Radiation therapy to metastatic sites among patients with high-risk neuroblastoma in first-line therapy

Relevance. Radiation therapy (RT) is one of the components of multimodal treatment among patients with high-risk neuroblastoma (NB), and in combination with surgical treatment is a mandatory element of local control of the primary tumor. At the same time, RT for metastatic sites persisting after completion of induction therapy is not a standard protocol treatment in primary patients with high-risk NB. The effect of RT on metastatic sites on improving long-term survival and reducing recurrence rates continues to be studied.

Aim to the study – to investigate approaches to RT for single metastatic foci persisting after induction therapy among patients with NB highrisk group as part of the consolidation phase of first-line therapy.

Materials and methods. The retrospective analysis included 11 patients with high-risk NB who underwent RT for metastatic foci as part of first-line therapy at the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Ministry of Health of Russia from 01.2012 to 12.2023. Patients received therapy according to the modified protocol GPON-NB2004. The indication for RT was the persistence of a single metastatic site detected by 123I-metaiodobenzylguanidine scintigraphy or computed tomography/magnetic resonance imaging after completion of induction chemotherapy.

Results. The median age was 31.9 months (range 9.4–128.6 months). All patients were initially with stage 4 disease (one patient had metastatic focus in the orbit without detection of the primary tumor). MYCN gene amplification was detected in 4/11 (36 %) cases. 10/11 (91 %) patients achieved а partial response after induction therapy. In all cases, only one metastatic focus was irradiated. 2/11 patients received radiation to both the primary tumor and metastatic focus.

10/11 patients received RT to metastatic sites localized in skeletal bones, 1/11 – to a distant lymph node. Seven of 11 sites received 21 Gy in 14 fractions. The median follow-up was 40 months (range 13–97 months). Only 1 of 11 patients receiving metastatic site irradiation experienced relapse in an irradiated distant site 24 months later. The 3-year relapse-free survival and overall survival were 54 % and 80 % respectively.

Conclusions. RT may be an effective method of local control in oligometastatic disease and in case of persisted single metastatic foci after induction chemotherapy in the treatment of high-risk NB. Additional large studies are needed to confirm the role of RT in improving survival with irradiation of metastatic sites.

1. Maris J.M. Recent advances in neuroblastoma. N Engl J Med. 2010;362(23):2202–11. doi: 10.1056/NEJMra0804577.

2. Simon T., Hero B., Faldum A., Handgretinger R., Schrappe M., Klingebiel T., Berthold F. Long term outcome of high-risk neuroblastoma patients after immunotherapy with antibody ch14.18 or oral metronomic chemotherapy. BMC cancer. 2011;11:21. doi: 10.1186/1471-2407-11-21.

3. Shamanskaya T.V., Varfolomeeva S.R., Kachanov D.Yu., Moiseenko R.A., Teleshova M.V., Konovalov D.M., Roshchin V.Yu., Kazakova A.N., Zemtsova L.V., Drui A.E., Yadgarov M.Ya., Tereshchenko G.V., Shcherbakov A.P., Likar Yu.N., Sukhov M.N., Grachev N.S., Akhaladze D.G., Maschan M.A., Nechesnyuk A.V., Pshonkin A.V., Kurnikova E.E., Skorobogatova E.V., Khachatryan L.A., Fomin D.K., Maschan A.A., Rumyantsev A.G., Novichkova G.A. The results of therapy in patients with high-risk neuroblastoma: the experience of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology. Voprosy gematologii/onkologii i immunopatologii v pediatrii = Pediatric Hematology/Oncology and Immunopathology. 2023;22(2):65–91. (In Russ.)].

4. Matthay K.K., Edeline V., Lumbroso J., Tanguy M.L., Asselain B., Zucker J.M., Valteau-Couanet D., Hartmann O., Michon J. Correlation of early metastatic response by 123I-metaiodobenzylguanidine scintigraphy with overall response and event-free survival in stage IV neuroblastoma. J Clin Oncol. 2003;21:2486–91. doi: 10.1200/JCO.2003.09.122.

5. Shamanskaya T.V., Kachanov D.Yu., Yadgarov M.Ya. The impact of response to induction chemotherapy on the event-free and overall survival in patients with high-risk neuroblastoma: a systematic review and meta-analysis. Voprosy gematologii/onkologii i immunopatologii v pediatrii = Pediatric Hematology/Oncology and Immunopathology. 2022;21(2):141–56. (In Russ.)].

6. Kazantsev I.V., Gevorgyan A.G., Yukhta T.V., Tolkunova P.S., Zvyagintseva D.A., Kozlov A.V., Golenkova M.S., Babenko E.V., Kuga P.S., Shvetsov A.N., Nikolaev I.Yu., Morozova E.V., Safonova S.A., Punanov Yu.A., Zubarovskaya L.S., Afanasyev B.V. The complex intensive therapy regimen as curative therapy in patients with primary-resistant and relapsed neuroblastoma: R.M. Gorbacheva Memorial Institute for Children Oncology, Hematology and Transplantation experience. Voprosy gematologii/ onkologii i immunopatologii v pediatrii = Pediatric Hematology/ Oncology and Immunopathology. 2020;19(2):129–40. (In Russ.)].

