1 Department of Pediatric Hematology and Oncology, University. 3 Department of Pediatrics, University of Erlangen, Erlangen,

Transcription

1 Pediatr Blood Cancer 2011;57: Frequency, Risk-Factors and Survival of Children With Atypical Teratoid Rhabdoid Tumors (AT/RT) of the CNS Diagnosed between 1988 and 2004, and Registered to the German HIT Database Katja von Hoff, MD, 1,2 * Bernward Hinkes, MD, 2,3 Elke Dannenmann-Stern, MD, 4 André O. von Bueren, MD, PhD, 1 Monika Warmuth-Metz, MD, 5 Niels Soerensen, MD, 6,7 Angela Emser, MSc, 8 Isabella Zwiener, MSc, 8 Paul G. Schlegel, MD, 2 Joachim Kuehl, MD, 2y Michael C. Frühwald, MD, PhD, 9,10 Rolf D. Kortmann, MD, 11 Torsten Pietsch, MD, 12 and Stefan Rutkowski, MD 1 Purpose. To analyze the frequency, prognostic factors, and outcome of children with atypical teratoid/rhabdoid tumors (AT/RT), a rare and highly malignant embryonal brain tumor. Materials and Methods. Clinical data of patients diagnosed between 1988 and 2004 with AT/RT who were registered to the German HIT trial center, were correlated with outcome. Patient numbers for AT/RT were compared to numbers for primitive neuroectodermal tumors and medulloblastomas (PNET/MB) registered to the populationbased HIT trials. Results. We identified 56 patients with the centrally confirmed histopathological diagnosis of AT/RT with a median age of 1.2 years (range, years). The AT/RT:PNET/MB ratio was 1:12.2 for all children, and 1:1.5 for children younger than 1 year at diagnosis. Three-year overall survival (OS) and event-free survival (EFS) for all patients were 22% and 13%, respectively. Eight patients (14%) are considered long-term event-free survivors (follow-up years). By univariable analyses, younger age, metastatic disease, infratentorial location, and less than complete remission at the end of chemotherapy were identified as negative influencing factors for OS. By multivariable analyses, younger age (OS, EFS) and metastatic disease (OS) were identified as independent risk factors. Conclusion. The incidence of AT/RT in children below 1 year is higher than previously reported. A subset of patients with favorable clinical risk factors profits from intensive multimodal treatment. Prospective clinical and biological studies are needed to further define prognostic factors and optimize therapy. Pediatr Blood Cancer 2011;57: ß 2011 Wiley-Liss, Inc. Key words: AT/RT; brain tumors; children; CNS tumors; frequency; rhabdoid INTRODUCTION Atypical teratoid/rhabdoid tumor of the central nervous system (AT/RT) represents a highly malignant (WHO grade IV) embryonal brain tumor with a rather dismal prognosis manifesting predominantly during early childhood. Before its definition as an entity by Rorke et al. [1] and its inclusion in the WHO classification of CNS tumors [2], AT/RT were often misclassified as primitive neuroectodermal tumors (PNET), glioblastomas, or carcinomas of the plexus choroideus [3,4]. Meanwhile, AT/RT have received recognition as a rare but important differential diagnosis in pediatric neuro-oncology [5]. Alterations of the SMARCB1/hSNF5/INI1 gene in chromosome band 22q11.2, a functional tumor suppressor, have been detected in up to 100% of tumors, and are functionally involved in aggressive tumor growth [6 10]. Despite the major advances, which have been achieved in the elucidation of the biology, treatment of AT/RT remains a challenge. Disease-specific protocols have recently been opened and show encouraging, albeit preliminary results [11]. Such protocols face the difficulty of treating a rare and highly aggressive brain tumor in predominantly very young children with no standard therapy available. Therefore, retrospective analyses of AT/RT cases represent an important source of information for future treatment strategies [12 16]. The objective of this study was to gain information on the frequency and clinical course of CNS AT/RT by analyzing patients documented to a national database for children and young adults with malignant brain tumors in German-speaking countries. MATERIALS AND METHODS Patients and Data Registration Following informed consent by their legal representatives, patients were