In this protocol the term high-risk neuroblastoma refers to children with either

        -  disseminated disease (INSS stage 4: about 40 to 50% of all neuroblastoma) over the age
           of one or

        -  INSS stage 2 and 3 disease with amplification of the MycN proto-oncogene Between 10% and
           20% of children with stage 3 and occasional patients with stage 2 disease are
           characterized by amplification of the MycN gene in their tumours. This biological
           characteristic has clearly been shown to be associated with a greater risk of relapse
           and death from disease progression. These patients may benefit from very aggressive
           treatment and, based on this hypothesis, they are included in this protocol. Infants (<
           12 months at diagnosis) with MYCN amplified tumors are included.

      Children with this type of presentation and age represent the largest neuroblastoma subgroup.
      Their prognosis remains poor in most cases and our ability to predict the clinical course and
      the outcome of the individual patient is modest.

      Primary objectives:

      R0 randomization: R0 was opened with the study activation in February 2002 and closed in
      November 2005. The randomized use of G-CSF during COJEC induction resulted in the
      recommendation of the prophylactic use of G-CSF to prevent episodes of febrile neutropenia
      (Ladenstein R, Valteau-Couanet D, Brock P, et al. Randomized Trial of prophylactic
      granulocyte colony-stimulating factor during rapid COJEC induction in pediatric patients with
      high-risk neuroblastoma: the European HR-NBL1/SIOPEN study. J Clin Oncol. 2010 Jul
      20;3516-24).

      R1 randomization: R1 was opened with the study activation in February 2002 and closed in
      10/2010 following the results showing significant superiority of myeloablative therapy (MAT)
      with busulfan and melphalan over continuous infusion of carboplatin, etoposide and melphalan
      (CEM). BuMel is now the standard MAT (Ladenstein R, Pötschger U, Pearson ADJ, et al. Busulfan
      and melphalan versus carboplatin, etoposide, and melphalan as high-dose chemotherapy for
      high-risk neuroblastoma (HR-NBL1/SIOPEN): an international, randomized, multi-arm,
      open-label, phase 3 trial. Lancet Oncol. 2017 Apr;500-14).

      R2 randomization: R2 was activated in November 2006 (13-cis retinoic acid +/- chimeric
      ch14.18/CHO antibody), modified in July 2009 and suspended in August 2013. R2 randomization
      tested the hypothesis that immunotherapy with ch14.18/CHO and subcutaneous aldesleukin (IL-2,
      Proleukin®), following MAT and autologous stem cell transplantation, in addition to
      differentiation therapy with 13-cis retinoic acid, will improve 3-year EFS in patients with
      high-risk neuroblastoma (ASCO 2016: Ladenstein R, et al J Clin Oncol 34, 2016 (suppl; abstr
      10500)).

      R3 randomization: R3 was opened in June 2011 and tests the hypothesis that modified N7
      induction regimen will improve the metastatic response rates or event free survival (EFS) as
      compared to Rapid COJEC. As of June 8th, 2017 R3 randomization reached the target of 630
      randomized patients as planned. There was no difference in event free survival rate between
      both regimens (Rapid COJEC and modified N7), but modified N7 had a significantly higher grade
      3 and 4 toxicity profile. Therefore, Rapid COJEC is maintained as the SIOPEN standard
      induction treatment with G-CSF support based on the results of the R0 randomization open from
      2002 top 2005 This change has been implemented in amendment 8 of the protocol.

      R4 randomization: R4 was activated in April 2014. The SIOPEN long term infusion (LTI)
      ch14.18/CHO trial successfully lowered the toxicity profile by prolonging the infusion time
      of the same total ch14.18/CHO antibody dose of 100 mg/m² to 10 days of continuous infusion in
      relapsed /refractory patients. Hence the HRNBL1/SIOPEN study committee wished to implement
      this more favorable immunotherapy dosing schedule for the time till the induction question R3
      was answered and the HRNBL1/SIOPEN trial may be closed. Considering the high R2 dropout rate
      of patients unable to receive all immunotherapy cycles in the IL-2 s.c. combination treatment
      arm and not observing this effect in the current SIOPEN LTI trial, it is suggested to address
      the IL-2sc dose in the new R4. Therefore the potential synergistic effect of sc IL-2 will be
      addressed again with 50% of the original s.c. IL-2 dose. The IL-2sc dose will hence be
      reduced to 3 x 106 IU IL-2/m2/day s.c. in the HR-NBL1/SIOPEN R4 amendment instead of 6 x 106
      IU IL-2/m2/day s.c as used in the SIOPEN LTI trial. In the second week of each IT course
      s.c.IL-2 will be given on days 2, 4, 6, 8, 10 in parallel to the ch14.18/CHO ctn infusion and
      not during the first 5 days in week 2 as scheduled in the SIOPEN LTI trial. R4 randomization
      is closed for patients diagnosed after June 8th, 2017, the closure date of R3 randomization.
      For these patients the use of ch14.18/CHO antibody is recommended without scIL-2 as
      continuous infusion (total dose 100 mg/m² over 10 days) as standard of care outside of
      controlled trials without scIL-2. The ch14.18/CHO monoclonal antibody received marketing
      authorization by EMA in May 2017 (dinutuximab beta, Qarziba®).