High dose melphalan in the treatment of advanced neuroblastoma: Results of a randomised trial (ENSG‐1) by the European Neuroblastoma Study Group

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Abstract
Background High dose myeloablative chemotherapy (“megatherapy”), with haematopoietic stem cell support, is now widely used to consolidate response to induction chemotherapy in patients with advanced neuroblastoma. Procedure In this study (European Neuroblastoma Study Group, ENSG1), the value of melphalan myeloablative “megatherapy” was evaluated in a randomised, multi‐centre trial. Between 1982 and 1985, 167 children with stages IV and III neuroblastoma (123 stage IV > 1 year old at diagnosis and 44 stage III and stage IV from 6 to 12 months old at diagnosis) were treated with oncovin, cisplatin, epipodophyllotoxin, and cyclophosphamide (OPEC) induction chemotherapy every 3 weeks. After surgical excision of primary tumour, the 90 patients (69% of the total) who achieved complete response (CR) or good partial response (GPR) were eligible for randomisation either to high dose melphalan (180 mg per square meter) with autologous bone marrow support or to no further treatment. Results Sixty‐five (72%) of eligible children were actually randomised and 21 of these patients were surviving at time of this analysis, with median follow‐up from randomisation of 14.3 years. Five year event‐free survival (EFS) was 38% (95% confidence interval (CI) 21–54%) in the melphalan‐treated group and 27% (95% CI 12–42%) in the “no‐melphalan” group. This difference was not statistically significant (P = 0.08, log rank test) but for the 48 randomised stage IV patients aged >1 year at diagnosis outcome was significantly better in the melphalan‐treated group‐5 year EFS 33% versus 17% (P = 0.01, log rank test). Conclusions In this trial, high dose melphalan improved the length of EFS and overall survival of children with stage IV neuroblastoma >1 year of age who achieved CR or GPR after OPEC induction therapy and surgery. Multi‐agent myeloablative regimens are now widely used as consolidation therapy for children with stage IV disease and in those with other disease stages when the MYCN gene copy number in tumour cells is amplified. Because they are more toxic, complex, and costly these combination megatherapy regimens should be compared with single agent melphalan in randomised clinical trials.