registered to the HIT database between 1988 and The HIT trials are used within the German Society for ß 2011 Wiley-Liss, Inc. DOI /pbc Published online 27 July 2011 in Wiley Online Library (wileyonlinelibrary.com). Paediatric Oncology and Haematology (GPOH) for treatment of children with brain tumors. About 90% of newly diagnosed children with CNS-PNET/medulloblastoma (MB) were registered during the last decade. Consequently, the HIT registry serves as a national center for collecting clinical data on childhood PNET/ MB and related brain tumors in a population-based setting. Additional supporting information may be found in the online version of this article. 1 Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; 2 Department of Pediatrics, University of Wuerzburg, Wuerzburg, Germany; 3 Department of Pediatrics, University of Erlangen, Erlangen, Germany; 4 Department of Radiotherapy, University of Tuebingen, Tuebingen, Germany; 5 Department of Neuroradiology, University of Wuerzburg, Wuerzburg, Germany; 6 Department of Pediatric Neurosurgery, University of Wuerzburg, Wuerzburg, Germany; 7 Department of Neurosurgery, ev. Hospital Oldenburg, Germany; 8 Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany; 9 Children s Hospital Augsburg, Augsburg, Germany; 10 Department of Pediatric Hematology and Oncology, University Children s Hospital Muenster, Muenster, Germany; 11 Department of Radiation Oncology, University of Leipzig, Leipzig, Germany; 12 Department of Neuropathology, University of Bonn, Bonn, Germany Grant sponsor: German Children s Cancer Foundation (Deutsche Kinderkrebsstiftung). Conflicts of interest: Nothing to declare. y Deceased. Katja von Hoff and Bernward Hinkes contributed equally to this work. *Correspondence to: Katja von Hoff, MD, Department of Pediatric Hematology and Oncology, University Medical Center Hamburg- Eppendorf, Martinistr. 52, D Hamburg, Germany. k.von-hoff@uke.de Received 6 September 2010; Accepted 18 May 2011

2 Atypical Teratoid Rhabdoid Tumors of the CNS 979 Standardized documentation is provided by 80 participating pediatric oncology centers in Germany, Austria, and Switzerland. Sixty-three children with AT/RT were identified. In four children tumor material was not available for central histopathological review, these were excluded from the following analyses. Two children were excluded as they did not receive curative anti-tumor therapy. In addition, consent for data acquisition could not be obtained for one child. Consequently, 56 children with central histopathological confirmed diagnosis of AT/RT based on published WHO criteria [2] were eligible for this retrospective analysis. Patients diagnosed between 1988 and 1999 might be already published [17]. Histopathology Central neuropathological review was part of the initial standard diagnostic procedure, and was performed at the Institute of Neuropathology, University of Bonn Medical Center. For this analysis all tumors of the 56 identified patients were recently reevaluated by at least two board certified neuropathologists according to the revised WHO classification of brain tumors. Paraffin embedded tumor material was stained with hematoxylin/eosin, and silver for reticulin fibers. The following antibodies were used for immunophenotyping: anti-epithelial membrane antigen (EMA), vimentin, glial fibrillary acidic protein (GFAP), Ki-67, smooth muscle actin, Desmin, S-100 protein, synaptophysin, p53 (all from Dako), cytokeratin (clone Lu-5, Bachem), and Oct3/4 (polyclonal, Santa Cruz Biotechnology, Santa Cruz, CA). After commercial availability, also an antibody against INI-1 protein was used (monoclonal, BAF47, BD Biosciences, Franklin Lakes, NJ). Because of the recruiting period, INI-1 staining was not performed in the early patients, of whom mostly also no tumor material was available for retrospective staining. Staging and Treatment Initial tumor staging was performed according to standard criteria [18], and central review of neuroimaging and cerebrospinal fluid samples were recommended since Patients in whom cerebrospinal fluid was not assessed for microscopic dissemination, and who had no macroscopic