The clinical outcome for patients with a MB varies according to age, tumor remnants, and metastatic stage [1
]; therefore, risk-adapted treatments are required to not only increase survival but to also reduce toxicity that can impact on a patient's quality of life. Among pediatric brain tumors, MB has the greatest potential for extraneural spread. In patients with a metastatic (M2-3) MB, progression-free survival rates of 24-40% have been reported [17
]. Although combined treatment with chemotherapy and radiotherapy has improved the survival rate in recent years, a substantial number of patients have recurrent PD after multimodal treatment, including surgery, radiation, and chemotherapy [1
]. Recently, HDCT with ASCR has been used to treat pediatric patients with advanced solid tumors or brain tumors and to avoid the deleterious side-effects of RT in infants and very young children with brain tumors [12
]; however, few studies have demonstrated the utility of HDCT with ASCR in the front-line treatment of young children with high-risk MB or sPNET [14
A 10 Gy dose of CSRT could lead to a 10-point decrease in the intelligence quotient of the recipient and significantly increases the risk of growth hormone deficiency. Packer et al. [21
] reported a growth hormone deficiency in all patients who received 36 Gy of CSRT and in 50% of patients who received 23.4 Gy. The extent to which RT could be decreased, in dose or volume, without a substantial increase in the disease relapse rate is unknown; thus, the CSRT dose should be reduced to the smallest dose that does not result in the relapse of the disease, and together with HDCT, could improve the OS and reduce the risk of RT-related cognitive and endocrine defects [20
]. Gajjar et al. [20
] have shown a special interest in reducing the amount of chemotherapy not only in terms of dosage but also of duration. This phase II clinical trial used risk-adapted CSRT followed by a short, dose-intensive, cyclophosphamide-based regimen with serial, autologous PBSC rescues, resulting in a 5-year EFS rate of 85% in average-risk patients and 70% in high-risk patients.
In our study, 23.4 Gy CSRT followed by tandem HDCT with ASCR was acceptable in terms of toxicity and the survival rate. The 3-year EFS rate for high-risk MB and sPNET patients was 76.9%. One patient had a relapse, another patient progressed before HDCT, and a third patient died of sepsis after chemotherapy; however, the 3-year EFS rate for those patients who actually received HDCT with ASCR was 100%. Compared with other studies of high-risk brain tumors, the EFS rate of our patients was encouraging, and no toxicity-related death occurred during tandem HDCT; however, the optimal therapy for patients with a relapse or PD before HDCT with ASCR should be investigated further. The patients who relapsed or progressed before HDCT with ASCR were older and had stage M3 disease at the time of diagnosis. Therefore, patients older than 6 years of age or with M2-3 disease at presentation may need a higher dose CSRT (at least 30.6 Gy).
Carboplatin, etoposide, and thiotepa were used for HDCT1, whereas cyclophosphamide and melphalan were used for HDCT2 in this study. These regimens were tolerable, and no toxic death or relapse was observed after HDCT. Busulfan was avoided, as it might cause hepatic VOD. In a recent retrospective study, Cheuk et al. [22
] speculated that for patients with a MB or sPNET, treatment with carboplatin and thiotepa or etoposide was among the safest and most effective regimens. The optimal combined regimen for consecutive tandem HDCT has yet to be determined for patients with high-risk brain tumors; however, we suggest that the use of different drug combinations between the first and second round of HDCT is a reasonable approach to avoid drug resistance and overlapping drug toxicities [15
It has been speculated that the second round of therapy in tandem HDCT should be initiated soon after HDCT1 to eradicate possible residual tumor cells and to prevent a relapse, and that delayed HDCT2 might be a cause of relapse [15
]. However, in the present study, a high rate of adverse events occurred during HDCT1 compared to HDCT2; thus, sufficient rest was needed after HDCT1. The high rate of adverse events appeared to be related to differences in the intensities of the regimens, but no TRM occurred during tandem HDCT.
In this study, the follow-up durations were too short to evaluate neurological sequelae or hormonal imbalances. The reduced-dose CSRT before HDCT with ASCR may have a favorable impact not only on survival but also on the patient's quality of life, especially in terms of neurological function and hormonal balance. At present, we are conducting outcome studies of neurological and hormonal functions in the long-term survivors of this study.
Although the follow-up period was short and the patient cohort was small in size, the results of this study are encouraging. The limited toxicity and favorable EFS rate observed in children treated with reduced-dose CSRT followed by tandem HDCT and ASCR warrant further exploration in a larger study population.