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.

  • Original Article
  • Published:

Solid Cancers

Tandem high-dose chemotherapy with thiotepa and busulfan–melphalan and autologous stem cell transplantation in very high-risk neuroblastoma patients

Bone Marrow Transplantation volume 51, pages 227–231 (2016)Cite this article

Subjects

Abstract

High-risk neuroblastoma is characterised by poor long-term survival, especially for very high-risk (VHR) patients (poor response of metastases after induction therapy). We report the results of an intensified high-dose chemotherapy (HDC) strategy to improve the prognosis of VHR patients. This strategy was based on tandem HDC with thiotepa and busulfan–melphalan (Bu–Mel) followed by autologous stem cell transplantation (ASCT). All data were prospectively recorded in the Gustave Roussy Paediatric ASCT database. From April 2004 to August 2011, 26 patients were eligible for tandem HDC. The median age at diagnosis was 4.4 years (1–15.9). All patients had metastatic disease. MYCN was amplified in 5/26 tumours. Despite the cumulative toxicity of alkylating agents, the toxicity of the intensified HDC strategy was manageable. Thiotepa-related toxicity was mainly digestive, whereas sinusoidal obstruction syndrome was the main toxicity observed after Bu–Mel. The 3-year event-free survival of this cohort was 37.3% (21.3–56.7). This strategy will be compared with combined 131I-mIBG/Bu–Mel in the upcoming SIOPEN VHR Neuroblastoma Protocol.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

References

  1. 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: 1007–1013 Errata, J Clin Oncol 2014;32:1862–1863.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Cheung NV, Modak S, Ostrovnaya I, Roberts SS, Basu EM, Kramer K et al. When overall survival fails to confirm event-free survival, should the latter be used to set the standard of care? J Clin Oncol 2014; 32: 4173–4174.

    Article  PubMed  Google Scholar 

  3. Matthay K, London WB, Maris J, Adamson PC, Park JR . Reply to N.-K.V. Cheung et al. J Clin Oncol 2014; 32: 4174–4175.

    Article  PubMed  Google Scholar 

  4. 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: 649–658.

    Article  CAS  PubMed  Google Scholar 

  5. 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 randomized trial (ENSG-1) by the European Neuroblastoma Study Group. Pediatr Blood Cancer 2005; 44: 348–357.

    Article  PubMed  Google Scholar 

  6. Hartmann O, Valteau-Couanet D, Vassal G, Lapierre V, Brugières L, Delgado R et al. Prognostic factors in metastatic neuroblastoma in patients over 1 year of age treated with high-dose chemotherapy and stem cell transplantation: a multivariate analysis in 218 patients treated in a single institution. Bone Marrow Transplant 1999; 23: 789–795.

    Article  CAS  PubMed  Google Scholar 

  7. Ladenstein R, Poetschger U, Luksch R, Brock P, Castel V, Yaniv I et al. Busulphan-melphalan as a myeloablative therapy (MAT) for high-risk neuroblastoma: results from the HR-NBL1/SIOPEN trial. J Clin Oncol 2011 29(Suppl abstr 2): 2.

  8. Valteau-Couanet D, Le Deley MC, Bergeron C, Ducassou S, Michon J, Rubie H et al. Long-term results of the combination of the N7 induction chemotherapy and the busulfan-melphalan high-dose chemotherapy. Pediatr Blood Cancer 2014; 61: 977–981.

    Article  CAS  PubMed  Google Scholar 

  9. Ladenstein R, Philip T, Lasset C, Hartmann O, Garaventa A, Pinkerton R et al. Multivariate analysis of risk factors in stage 4 neuroblastoma patients over the age of one year treated with megatherapy and stem-cell transplantation: a report from the European Bone Marrow Transplantation Solid Tumor Registry. J Clin Oncol 1998; 16: 953–965.

    Article  CAS  PubMed  Google Scholar 

  10. Decarolis B, Schneider C, Hero B, Simon T, Volland R, Roels F et al. Iodine-123 metaiodobenzylguanidine scintigraphy scoring allows prediction of outcome in patients with stage 4 neuroblastoma: results of the Cologne interscore comparison study. J Clin Oncol 2013; 31: 944–951.

    Article  CAS  PubMed  Google Scholar 

  11. Bostrom B, Enockson K, Johnson A, Bruns A, Blazar B . Plasma pharmacokinetics of high-dose oral busulfan in children and adults undergoing bone marrow transplantation. Pediatr Transplant 2003; 7: 12–28.

    Article  PubMed  Google Scholar 

  12. Vassal G, Michel G, Espérou H, Gentet JC, Valteau-Couanet D, Doz F et al. Prospective validation of a novel IV busulfan fixed dosing for paediatric patients to improve therapeutic AUC targeting without drug monitoring. Cancer Chemother Pharmacol 2008; 61: 113–123.