metastases were classified as stage M0/M1. With no treatment protocol for AT/RT recruiting at the time, patients in this retrospective study had been treated according to various multimodal treatment approaches. Due to the young age of most patients, the most frequent treatment sequence consisted of neurosurgery followed by chemotherapy and, in a subgroup of patients, successive radiotherapy. Chemotherapeutic treatment was based on different HIT protocols in 39 patients: HIT 2000 trial (n ¼ 18) [19], HIT-SKK-92 (n ¼ 9) [20], HIT-91 (n ¼ 6) [21], and HIT-SKK-87 (n ¼ 6) [22]. Seventeen patients were treated according to individual decisions of the local physicians or employing approaches based on protocols used for extracranial rhabdoid tumors such as CWS-96 [23], and SIOP [24]. As documentation of chemotherapeutic regimens was incomplete, analysis of the influence of specific chemotherapeutic agents was not performed. Radiotherapy was administered to 29 patients dependent on age, stage, treatment protocol, and individual decision, either as craniospinal or local radiotherapy following primary chemotherapy, or at relapse or progression. Statistical Analysis Survival rates were estimated using the Kaplan Meier method. The estimated 3-year event-free (EFS) and overall survival (OS) rates with the respective standard errors are stated. The outcome of subgroups was compared exploratively by log-rank test. No significance level was fixed. The impact of radiotherapy could not be evaluated conclusively since in many cases the decision to irradiate was based on individual decisions. An univariable comparison of the outcome of patients with and without radiotherapy starting at time of diagnosis seemed inappropriate, as decision for or against radiotherapy was not yet clear at that time point. With no standard treatment or prospective study in force, these decisions were based on the knowledge of the individual patient s course at a later time point. An analysis of treatment with radiotherapy as being known from date of diagnosis, would lead to a time-dependent bias, and to a biased effect estimator [25]. Multivariable Cox regression was applied to analyze the prognostic value of the following factors with respect to EFS and OS: age at diagnosis (continuous), tumor stage (M0 vs. M1 or M2/3), localization (supratentorial vs. infratentorial), and extent of resection (R0 vs. Rþ). Application of radiotherapy was not included in the multivariable analyses due to the mentioned reasons. Models were built using a backward stepwise variable selection procedure with the use of a P-value of the likelihood ratio test >0.10 as exclusion, and 0.05 as inclusion criterion. The effects of variables are stated by the hazard ratio and the P-value of the likelihood ratio test. The multivariable Cox regression analyses are regarded as explorative. Frequency of AT/RT: After the description of AT/RT, and inclusion into the WHO classification [1,2,26], an increased number of children with this diagnosis were registered to the database. As the increase reflected higher rates of diagnosed AT/RT rather than increasing occurrence, our analyses on frequency were performed on patients diagnosed between January 2000 and December The numbers of AT/RT and MB/CNS-PNET cases in the HIT database were calculated for five age groups. RESULTS We evaluated the clinical course of 56 eligible children with AT/RT. The median survival of all patients was 1.2 years (range: years). Forty-three children (77%) died, 40 of their disease after a median survival of 1.0 years (range: years). Three patients died due to therapy related complications (sepsis, 2; brainstem hemorrhagic infarction, 1). Three year-efs and 3y- OS of all 56 patients were 13 5% and 22 6% (Fig. 1). At the time of analysis 13 of 56 patients were alive with a median followup of 3.3 years (range: years). Eight of these (14%) were alive without tumor progression or relapse with a median follow up of 4.4 years (range: years), one of them with persistent stable disease. Five (9%) survivors experienced progression or relapse at a median time of 0.4 years ( years) and were alive at last follow up years (median 3.0). The clinical characteristics of 56 children with AT/RT, and the results of univariable analyses are available online as Supplementary Tables I and II. Histopathology Most tumors contained areas with typical rhabdoid cells. Some cases showed advanced epithelial differentiation or glial

