Although the strategy of using HDCT/ASCR has improved the survival of patients with high-risk neuroblastoma, the survival rate after a single HDCT/ASCR has been unsatisfactory (2
). Therefore, investigators have examined the efficacy of tandem HDCT/ASCR to further improve the outcome of high-risk neuroblastoma patients, and have shown that tandem HDCT/ASCR is a feasible approach which might result in further improvements in the survival of high-risk neuroblastoma patients (7
). However, no study has compared the efficacy of single with tandem HDCT/ASCR for the treatment of high-risk neuroblastoma. Therefore, the present study retrospectively compared the efficacy of single and tandem HDCT/ASCR. The results showed that the tandem HDCT/ASCR strategy is significantly better than single HDCT/ASCR strategy for improved survival of patients with high-risk neuroblastoma. The survival rate in the tandem group, in the present study, was similar to other prior studies that have reported on the tandem double and tandem triple HDCT/ASCR strategies (7
In the present study, the number of cases with tumor progression prior to the first HDCT/ASCR, and the number of TRM during the first HDCT were higher in the single group than in the tandem group. These findings suggest that the quality of medical treatment might not have been the same for the single and tandem groups. These findings might have affected the outcome of the patients (worse EFS in the single group) and create doubt as to whether the tandem HDCT/ASCR itself resulted in a better outcome compared to the single HDCT/ASCR in the present study. However, when the analysis was confined to the patients that successfully preceded to HDCT/ASCR, as assigned at diagnosis, the probability of the 5-yr RFS, after the first HDCT, was still higher in the tandem group than in the single group, particularly in the patients who were not in CR prior to the first HDCT. Taken together, these findings suggest that the tandem HDC T/ASCR strategy can provide better outcomes in patients with high-risk neuroblastoma than single HDCT/ASCR strategy.
While neutrophil recovery after the second HDCT/ASCR was as rapid as after the first HDCT/ASCR, the platelet recovery was significantly delayed after the second HDCT/ASCR compared to the first HDCT/ASCR. However, this was not clinically significant. A total of 6 TRMs were noted during the second HDCT/ASCR in the tandem group. However, this TRM rate might be acceptable considering that the tumor relapsed in 19 patients even after the tandem HDCT/ASCR. Taken together, these findings suggest that the tandem HD CT/ASCR strategy can provide better outcomes than single HDCT/ASCR strategy despite the additional toxicity risks during the second HDCT/ASCR.
TBI was administered as a part of the HDCT/ASCR in 38 out of 59 patients who completed the tandem HDCT, but not in the remaining 21 patients. The probability of RFS after the tandem HDCT was significantly higher in the TBI group compared to the non-TBI group, although the TRM rate during the second HDCT/ASCR was slightly higher in the TBI group than in the non-TBI group. Of note is that there was no TRM during the second HDCT in the patients who received TBI during the second HDCT. All TRMs during the second HDCT in the TBI group occurred in patients who received TBI during the first HDCT. These findings are consistent with the findings in the report by Sung et al (8
). They reported that TBI during the first HDCT/ASCR was significantly associated with a higher TRM rate in the second HDCT; they recommended that TBI should be included in the second HDCT/ASCR if TBI is to be included in the tandem HDCT regimen. Taken together, administration of TBI was associated with a higher RFS despite the high TRM rate, and TBI might improve the EFS if TBI is included in the second HDCT/ASCR.
Intensive tandem HDCT/ASCR and radiation therapy (particularly TBI) may improve the survival of patients with high-risk neuroblastoma, but may also increase the frequency and severity of long-term side effects such as a secondary malignancy (11
). Although no secondary malignancy developed in the patients who completed the tandem HDCT/ASCR, a longer follow-up will be needed to consider this possibility. The optimal combination of regimens for the tandem HDCT has yet to be determined. Further study will be needed to reduce the TRM rate during the second HDCT/ASCR as well as the long-term side effects whilst maintaining or reducing the relapse rate after intensive tandem HDCT/ASCR.
In summary, the results of the present retrospective study demonstrated that the tandem HDCT/ASCR strategy is significantly better than the single HDCT/ASCR strategy in terms of survival for the treatment of patients with high-risk neuroblastoma, particularly when the patient is not in CR prior to the HDCT/ASCR. A randomized prospective study will be needed in the future to explore the safety and efficacy of tandem HDCT/ASCR compared to single HDCT/ASCR, and to confirm our findings.