Although the prognosis of stage 3 neuroblastoma is generally good (1
), the prognosis of stage 3 neuroblastoma with unfavorable biologic factors, especially N-myc
amplification, is poor with conventional chemoradiotherapy (1
). In addition, the prognosis of stage 3 neuroblastoma with a poor response to conventional treatment (4
) or with a relapse during conventional treatment is also poor even when the tumor did not have unfavorable biologic factors. In this context, HDCT/ASCR was given to patients with high-risk stage 3 neuroblastoma in the present study. As a result, the 5-yr EFS from diagnosis, in patients with N-myc
amplified tumor, was 71.6±14.0%. In addition, 12 out of 14 patients who underwent HDCT/ASCR remained event free resulting in an 85.1±9.7% 5-yr EFS after the first HDCT/ASCR. Survival rate in the present study is higher than those reported in the previous trials in which conventional chemotherapy was given for the treatment of high-risk stage 3 neuroblastoma (1
). These findings suggest that HDCT/ASCR might improve the survival of patients with high-risk stage 3 neuroblastoma.
Generally, the prognosis of stage 3 neuroblastoma without N-myc
amplification is good with conventional chemotherapy alone (1
). However, even in these patients, the prognosis is poor, if the tumor response to conventional chemotherapy is poor (4
) or gross residual tumor remained after surgery (5
). In this context, HDCT/ASCR was given to two patients with a poor response to conventional chemotherapy and two patients with a gross residual mass after surgery as well as patients with N-myc
amplified tumor. These four patients remained event free; the 5-yr EFS for patients without N-myc
amplification was 87.8±8.1% in the present study. In the present study, HDCT/ASCR contributed to the excellent survival rate in patients without N-myc
amplification in whom the tumor response to conventional chemotherapy was poor.
In our recent report, on patients over 1 yr of age with stage 4 neuroblastoma, the EFS in patients who received TBI was better than for patients who did not receive TBI (12
). This suggested that a regimen with TBI was better than a regimen without, for the survival of patients, over 1 yr of age, with stage 4 neuroblastoma. However, TBI was not included in the HDCT regimen for high-risk stage 3 patients in the present study. Although the tumor relapsed in 2 of 14 patients who underwent HDCT/ASCR, the remaining 12 high-risk patients remained event free without TBI. TBI may increase the frequency and severity of short-term side effects as well as long-term side effects such as a secondary malignancy several years after treatment (17
). The fact that there was no toxicity-related death during the HDCT/ASCR, in the present study, might be attributed to the absence of TBI in our HDCT regimen. Taken together, these findings suggest that our regimen without TBI might be safe and effective for patients with high-risk stage 3 neuroblastoma.
Although the strategy with the HDCT/ASCR improved the survival of patients with high-risk neuroblastoma, the survival rate after a single HDCT/ASCR has been unsatisfactory (7
). Our recent report, which examined the efficacy of tandem HDCT/ASCR to further improve the treatment outcome of stage 4 neuroblastoma patients over 1 yr of age, showed a better long-term EFS compared to studies reporting on a single HDCT/ASCR strategy (12
). The strategy using a tandem HDCT/ASCR was based on the hypothesis that further dose escalation might result in further improvements in the EFS of high-risk neuroblastoma patients. In the present study, the tandem HDCT/ASCR was given only if a CR was not achieved, even after the first HDCT/ASCR, in the early period of the study. However, all patients underwent tandem HDCT/ASCR during the late study period. As a result, while the tumor relapsed in two of eight patients in the single HDCT group, all 6 patients in the tandem HDCT group remained relapse free. These findings suggest that the tandem HDCT strategy may be better than the single HDCT strategy for improved survival even in patients with high-risk stage 3 neuroblastoma, although it was not statistically significant in the present study. Further study will be needed to evaluate whether tandem HDCT/ASCR is better than single HDCT/ASCR in the treatment of high-risk stage 3 neuroblastoma. In six patients who underwent tandem HDCT/ASCR, the short-term toxicities were acceptable during the second HDCT/ASCR. There was no life-threatening toxicity during the second HDCT/ASCR. However, long-term follow-up is needed to evaluate the long-term toxicities of the tandem HDCT/ASCR.
According to previous reports, patients treated for longer periods, prior to HDCT/ASCR, had better long-term EFS than those patients treated for shorter periods (9
). While all the patients in the late study period received 9 cycles of chemotherapy prior to the HDCT/ASCR, most of the patients in the early study period received 6 or 7 cycles of chemotherapy. The two patients in whom the tumor relapsed after the HDCT/ASCR received 6 cycles of chemotherapy prior to HDCT/ASCR, although they were in the CR or VGCR prior to the HDCT/ASCR. Similarly, the tumor relapsed in two of six patients who received 6 cycles of chemotherapy prior to the HDCT, although the tumor status prior to the first HDCT was CR in three patients and VGPR in three, respectively. However, it is unclear whether the short duration of conventional chemotherapy was related to the high relapse rate after HDCT/ASCR in the present study, because all but one patient in the single HDCT/ASCR group received 6 or 7 cycles of chemotherapy prior to the first HDCT/ASCR while all patients in the tandem HDCT/ASCR group received 9 cycles of chemotherapy.
Immunotherapy with IL-2 along with CRA was provided in an attempt to control the minimal residual disease after the HDCT/ASCR. These two drugs were used simultaneously because their major toxicities do not overlap and their different mechanisms of action could synergistically eradicate any minimal residual disease. While the efficacy of CRA has been demonstrated (19
), there have been few studies that have evaluated the efficacy of IL-2 therapy (16
). Therefore, it is unclear if IL-2 therapy contributed to the improved survival in the present study. However, there was no life-threatening toxicity and an increase in the number of natural killer cells was observed after IL-2 therapy (22
). More study will be needed to evaluate the efficacy of the IL-2 treatment after HDCT/ASCR.
The present study demonstrates that HDCT/ASCR, especially tandem HDCT/ASCR, may improve the prognosis of patients with high-risk stage 3 neuroblastoma. However, throughout this study, multiple modifications were made in the treatment plan, which resulted in significant variability over time between the patients. This variability may create doubt as to whether tandem HDCT/ASCR actually resulted in the improved outcomes. For example, a longer pre-HDCT treatment in the tandem HDCT group compared with the single HDCT group might have had an impact on the EFS in the present study. Further study will be needed to evaluate the efficacy of tandem HDCT/ASCR in the treatment of high-risk stage 3 neuroblastoma.