Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Long-term follow-up of high-risk neuroblastoma survivors treated with high-dose chemotherapy and stem cell transplantation rescue

Abstract

Intensive treatments including high-dose chemotherapy (HDC) with autologous stem cell rescue have improved high-risk neuroblastoma (HRNB) survival. We report the long-term health status of 145 HRNB survivors, alive and disease-free 5 years post HDC. Median follow-up was 15 years (range = 5–34). Six patients experienced late relapses, 11 developed second malignant neoplasms (SMNs), and 9 died. Event-free and overall survivals 20 years post HDC were 82% (95% CI = 70%–90%) and 89% (78%–95%), respectively. Compared with the French general population, the standardized mortality ratio was 19 (95% CI = 8.7–36.1; p < 0.0001) and the absolute excess risk was 37.6 (19.2–73.5). Late effects were observed in 135/145 patients (median = 3 events/patient); 103 had at least one severe event. SMNs arose at a median of 20 years post HDC and included carcinoma (n = 5), sarcoma (2), acute myeloid leukemia (2), melanoma (1), and malignant glioma (1). Non-oncologic health events included dental maldevelopment (60%), severe hearing loss (20% cumulative probability at 15 years), hepatic focal nodular hyperplasia (14%), thyroid (11%), cardiac (8%), and renal (7%) diseases and growth retardation (height-for-age z-score ≤ −2 for 21%). Gonadal insufficiency was near-universal after busulfan (40/43 females, 33/35 males). Severe late effects are frequent and progressive in HRNB survivors needing systematic very long-term follow-up.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Fig. 1: Participants flow diagram.
Fig. 2: Event-free and overall survival (EFS and OS) Kaplan–Meier curves of the 145 patients included in this study (patients treated for neuroblastoma with highdose chemotherapy followed by autologous stem cell rescue, ASCR, at Gustave Roussy in 1980–2012, alive and disease-free at 5-year post transplant).
Fig. 3: Cumulative probability curves of second health events.

References

  1. Lacour B, Guyot-Goubin A, Guissou S, Bellec S, Desandes E, Clavel J. Incidence of childhood cancer in France: National Children Cancer Registries. Eur J Cancer Prev. 2010;19:173–81.

    Article  PubMed  Google Scholar 

  2. Cohn SL, Pearson ADJ, London WB, Monclair T, Ambros PF, Brodeur GM, et al. The International Neuroblastoma Risk Group (INRG) classification system: an INRG Task Force report. J Clin Oncol. 2009;27:289–97.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Matthay KK, Villablanca JG, Seeger RC, Stram DO, Harris RE, Ramsay NK, et al. Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. Children’s Cancer Group. N Engl J Med. 1999;341:1165–73.

    Article  CAS  PubMed  Google Scholar 

  4. Matthay KK, Reynolds CP, Seeger RC, Shimada H, Adkins ES, Haas-Kogan D, et al. Long-term 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;27:1007–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Berthold F, Boos J, Burdach S, Erttmann R, Henze G, Hermann J, et al. Myeloablative megatherapy with autologous stem-cell rescue versus oral maintenance chemotherapy as consolidation treatment in patients with high-risk neuroblastoma: a randomised controlled trial. Lancet Oncol. 2005;6:649–58.

    Article  CAS  PubMed  Google Scholar 

  6. Pritchard J, Cotterill SJ, Germond SM, Imeson J, de Kraker J, Jones DR. High dose melphalan in the treatment of advanced neuroblastoma: results of a randomised trial (ENSG-1) by the European Neuroblastoma Study Group. Pediatr Blood Cancer. 2005;44:348–57.

    Article  PubMed  Google Scholar 

  7. Park JR, Kreissman SG, London WB, Naranjo A, Cohn SL, Hogarty MD, 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;322:746–55.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Ladenstein R, Pötschger U, Pearson ADJ, Brock P, Luksch R, Castel V, et al. Busulfan and melphalan versus carboplatin, etoposide, and melphalan as high-dose chemotherapy for high-risk neuroblastoma (HR-NBL1/SIOPEN): an international, randomised, multi-arm, open-label, phase 3 trial. Lancet Oncol. 2017;18:500–14.

    Article  CAS  PubMed  Google Scholar 

  9. de Vathaire F, Hardiman C, Shamsaldin A, Campbell S, Grimaud E, Hawkins M, et al. Thyroid carcinomas after irradiation for a first cancer during childhood. Arch Intern Med. 1999;159:2713–9.

