Unacceptable adverse effects of RT, particularly craniospinal RT, for very young children with brain tumors has led a number of institutions and national groups to adopt chemotherapy-based strategies designed to avoid or delay RT (20
). Actually cure has been documented in several cases even in the absence of RT (1
). In a phase I study using novel chemotherapy regimen including thiotepa, carboplatin, and carmustine for recurrent brain tumor in children, two patients with relapsed ATRT were reported to remain alive longer than 7 yr after HDCT/autoSCT (24
). These data suggested that HDCT has significant activity against ATRT. In the present study, we evaluated the feasibility and effectiveness of tandem HDCT/autoSCT in very young children with ATRT, aiming to improve survival and to avoid or defer RT until after the most radiosensitive neurodevelopmental mileposts. To our knowledge, the present study is the first trial employing the tandem HDCT/autoSCT strategy for very young children with ATRT.
ATRT was very rare and previously misdiagnosed as other CNS embryonal tumors such as primitive neuro-ectodermal tumor or germ cell tumor. However, recently diagnostic confirm was possible using diverse immunohistochemical staining and detecting INI1
gene loss. The majority of rhabdoid tumor arises as a result of homozygous inactivating deletions or mutations of the INI1
gene located in chromosome band 22q11.2 (25
In our small cohort, tumors progressed or relapsed in seven of nine patients. Interestingly, all relapses/progressions occurred at primary sites even in patients with leptomeningeal seeding. However, four of five patients who received RT after relapse/progression are still alive. Recent studies have showed that RT might be more efficacious than chemotherapy for ATRT patients, even for very young children (3
). Chi et al. (27
) recently reported encouraging results of a single arm trial for newly diagnosed ATRT patients, in which local RT was administered during the early treatment period irrespective of age. Taken together, these findings suggest that RT is effective in ATRT and that early administration of RT, at least local RT, might prevent early relapse/progression during induction chemotherapy, resulting in improved outcomes.
In our study, only 3 patients completed induction chemotherapy and could proceed to tandem HDCT/autoSCT as scheduled without relapse/progression. These findings suggest that our induction chemotherapy regimen might be ineffective for preventing tumor relapse/progression. A few investigators have described long-term survivors who had received RT and chemotherapy which had been used for the treatment of rhabdomyosarcoma patients (6
). Taken together, a novel chemotherapy regimen as well as early administration of RT is needed to improve outcomes in the treatment of ATRT.
Recently, Rosenfeld et al. (28
) reported the feasibility of tandem HDCT/autoSCT in patients with brain tumors. They used the same tandem HDCT regimen (CTE/CM) as ours. Two of 19 patients who received the first HDCT/autoSCT and 4 of 11 patients who received the second HDCT/autoSCT died of toxicity. The authors concluded that the CTE/CM regimen is not feasible due to toxicity. On the contrary, toxicities in our present study were manageable and transient, and no toxic death occurred. The only difference between the two studies was the interval between the first and second HDCT/autoSCT. While the second HDCT began by day 50 with an ANC > 1,000/µL and resolutions of all significant toxicities in the study by Rosenfeld et al. (28
), we allowed a 12-16 week interval between the first and second HDCT/autoSCT as a cautionary measure of potential toxicity during the second HDCT/autoSCT. We previously reported that a shorter interval (< 12 weeks) between the first and second HDCT/autoSCT might be associated with higher toxic death rate in the second HDCT/autoSCT (29
). Taken together, our tandem HDCT protocol is relatively safe if patients have sufficient rest between the first and second HDCT/autoSCT.
A total of six patients received tandem HDCT/autoSCT, and three of them received tandem HDCT/autoSCT as a salvage treatment after relapse/progression. Although three patients remained progression free after tandem HDCT/autoSCT, the effectiveness of tandem HDCT/autoSCT is unclear, because all survivors received RT as well as tandem HDCT/autoSCT.
In summary, our tandem HDCT/autoSCT is feasible; however, early administration of RT prior to tandem HDCT/autoSCT should be considered to improve the outcome after tandem HDCT/autoSCT even in very young patients.