Treatment of relapse/progression of the disease in patients with neuroblastoma in the Republic of Belarus over a 20-year period: a cohort study

Introduction. Neuroblastoma (NB) — is a malignant tumor of sympathetic nervous system in children. In our country there are about 50 % of patients in high risk group, 50 % have a relapse or a progression of the disease which is the main reason for their death.

The purpose of the study. Our aim was to characterize a relapse/progression of NB in children in the Republic of Belarus, the analysis of results of treatment of patients from 1997 till 2017.

Materials and methods. From October, 1997 to December, 2017 in Republican Scientific and Practical Center for Pediatric Oncology, Hematology and Immunology 293 protocol and observed patients received 1st line therapy. Out of them 73 patients had a progression or a relapse of the disease. This group of patients was taken for the analysis.

Results. 14-year overal survival of patients with a relapse/progression of the disease was 21 + 6 % (n = 73), event free survival 18 + 5 % (n = 53). Patients older than 12 months at the time of diagnosis were statistically significantly more likely to recur, with 4th stage disease and having N-MYC amplification, diploid karyotype in the tumor. Adverse relapse options for localization are about 65 % (generalized — 41 %, osteomedullary — 12.3 %, relapses with CNS damage — 12.3 %). The most curable variants of relapses are found in 35 % (n = 25) of cases. In patients from the group of favorable and intermediate prognosis, relapses in the zone of primary tumor localization were significantly more frequent (p < 0.0001), bone loss in the relapse of the disease was significantly less common (p < 0.0001). The best results with the use of standard therapies are relapse with the primary tumor zone and soft tissue relapse (by 5 year relapse-free survival — 25% and 36 % respectively). Treatment of osteomedullary and generalized relapses using the methods available to us is not effective (EFS is 0).

Conclusion. Further detailed study of the biology of the tumor is necessary, in order to create for the therapy of the disease targeted drugs and other biologically based approaches, such various types of immunotherapy.

1. Proleskovskaya I.V., Kochubinsky D.V., Volochnik E.V., Aleinikova O.V. Neuroblastoma in children of the Republic of Belarus (incidence, diagnosis, treatment results): 20 years’ experience. Gematologiya. Transfuziologiya. Vostochnaya Yevropa = Hematology. Transfusiology. Eastern Europe 2017;3(3):308-17. (In Russ.).

2. Maris J.M., Hogarty M.D., Bagatell R., Cohn S.L. Neuroblastoma. Lancet 2007;369:2106-20. doi: 10.1016/S0140-6736(07)60983-0.

3. Brodeur G.M. Neuroblastoma: Biological insights into a clinical enigma. Nat Rev Cancer 2003;3:203-16. doi: 10.1038/nrc1014.

4. Attiyeh E.F., London W.B., Mosse Y.P., Wang Q., Winter C., Khazi D., McGrady P.W., Seeger R.C., Look A.T., Shimada H., Brodeur G.M., Cohn S.L., Matthay K.K., Maris J.M.; Children’s Oncology Group. Chromosome 1p and 11q deletions and outcome in neuroblastoma. N Engl J Med 2005;353(21):2243-53. doi: 10.1056/NEJMoa052399.

5. Berthold F., Spix C., Kaatsch P, Lampert F. Incidence, Survival, and Treatment of Localized and Metastatic Neuroblastoma in Germany 1979-2015. Paediatr Drugs 2017;19(6):577-93. doi: 10.1007/s40272-017-0251-3.

6. Kushner B.H., Cohn S.L. Intermediate-risk neuroblastoma. In: Neuroblastoma. Cheung N.-K.V., Cohn S.L. (eds.). Heidelberg, Germany, Springer-Verlag, 2005. Pp. 131-137.

7. Kreissman S.G., Seeger R.C., Matthay K.K., London W.B., Sposto R., Grupp S.A., Haas-Kogan D.A., Laquaglia M.P., Yu A.L., Diller L., Buxton A., Park J.R., Cohn S.L., Maris J.M., Reynolds C.P., Villablanca J.G. Purged versus non-purged peripheral blood stem-cell transplantation for high-risk neuroblastoma (COG A3973): A randomised phase 3 trial. Lancet Oncol 2013;14:999-1008. doi: 10.1016/S1470-2045(13)70309-7.