3 980 von Hoff et al. diagnosis 0.9 years; range years) than patients with supratentorial location (median age 2.4; range ; P < 0.001), they also presented more often with metastasic disease (Mþ: infratentorial, 9 of 27; supratentorial 3 of 26, 1 unknown; P ¼ 0.058). Staging Tumor staging according to Chang et al. [18] was M0 in 30 children (54%). Thirteen children (23%) were classified as M0/ M1 as no cerebrospinal fluid had been analyzed in the absence of macroscopic metastases, four children (7%) had M1-stage, and eight (14%) had M2/3-stage (n ¼ 1, M stage unknown). Age at diagnosis was not different for patients with localized or metastatic disease (P ¼ 0.219). Overall survival was lower for patients with M1, and M2/3 disease (3y-OS: 0 0%) compared to patients with M0 disease (3y-OS: 31 9%, P ¼ 0.009; Fig. 2c). Event-free survival tended to be lower for patients with M1, and M2/3 compared to M0 disease (3y-EFS 0 0% vs. 17 7%, P ¼ 0.054). Fig. 1. differentiation; few cases were mostly composed mainly of immature small cells. Immunohistochemistry showed strong coexpression of vimentin and EMA. The germ cell tumor marker Oct3/4 was negative in all tumor samples. Tumors frequently showed P53 protein accumulation in 3 10% of cells. The proliferation marker Ki-67 (Mib-1) labeled more than 5% in all tumors with cases with focal labeling indices of more than 30% of cells. Twenty-seven tumors could be assayed for loss of the INI-1 protein. Twenty-five of these cases showed a complete loss of this protein in the tumor cell nuclei while two cases retained INI-1 protein expression. The latter showed otherwise typical histological features and immunophenotype of AT/RT. Age at Diagnosis and Gender Patients presented predominantly during early childhood with a median age at diagnosis of 1.2 years ( years). Children older than the median age at diagnosis (1.2 years) had higher EFS (P ¼ 0.044), and OS (P ¼ 0.002) than younger children (3y-EFS: 21 8% vs. 5 5%, 3y-OS: 37 10% vs. 5 5%) (Fig. 2a). Tumor Localization OS and EFS of 56 patients with CNS AT/RT. Tumor localization was equally distributed to the supratentorial (n ¼ 27) and infratentorial (n ¼ 27) compartments. In two children, the tumor had extended both supra- and infratentorially by the time of diagnosis. Overall survival was higher in patients with supratentorial tumor localization (3y-OS: 38 10%) compared to patients with infratentorial tumor localisation (3y-OS: 5 4%, P ¼ 0.003, Fig. 2b), while EFS was not different (supratentorial vs. infratentorial: 3y EFS 20 8% vs. 4 4%, P ¼ 0.10). Distribution of patients with or without gross total resection was equal between patients with infratentorial and supratentorial localization (Qui-Square P ¼ 0.74). Patients with infratentorial tumor location were younger (median age at Surgery Surgery was performed as the initial treatment in all 56 children. Seven patients received a second surgery subsequent to initial surgery (3) or while on induction chemotherapy (4). Gross total resection was achieved in 18, subtotal in 25, and partial in 13 cases. Four of 18 patients achieved complete resection through second surgery. EFS of patients with gross total resection tended to be higher than of patients with less than total resection (3y- EFS: 19 10% vs. 11 5%, P ¼ 0.057). OS was not different (3y-OS: 25 11% vs. 22 7%, P ¼ 0.214, Fig. 2d). Chemotherapy Chemotherapy was administered in 55 of 56 patients, and given as isolated first postoperative treatment modality in 53 patients, as a combined radiotherapy chemotherapy in one case and in palliative intent following radiotherapy in one case. Response to chemotherapy was assessable in all 54 patients with isolated postoperative chemotherapy or combined radiotherapy chemotherapy. Evaluation of response to chemotherapy in 37 patients with less than total resection was complete remission