Tandem high-dose chemotherapy and auto-sct for malignant brain tumors in children under 3 years of age

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1 Bone Marrow Transplantation (2013) 48, & 2013 Macmillan Publishers Limited All rights reserved /13 ORIGINAL AICLE Tandem high-dose chemotherapy and auto-sct for malignant brain tumors in children under 3 KW Sung 1,7, DH Lim 2,7,SHLee 1,KHYoo 1, HH Koo 1, JH Kim 3, Y-L Suh 4, YS Joung 5 and HJ Shin 6 In an effort to improve survival and reduce late adverse effects of radiation therapy (), 25 children o3 with malignant brain tumors received tandem high-dose chemotherapy (HDCT) and auto-sct following six cycles of induction chemotherapy. was either not given or deferred until 3 if the patient was in CR after tandem HDCT/auto-SCT. Tumors relapsed or progressed in nine patients (five during induction treatment), and two of these patients survived after receiving salvage treatment, including. Two patients died due to toxicities during tandem HDCT/auto-SCT. A total of 16 patients survived to a median follow-up period of 52 months (range 18 96) from the time of diagnosis. Four of these patients did not receive, two received local (L-), three received craniospinal (CS), and seven received both L- and CS. The 5-year OS and EFS rates were 67.8±9.4% and 55.5±10.0%, respectively. Neuroendocrine and neurocognitive functions evaluated 3 years after tandem HDCT/auto-SCT were acceptable. Our results indicate that tandem HDCT/auto-SCT may improve survival in young children with malignant brain tumors with an acceptable level of risk of long-term toxicity. Bone Marrow Transplantation (2013) 48, ; doi: /bmt ; published online 14 January 2013 Keywords: brain tumor; high-dose chemotherapy; auto-sct; radiation therapy; late effects INTRODUCTION Treatment of malignant brain tumors in young children is challenging, as radiation therapy () is used minimally due to the risk of functional impairment of the developing brain, and late adverse effects, including global reduction in the intelligence quotient, cognitive deficits, and neuroendocrine dysfunction. 1 4 In an effort to minimize these effects, a number of institutions and national groups have adopted chemotherapy-based strategies designed to avoid or delay, though outcomes have been largely unsatisfactory. 5 7 A treatment strategy that uses high-dose chemotherapy (HDCT) and auto-sct has helped to improve the prognosis of recurrent or high-risk solid tumors in children Clinical trials using HDCT/auto-SCT for treatment of infants and young children with malignant brain tumors have shown that it is possible to avoid or defer until 3 while maintaining or improving survival rates Additionally, several recent studies have suggested that dose-escalation using tandem HDCT/auto-SCT might further improve outcomes in the treatment of recurrent or high-risk brain tumors. 14,15 In the present study, we prospectively evaluated the feasibility and effectiveness of tandem HDCT/auto-SCT in children o3 years of age with malignant brain tumors. was either not given or deferred until 3 if the patient achieved CR after tandem HDCT/auto-SCT. Local (L-) was given only if gross residual tumor (41.5 cm 2 ) remained after surgery, and craniospinal (CS) was given only if leptomeningeal seeding was present at the time of diagnosis. This new treatment strategy aimed to simultaneously improve survival and reduce the risk of significant late adverse effects of. PATIENTS AND METHODS Patients Children o3 diagnosed with malignant brain tumors between September 2004 and March 2011 were eligible for enrollment in our study. A pediatric neuropathologist reviewed all cases according to the World Health Organization criteria. The extent of disease at the time of diagnosis was assessed using brain and spinal magnetic resonance imaging and cerebrospinal fluid cytology. The Samsung Medical Center Institutional Review Board approved this study, and informed consent was obtained from all the parents or guardians. Induction treatment before HDCT/auto-SCT Figure 1 shows the treatment scheme used in this study. Surgery was the primary treatment for all resectable tumors. Second-look surgery was performed whenever possible. Six cycles of induction