., Cohn S.L. Clinical significance of MYCN amplification and ploidy in favorable-stage neuroblastoma: a report from the Children's Oncology Group. J Clin Oncol 2008; 26 (6): 913–8.
17. De Bernardi B., Mosseri V., Rubie H., Castel V., Foot A., Ladenstein R., et al. Treatment of localised resectable neuroblastoma. Results of the LNESG1 study by the SIOP Europe Neuroblastoma Group. Br J Cancer 2008; 99 (7): 1027–33.
18. Monclair T., Brodeur G.M., Ambros P.F., Brisse H.J., Cecchetto G., Holmes K., et al. The International Neuroblastoma Risk Group (INRG) staging system: an INRG Task Force report. J Clin Oncol 2009; 27 (2): 298–303.
19. Cohn S.L., Pearson A.D., London W.B., Monclair T., Ambros P.F., Brodeur G.M., et al. The International Neuroblastoma Risk Group (INRG) classification system: an INRG Task Force report. J Clin Oncol 2009; 27 (2): 289–97.
20. Strother D.R., London W.B., Schmidt M.L., Brodeur G.M., Shimada H., Thorner P., et al. Outcome after surgery alone or with restricted use of chemotherapy for patients with low-risk neuroblastoma: results of Children's Oncology Group study P9641. J Clin Oncol 2012; 30 (15): 1842–8.
21. ANBL1232. Response and Biology-Based Risk Factor-Guided Therapy in Treating Younger Patients With Non-high Risk Neuroblastoma. NCT02176967.
22. ANBL00B1. Biomarkers in Tumor Tissue Samples From Patients With Newly Diagnosed Neuroblastoma or Ganglioneuroblastoma. NCT00904241.
23. Irwin M.S., Naranjo A., Zhang F.F., Cohn S.L., London W.B., Gastier-Foster J.M., et al. Revised Neuroblastoma Risk Classification System: A Report From the Children's Oncology Group. J Clin Oncol 2021; 39 (29): 3229–41.
24. European Low and Intermediate Risk Neuroblastoma Protocol. Clinical trial identifier. NCT01728155.
25. Berthold F., Faldum A., Ernst A., Boos J., Dilloo D., Eggert A., et al. Extended induction chemotherapy does not improve the outcome for high-risk neuroblastoma patients: results of the randomized open-label GPOH trial NB2004-HR. Ann Oncol 2020; 31 (3): 422–9.
