Busulfan and Melphalan vs Carboplatin, Etoposide, and Melphalan in High-Risk Neuroblastoma

Key Points

  • In patients with high-risk neuroblastoma and adequate disease response to induction therapy, busulfan and melphalan improved event-free survival compared with carboplatin, etoposide, and melphalan.
  • Busulfan and melphalan was associated with a lower risk of severe toxicity.

In a phase III trial reported in The Lancet Oncology, Ladenstein et al found that high-dose chemotherapy with busulfan and melphalan vs carboplatin, etoposide, and melphalan was associated with an improved event-free survival in patients with high-risk neuroblastoma and adequate disease response to induction therapy.

Study Details

In the open-label trial, 598 patients aged 1 to 20 years from 128 sites in 18 countries were randomized between June 2002 and October 2010 to receive busulfan and melphalan (n = 296) or carboplatin, etoposide, and melphalan (n = 302). Patients had completed an induction regimen with cisplatin, carboplatin, cyclophosphamide, vincristine, and etoposide with or without topotecan, vincristine, and doxorubicin, with adequate disease response.

The busulfan and melphalan regimen initially consisted of oral busulfan at 150 mg/m² given on 4 days consecutively in 4 equal doses, with a switch in November 2007 to intravenous busulfan at 0.8 to 1.2 mg/kg/dose for 16 doses, with melphalan at 140 mg/m² given 24 hours after busulfan. The carboplatin, etoposide, and melphalan regimen consisted of carboplatin AUC = 4.1/d for 4 days via continuous infusion, etoposide continuous infusion of 338 mg/m²/d for 4 days, and melphalan at 70 mg/m²/d for 3 days. Stem cell rescue was given after the last dose of chemotherapy, and all patients received local radiotherapy to the primary tumor site followed by maintenance therapy. The primary endpoint was 3-year event-free survival in the intent-to-treat population.

Event-Free Survival

Median follow-up was 7.2 years. Three-year event-free survival was 50% (95% confidence interval [CI] = 45%–56%) in the busulfan and melphalan group vs 38% (95% CI = 32%–43%) in the carboplatin, etoposide, and melphalan group (P = .0005). Five-year event-free survival was 45% vs 33% (overall P =.0005), and 5-year overall survival was 54% vs 41% (overall P = .0010).

Toxicity

Severe life-threatening toxicity consisting of transplantation-related mortality or need for intensive care in the first 100 days after high-dose chemotherapy occurred in 4% of the busulfan and melphalan group and 10% of the carboplatin, etoposide, and melphalan group. The most frequent grade 3 and 4 adverse events were general condition (ie, bedridden and in need of care or in intensive care and very sick; 26% vs 38%), infection (19% vs 27%), and stomatitis (49% vs 59%). Bearman grade 1 to 3 pulmonary toxicity occurred in 5% vs 10% and Bearman grade 1 to 3 veno-occlusive disease occurred in 22% vs 9%.

The investigators concluded: “Busulfan and melphalan improved event-free survival in children with high-risk neuroblastoma with an adequate response to induction treatment and caused fewer severe adverse events than did carboplatin, etoposide, and melphalan. Busulfan and melphalan should thus be considered standard high-dose chemotherapy and ongoing randomised studies will continue to aim to optimise treatment for high-risk neuroblastoma.”

The study was funded by a European Commission 5th Framework Grant and the St. Anna Kinderkrebsforschung.

Ruth Ladenstein, MD, of Children’s Cancer Research Institute–S2IRP, Vienna, is the corresponding author of The Lancet Oncology article.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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