7. Zhao Q., Liu Y., Zhang Y., Meng L., Wei J., Wang B., Xin Y., Dong L., Jiang X. Role and toxicity of radiation therapy in neuroblastoma patients: A literature review. Crit Rev Oncol Hematol. 2020;149:102924. doi: 10.1016/j.critrevonc.2020.102924.

8. Rich D.C., Corpron C.A., Smith M.B., Black C.T., Lally K.P., Andrassy R.J. Second malignant neoplasms in children after treatment of soft tissue sarcoma. J Pediatr Surg.1997;32(2):369–72. doi: 10.1016/S0022-3468(97)90213-X.

9. Polishchuk A.L., Li R., Hill-Kayser C., Little A., Hawkins R.A., Hamilton J., Lau M., Tran H.C., Strahlendorf C., Lemons R.S., Weinberg V., Matthay K.K., Du Bois S.G., Marcus K.J., Bagatell R., Haas-Kogan D.A. Likelihood of bone recurrence in prior sites of metastasis in patients with high-risk neuroblastoma. Int J Radiat Oncol Biol Phys. 2014;89(4):839–45. doi: 10.1016/j.ijrobp.2014.04.004.

10. Sibley G.S., Mundt A.J., Goldman S., Nachman J., Reft C., Weichselbaum R.R., Hallahan D.E., Johnson L. Patterns of failure following total body irradiation and bone marrow transplantation with or without a radiotherapy boost for advanced neuroblastoma. Int J Radiat Oncol Biol Phys. 1995;32(4):1127–35. doi: 10.1016/0360-3016(95)00011-m.

11. Sangthawan D., DesRosiers P.M., Randall M.E., Robertson K., Goebel S., Fallon R. Relapse in the skull after myeloablative therapy for high-risk neuroblastoma. Pediatr Hematol Oncol. 2003;20(1):23–30. doi: 10.1080/08880010390158504.

12. Casey D.L., Pitter K.L., Kushner B.H., Cheung N.-K. V., Modak S., LaQuaglia M.P., Wolden S.L. Radiation therapy to sites of metastatic disease as part of consolidation in high-risk neuroblastoma: can longterm control be achieved? Int J Radiat Oncol Biol Phys. 2018;100(5):1204–9. doi: 10.1016/j.ijrobp.2018.01.008.

13. Keshwani K., Boterberg T., Dieckmann K., Janssens G.O., Laprie A., Timmermann B., Gaze M.N. Radical skeletal metastatic site irradiation in high-risk neuroblastoma: systematic review and proposal for a randomised trial: a report from the SIOPEN Radiotherapy Committee. J Cancer Metastasis Treat. 2023;9(1). doi: 10.20517/2394-4722.2022.32.

14. Jazmati D., Butzer S., Hero B., Doyen J., Khalil D.A., Steinmeier T., Schleithoff S.S., Eggert A., Simon T., Timmermann B. Long-term follow-up of children with neuroblastoma receiving radiotherapy to metastatic lesions within the German Neuroblastoma Trials NB97 and NB 2004. Strahlentherapie und Onkologie. 2021;197:683–9. doi: 10.1007/s00066-020-01718-5.

15. Kandula S., Prabhu R.S., Nanda R., Switchenko J. M., Cash T., Qayed M., Katzenstein H., Esiashvili N. Outcomes after radiation therapy to metastatic sites in patients with stage 4 neuroblastoma. J Pediatr Hematol Oncol. 2015;37(3):175–80. doi: 10.1097/MPH.0000000000000264

16. Bradfi eld S.M., Douglas J.D., Hawkins D.S., Sanders J.E., Park J.R. Fractionated low‐dose radiotherapy after myeloablative stem cell transplantation for local control in patients with high‐risk neuroblastoma. Cancer. 2004;100(6):1268–75. doi: 10.1002/cncr.20091.

17. Mazloom A., Louis C.U., Nuchtern J., Kim E., Russell H., AllenRhoades W., Krance R., Paulino A.C. Radiation therapy to the primary and postinduction chemotherapy MIBG-avid sites in highrisk neuroblastoma. Int J Radiat Oncol Biol Phys. 2014;90(4):858–62. doi: 10.1016/j.ijrobp.2014.07.019.

18. Brodeur G.M., Pritchard J., Berthold F., Carlsen N.L., Castel V., Castelberry R.P., Bernardi B., De Evans A.E., Favrot M., Hedborg F. Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment. J Clin Oncol. 1993;11(8):1466–77. doi: 10.1200/JCO.1993.11.8.1466.

19. Yanik G.A., Parisi M.T., Shulkin B.L., Naranjo A., Kreissman S.G., London W.B., Villablanca J.G., Maris J.M., Park J.R., Cohn S.L., McGrady P., Matthay K.K. Semiquantitative mIBG scoring as a prognostic indicator in patients with stage 4 neuroblastoma: a report from the Children’s oncology group. J Nucl Med. 2013;54(4):541–8. doi: 10.2967/jnumed.112.112334.