8. Matthay K.K., Reynolds C.P., Seeger R.C., Shimada H., Adkins E.S., Haas-Kogan D., Gerbing R.B., London W.B., Villablanca J.G. Longterm results for children with high-risk neuroblastoma treated on a randomized trial of myeloablative therapy followed by 13-cis-retinoic acid: a children’s oncology group study. J Clin Oncol 2009;27(7):1007-13. doi: 10.1200/JCO.2007.13.8925.

9. Proleskovskaya I.V. Progression of the disease and relapse in children with neuroblastoma in the Republic of Belarus, characteristics and outcomes. Yevraziyskiy onkologicheskiy zhurnal = Eurasian Oncology Journal 2015;1(4):34-46. (In Russ.).

10. Bagatell R., London W.B., Wagner L.M., Voss S.D., Stewart C.F., Maris J.M., Kretschmar C., Cohn S.L. Phase II study of irinotecan and temozolomide in children with relapsed or refractory neuroblastoma: a Children’s Oncology Group study. J Clin Oncol 2011;29(2):208-13. doi: 10.1200/JCO.2010.31.7107.

11. London W.B., Frantz C.N., Campbell L.A., Seeger R.C., Brumback B.A., Cohn S.L., Matthay K.K., Castleberry R.P., Diller L. Phase II randomized comparison of topotecan plus cyclophosphamide vs topotecan alone in children with recurrent or refractory neuroblastoma: a Children’s Oncology Group study. J Clin Oncol 2010;28(24):3808-15. doi: 10.1200/JCO.2009.27.5016.

12. DuBois S.G., Matthay K.K. Radiolabeled metaiodobenzylguanidine for the treatment of neuroblastoma. Nucl Med Biol 2008;35 Suppl 1:S35-48. doi: 10.1016/j.nucmedbio.2008.05.002.

13. Brodeur G.M., Pritchard J., Berthold F., Carlsen N.L., Castel V., Castelberry R.P., De Bernardi B., 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.

14. Eisenhauer E.A., Therasse P., Bogaerts J., Schwartz L.H., Sargent D., Ford R., Dancey J., Arbuck S., Gwyther S., Mooney M., Rubinstein L., Shankar L., Dodd L., Kaplan R., Lacombe D., Verweij J. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45(2):228-47. doi:10.1016/j.ejca.2008.10.026.

15. Basta N.O., Halliday G.C., Makin G., Birch J., Feltbower R., Bown N., Elliott M., Moreno L., Barone G., Pearson A.D., James P.W., Tweddle D.A., McNally R.J. Factors associated with recurrence andsurvival length following relapse in patients with neuroblastoma. Br J Cancer 2016;115(9):1048-57. doi: 10.1038/bjc.2016.302.

16. Murphy J.M., Lim I.I., Farber B.A., Heaton T.E., Basu E.M., Roberts S.S., Modak S., Kushner B.H., LaQuaglia M.P. Salvage rates after progression of high-risk neuroblastoma with a soft tissue mass. J Pediatr Surg 2016;51(2):285-8. doi: 10.1016/jjpedsurg.2015.10.075.

17. Garaventa A., Parodi S., De Bernardi B., Dau D., Manzitti C., Conte M., Casale F., Viscardi E., Bianchi M., D’Angelo P., Zanazzo G.A., Luksch R., Favre C., Tamburini A., Haupt R. Outcome of children with neuroblastoma after progression or relapse. A retrospective study of the Italian neuroblastoma registry. Eur J Cancer 2009;45(16):2835-42. doi: 10.1016/j.ejca.2009.06.010.

18. Fox E., Mosse Y.P., Meany H.M., Gurney J.G., Khanna G., Jackson H.A., Gordon G., Shusterman S., Park J.R., Cohn S.L., Adamson P.C., London W.B., Maris J.M., Balis F.M. Time to disease progression in children with relapsed or refractory neuroblastoma treated with ABT-751: a report from the Children’s Oncology Group (ANBL0621). Pediatr Blood Cancer 2014;61(6):990-6. doi: 10.1002/pbc.24900.