    Article  PubMed  Google Scholar 

  10. Veres C, Allodji RS, Llanas D, Vu Bezin J, Chavaudra J, Mège JP, et al. Retrospective reconstructions of active bone marrow dose-volume histograms. Int J Radiat Oncol Biol Phys. 2014;90:1216–24.

    Article  PubMed  Google Scholar 

  11. Demoor-Goldschmidt C, Allodji RS, Journy N, Rubino C, Zrafi WS, Debiche G, et al. Risk factors for small adult height in childhood cancer survivors. J Clin Oncol. 2020;38:1785–96.

  12. Brock PR, Bellman SC, Yeomans EC, Pinkerton CR, Pritchard J. Cisplatin ototoxicity in children: a practical grading system. Med Pediatr Oncol. 1991;19:295–300.

    Article  CAS  PubMed  Google Scholar 

  13. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53:457–81.

    Article  Google Scholar 

  14. Rothman KJ. Estimation of confidence limits for the cumulative probability of survival in life table analysis. J Chronic Dis. 1978;31:557–60.

    Article  CAS  PubMed  Google Scholar 

  15. Schemper M, Smith TL. A note on quantifying follow-up in studies of failure time. Control Clin Trials. 1996;17:343–6.

    Article  CAS  PubMed  Google Scholar 

  16. Breslow NE, Day NE. Statistical methods in cancer research. Volume II—the design and analysis of cohort studies. IARC Sci Publ. 1987;82:1–406.

    Google Scholar 

  17. Teepen JC, van Leeuwen FE, Tissing WJ, van Dulmen-den Broeder E, van den Heuvel-Eibrink MM, van der Pal HJ, et al. Long-term risk of subsequent malignant neoplasms after treatment of childhood cancer in the DCOG later study cohort: role of chemotherapy. J Clin Oncol. 2017;35:2288–98.

    Article  CAS  PubMed  Google Scholar 

  18. Sanders JE, Hawley J, Levy W, Gooley T, Buckner CD, Deeg HJ, et al. Pregnancies following high-dose cyclophosphamide with or without high-dose busulfan or total-body irradiation and bone marrow transplantation. Blood. 1996;87:3045–52.

    Article  CAS  PubMed  Google Scholar 

  19. Teinturier C, Hartmann O, Valteau-Couanet D, Benhamou E, Bougneres PF. Ovarian function after autologous bone marrow transplantation in childhood: high-dose busulfan is a major cause of ovarian failure. Bone Marrow Transplant. 1998;22:989–94.

    Article  CAS  PubMed  Google Scholar 

  20. Thibaud E, Rodriguez-Macias K, Trivin C, Espérou H, Michon J, Brauner R. Ovarian function after bone marrow transplantation during childhood. Bone Marrow Transplant. 1998;21:287–90.

    Article  CAS  PubMed  Google Scholar 

  21. Cohen A, Békássy AN, Gaiero A, Faraci M, Zecca S, Tichelli A, et al. Endocrinological late complications after hematopoietic SCT in children. Bone Marrow Transplant. 2008;41:S43–8.

    Article  CAS  PubMed  Google Scholar 

  22. Borgmann-Staudt A, Rendtorff R, Reinmuth S, Hohmann C, Keil T, Schuster FR, et al. Fertility after allogeneic haematopoietic stem cell transplantation in childhood and adolescence. Bone Marrow Transplant. 2012;47:271–6.

    Article  CAS  PubMed  Google Scholar 

  23. Bresters D, Emons JAM, Nuri N, Ball LM, Kollen WJW, Hannema SE, et al. Ovarian insufficiency and pubertal development after hematopoietic stem cell transplantation in childhood. Pediatr Blood Cancer. 2014;61:2048–53.

    Article  PubMed  Google Scholar 

  24. Panasiuk A, Nussey S, Veys P, Amrolia P, Rao K, Krawczuk-Rybak M, et al. Gonadal function and fertility after stem cell transplantation in childhood: comparison of a reduced intensity conditioning regimen containing melphalan with a myeloablative regimen containing busulfan. Br J Haematol. 2015;170:719–26.

    Article  CAS  PubMed  Google Scholar 

  25. van As JW, van den Berg H, van Dalen EC. Platinum-induced hearing loss after treatment for childhood cancer. Cochrane Database Syst Rev. 2016;2016:CD010181.