in 6, partial remission in 2, stable disease in 5 and progressive disease in 24 patients. Seventeen patients with gross total resection showed continuous complete remission in 11 and progressive disease in 6 patients. Thus, 56% (30/54) of patients had tumor progression or relapse on initial postoperative chemotherapy, and 3 of these died during chemotherapy. Conversely, effective disease control to induction chemotherapy was associated with improved survival. Patients with complete remission after induction chemotherapy had a higher OS than patients with less than complete remission (3y-OS: 35 12% vs. 16 7%, P ¼ 0.006, Fig. 3). Of 17 patients who had achieved complete remission after chemotherapy, relapse occurred in 10 and was local in 6, and combined in 3. An isolated distant relapse was reported in one patient. Intraventricular methotrexate was administered to 40 of 54 children (2 unknown). We could not determine the influence of intraventricular therapy since decision for or against intraventricular therapy was not determined at start of therapy and date of first administration was not known in our series.

4 Atypical Teratoid Rhabdoid Tumors of the CNS 981 Fig. 2. OS according to disease presentation: influence of age (a), tumor location (b), presence of metastases (c), extent of resection (d). Radiotherapy Radiotherapy was administered to 29 patients (52%). Age at diagnosis for children who received radiotherapy was higher (2.5 years; range years) than for children who were not irradiated (0.8 years; range years; P < 0.001). Radiotherapy was administered as primary therapy in 15 patients (after chemotherapy, 12; after surgery, 2; combined with postoperative chemotherapy, 1; median age 6.1 years; range ), or after tumor progression or relapse in 14 patients (relapse, 11; progression, 3; median age 2.2 years; range ). Ten of 29 irradiated patients received local radiation therapy only (all without evidence of metastasis). For local therapy a dose range from 44.5 to 59.4 Gy was given (mean 53.1 Gy). In one patient radiosurgery was performed with 16 Gy. In 19 patients craniospinal irradiation was performed (M0, M0/1, 16; M1, 1; M2/3, 2). Dose prescription to the craniospinal axis was Gy, (mean 31.6 Gy) for 18 patients with conventional fractionation. Six of these patients received the HIT 91-protocol with 35.2 Gy/1.6 Gy fractionated dose. Boost doses ranged between: 19.8 and 40.0 Gy (mean 26.3 Gy). In one patient hyperfractionated radiotherapy was given (craniospinal axis 36 Gy, boost 32 Gy). Overall survival after starting radiotherapy was not different between patients who received radiotherapy as primary therapy and patients who were irradiated as salvage therapy for relapse or progression (3y-OS 43 14% vs %; P ¼ 0.314, Fig. 4a). No difference in outcome between patients who received cranio-spinal or local irradiation was observed for overall survival (3y-OS 29 12% vs %; P ¼ 0.578, Fig. 4b). Excluding the three patients with metastatic disease from this analysis does not change the results (CSI, 3y-OS 34 14%, P ¼ 0.861). Multivariable Analysis Age at diagnosis was the only independent prognostic factors for EFS on multivariable analysis. Older age had protective effects (hazard ratio, HR: 0.84 per every increasing year at diagnosis, P ¼ 0.011). Age (HR 0.81, P ¼ 0.020), and presence of metastases (HR 2.32, P ¼ 0.038) were identified as independent prognostic factors for OS (Table I). Frequency of AT/RT Compared to PNET/MB Thirty-five patients with CNS-AT/RT (16 supratentorial, 18 infratentorial, 1 infra- and supratentorial) and 428 children with