    Article  CAS  PubMed  Google Scholar 

  13. Veal GJ, Nguyen L, Paci A, Riggi M, Amiel M, Valteau-Couanet D et al. Busulfan pharmacokinetics following intravenous and oral dosing regimens in children receiving high-dose myeloablative chemotherapy for high-risk neuroblastoma as part of the HR-NBL-1/SIOPEN trial. Eur J Cancer 2012; 48: 3063–3072.

    Article  CAS  PubMed  Google Scholar 

  14. Bouligand J, Boland I, Valteau-Couanet D, Deroussent A, Kalifa C, Hartmann O et al. In children and adolescents, the pharmacodynamics of high-dose busulfan is dependent on the second alkylating agent used in the combined regimen (melphalan or thiotepa). Bone Marrow Transplant 2003; 32: 979–986.

    Article  CAS  PubMed  Google Scholar 

  15. Vassal G, Deroussent A, Hartmann O, Challine D, Benhamou E, Valteau-Couanet D et al. Dose-dependent neurotoxicity of high-dose busulfan in children: a clinical and pharmacological study. Cancer Res 1990; 50: 6203–6207.

    CAS  PubMed  Google Scholar 

  16. Hartmann O . New strategies for the application of high-dose chemotherapy with haematopoietic support in paediatric solid tumours. Ann Oncol 1995; 6: 13–16.

    Article  PubMed  Google Scholar 

  17. Corbacioglu S, Cesaro S, Faraci M, Valteau-Couanet D, Gruhn B, Rovelli A et al. Defibrotide for prophylaxis of hepatic veno-occlusive disease in paediatric haemopoietic stem-cell transplantation: an open-label, phase 3, randomised controlled trial. Lancet 2012; 379: 1301–1309.

    Article  CAS  PubMed  Google Scholar 

  18. Bearman SI, Appelbaum FR, Buckner CD, Petersen FB, Fisher LD, Clift RA et al. Regimen-related toxicity in patients undergoing bone marrow transplantation. J Clin Oncol 1988; 6: 1562–1568.

    Article  CAS  PubMed  Google Scholar 

  19. Matthay KK, Shulkin B, Ladenstein R, Michon J, Giammarile F, Lewington V et al. Criteria for evaluation of disease extent by (123)I-metaiodobenzylguanidine scans in neuroblastoma: a report for the International Neuroblastoma Risk Group (INRG) Task Force. Br J Cancer 2010; 102: 1319–1326.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Rothman KJ . Estimation of confidence limits for the cumulative probability of survival in life table analysis. J Chronic Dis 1978; 31: 557–560.

    Article  CAS  PubMed  Google Scholar 

  21. Schemper M, Smith TL . A note on quantifying follow-up in studies of failure time. Control Clin Trials 1996; 17: 343–346.

    Article  CAS  PubMed  Google Scholar 

  22. Brodeur GM, Pritchard J, Berthold F, Carlsen NL, Castel V, Castelberry RP et al. Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment. J Clin Oncol 1993; 11: 1466–1477.

    Article  CAS  PubMed  Google Scholar 

  23. Yanik GA, Parisi MT, Shulkin BL, Naranjo A, Kreissman SG, London WB et al. 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: 541–548.

    Article  CAS  PubMed  Google Scholar 

  24. Gaspar N, Hartmann O, Munzer C, Bergeron C, Millot F, Cousin-Lafay L et al. Neuroblastoma in adolescents. Cancer 2003; 98: 349–355.

    Article  PubMed  Google Scholar 

  25. Haut PR, Cohn S, Morgan E, Hubbell M, Danner-Koptik K, Olszewski M et al. Efficacy of autologous peripheral blood stem cell (PBSC) harvest and engraftment after ablative chemotherapy in pediatric patients. Biol Blood Marrow Transplant 1998; 4: 38–42.

    Article  CAS  PubMed  Google Scholar 

  26. Hartmann O, Valteau-Couanet D, Benhamou E, Vassal G, Rubie H, Beaujean F et al. Stage IV neuroblastoma in patients over 1 year of age at diagnosis: consolidation of poor responders with combined busulfan, cyclophosphamide and melphalan followed by in vitro mafosfamide-purged autologous bone marrow transplantation. Eur J Cancer 1997; 33: 2126–2129.

    Article  CAS  PubMed  Google Scholar 

  27. Hartmann O, Kalifa C, Beaujean F, Patte C, Flamant F, Jullien C et al. Treatment of advanced neuroblastoma with high-dose melphalan and autologous bone marrow transplantation as consolidation therapy in metastatic neuroblastoma. Cancer Chemother Pharmacol 1986; 16: 165–169.

    Article  CAS  PubMed  Google Scholar 

  28. Kletzel M, Abella EM, Sandler ES, Williams LL, Ogden AK, Pollock BH et al. Thiotepa and cyclophosphamide with stem cell rescue for consolidation therapy for children with high-risk neuroblastoma: a phase I/II study of the Pediatric Blood and Marrow Transplant Consortium. J Pediatr Hematol Oncol 1998; 20: 49–54.

