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

Abstract

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.

Busulfan–melphalan in high-risk neuroblastoma: the 30-year experience of a single institution

“…The impact of this strategy has been demonstrated by the results of three pediatric randomized trials. [2][3][4] These trials explored the impact on survival of consolidation regimens consisting of HD CEM and TBI, 2 CEM 3 and HD Mel. 4 They showed a significant improvement of survival in patients with stage 4 HR-NBL.…”

“…Patient characteristics are described in Table 1. Before HDC, patients received a median number of six courses of conventional chemotherapy (range [4][5][6][7][8][9][10][11][12][13][14], over a median duration of 6 months (range 3-23). Good and poor responses after the first line of conventional chemotherapy were obtained in 73 (34%) and 142 (66%) patients, respectively.…”

“…1 In the HR-NBL population, a correlation between survival and dose intensity has been reported, and three randomized studies showed that HDC followed by autologous stem cell transplantation (ASCT) or autologous bone marrow transplantation (ABMT) improved survival rates. [2][3][4] As NBL is notoriously radiosensitive, hyperfractionated TBI was incorporated into the conditioning regimen and has yielded encouraging results. 5 Alkylating agents were demonstrated to produce a log-linear dose response against tumor cells in vitro.…”

Rationale for the treatment of children with CCSK in the UMBRELLA SIOP–RTSG 2016 protocol

“…Melphalan was the most commonly used high-dose agent in the SIOP-AIEOP relapsed CCSK study; eight patients were treated with high-dose melphalan, of whom four patients were alive without disease and four patients died of disease after a median follow-up time of 29 months 21 . Moreover, highdose melphalan has previously been successfully used in the treatment of other recurrent paediatric solid tumours, such as neuroblastoma 59,60 .…”

Not too little, not too much—just right! (Better ways to give high dose melphalan)

“…Modern, cisplatin-based chemotherapy provided for relatively poor long-term survival in neuroblastoma, 58 but this result was improved significantly with the addition of a single high-dose of melphalan and HCT. 59 Attempts to intensify the melphalan were associated with what was a high TRM, when this was a 'kill or cure' strategy (Lodenstein et al 60 Figure 1), but a subsequent randomised controlled trial confirmed the value of a melphalan-based combination including TBI, when compared to three courses of intensive multiagent chemotherapy. 61 This study also confirmed the benefit of the randomised addition of retinoid therapy post transplant, confirmed with much longer follow-up.…”