chemotherapy were administered before HDCT/auto-SCT, consisting of alternating CECV (cisplatin þ etoposide þ cyclophosphamide þ vincristine) and CEIV (carboplatin þ etoposide þ ifosfamide þ vincristine) regimens (Table 1). Each induction chemotherapy cycle was scheduled to be 28 days apart, but some delays were permitted to allow for recovery of the ANC and platelet count to /l and /l, respectively. PBSCs were collected during the recovery phase of the first chemotherapy cycle. Tandem HDCT/auto-SCT CTE (carboplatin þ thiotepa þ etoposide) and CM (cyclophosphamide þ melphalan) regimens were used for the first and second HDCT/auto-SCT, respectively (Table 1). We allowed an approximately 12-week interval between the first and second HDCT/auto-SCT to minimize toxicity experienced during the second HDCT/auto-SCT. Roughly half of the PBSCs 1 Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; 2 Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; 3 Department of Radiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; 4 Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; 5 Department of Psychiatry, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea and 6 Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. Correspondence: Professor HJ Shin, Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-Dong, Gangnam-Gu, Seoul , Republic of Korea. shinhj@skku.edu 7 These authors contributed equally to this work. Received 15 October 2012; revised 22 November 2012; accepted 22 November 2012; published online 14 January 2013

2 Tandem HDCT/auto-SCT for brain tumors in young children 933 Surgery Induction chemotherapy (A-B-A-B-A-B) Tandem HDCT/autoSCT (CTE-CM) < CR CS 23.4 Gy + L Gy immediately R+ at Dx: L Gy after 3 M+ at Dx: CS 23.4 Gy after 3 R0 M0 at Dx: No A: CECV regimen B: CEIV regimen CR Figure 1. Treatment scheme. Surgery was the primary treatment for all resectable tumors. Six cycles of conventional induction chemotherapy were administered before HDCT/auto-SCT. CECV and CEIV regimens were used in alternation. CTE and CM regimens were used for the first and second HDCT, respectively. If the patient was not in CR after tandem HDCT/auto-SCT, both L- and craniospinal were immediately given. If the patient was in CR after tandem HDCT/auto-SCT, was not given or was deferred until 3. The type of given was determined according to the tumor status at the time of diagnosis (Dx). L- (30.6 Gy, 1.8 Gy/fraction) was given after 3 only if gross residual tumor (41.5 cm 2,Rþ) remained after initial or second-look surgery. CS (23.4 Gy, 1.8 Gy/fraction) was given after 3 years of age only if leptomeningeal seeding was present at the time of diagnosis (M þ ). However, was not given to patients who had neither gross residual tumor after surgery nor leptomeningeal seeding at the time of diagnosis (R0 M0). Table 1. Chemotherapy regimens Regimen Drug Dose Schedule Total dose Induction regimens CECV Cisplatin 3 mg/kg/day Day 0 3 mg/kg Etoposide 2.5 mg/kg/day Days mg/kg Cyclophosphamide 50 mg/kg/day Days 1 and mg/kg Vincristine 0.05 mg/kg/day Days 0 and mg/kg CEIV Carboplatin 10 mg/kg/day Days 0 and 1 20 mg/kg Etoposide 2.5 mg/kg/day Days mg/kg Ifosfamide 50 mg/kg/day Days mg/kg Vincristine 0.05 mg/kg/day Days 0 and mg/kg First HDCT regimen CTE Carboplatin 500 mg/m 2 /day Days 8to mg/m 2 Thiotepa 300 mg/m 2 /day Days 5to mg/m 2 Etoposide 250 mg/m 2 /day Days 5to mg/m 2 Second HDCT regimen CM Cyclophosphamide 1500 mg/m 2 /day Days 8to mg/m 2 Melphalan 60 mg/m 2 /day Days 4to mg/m 2 Abbreviations: CECV ¼ cisplatin þ etoposide þ cyclophosphamide þ vincristine; CEIV ¼ carboplatin þ etoposide þ ifosfamide þ vincristine; CM ¼ cyclophosphamideþ melphalan; CTE¼ carboplatin þ thiotepa þ etoposide; HDCT¼ high-dose chemotherapy. collected during a single round of leukapheresis were infused for marrow rescue during each HDCT/auto-SCT session. was either not given or was deferred until 3 if the patient achieved CR after tandem HDCT/auto-SCT. Use of was determined according to the tumor status at the time of diagnosis. L- (30.6 Gy, 1.8 Gy/fraction) was given after the patient reached 3 only if gross residual tumor (41.5 cm 2 ) remained after initial or second-look surgery. For L- to the primary site, the radiation