This long-term analysis with an 8-year median follow-up validates our previously reported results that showed the unequivocal benefit of myeloablative therapy in high-risk neuroblastoma. There is a trend for consistently better outcome for each randomly assigned therapy separately, for all patients and for those with stage 4 disease, and for both EFS and OS, although this is statistically significant by log-rank comparison only for the ABMT versus CC random assignment for EFS. By using a comparison of the log(−log(.)) transformation of the survival estimates at 5 years, OS was significantly higher for each random assignment separately, and OS was higher for the ABMT and the cis-RA groups. Because more than 91% of the expected events are already observed, the results of this analysis are stable. For patients who underwent both random assignments, the EFS and OS were significantly higher for patients assigned to ABMT and cis-RA compared with those assigned to CC and no cis-RA.
Two other randomized trials showed a significant improvement in EFS for patients who received myeloablative therapy compared with chemotherapy or with no further treatment. Neither of these randomized trials showed a significant advantage for OS, despite the comparison to no further therapy in one study and to low-dose oral maintenance therapy in the other study.14,15
The 5-year EFS rate for all patients on CCG-3891 was 30% compared with 38% for the European Neuroblastoma Study Group 1 study, in which the random assignment occurred later and was limited to patients who achieved good response. The improvement in OS was significant in the European Neuroblastoma Study Group 1 study when analysis was restricted to patients with stage 4 disease who were older than 1 year of age.15
The more recent German study that used peripheral blood stem cells and incorporated immunotherapy resulted in a 5-year EFS rate of approximately 38%.14
Although CCG-3891 incorporated total-body irradiation in the conditioning regimen, neither European study used this modality, and there was no apparent detriment to EFS. Because of increased late effects with total-body irradiation,16
it has been deleted in the majority of current high-risk neuroblastoma trials.
Outcome was improved additionally with cis
-RA compared with no further therapy, and there was a significant increase in the 5-year OS by the log(−log(.)) transformation. This study likely showed more benefit than the study reported by Kohler et al,17
because the latter used a much lower dose of cis
-RA than was shown effective in preclinical studies.18
Although the rate of occurrence of events and deaths appeared similar between the two therapies within the first 2 years after transplantation, cis
-RA appeared beneficial in patients who survived, event free, beyond 2 years from transplantation. One possible explanation is that cis
-RA is effective only against minimal residual disease and does not prevent recurrence from larger amounts of tumor. Therefore, a test at a fixed point in time is appropriate for the measurement of the late benefit of cis
-RA instead of the log-rank test, which equally weights all parts of the survival curves. By using the test of the log(−log(.)) transformation of the survival estimates at 5 years, OS was significantly improved for patients who were randomly assigned to receive 13-cis
Characteristics that were significant for all patients in univariate analyses of EFS and OS included stage, serum ferritin, MYCN
gene copy number, histopathology, and response to induction therapy.8
Prognostic variables for EFS in multivariable analyses for all randomly assigned patients for the first random assignment of ABMT versus CC were response to induction, whereas MCYN
amplification and response were significant for OS. The importance of disease response has been reported in other analyses of myeloablative therapy,19
though some suggest intensive consolidation can overcome this difference.20
Retrospective multivariable analyses of 529 patients who were on an European Bone Marrow Transplant registry found that the only significant factors for EFS were presence of disease by MIBG scan or persistent bone marrow disease at the end of induction.21 MYCN
status and stage disappear as prognostic variables for EFS in the patients who underwent ABMT in our study, similar to other reports. For the second random assignment that tested cis
-RA, the most constant significant variables for both EFS and OS in both arms were MYCN
amplification and disease stage 4. Response to induction lost significance, perhaps because eligibility for the cis
-RA random assignment excluded documented persistent disease.
In conclusion, long-term follow-up of this randomized trial showed significantly better 5-year EFS and OS rates for myeloablative therapy with purged ABMT than for non–myeloablative chemotherapy, and cis-RA given after intensive therapy resulted in significant improvement in 5-year OS rates, regardless of the type of consolidation.