19. London W.B., Castel V., Monclair T., Ambros P.F., Pearson A.D., Cohn S.L., Berthold F., Nakagawara A., Ladenstein R.L., Iehara T., Matthay K.K. Clinical and biologic features predictive of survival after relapse o neuroblastoma: a report from the International Neuroblastoma Risk Group project. J Clin Oncol 2011;29(24):3286-92. doi: 10.1200/JCO.2010.34.3392.

20. Mody R., Naranjo A., Van Ryn C., Yu A.L., London W.B., Shulkin B.L., Parisi M.T., Servaes S.E., Diccianni M.B., Sondel P.M., Bender J.G., Maris J.M., Park J.R., Bagatell R. Irinotecan-temozolomide with temsirolimus or dinutuximab in children with refractory or relapsed neuroblastoma (COG ANBL1221): an open-label, randomised, phase 2 trial. Lancet Oncol 2017;18(7):946-57. doi: 10.1016/S1470-2045(17)30355-8.

21. Mueller I., Ehlert K., Endres S., Pill L., Siebert N., Kietz S., Brock P., Garaventa A., Valteau-Couanet D., Janzek E., Hosten N., Zinke A., Barthlen W., Varol E., Loibner H., Ladenstein R., Lode H.N. Tolerability, response and outcome of high-risk neuroblastoma patients treated with long-term infusion of anti-GD2 antibody ch14.18/CHO. MAbs 2018;10(1):55-61. doi: 10.1080/19420862.2017.1402997.

22. Illhardt T., Toporski J., Feuchtinger T., Turkiewicz D., Teltschik H.M., Ebinger M., Schwarze C.P., Holzer U., Lode H.N., Albert M.H., Gruhn B., Urban C., Dykes J.H., Teuffel O., Schumm M., Handgretinger R., Lang P. Haploidentical Stem Cell Transplantation for Refractory/Relapsed Neuroblastoma. Biol Blood Marrow Transplant 2018;24(5):1005-12. doi: 10.1016/j.bbmt.2017.12.805.

23. Kang M.H., Reynolds C.P., Maris J.M., Gorlick R., Kolb E.A., Lock R., Carol H., Keir S.T., Wu J., Lyalin D., Kurmasheva R.T., Houghton P. J., Smith M.A. Initial testing (stage 1) of the investigational mTOR kinase inhibitor MLN0128 by the pediatric preclinical testing program. Pediatr Blood Cancer 2014;61(8):1486-9. doi: 10.1002/pbc.24989.

24. Kiessling M.K., Curioni-Fontecedro A., Samaras P., Lang S., Scharl M., Aguzzi A., Oldrige D.A., Maris J.M., Rogler G. Targeting the mTOR Complex by Everolimus in NRAS Mutant Neuroblastoma. PLoS One 2016;11(1):e0147682. doi: 10.1371/journal.pone.0147682.

25. Wagner L.M., Adams V.R. Targeting the PD-1 pathway in pediatric solid tumors and brain tumors. OncoTargets Ther 2017:10:2097-2106. doi: 10.2147/OTT.S124008.

26. Pierini S., Perales-Linares R., Uribe-Herranz M., Pol J.G., Zitvogel L., Kroemer G., Facciabene A., Galluzzi L. Trial watch: DNA-based vaccines for oncological indications. Oncoimmunology 2017;6(12):e1398878. doi: 10.1080/2162402X.2017.1398878.

27. Heczey A., Louis C.U., Savoldo B., Dakhova O., Durett A., Grilley B., Liu H., Wu M.F., Mei Z., Gee A., Mehta B., Zhang H., Mahmood N., Tashiro H., Heslop H.E., Dotti G., Rooney C.M., Brenner M.K. CAR T Cells Administered in Combination with Lymphodepletion and PD-1 Inhibition to Patients with Neuroblastoma. Mol Ther 2017;25(9):2214-24. doi: 10.1016/j.ymthe.2017.05.012.