target volume was not the entire posterior fossa but rather the surgical defect with 1 2 cm margins. This L- to the primary site was performed by three-dimensional conformal. CS (23.4 Gy, 1.8 Gy/fraction) was given after the patient reached 3 only if leptomeningeal seeding was present at the time of diagnosis. If the patient had not achieved CR after tandem HDCT/auto-SCT, both L- and CS were immediately given. In one patient with anaplastic ependymoma (AE), L- was given for persistent residual tumor at the primary site after tandem HDCT/auto-SCT. Response and toxicity criteria Disease response was evaluated by the brain and spinal magnetic resonance imaging and cerebrospinal fluid cytology after the second, fourth, and sixth induction chemotherapy cycles preceding HDCT/auto- SCT, between the first and second HDCT/auto-SCT, every 3 months for the first year after completion of HDCT/auto-SCT, every 4 months for the second year, and every 6 months thereafter. Tumor size was estimated by magnetic resonance imaging as the product of the greatest diameter and the longest perpendicular diameter. Disease response was categorized as follows: progressive disease (PD), 425% increase in tumor size or the appearance of a new tumor; stable disease, o25% change in tumor size; minor response, a 25 50% decrease in tumor size; PR, 450% decrease in tumor size; and CR, complete disappearance of all previously measurable tumor. Toxicities were graded using the National Cancer Institute s Common Terminology Criteria (version 4.0). Evaluation of late adverse effects Late adverse effects were evaluated yearly after completion of the second HDCT/auto-SCT. The diagnosis of growth hormone deficiency was based on a declining growth rate as well as biochemical confirmation. Hypothyroidism was diagnosed in cases of elevated thyrotropin. The diagnosis of adrenal insufficiency was based on failure to increase serum cortisol after administration of corticotropin-releasing hormone. Cognitive function was evaluated using the Korean-Wechsler Preschool and Primary Scale of Intelligence. Cardiac, renal, hepatic, auditory, ophthalmologic, and immune functions were also evaluated. Statistics EFS was determined from the date of diagnosis to the date of relapse, progression, or death (whichever occurred first). OS was determined from the date of diagnosis to death from any cause. Survival rates and s.es. were estimated using the Kaplan Meier method. Differences in the survival rates between the groups were compared using log-rank tests. P-values o0.05 were considered to be statistically significant. RESULTS Patient characteristics Twenty-five consecutive patients (12 boys and 13 girls) with malignant brain tumors, including 8 medulloblastomas (MBs), & 2013 Macmillan Publishers Limited Bone Marrow Transplantation (2013)

3 934 Table 2. Tandem HDCT/auto-SCT for brain tumors in young children Patient characteristics No. Sex/age (months) Dx Residual tumor 41.5 cm 2 M stage Status after induction Status after HDCT1 Status after CS (Gy) L- (Gy) Reason for Age at (months) Outcome (followup from Dx) 1 M/18 MB-C No 0 CR CR CR 0 0 ND 96 months þ, 2 F/23 PNET Yes 0 PR CR PD PD after months þ, PD at 11 months 3 F/20 AT No 1 PD 3 months, PD at 2 months 4 F/14 MB-DN Yes 2 CR CR CR Reached months þ, 5 F/18 MB-DN Yes 2 PR PR PR PR after months þ, 6 M/16 AE No a 0 CR CR CR 0 0 ND 77 months þ, 7 F/18 MB-A Yes 0 CR CR CR Reached months þ, 8 M/10 MB-U Yes 3 PR 7 months, TRM (VOD) 9 F/28 AE Yes 2 PR PR PR PR after months, PD at 19 months 10 F/10 AE Yes 3 CR CR CR Reached months þ, 11 F/3 AT No 3 PR PR PD 15 months, PD at 14 months 12 F/11 PNET Yes 1 PR 13 months, TRM (sepsis) 13 M/35 MB-C No 3 PR PR CR Reached months þ, 14 M/16 AE Yes 0 PR PR CR Reached months þ, 15 M/2 MFH No 0 CR CR CR 0 0 ND 51 months þ, 16 M/4 GM Yes 3 PD 4 months, PD at 2 months 17 M/14 MB-C No 3 PR CR CR Reached months þ, 18 M/1 PNET Yes 3 PR PR CR Reached months þ, 19 M/12 AE No 3 PR PR CR Reached months þ, 20 F/28 AT Yes 3 PR CR CR Reached months, PD at 22 months 21 F/9 AT Yes 3 PD PR PR PR after months þ, PD at 7 months 22 F/2 AT Yes 2 PD 6 months, PD at 5 months 23 F/3 GM No 0 CR CR CR 0 0 ND 26 months þ, 24 F/29 MB-A Yes 2 PD 28.8 b PD during induction 34 7 m, PD