5 982 von Hoff et al. Fig. 3. OS (measured from time of rating status, after induction chemotherapy) according to induction therapy induced disease control. CR, complete response. CNS-PNET or Medulloblastoma (PNET/MB) (73 supratentorial, 355 infratentorial) were registered during the 4-year evaluation period between 2000 and The AT/RT to PNET/MB ratio was 1:12.2 for all children, 1:4 for children <4 years, and 1:1.5 for children <1 year. The highest frequencies were recorded for AT/RT below 1 year of age, and between 5 and 9 years for PNET (Table II). DISCUSSION Although substantial progress has been made elucidating the biology of AT/RT [27 30], reports on clinical data and treatment are still limited. The cohort of patients described in this manuscript is based on a pre-existing population-based data registry. Therefore it is a valuable cohort to further describe disease characteristics and prognostic factors. Our results confirm a poor prognosis for patients with AT/RT treated by conventional therapy designed for other disease entities (i.e., medulloblastoma, PNET, and extracranial rhabdoid tumors). Forty-three of 56 (77%) children died of their disease after a median survival time of 1.2 years. Comparable retrospective studies showed similar discouraging results, underlining the strong need to establish prospective treatment protocols for systematic evaluation of potentially more effective treatment strategies [14,15,31]. The necessity for future trials to use defined diagnostic markers including SMARCB1/INI1 immunohistology is unquestionable. However, due to the early recruiting period, INI-1 immunohistology could not be performed in all cases within our cohort. Twenty-five of 27 analyzed patients showed a loss of this protein in tumor cell nuclei, which is in line with the current knowledge that there are single rhabdoid tumors with retained INI-1 protein expression [15,32,33]. Our finding of a very high frequency of AT/RT in early infancy further underlines the necessity to consider and routinely screen Fig. 4. OS (measured from start of radiotherapy) according to radiotherapy indication (a), and extent (b). RT, radiotherapy; CSI, craniospinal irradiation. for AT/RT features in infant patients with embryonal brain tumors, including routine INI-1 staining. We demonstrated an AT/RT to PNET/MB ratio of 1:1.5 for children younger than 1 year. This frequency is higher than previously described [34]. Our data show that AT/RT is mainly a tumor of young age. Median age at diagnosis was 1.2 years in our study, which compares well with published data [1,3,14,15]. This is even more important, as young age has been confirmed to be an important risk factor for EFS and OS in our and other retrospective studies [1,14,15,31]. Most case reports on long-term survivors document older patients [31,35 38]. This negative impact of young age might be in part due to a restrictive use of radiotherapy, but it

6 Atypical Teratoid Rhabdoid Tumors of the CNS 983 TABLE I. Multivariable Analyses Comparison HR 95% CI P EFS Age Continuous OS Age Continuous Metastases M1/2/3 vs. M HR, hazard ratio; CI, confidence interval; P, P-value of the likelihood ratio test. Reference category in bold letters. TABLE II. Number of Children with CNS-AT/RT and PNET/MB Registered from 1/ /2003 <1 y 1 4 y 5 9 y y 15 y 1 : 1.2 (12/14) 1 : 2.5 (4/10) 1 : 10.7 (7/75) 1 : 3 (7/21) (0/141) 1 : 6.7 (3/20) (0/90) 1 : 6 (2/12) (0/35) (0/10) 1 : 1.5 (16/24) 1 : 6.9 (14/96) 1 : 53.7 (3/161) 1 : 51 (2/102) (0/45) 1 : 4.7 (19/89) (0/266) 1 : 2.8 (11/31) 1 : 8.4 (5/42) 1 : 4 (30/120) 1 : 61.6 (5/308) 1 : 12.2 (35/428) Ratios of diagnosed AT/RT to CNS-PNET and Medulloblastoma (PNET/MB) according to age and tumor localization. The relative frequency of AT/RT is highest at young age. No children older than 14 year were diagnosed with AT/RT. infratentorial, supratentorial, combined. is very likely that young age is also associated to a biologically more aggressive behavior. A SMARCB1/INI1 germline mutation and therefore rhabdoid tumor predisposition syndrome has been observed in up to 35% of cases. It is more frequently found in younger children and is associated with more aggressive clinical behavior [39 41]. Except age, no other prognostic disease factor has been reproducibly described so far. In the present study, metastatic disease was an independent negative prognostic factor for overall survival. No patient with disseminated disease was alive 3 years following diagnosis. Frequency of metastases was 21% in our study, which is in line with previous reports [1,3,11,14,15,17,42], while the prognostic impact in other studies varies, possibly reflecting different staging quality and intensity of therapy. Localization