    PubMed Central  Google Scholar 

  26. Brock PR, Knight KR, Freyer DR, Campbell KCM, Steyger PS, Blakley BW, et al. Platinum-induced ototoxicity in children: a consensus review on mechanisms, predisposition, and protection, including a new International Society of Pediatric Oncology Boston ototoxicity scale. J Clin Oncol. 2012;30:2408–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Whelan K, Stratton K, Kawashima T, Leisenring W, Hayashi S, Waterbor J, et al. Auditory complications in childhood cancer survivors: a report from the childhood cancer survivor study. Pediatr Blood Cancer. 2011;57:126–34.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Grewal S, Merchant T, Reymond R, McInerney M, Hodge C, Shearer P. Auditory late effects of childhood cancer therapy: a report from the Children’s Oncology Group. Pediatrics. 2010;125:e938–50.

    Article  PubMed  Google Scholar 

  29. Li Y, Womer RB, Silber JH. Predicting cisplatin ototoxicity in children: the influence of age and the cumulative dose. Eur J Cancer. 2004;40:2445–51.

    Article  CAS  PubMed  Google Scholar 

  30. van As JW, van den Berg H, van Dalen EC. Different infusion durations for preventing platinum-induced hearing loss in children with cancer. Cochrane Database Syst Rev. 2018;7:CD010885.

    PubMed  Google Scholar 

  31. Schell MJ, McHaney VA, Green AA, Kun LE, Hayes FA, Horowitz M, et al. Hearing loss in children and young adults receiving cisplatin with or without prior cranial irradiation. J Clin Oncol. 1989;7:754–60.

    Article  CAS  PubMed  Google Scholar 

  32. Bertolini P, Lassalle M, Mercier G, Raquin MA, Izzi G, Corradini N, et al. Platinum compound-related ototoxicity in children: long-term follow-up reveals continuous worsening of hearing loss. J Pediatr Hematol Oncol. 2004;26:649–55.

    Article  PubMed  Google Scholar 

  33. Bitner-Glindzicz M, Rahman S. Ototoxicity caused by aminoglycosides. BMJ. 2007;335:784–5.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Gallagher KL, Jones JK. Furosemide-induced ototoxicity. Ann Intern Med. 1979;91:744–5.

    Article  CAS  PubMed  Google Scholar 

  35. Parsons SK, Neault MW, Lehmann LE, Brennan LL, Eickhoff CE, Kretschmar CS, et al. Severe ototoxicity following carboplatin-containing conditioning regimen for autologous marrow transplantation for neuroblastoma. Bone Marrow Transplant. 1998;22:669–74.

    Article  CAS  PubMed  Google Scholar 

  36. Knight KRG, Kraemer DF, Neuwelt EA. Ototoxicity in children receiving platinum chemotherapy: underestimating a commonly occurring toxicity that may influence academic and social development. J Clin Oncol. 2005;23:8588–96.

    Article  PubMed  Google Scholar 

  37. Weiss A, Sommer G, Kasteler R, Scheinemann K, Grotzer M, Kompis M, et al. Long-term auditory complications after childhood cancer: a report from the Swiss Childhood Cancer Survivor Study. Pediatr Blood Cancer. 2017;64:364–73.

    Article  CAS  PubMed  Google Scholar 

  38. Landier W, Knight K, Wong FL, Lee J, Thomas O, Kim H, et al. Ototoxicity in children with high-risk neuroblastoma: prevalence, risk factors, and concordance of grading scales-a report from the Children’s Oncology Group. J Clin Oncol. 2014;32:527–34.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Laverdière C, Cheung N-KV, Kushner BH, Kramer K, Modak S, LaQuaglia MP, et al. Long-term complications in survivors of advanced stage neuroblastoma. Pediatr Blood Cancer. 2005;45:324–32.

    Article  PubMed  Google Scholar 

  40. Ladenstein R, Pötschger U, Pearson ADJ, Brock P, Luksch R, Castel V, et al. Busulfan and melphalan versus carboplatin, etoposide, and melphalan as high-dose chemotherapy for high-risk neuroblastoma (HR-NBL1/SIOPEN): an international, randomised, multi-arm, open-label, phase 3 trial. Lancet Oncol. 2017;18:500–14.

    Article  CAS  PubMed  Google Scholar 

  41. Reddel RR, Kefford RF, Grant JM, Coates AS, Fox RM, Tattersall MH. Ototoxicity in patients receiving cisplatin: importance of dose and method of drug administration. Cancer Treat Rep. 1982;66:19–23.