at 5 months 25 M/25 AE Yes 3 PR PR PR Reached months þ, Abbreviations: AE ¼ anaplastic ependymoma; AT ¼atypical teratoid/rhabdoid tumor; CS ¼ craniospinal radiotherapy; Ds ¼ disease; Dx ¼ diagnosis; GM¼ glioblastoma multiforme; HDCT1 ¼ first high-dose chemotherapy; ¼ second HDCT; MB-A ¼ anaplstic/large cell MB; MB-C ¼ classic medulloblastoma; MB-DN¼ desmoplastic/nodular MB; MB-U ¼ MB of unknown pathology; MFH ¼ malignant fibrous histiocytoma; ND ¼ not done; PD ¼ progressive disease; PNET ¼ primitive neuroectodermal tumor; TRM ¼ treatment-related mortality; VOD ¼ veno-occlusive disease. a No residual tumor remained after second-look surgery. b was not completed owing to PD during. 3 primitive neuroectodermal tumors, 5 atypical teratoid/rhabdoid tumors (ATs), 6 AEs, 2 glioblastoma multiformes, and 1 malignant fibrous histiocytoma were enrolled in this study. Patient characteristics are shown in Table 2. The median age at the time of diagnosis was 15 months (range 1 35). Seventeen patients had significant residual tumor (41.5 cm 2 ) after initial surgery, and leptomeningeal seeding was present at the time of diagnosis in 18 patients. Induction treatment Induction chemotherapy was successfully administered without significant organ toxicity, though all patients experienced neutropenic fever. The median number of CD34 þ cells collected during three leukapheresis events was cells/kg (range ). Five patients experienced PD during induction treatment. In one patient, a gross total resection of the tumor was performed following six cycles of induction chemotherapy. All 20 patients who remained progression-free during induction treatment proceeded to the first HDCT/auto-SCT and their tumor statuses were CR in 7 patients and PR in 13 patients. One of the five patients who experienced PD during induction treatment also proceeded to HDCT/auto-SCT after second-look surgery (Figure 2). Tandem HDCT/auto-SCT The median age at the first HDCT/auto-SCT was 23 months (range 7 43). The median time from the first infusion of PBSCs to the initiation of the second HDCT/auto-SCT was 83 days (range ). Second-look surgery was performed after the first HDCT/auto-SCT in one patient. Table 3 shows the characteristics of tandem HDCT/auto-SCT. Neutrophil and platelet counts recovered rapidly during both the first and second HDCT/auto- SCT. Frequent grade 3/4 toxicities during the first HDCT/auto-SCT included fever, stomatitis, diarrhea, elevation of liver enzymes, and hypokalemia. One patient died from hepatic veno-occlusive Bone Marrow Transplantation (2013) & 2013 Macmillan Publishers Limited

4 Tandem HDCT/auto-SCT for brain tumors in young children After induction After HDCT1 After During follow-up Final outcome 935 HDCT1 (n = 21) (n = 20) 7 CRs 7 CRs 7 CRs 7 CRs 7 ailve 13 PRs 3 CRs 2 CRs 1 CR 1 REL 1 ailve 1 dead 1 alive 1 PD 1 CR 25 enrolled 9 PRs 4 CRs 4 CRs 3 PRs 2 CRs 4 alive 2 alive 1 TRM 1 PD 1 dead or surgery 1 PD 1 TRM 1 dead 5 PDs 1 PR 1 PR 1 alive 4 off-tx 4 dead Figure 2. Flow of patients. Twenty-five consecutive patients with malignant brain tumors were enrolled in this study. All 20 patients who remained progression free during induction treatment proceeded to the first HDCT/auto-SCT, 7 of which achieved CR and 13 achieved PR. There was tumor progression during induction treatment in five patients, and one of these patients also proceeded to HDCT/auto-SCT after second-look surgery. Five patients received immediately after the second HDCT/auto-SCT, because they remained in PR after tandem HDCT/auto-SCT (n ¼ 4) or experienced PD after the second HDCT/auto-SCT (n ¼ 1). Tumors relapsed or progressed in nine patients (five during induction treatment and four after tandem HDCT/auto-SCT), two of whom survived after salvage treatment, including. Two patients died from toxicities during tandem HDCT/auto-SCT. A total of 16 patients survived. TRM, treatment-related mortality; REL, relapse; off-tx, off treatment. Table 3. Parameters Characteristics of tandem HDCT/auto-SCT First HDCT/ auto-sct (n ¼ 21) Second HDCT/ auto-sct (n ¼ 20) Hematological toxicity CD34 þ cells ( 10 6 /kg) 21.2 ( ) a 18.8 ( ) a Time (days) to reach an 9 (8 12) 9 (7 16) ANC /l b Time (days) to reach a 19 (14 66) 28 (17 100) platelet