of the tumor was evenly distributed among the supra- and infratentorial compartment in our study, which reflects the descriptions in the literature [14,15,43]. In our study infratentorial location was associated with impaired overall survival, which is possibly explained by the younger age of patients with infratentorial location. Less than complete resection was associated with a trend for worse EFS in our study. This is consistent with the literature, where gross total resection is discussed as a positive prognostic factor [13,14]. Our data encourage consideration of second surgical procedure whenever possible. In spite of the heterogeneous treatment regimens applied, our data confirm that a subset of AT/RT is chemosensitive. Furthermore, we found that therapy induced disease control was positive prognostic to further OS. While 35% of patients with CR after chemotherapy survived longer than 3 years, only 16% of patients with residual tumor did so, irrespective of further treatment. This is of special interest, as it suggests that tumor control by postoperative chemotherapy is not only desirable in the cohort of children who are too young for radiotherapy, but is likely also of value for older children. The advent of more dose intense strategies, including intraventricular therapy and high dose chemotherapy, has produced encouraging results [13,14], which however should be balanced against the toxic side effects [11,38]. According to other retrospective data, long-term survivorship is often associated with application of radiotherapy [14,15,44,45], but interpretation is hampered by the fact that patients receiving radiotherapy were often older, and selection for radiotherapy was probably biased by the course of therapy in most cases. There is one retrospective study showing a positive influence of total radiation dose and time to radiation, substantiating the effectivity of radiotherapy in this disease [12]. However, there are reports describing single or small series of infant patients who survived with application of dose intensive chemotherapy only, suggesting that there is a limited subset of patients who can be effectively treated without radiotherapy [13,14,38,46,47]. Also in our series, there is one event-free long-term survivor, who did not receive radiotherapy. Although it is methodologically not possible to evaluate the general impact of radiotherapy on outcome in our cohort, we compared the survival of patients who received radiotherapy either as primary therapy or at relapse/progression. Survival measured from the start of radiotherapy was not different between these two groups, which suggest that delay of radiotherapy might be possible in young children. In addition, we compared the outcome of patients who received craniospinal irradiation with patients who received local radiotherapy. Survival rates after local radiotherapy were not inferior. This is in line with our finding that local involvement was present in 9 of 10 relapses after achievement of complete remission. Local recurrence was also described as the major site of recurrence previously [3,15]. The role of radiotherapy and its timing in the very young children

7 984 von Hoff et al. warrants future research in order to avoid the detrimental effects of irradiation in this age group. Our data show a high frequency of AT/RT in children below 1 year. A subset of patients with favorable clinical risk factors profits from intensive multimodal treatment. Nevertheless the significance of our results is limited by the retrospective nature of this analysis. Prospective studies are needed, and have recently been initiated by different groups. In addition to clinical experiences, increasing knowledge on the pathogenesis of this entity will contribute to improvement of treatment outcomes. ACKNOWLEDGMENT This HIT trial office is supported by German Children s Cancer Foundation (Deutsche Kinderkrebsstiftung). We thank the participating centers for their collaboration, and Wiebke Treulieb and Julia Becker for excellent data management. REFERENCES 1. Rorke LB, Packer RJ, Biegel JA. 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