    CAS  PubMed  Google Scholar 

  42. Coze C, Hartmann O, Michon J, Frappaz D, Dusol F, Rubie H, et al. NB87 induction protocol for stage 4 neuroblastoma in children over 1 year of age: a report from the French Society of Pediatric Oncology. J Clin Oncol. 1997;15:3433–40.

    Article  CAS  PubMed  Google Scholar 

  43. Trahair TN, Vowels MR, Johnston K, Cohn RJ, Russell SJ, Neville KA, et al. Long-term outcomes in children with high-risk neuroblastoma treated with autologous stem cell transplantation. Bone Marrow Transplant. 2007;40:741–6.

    Article  CAS  PubMed  Google Scholar 

  44. Elzembely MM, Dahlberg AE, Pinto N, Leger KJ, Chow EJ, Park JR, et al. Late effects in high-risk neuroblastoma survivors treated with high-dose chemotherapy and stem cell rescue. Pediatr Blood Cancer. 2018;66:e27421.

    Article  PubMed  CAS  Google Scholar 

  45. Kohler JA, Ellershaw C, Machin D, Neuroblastoma Working Group of the Children’s Cancer and Leukaemia Group. Response to N7 induction chemotherapy in children more than one year of age diagnosed with metastatic neuroblastoma treated in UKCCSG centers. Pediatr Blood Cancer. 2007;49:234–9.

    Article  CAS  PubMed  Google Scholar 

  46. Moreno L, Vaidya SJ, Pinkerton CR, Lewis IJ, Imeson J, Machin D, et al. Long-term follow-up of children with high-risk neuroblastoma: the ENSG5 trial experience. Pediatr Blood Cancer. 2013;60:1135–40.

    Article  PubMed  Google Scholar 

  47. Pearson ADJ, Pinkerton CR, Lewis IJ, Imeson J, Ellershaw C, Machin D, et al. High-dose rapid and standard induction chemotherapy for patients aged over 1 year with stage 4 neuroblastoma: a randomised trial. Lancet Oncol. 2008;9:247–56.

    Article  CAS  PubMed  Google Scholar 

  48. Clemens E, de Vries AC, Pluijm SF, Am Zehnhoff-Dinnesen A, Tissing WJ, Loonen JJ, et al. Determinants of ototoxicity in 451 platinum-treated Dutch survivors of childhood cancer: a DCOG late-effects study. Eur J Cancer. 2016;69:77–85.

    Article  CAS  PubMed  Google Scholar 

  49. Dean JB, Hayashi SS, Albert CM, King AA, Karzon R, Hayashi RJ. Hearing loss in pediatric oncology patients receiving carboplatin-containing regimens. J Pediatr Hematol Oncol. 2008;30:130–4.

    Article  CAS  PubMed  Google Scholar 

  50. Hobbie WL, Moshang T, Carlson CA, Goldmuntz E, Sacks N, Goldfarb SB, et al. Late effects in survivors of tandem peripheral blood stem cell transplant for high-risk neuroblastoma. Pediatr Blood Cancer. 2008;51:679–83.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Cohen LE, Gordon JH, Popovsky EY, Gunawardene S, Duffey-Lind E, Lehmann LE, et al. Late effects in children treated with intensive multimodal therapy for high-risk neuroblastoma: high incidence of endocrine and growth problems. Bone Marrow Transplant. 2014;49:502–8.

    Article  CAS  PubMed  Google Scholar 

  52. Lackner H, Urban C, Sovinz P, Nebl A, Schmidt S, Benesch M, et al. Hypothyroidism after treatment of metastatic neuroblastoma. Pediatr Blood Cancer. 2010;55:768.

    Article  PubMed  Google Scholar 

  53. Perwein T, Lackner H, Sovinz P, Benesch M, Schmidt S, Schwinger W, et al. Survival and late effects in children with stage 4 neuroblastoma. Pediatr Blood Cancer. 2011;57:629–35.

    Article  PubMed  Google Scholar 

  54. Zheng L, Yan W, Kong Y, Liang P, Mu Y. An epidemiological study of risk factors of thyroid nodule and goiter in Chinese women. Int J Clin Exp Med. 2015;8:11379–87.

