Children with relapsed medulloblastoma have a dismal outcome with standard or alternative treatments (1
). Two-year survival rates for relapsed medulloblastoma were reported to be below 20% (8
). Recently, sequential cycles of dose-intensive chemotherapy or tandem transplantation have been tried in the treatment of chemo-sensitive high-risk or recurrent brain tumors, including recurrent medulloblastoma (9
). The survival rate was reported as a broad range, 5-54%, by studies done in various different situations with regard to pre-transplant conventional chemotherapy, conditioning regimens, disease status prior to HDCT, and adjuvant therapy. Some studies did not separate recurrent medulloblastoma from high-risk medulloblastoma or other brain tumors types in their study group (8
). Grururangan et al. (13
) reported a 3-yr overall survival rate of 14% in recurrent medulloblastoma patients who underwent HDCT/ASCT and received no irradiation before relapse, while no survival was found in those who underwent HDCT/ASCT receiving irradiation before relapse and in those who did not undergo HDCT/ASCT and received only standard SC. Our study, focusing on relapsed medulloblastoma, showed a 3-yr EFS and 3-yr OS of 31% and 29%, respectively ().
A few reports have shown that pre-HDCT disease status is most important when it comes to predicting survival rates in relapsed or high-risk brain tumor cases. The survival rate is highest in patients with previous CR status and less high in patients with minimal residual disease, but nearly absent in patients with bulky disease before ASCT (2
). Therefore, some reports that studied patients with relapsed brain tumor focused mainly on those with a PR or CR disease status prior to HDCT (10
). However, our study included data of PD or SD status, as well as CR or PR status, prior to HDCT1. In our study, the 3-yr OS rates in patients with PR or CR status prior to HDCT was 40%, compared to no survival in patients with PD or SD status ().
Most recent reports of high-risk or relapsed brain tumors treated with HDCT/ASCT at CR status show favorable survival rates. Fagioli et al. (12
) reported that patients with CR status following a poor prognosis brain tumor had a survival rate of 50.6% compare to 19.6% for those without CR status. Cheuk et al. (14
) reported that long-term survival in CR patients before HDCT was 63% (5 out of 8 CR patients survived), but that 5 PR patients all died in the study of single transplantation in high-risk or recurrent CNS tumors. In our study, 4 patients who had both local and disseminated relapsed tumors achieved CR status at the time of their HDCT1. Two survived and were disease free with a 3-yr EFS rate of 50%. Relapsed patients with a previous CR status after multimodality salvage therapy, treated with HDCT/ASCT, are curable.
Some studies reported that patients with PR status before HDCT would die eventually from PD since the treatment of HDCT cannot eradicate their residual malignancies (12
). The recent study by Cheuk et al. reported that 5 patients with PR disease status before HDCT, who had a median 8-month disease free period, did not survive a long-term (12
). However some researchers suggest that using multiple sequential intensive therapy or tandem transplantation has some benefit in this disease status before HDCT, because a single application of HDCT cannot eradicate the disease (9
). Sung et al. (10
) reported that of 9 patients with PR status before HDCT, whose tumors were high-risk or relapsed medulloblastoma and supratentorial primitive neuroectodermal tumor, 8 who received tandem transplantation were alive with a median follow-up of 18 month and 7 of those were disease free. In our study, 6 patients had PR status pre-HDCT; of those, 2 of 3 patients who received tandem transplantation were alive and disease free (44 and 38 months), but 3 patients who did not receive tandem transplantation died. These results show that tandem transplantation has the possibility of prolonging survival of relapsed pediatric medulloblastoma patients with PR status in response to upfront chemotherapy. In the future the role of tandem transplantation may need to be defined for patients with a status of PR after upfront chemotherapy before HDCT.
Of the total 15 patients, 4 who had no response or disease progression during the period of upfront SC died, although 3 were treated with tandem transplantation. Some other studies concerning the treatment of recurrent brain tumors using single or tandem transplantation showed similar results. Because the relapsed tumors achieved only PR or SD status after SC with or without surgery or irradiation, patients with PR or SD status at HDCT1 were not able to be cured with HDCT/ASCT, even with tandem transplantation.
Surgery, radiotherapy, and SC are common treatment methodologies used to reduce tumor burden prior to HDCT. Children diagnosed with relapsed medulloblastoma who were radiotherapy naïve and chemo-responsive were able to be cured. Butturini et al. (7
) reported the 3-yr post-transplant EFS rate in unirradiated versus previously irradiated children to be 83% vs. 20% respectively, using a thiotepa based conditioning regimen. Our study had a similar result for 2 patients newly diagnosed before 3 yr of age who were unirradiated before relapse. These 2 patients, #2 and #13, received craniospinal irradiation following relapse and then received tandem transplantation and are now surviving disease-free.
Our study had 1 patient who died of VOD with sepsis at HDCT1 and ASCT, resulting in a TRM rate of 6.7%. Some reports, most of which had a conditioning regimen different from ours, showed that tandem or sequential courses of HDCT were tolerable in their toxicity (11
). In our study, no TRM was seen in the cases of tandem transplantation and no elevation of liver enzymes was shown with tandem transplantation compared to single transplantation (). Rosenfeld et al. (15
), who used the same conditioning regimens as our study at HDCT1 and HDCT2, reported 6 TRMs (32%) which included 4 cases of VOD, 4 incidences of sepsis, and 1 myelodysplastic syndrome in 19 patients who underwent single or tandem transplantation for treatment of recurrent CNS tumors including 9 medulloblastoma. The rate of VOD was 11% at HDCT1 using CTE regimen, and 18% at HDCT2 using CM regimen. The interval between HDCT1 and HDCT2 was approximately 50 days. While our study showed a VOD incidence rate similar to this report, the incidence was less at HDCT2 (only one patient; 14%) compared to HDCT1 (23%). Our study recommended HDCT2 be delayed about 12 weeks from HDCT1 according to reports that recommended 12 week intervals between HDCTs to prevent VOD (6
). The longer intervals between HDCT1 and HDCT2 in our study may explain why we encountered less TRM and VOD at HDCT2 than reported by Rosenfeld.
This study was a multi-center trial; however, there were some limitations that should be addressed: first, it was impossible to compare the survival outcome between tandem and single transplantation because this study was not randomly compared; second, this study had a relatively short-term follow-up period so we could not formally evaluate long-term side effects using neuropsychological testing or quality of life assessment.
In conclusion, this study shows acceptable survival outcomes compared to other recent studies that utilized HDCT/ASCT in pediatric patients with relapsed medulloblastoma. Tandem transplantation is tolerated in pediatric patients with relapsed brain tumor. Patients with PD does not respond to tandem transplantation even following several courses of intensive SC, but this treatment may be helpful to prolong the survival of patients whose status was PR pre-HDCT and achieved CR after HDCT1. Therefore, it is suggested that active application of tandem transplantation, especially in patients with PR status prior to HDCT/ASCT, will be helpful to prolong survival in cases of relapsed medulloblastoma. The role of tandem transplantation for those with a PR status reached after SC should be defined by a larger scale study.