count /l c Days of BT X38.0 o C 5 (0 13) 4 (0 14) Positive blood culture 3 (14.3%) 3 (15.0%) Non-hematological toxicity Stomatitis 16 (76.2%) 2 (10.0%) Vomiting 7 (33.3%) 4 (20.0%) Diarrhea 13 (61.9%) 13 (65.0%) Elevation of liver 16 (76.2%) 2 (10.0%) enzymes Hyperbilirubinemia 1 (4.8%) 0 (0%) Renal insufficiency d 0 (0%) 0 (0%) Hypokalemia 11 (52.4%) 8 (40.0%) Hyperkalemia 0 (0%) 1 (5.0%) Hyponatremia 2 (9.5%) 0 (0%) Hypernatremia 0 (0%) 0 (0%) Hepatic VOD e 1 (4.8%) 5 (25.0%) Myocarditis 0 (0%) 0 (0%) Treatment-related mortality 1 (4.8%) 1 (5.0%) Abbreviations: HDCT ¼ high-dose chemotherapy; BT ¼ body temperature; VOD ¼ veno-occlusive disease. a Median (range). b The first day when ANC exceeded /L for 3 consecutive days. c The first day when platelet count exceeded /dl without transfusion for 7 days. d Elevation of serum creatinine more than threefold of baseline. e At least two of the following three events within 20 days of transplantation: bilirubin level 42mg/dL, hepatomegaly or right upper quadrant pain of liver origin, or 42% weight gain secondary to fluid accumulation. disease during the first HDCT/auto-SCT. Frequent grade 3/4 toxicities during the second HDCT/auto-SCT included fever, hypokalemia, and hepatic veno-occlusive disease. One patient died from sepsis during the second HDCT/auto-SCT. One patient began after two cycles of induction chemotherapy due to PD, but this treatment was not completed due to further progression during. Only five patients who had achieved PR after tandem HDCT/auto-SCT (n ¼ 4), or had experienced PD after the second HDCT/auto-SCT (n ¼ 1), received immediately after the second HDCT/auto-SCT (Figure 2). Four of these patients received both CS and L-, and one patient received only L-. In the 13 patients who remained in CR until 3, was either deferred until after 3 (n ¼ 9) or was not given (n ¼ 4). Overall, 15 patients received (L- alone in 3, CS alone in 4, and both L- and CS in 8 patients). The median age at the time of was 39 months (range 24 48). Among the 16 survivors, 4 patients received no, 2 received L- alone, 3 received CS alone, and 7 received both L- and CS. was initiated before 3 in 3 of 16 survivors. Survival Tumors relapsed or progressed in nine patients (five during induction treatment and four after tandem HDCT/auto-SCT), two of which survived after receiving salvage treatment, including. Two patients died from toxicities during tandem HDCT/auto-SCT (Figure 2). A total of 16 patients remained alive at a median followup period of 52 months (range 18 96) from the time of diagnosis. The 5-year OS and EFS rates were 67.8±9.4% and 55.5±10.0%, respectively (Figure 3a). Table 4 shows survival rates with respect to clinical characteristics. The 5-year OS and EFS rates were higher in M0 patients than in M þ patients (OS 100 vs 55.0±11.9%, P ¼ 0.022; EFS 85.7±13.2% vs 43.2±11.9%, P ¼ 0.078). The survival rates for the 5 AT patients were disappointing due to early progression of disease (5-year OS and EFS: 20.0±17.9% and & 2013 Macmillan Publishers Limited Bone Marrow Transplantation (2013)

5 936 Survival (%) OS (%) EFS (%) 100 OS EFS Tandem HDCT/auto-SCT for brain tumors in young children Months from diagnosis Months from diagnosis Months from diagnosis Figure 3. Survival rates. (a) The 5-year OS and EFS rates were 67.8±9.4% and 55.5±10.0%, respectively. The survival rates for the five AT patients were disappointing due to early disease progression. (b, c) However, the survival rates of the remaining patients with malignant brain tumors other than AT were encouraging. Six of 8 MB patients, 2 of 3 primitive neuroectodermal tumor (PNET) patients, 5 of 6 AE patients, 1 of 2 glioblastoma multiforme patients, and 1 malignant fibrous histiocytoma patient survived. 