Myeloablative megatherapy with autologous stem-cell rescue versus oral maintenance chemotherapy as consolidation treatment in patients with high-risk neuroblastoma: a randomised controlled trial.
BACKGROUND
Myeloablative megatherapy is commonly used to improve the poor outlook of children with high-risk neuroblastoma, yet its role is poorly defined. We aimed to assess whether megatherapy with autologous stem-cell transplantation could increase event-free survival and overall survival compared with maintenance chemotherapy.


METHODS
295 patients with high-risk neuroblastoma (ie, patients with stage 4 disease aged older than 1 year or those with MYCN-amplified tumours and stage 1, 2, 3, or 4S disease or stage 4 disease and <1 year old) were randomly assigned to myeloablative megatherapy (melphalan, etoposide, and carboplatin) with autologous stem-cell transplantation (n=149) or to oral maintenance chemotherapy with cyclophosphamide (n=146). The primary endpoint was event-free survival. Secondary endpoints were overall survival and the number of treatment-related deaths. Analyses were done by intent to treat, as treated, and treated as randomised.


RESULTS
Intention-to-treat analysis showed that patients allocated megatherapy had increased 3-year event-free survival compared with those allocated maintenance therapy (47% [95% CI 38-55] vs 31% [95% CI 23-39]; hazard ratio 1.404 [95% CI 1.048-1.881], p=0.0221), but did not have significantly increased 3-year overall survival (62% [95% CI 54-70] vs 53% [95% CI 45-62]; 1.329 [0.958-1.843], p=0.0875). Improved 3-year event-free survival and 3-year overall survival were also recorded for patients given megatherapy in the as-treated group (n=212) and in the treated-as-randomised group (n=145). Two patients died from therapy-related complications during induction treatment. No patients given maintenance therapy died from acute treatment-related toxic effects. Five patients given megatherapy died from acute complications related to megatherapy.


CONCLUSIONS
Myeloablative chemotherapy with autologous stem-cell transplantation improves the outcome for children with high-risk neuroblastoma despite the raised risk of treatment-associated death.
Berthold
Frank
F
Children's Hospital and Centre for Molecular Medicine, University of Cologne, Cologne, Germany. frank.berthold@uk-koeln.de
Boos
Joachim
J
Burdach
Stefan
S
Erttmann
Rudolf
R
Henze
Günter
G
Hermann
Johann
J
Klingebiel
Thomas
T
Kremens
Bernhard
B
Schilling
Freimut H
FH
Schrappe
Martin
M
Simon
Thorsten
T
Hero
Barbara
B
D000293:Adolescent; D000328:Adult; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000627:therapeutic use*; D018572:Disease-Free Survival; D005858:Germany / Q000453:epidemiology; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D015999:Multivariate Analysis; D009447:Neuroblastoma / Q000401:mortality / Q000628:therapy*; D016016:Proportional Hazards Models; D033581:Stem Cell Transplantation; D015996:Survival Rate; D013557:Switzerland / Q000453:epidemiology; D019172:Transplantation Conditioning
D018906:Antineoplastic Agents, Alkylating; D003520:Cyclophosphamide