    PubMed  PubMed Central  Google Scholar 

  55. Michel G, Socié G, Gebhard F, Bernaudin F, Thuret I, Vannier JP, et al. Late effects of allogeneic bone marrow transplantation for children with acute myeloblastic leukemia in first complete remission: the impact of conditioning regimen without total-body irradiation-a report from the Société Française de Greffe de Moelle. J Clin Oncol. 1997;15:2238–46.

    Article  CAS  PubMed  Google Scholar 

  56. Cohen A, Rovelli A, Bakker B, Uderzo C, van Lint MT, Esperou H, et al. Final height of patients who underwent bone marrow transplantation for hematological disorders during childhood: a study by the Working Party for Late Effects-EBMT. Blood. 1999;93:4109–15.

    Article  CAS  PubMed  Google Scholar 

  57. Huma Z, Boulad F, Black P, Heller G, Sklar C. Growth in children after bone marrow transplantation for acute leukemia. Blood. 1995;86:819–24.

    Article  CAS  PubMed  Google Scholar 

  58. Giorgiani G, Bozzola M, Locatelli F, Picco P, Zecca M, Cisternino M, et al. Role of busulfan and total body irradiation on growth of prepubertal children receiving bone marrow transplantation and results of treatment with recombinant human growth hormone. Blood. 1995;86:825–31.

    Article  CAS  PubMed  Google Scholar 

  59. Hovi L, Rajantie J, Perkkiö M, Sainio K, Sipilä I, Siimes MA. Growth failure and growth hormone deficiency in children after bone marrow transplantation for leukemia. Bone Marrow Transplant. 1990;5:183–6.

    CAS  PubMed  Google Scholar 

  60. Clement-De Boers A, Oostdijk W, Van Weel-Sipman MH, Van den Broeck J, Wit JM, Vossen JM. Final height and hormonal function after bone marrow transplantation in children. J Pediatr. 1996;129:544–50.

    Article  CAS  PubMed  Google Scholar 

  61. Sanders JE, Guthrie KA, Hoffmeister PA, Woolfrey AE, Carpenter PA, Appelbaum FR. Final adult height of patients who received hematopoietic cell transplantation in childhood. Blood. 2005;105:1348–54.

    Article  CAS  PubMed  Google Scholar 

  62. Thomas BC, Stanhope R, Plowman PN, Leiper AD. Endocrine function following single fraction and fractionated total body irradiation for bone marrow transplantation in childhood. Acta Endocrinol. 1993;128:508–12.

    Article  CAS  Google Scholar 

  63. Allodji RS, Diallo I, El-Fayech C, Kahlouche A, Dumas A, Schwartz B, et al. Association of radiation dose to the eyes with the risk for cataract after nonretinoblastoma solid cancers in childhood. JAMA Ophthalmol. 2016;134:390–7.

    Article  PubMed  Google Scholar 

  64. Suesskind D, Schrader M, Foerster MH, Ernemann U, Aisenbrey S. Cataract formation: a possible complication of intra-arterial chemotherapy for retinoblastoma. Eur J Ophthalmol. 2014;24:449–53.

    Article  PubMed  Google Scholar 

  65. Stuber ML, Meeske KA, Krull KR, Leisenring W, Stratton K, Kazak AE, et al. Prevalence and predictors of posttraumatic stress disorder in adult survivors of childhood cancer. Pediatrics. 2010;125:e1124–34.

    Article  PubMed  Google Scholar 

  66. Poulet-Coulibando P, Testas A. Le niveau d’études de la population et des jeunes. État de l’Enseignement supérieur et de la Recherche en France - 49 indicateurs. 2017. https://publication.enseignementsup-recherche.gouv.fr/eesr/10/EESR10_ES_20-le_niveau_d_etudes_de_la_population_et_des_jeunes.php. Accessed 26 Jan 2021.

Download references

Acknowledgements

We acknowledge Lucy Metayer (MD) for her proofreading and editing work and Juliana Ollivier (psychology student) for data collection on psychological interviews.

Funding

The Gustave Roussy Foundation, The French Ligue Against Cancer (“Equipe Labélisée” Program), The Fondation ARC (POPHARC program), and The French National Research Agency (ANR, HOPE-EPI project).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Brice Fresneau.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Haghiri, S., Fayech, C., Mansouri, I. et al. Long-term follow-up of high-risk neuroblastoma survivors treated with high-dose chemotherapy and stem cell transplantation rescue. Bone Marrow Transplant 56, 1984–1997 (2021). https://doi.org/10.1038/s41409-021-01258-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41409-021-01258-1

This article is cited by

Search

Quick links