0%, respectively). However, the survival rates of the remaining patients with malignant brain tumors other than AT were encouraging (5-year OS and EFS: 80.0±8.9% and 69.6±10.4%, respectively) (Figures 3b and c). Six of 8 MB patients, 2 of 3 primitive neuroectodermal tumor patients, 5 of 6 AE patients, 1 of 2 glioblastoma multiforme patients, and 1 malignant fibrous histiocytoma patient remained alive. Late adverse effects Ten patients who remained event free for 43 years after the second HDCT/auto-SCT were evaluated for various late adverse effects (Table 5). Frequent late adverse effects included hypothyroidism, growth hormone deficiency, hearing loss, and AE MB PNET GM AT AE MB PNET GM AT renal tubulopathy. Until 3 years after tandem HDCT/auto-SCT, a prominent deceleration in vertical growth was observed. The median height at 3 years after the second HDCT/auto-SCT was 2.5 s.ds. from the mean (range from 0.2 to 4.8) height with respect to patient age. The median values for full-scale, verbal, and performance intelligence quotient evaluated at a median follow-up period of 45 months (range 35 70) after the second HDCT/auto-SCT were found to be 75 (range 67 90), 83 (range ), and 71 (range 69 86), respectively. DISCUSSION In the present study, we prospectively evaluated the use of tandem HDCT/auto-SCT in children with malignant brain tumors, aiming to both improve survival and avoid or defer until after the most radiosensitive neurodevelopmental milestones. Our results suggest that treatment with tandem HDCT/auto-SCT is feasible and may improve survival with acceptable rates of longterm toxicity. We found that patients tolerated induction chemotherapy well, without prolonged cytopenia sufficient to delay chemotherapy. All patients did experience neutropenic fever; however, no significant organ toxicity occurred during induction chemotherapy. Toxicities experienced during the first HDCT/auto-SCT were generally tolerable, although severe mucositis-related toxicity was difficult to manage. The frequency and severity of mucositis-related toxicity was much lower during the second HDCT/auto-SCT. Two patients died from toxicities during tandem HDCT/auto-SCT; however, we believe that this toxic death rate may be acceptable considering the otherwise poor outcomes seen in young children with malignant brain tumors. Exclusion or reduction of has been associated with fewer late adverse effects but also lower survival rates in the treatment of young children with malignant brain tumors. In the Head Start I and II studies, patients received only if residual tumor remained at the time of HDCT/auto-SCT or if the tumor had relapsed after HDCT/auto-SCT In the present study, the use of was determined by the tumor status after initial surgery but not the tumor status after chemotherapy, including HDCT/auto-SCT. Therefore, 9 of 13 patients who were in CR after tandem HDCT/ auto-sct received after 3 according to the tumor status at the time of diagnosis (L- alone in 2, CS alone in 3, and both L- and CS in 4 patients). All these patients except 1 diagnosed with AT remained event free. Although some of these survivors may have remained in CR without, it remains unclear who should receive and at what dose and volume in order to prevent relapse in these patients. Further studies are needed to address these issues. Tumor type is also an important factor to be considered in determining treatment strategies, including in young children with malignant brain tumors. In the present study, all patients received uniform treatment regardless of tumor type. Our results show that survival rates were reasonably good in cases of malignant brain tumors other than AT. Of note, survival rates of non-embryonic brain tumors, particularly AE, were encouraging. The prognosis in cases of AT was poor, however, as all five AT patients experienced early progression or relapse and only one survived after receiving before 3. These findings suggest that our strategy to avoid or defer until after 3 years of age may not be as useful in AT patients. Recent studies have shown that might be more efficacious than chemotherapy for AT patients, even in young children. 16,17 Chi et al. 18 recently reported encouraging results of a single-arm trial for newly diagnosed AT patients, in which L- was administered during the early treatment period irrespective of age. Taken together, these findings suggest that our treatment strategy needs to be tailored according to the pathological diagnosis in young children with malignant brain tumors, particularly in cases of AT. Bone Marrow Transplantation (2013) & 2013 Macmillan Publishers Limited