    Article  CAS  PubMed  Google Scholar 

  29. Lucidarme N, Valteau-Couanet D, Oberlin O, Couanet D, Kalifa C, Beaujean F et al. Phase II study of high-dose thiotepa and hematopoietic stem cell transplantation in children with solid tumors. Bone Marrow Transplant 1998; 22: 535–540.

    Article  CAS  PubMed  Google Scholar 

  30. Kletzel M, Katzenstein HM, Haut PR, Yu AL, Morgan E, Reynolds M et al. Treatment of high-risk neuroblastoma with triple-tandem high-dose therapy and stem-cell rescue: results of the Chicago Pilot II Study. J Clin Oncol 2002; 20: 2284–2292.

    Article  CAS  PubMed  Google Scholar 

  31. Grupp SA, Stern JW, Bunin N, Nancarrow C, Ross AA, Mogul M et al. Tandem high-dose therapy in rapid sequence for children with high-risk neuroblastoma. J Clin Oncol 2000; 18: 2567–2575.

    Article  CAS  PubMed  Google Scholar 

  32. George RE, Li S, Medeiros-Nancarrow C, Neuberg D, Marcus K, Shamberger RC et al. High-risk neuroblastoma treated with tandem autologous peripheral-blood stem cell-supported transplantation: long-term survival update. J Clin Oncol 2006; 24: 2891–2896.

    Article  PubMed  Google Scholar 

  33. Granger M, Grupp SA, Kletzel M, Kretschmar C, Naranjo A, London WB et al. Feasibility of a tandem autologous peripheral blood stem cell transplant regimen for high risk neuroblastoma in a cooperative group setting: A Pediatric Oncology Group study: a report from the Children’s Oncology Group. Pediatr Blood Cancer 2012; 59: 902–907.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Seif AE, Naranjo A, Baker DL, Bunin NJ, Kletzel M, Kretschmar CS et al. A pilot study of tandem high-dose chemotherapy with stem cell rescue as consolidation for high-risk neuroblastoma: Children's Oncology Group study ANBL00P1. Bone Marrow Transplant 2013; 48: 947–952.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Matthay KK, Quach A, Huberty J, Franc BL, Hawkins RA, Jackson H et al. Iodine-131-metaiodobenzylguanidine double infusion with autologous stem-cell rescue for neuroblastoma: a new approaches to neuroblastoma therapy phase I study. J Clin Oncol 2009; 27: 1020–1025.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. DuBois SG, Chesler L, Groshen S, Hawkins R, Goodarzian F, Shimada H et al. Phase I study of vincristine, irinotecan, and ¹3¹I-metaiodobenzylguanidine for patients with relapsed or refractory neuroblastoma: a new approaches to neuroblastoma therapy trial. Clin Cancer Res 2012; 18: 2679–2686.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. French S, DuBois SG, Horn B, Granger M, Hawkins R, Pass A et al. 131I-MIBG followed by consolidation with busulfan, melphalan and autologous stem cell transplantation for refractory neuroblastoma. Pediatr Blood Cancer 2013; 60: 879–884.

    Article  CAS  PubMed  Google Scholar 

  38. Yanik GA, Villablanca JG, Maris JM, Weiss B, Groshen S, Marachelian A et al. 131I-Metaiodobenzylguanidine with intensive chemotherapy and autologous stem cell transplantation for high-risk neuroblastoma. a new approaches to neuroblastoma therapy (NANT) phase II study. Biol Blood Marrow Transplant 2015; 21: 673–681.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We are grateful to Lorna Saint Ange for editing, Sara Calmanti and Imène Hezam for their secretarial assistance.

Author information

Authors and Affiliations

  1. Department of Paediatric and Adolescent Oncology, Gustave Roussy Cancer Campus, Villejuif, France

    C Pasqualini, C Dufour, M-A Raquin & D Valteau-Couanet

  2. Biostatistics and Epidemiology Unit, Gustave Roussy Cancer Campus, Villejuif, France

    G Goma

  3. Cell Therapy Unit, Gustave Roussy Cancer Campus, Villejuif, France

    V Lapierre

Authors
  1. C Pasqualini
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C Dufour
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. G Goma
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M-A Raquin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. V Lapierre
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. D Valteau-Couanet
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to C Pasqualini.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Pasqualini, C., Dufour, C., Goma, G. et al. Tandem high-dose chemotherapy with thiotepa and busulfan–melphalan and autologous stem cell transplantation in very high-risk neuroblastoma patients. Bone Marrow Transplant 51, 227–231 (2016). https://doi.org/10.1038/bmt.2015.264

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/bmt.2015.264

This article is cited by

Search

Advanced search

Quick links