High-risk metastatic neuroblastoma is not cured by a single treatment. All patients who have become long-term survivors have received sequential treatments with various drugs.
For this reason, this trial does not compare two single treatments, but compares two sequential treatment strategies. In these two strategies, most of the components are evidence-based best practice, although the level of evidence supporting each component varies. There is one experimental component in each strategy. Indeed, none of these two treatment schedules can be considered as standard therapy, and none has been previously compared with any standard therapy in a randomised trial.
Although it might be considered that this trial should have a standard therapy arm as a comparator, analysis of patients treated in the SIOPEN HR NBL trial 1 who have failed to meet the R1 criteria has shown a wide heterogeneity of treatments. Therefore, there is no recognised or accepted standard treatment in this very high-risk patient group, and no guidelines exist for poor responders. Survival in this very high-risk group is currently very poor. Considering all these points, it is considered ethical to compare two experimental schedules without a standard comparator.
This trial compares two such strategies in a randomised way. Patients are eligible for entry into the trial if they fail to have an adequate response to induction and therefore cannot proceed directly within the high-risk study to BuMel PBSCR. Eligible patients will be randomised at that time point, even though further standard treatment will be administered before the randomised element, and there may be circumstances when an individual patient although randomised to a particular strategy, is unable to receive the randomised element of treatment. For example, if it proves impossible to perform an adequate PBSC harvest. All randomised patients will be analysed on an intention to treat basis.
Following randomisation, all patients will continue with standard dose chemotherapy with irinotecan and temozolomide for three courses to allow for PBSC harvest (it is not mandatory to have clear bone marrows before attempting a harvest) and to facilitate scheduling of the randomised element of the study which may necessitate referral to another centre.
The patients will then receive one of two investigational intensification therapies according to random allocation:
* high administered activity 131I-mIBG and topotecan and ASCR.
* high-dose thiotepa and ASCR Then all patients will proceed to second high-dose chemotherapy: BuMel and ASCR.
The intensified consolidation chemotherapy will be followed by external radiotherapy as appropriate, by local surgery of the tumour residues as appropriate.