20. Berthold F., Faldum A., Ernst A., Boos J., Dilloo D., Eggert A., Fischer M., Frühwald M., Henze G., Klingebiel T., Kratz C., Kremens B., Krug B., Leuschner I., Schmidt M., Schmidt R., Schumacher-Kuckelkorn R., Schweinitz von D., Schilling F.H., Theissen J., Simon T. 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. doi: 10.1016/j.annonc.2019.11.011.

21. Shamanskaya T.V., Papadakis V., Utalieva D.T., Nikolaev G.V., Zaсarinnaya O.S., Andreeva N.A., Kubirov M.S., Yakupova M.G., Rabaeva L.L., Litvinov D.V., Kachanov D.Yu. Intensifi cation of postconsolidation therapy in patients with high-risk neuroblastoma. Rossiyskiy zhurnal detskoy gematologii i onkologii = Russian Journal of Pediatric Hematology and Oncology. 2024;11(3):11–21. (In Russ.)].

22. Schmidt M., Simon T., Hero B., Schicha H., Berthold F. The prognostic impact of functional imaging with 123I-mIBG in patients with stage 4 neuroblastoma > 1 year of age on a high-risk treatment protocol: results of the German Neuroblastoma Trial NB97. Eur J Cancer. 2008;44(11):1552–8. doi: 10.1016/j.ejca.2008.03.013.

23. Ladenstein R., Lambert B., Pötschger U., Castellani M.-R., Lewington V., Bar-Sever Z., Oudoux A., Śliwińska A., Taborska K., Biassoni L., Yanik G., Naranjo A., Parisi M., Shulkin B., Nadel H., Gelfand M., Matthay K., Park J., Kreissman S., Valteau-Couanet D., Boubaker A. Validation of the mIBG skeletal SIOPEN scoring method in two independent high-risk neuroblastoma populations: the SIOPEN/ HR-NBL1 and COG-A3973 trials. Eur J Nucl Med Mol Imaging. 2018;45(2):292–305. doi: 10.1007/s00259-017-3829-7.

24. Shamanskaya T.V., Kachanov D.Yu., Lihotkina V.I., Tereschenko G.V., Ternovaya E.S., Shcherbakov A.P., Likar Yu.N., Roschin V.Yu., Olshanskaya Yu.V., Kazakova A.N., Varfolomeeva S.R. Lung metastases in childhood neuroblastoma. Voprosy gematologii/onkologii i immunopatologii v pediatrii = Pediatric Hematology/Oncology and Immunopathology. 2018;17(2):92–102. (In Russ.)].

25. Harreld J.H., Bratton E.M., Federico S.M., Li X., Grover W., Li Y., Kerr N.C., Wilson M.W., Hoehn M.E. Orbital metastasis is associated with decreased survival in stage M neuroblastoma. Pediatr Blood Cancer. 2016;63(4):627–33. doi: 10.1002/pbc.25847.

26. Scherer S., Mayer B.F.B., Dietzel M., Esser M., Warmann S.W., Lang P., Schuhmann M.U., Schmidt A., Fuchs J. The role of surgery in the treatment of neuroblastoma metastases at rare sites. J Cancer Res Clin Oncol. 2023;149(14):12913–21. doi: 10.1007/s00432-023-05147-6.

27. Wheldon T.E., OʼDonoghue J., Gregor A., Livingstone A., Wilson L. Radiobiological considerations in the treatment of neuroblastoma by total body irradiation. Radiother Oncol. 1986;6(4):317–26. doi: 10.1016/S0167-8140(86)80199-2.

28. Simon T., Hero B., Schulte J.H., Deubzer H., Hundsdoerfer P., Schweinitz von D., Fuchs J., Schmidt M., Prasad V., Krug B., Timmermann B., Leuschner I., Fischer M., Langer T., Astrahantseff K., Berthold F., Lode H., Eggert A. 2017 GPOH guidelines for diagnosis and treatment of patients with neuroblastic tumors. Klinische Pädiatrie.2017;229(03):147–67. doi: 10.1055/s-0043-103086.

29. Kandula S., Prabhu R.S., Nanda R., Switchenko J.M., Cash T., Qayed M., Katzenstein H., Esiashvili N. Outcomes after radiation therapy to metastatic sites in patients with stage 4 neuroblastoma. J Pediatr Hematol Oncol. 2015;37(3):175–80. doi:10.1097/MPH.0000000000000264

30. Rossillon L., Edeline V., Agrigoroaie L., Pasqualini C., Berlanga P., Bolle S., Valteau‐Couanet, D. Rationale for irradiation of persisting oligo‐skeletal metastases to improve survival of metastatic neuroblastoma patients with a poor response to chemotherapy: A retrospective study. Pediatr Blood Cancer. 2025;72(1):e31350. doi: 10.1002/pbc.31350.

31. Salim N., Tumanova K., Popodko A., Libson E. Second Chance for Cure: Stereotactic Ablative Radiotherapy in Oligometastatic Disease. JCO Glob Oncol. 2024;10:e2300275. doi: 10.1200/GO.23.00275