Comparison of Myeloablative Therapies for Children with High-Risk Neuroblastoma

Chicago—Children with high-risk neuroblastoma who took busulphan and melphalan (BUMEL) had significantly improved event-free survival and overall survival after 3 years compared with a group that received carboplatin, etoposide, and melphalan (CEM), according to a phase 3 trial. BUMEL and CEM are both considered myeloablative therapies. Ruth Ladenstein, MD, the study’s lead author, presented the results in the plenary session at the ASCO meeting. According to Dr. Ladenstein, neuroblastoma is a cancer of the sympathetic nervous system and the most common extracranial solid tumor for children. When diagnosed, >50% of patients have a high-risk profile, which includes widespread disease dissemination, >18 months of age, and an amplification of the MYCN oncogene. Neuroblastoma is associated with poor survival rates; Dr. Ladenstein noted that <40% of patients with the disease survive beyond 5 years. The HR-NLB1 study design included alternating treatments of carboplatin, etoposide, vincristine, cisplatin, and cyclophosphamide given every 10 days over an 80-day period. Patients were stem cell harvested and then were scheduled to undergo surgery (not all who were scheduled for surgery had the procedure). They were randomized to receive either BUMEL or CEM treatment and underwent radiotherapy at the primary tumor site. Patients in the BUMEL group took busulphan in its oral form before 2006 and busulphan intravenously after 2006. Eligibility criteria included children >1 year of age with high-risk neuroblastoma defined as stage 4 on the International Neuroblastoma Staging System (INSS) or stage 2 or 3 on the INSS with MYCN oncogene amplification; a complete or partial response of metastases; and adequate stem cell harvest. From 2002 through 2010, the study enrolled 1577 patients, of which 563 were randomized. There were 347 males and 216 females with a median age of 3 years and a median observation time of 3.5 years. In addition, 494 patients were classified as stage 4 on the INSS and 69 were classified as stage 2 or 3. After 3 years, 49% of patients in the BUMEL arm had event-free survival compared with 33% in the CEM arm (P<.001). Compared with the CEM group, the BUMEL group had a significantly higher event-free survival among patients who took busulphan orally (P=.034) as well as those who took busulphan intravenously (P=.002). Overall survival after 3 years also favored patients receiving BUMEL (60% vs 48%; P=.003). “We find [the results] quite extraordinary and above our expectations,” Dr. Ladenstein said. Dr. Ladenstein said BUMEL’s superiority was mainly based on the BUMEL group’s significantly lower relapse rate (47% vs 60%; P=.001) and not transplant-based mortality, which was 6% in the CEM group and 4% in the BUMEL group (P=.217). The authors also analyzed event-free survival by INSS stage and found patients who had stage 4 disease and received BUMEL had significant improvement compared with those who received CEM (43% vs 29%; P=.001), while patients with stage 2 or 3 disease who received BUMEL did not have a significant difference in event-free survival compared with the CEM group (84% vs 65%; P=.120). Dr. Ladenstein said that patients taking BUMEL had a significant decrease in deaths or admissions to the intensive care unit compared with the CEM group (P=.012), although the mortality rate was not statistically different between the groups (P=.421). “This is the first time in pediatric oncology that we can clearly demonstrate the choice of the myeloablative therapy really matters,” Dr. Ladenstein said. “Busulphan and melphalan is superior to CEM in high-risk neuroblastoma.”