6 Tandem HDCT/auto-SCT for brain tumors in young children 937 Table 4. Survival rates according to clinical characteristics Parameters No (%) 5-year EFS (±SE) (%) P-value 5-year OS (±SE) (%) P-value Age o12 months 10 (40%) 40.0± ±15.8 X12 months 15 (60%) 65.5± ± Sex Male 12 (48%) 30.8± ±13.8 Female 13 (52%) 83.3± ± Diagnosis MB 8 (32%) 75.0± ±15.3 PNET 3 (12%) 33.3± ±27.2 AT 5 (20%) ±17.9 a AE 6 (24%) 80.0± GM 2 (8%) 50.0±35.4 a 50.0±35.4 a MFH 1 (4%) Residual tumor o1.5 cm 2 9 (36%) 77.8± ± cm 2 16 (64%) 43.8± ± Metastasis No 7 (28%) 85.7± Yes 18 (72%) 43.2± ± Response to induction CR 7 (28%) PR 13 (52%) 51.9± ±13.2 PD 5 (20%) 0 o ±17.9 a o0.001 Abbreviations: AE ¼ anaplastic ependymoma; AT ¼atypical teratoid/rhabdoid tumor; GM ¼ glioblastoma multiforme; MB ¼ medulloblastoma; MFH ¼ malignant fibrous histiocytoma; PD ¼ progressive disease; PNET ¼ primitive neuroectodermal tumor. a Follow-up duration is o5 years. MB was the most common malignancy in the present study, and six of eight MB patients remained alive. These results are encouraging, although the number of patients studied was low. Rutkowski et al. 19 reported the results of a HIT-SKK 92 study in which intraventricular chemotherapy was introduced as a substitute for. In their study, treatment was completed without in children who achieved CR after 6 months of intensive chemotherapy, including high-dose MTX and intraventricular MTX. They reported that PFS rate was excellent, particularly for R0 M0 patients (5-year PFS 82%). These findings suggest that young patients diagnosed with MB without significant post-operative residual tumor and without leptomeningeal seeding can be cured without or HDCT/auto- SCT. It is notable, however, that outcomes were not satisfactory for patients with macroscopic metastasis (5-year PFS 33%). In our study, on the other hand, four of six MB patients with macroscopic metastases remained alive, with deaths due to PD and treatmentrelated mortality. Taken together, our treatment strategy may be a viable option for young children diagnosed with metastatic MB. Incorporation of high-dose MTX and intraventricular MTX into induction treatment can be considered in future studies in order to further improve outcomes and reduce the dose necessary to prevent relapse or progression. Among the 16 survivors, 4 patients did not receive, 5 received L- alone or CS alone, and 7 received both L- and CS. In addition, was initiated before 3 in 3 of 16 survivors. As a result, our small cohort of patients experienced an acceptable incidence of delayed adverse effects. Endocrine dysfunction was acceptable, and sensory neural hearing loss was mild. In addition, no major organ dysfunction was noted. The verbal intelligence of these patients, which is encouraging, will have a key role in their adjustment to daily life. These results are encouraging, because prevention of late adverse effects is a major consideration in treating very young children with malignant brain tumors. Table 5. Late adverse effects 3 years after tandem HDCT/auto-SCT In summary, our results suggest that tandem HDCT/auto-SCT is feasible and effective in young children with malignant brain tumors, and may be avoided or deferred until 3 without compromising survival in cases of malignant brain tumors other than AT. Further studies are needed, however, to determine the optimal strategy in young children undergoing tandem HDCT/auto-SCT. CONFLICT OF INTEREST The authors declare no conflict of interest. Grade 1 2 Grade 3 4 Total Endocrine (n ¼ 10) a Hypothyroidism Growth hormone deficiency Glucocorticoid deficiency Hearing loss (n ¼ 10) Cataracts (n ¼ 10) Chronic lung disease (n ¼ 10) Renal (n ¼ 10) Glomerulopathy Tubulopathy Cardiac (n ¼ 10) Second malignancy (n ¼ 10) a Late effects evaluated at a median of 36 months (range 35 37) after the second HDCT/auto-SCT were presented. & 2013 Macmillan Publishers Limited Bone Marrow Transplantation (2013)

