Busulfan–Melphalan Plus ASCT ‘Important Addition’ For High-Risk Ewing Sarcoma Care

For localised Ewing sarcoma patients with a poor prognosis after induction chemotherapy, busulfan plus melphalan and autologous stem cell transplantation may offer a better outcome than conventional chemotherapy

medwireNews: A high-dose consolidation regimen of busulfan and melphalan with autologous stem cell transplantation (ASCT) extends event-free survival (EFS) compared with standard chemotherapy, suggest results from the R2Loc trial of patients with localised Ewing sarcoma at high risk of relapse. 

The majority (78%) of the 240 participants, aged younger than 50 years (median 17.1 years), had localised disease with a poor histological response, defined as a 10% or greater proportion of viable cells, to six cycles of preoperative induction chemotherapy (vincristine, ifosfamide, doxorubicin and etoposide). 

The remainder had a tumour volume of at least 200 mL before or after surgery alone or with chemotherapy and/or radiation, explain Jeremy Whelan, from University College Hospital London in the UK, and colleagues. 

For these high-risk groups of patients, “[busulfan and melphalan] may be an important addition to the standard of care”, they write in the Journal of Clinical Oncology.

After a median 7.8 years of follow-up, intention-to-treat analysis gave a significant hazard ratio (HR) of 0.64 for the risk of an event, in favour of the busulfan–melphalan regimen compared with seven cycles of vincristine, dactinomycin and ifosfamide (VAI). The 3-year rate of EFS with the high-dose strategy was 69.0% versus 56.7% with the standard chemotherapy, with corresponding 8-year rates of 60.7% versus 47.1%. 

There was also a trend towards improved overall survival (OS) for the patients randomly assigned to receive busulfan–melphalan, with a nonsignificant HR of 0.63. The 3- and 8-year OS rates for the busulfan–melphalan and standard chemotherapy groups were 78.0% versus 72.2%, and 64.5% versus 55.6%, respectively. 

The researchers report two patient deaths related to busulfan–melphalan toxicity and one associated with standard chemotherapy.  

Patients given busulfan–melphalan experienced a higher rate of acute toxicity than their standard chemotherapy counterparts, as well as more grade 4 haematological and grade 3 or more severe nonhaematological events affecting the gastrointestinal tract and liver, and infection. 

“However, these types of toxicity were transient and occurred only once after [busulphan-mephalan] compared with repetitive hematologic toxicity with VAI courses”, the researchers observe. 

The team concludes: “Although the benefit was shown for a relatively small subgroup, the reliable demonstration of EFS and OS improvement indicates that [busulphan–melphalan] may be considered as a standard of care for patients with localized [Ewing sarcoma] fulfilling the definition of high-risk disease used in this trial and no contraindication to [busulphan–melphalan].” 



Whelan J, Le Deley M-C, Dirksen U, et al. High-dose chemotherapy and blood autologous stem-cell rescue compared with standard chemotherapy in localized high-risk Ewing sarcoma: Results of Euro- E.W.I.N.G.99 and Ewing-2008 . J Clin Oncol; Advance online publication 6 September 2018.
DOI: 10.1200/JCO.2018.78.2516

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