7 938 ACKNOWLEDGEMENTS Tandem HDCT/auto-SCT for brain tumors in young children This study was supported by a grant from the National R&D Program for Cancer Control, Ministry of Health and Welfare, Republic of Korea (No ). REFERENCES 1 Copeland DR, demoor C, Moore 3rd BD, Ater JL. Neurocognitive development of children after a cerebellar tumor in infancy: a longitudinal study. J Clin Oncol 1999; 17: Mulhern RK, Merchant TE, Gajjar A, Reddick WE, Kun LE. Late neurocognitive sequelae in survivors of brain tumours in childhood. Lancet Oncol 2004; 5: Lannering B, Marky I, Lundberg A, Olsson E. Long-term sequelae after pediatric brain tumors: their effect on disability and quality of life. Med Pediatr Oncol 1990; 18: Duffner PK. Long-term effects of radiation therapy on cognitive and endocrine function in children with leukemia and brain tumors. Neurologist 2004; 10: Duffner PK, Horowitz ME, Krischer JP, Friedman HS, Burger PC, Cohen ME et al. Postoperative chemotherapy and delayed radiation in children less than three with malignant brain tumors. N Engl J Med 1993; 328: Geyer JR, Zeltzer PM, Boyett JM, Rorke LB, Stanley P, Albright AL et al. Survival of infants with primitive neuroectodermal tumors or malignant ependymomas of the CNS treated with eight drugs in 1 day: a report from the Childrens Cancer Group. J Clin Oncol 1994; 12: Grill J, Sainte-Rose C, Jouvet A, Gentet JC, Lejars O, Frappaz D et al. Treatment of medulloblastoma with postoperative chemotherapy alone: an SFOP prospective trial in young children. Lancet Oncol 2005; 6: Matthay KK, Reynolds CP, Seeger RC, Shimada H, Adkins ES, Haas-Kogan D et al. Long-term results for children with high-risk neuroblastoma treated on a randomized trial of myeloablative therapy followed by 13-cis-retinoic acid: a children s oncology group study. J Clin Oncol 2009; 27: Berthold F, Boos J, Burdach S, Erttmann R, Henze G, Hermann J et al. Myeloablative megatherapy with autologous stem-cell rescue versus oral maintenance chemotherapy as consolidation treatment in patients with high-risk neuroblastoma: a randomised controlled trial. Lancet Oncol 2005; 6: Marachelian A, Butturini A, Finlay J. Myeloablative chemotherapy with autologous hematopoietic progenitor cell rescue for childhood central nervous system tumors. Bone Marrow Transplant 2008; 41: Mason WP, Grovas A, Halpern S, Dunkel IJ, Garvin J, Heller G et al. Intensive chemotherapy and bone marrow rescue for young children with newly diagnosed malignant brain tumors. J Clin Oncol 1998; 16: Fangusaro J, Finlay J, Sposto R, Ji L, Saly M, Zacharoulis S et al. Intensive chemotherapy followed by consolidative myeloablative chemotherapy with autologous hematopoietic cell rescue (AuHCR) in young children with newly diagnosed supratentorial primitive neuroectodermal tumors (spnets): report of the Head Start I and II experience. Pediatr Blood Cancer 2008; 50: Chi SN, Gardner SL, Levy AS, Knopp EA, Miller DC, Wisoff JH et al. Feasibility and response to induction chemotherapy intensified with high-dose methotrexate for young children with newly diagnosed high-risk disseminated medulloblastoma. J Clin Oncol 2004; 22: Gajjar A, Chintagumpala M, Ashley D, Kellie S, Kun LE, Merchant TE et al. Risk-adapted craniospinal radiotherapy followed by high-dose chemotherapy and stem-cell rescue in children with newly diagnosed medulloblastoma (St Jude Medulloblastoma-96): long-term results from a prospective, multicentre trial. Lancet Oncol 2006; 7: Sung KW, Yoo KH, Cho EJ, Koo HH, Lim do H, Shin HJ et al. High-dose chemotherapy and autologous stem cell rescue in children with newly diagnosed high-risk or relapsed medulloblastoma or supratentorial primitive neuroectodermal tumor. Pediatr Blood Cancer 2007; 48: Tekautz TM, Fuller CE, Blaney S, Fouladi M, Broniscer A, Merchant TE et al. Atypical teratoid/rhabdoid tumors (AT): Improved survival in children 3 years of age and older with radiation therapy and high-dose alkylator-based chemotherapy. J Clin Oncol 2005; 23: Chen YW, Wong TT, Ho DM, Huang PI, Chang KJ, Shiau CY et al. Impact of radiotherapy for pediatric CNS atypical teratoid/rhabdoid tumor (single institute experience). Int J Radiat Oncol Biol Phys 2006; 64: Chi SN, Zimmerman MA, Yao X, Cohen KJ, Burger P, Biegel JA et al. Intensive multimodality treatment for children with newly diagnosed CNS atypical teratoid rhabdoid tumor. J Clin Oncol 2009; 27: Rutkowski S, Bode U, Deinlein F, Ottensmeier H, Warmuth-Metz M, Soerensen N et al. Treatment of early childhood medulloblastoma by postoperative chemotherapy alone. N Engl J Med 2005; 352: Bone Marrow Transplantation (2013) & 2013 Macmillan Publishers Limited