Key Words. Infants Brain tumors Chemotherapy Radiation therapy

Transcription

1 The Oncologist The Oncologist CME Program is located online at To take the CME activity related to this article, you must be a registered user. Pediatric Oncology Current Treatment Approaches for Infants with Malignant Central Nervous System Tumors LUCIE LAFAY-COUSIN,DOUGLAS STROTHER Alberta Children s Hospital and Departments of Oncology and Pediatrics, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada Key Words. Infants Brain tumors Chemotherapy Radiation therapy Disclosures Lucie Lafay-Cousin: None; Douglas Strother: None. Section editors Susan M. Blaney and Ross Pinkerton have disclosed no financial relationships relevant to the content of this article. The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. LEARNING OBJECTIVES 1. Evaluate the challenges of identifying very young children with brain tumors so that they can be enrolled in clinical trials. 2. Identify prognostic factors for children with certain brain tumors and assess the influence of these factors on current therapeutic strategies. 3. Outline factors affecting survival and neurocognitive outcome of children with malignant brain tumors. CME This article is available for continuing medical education credit at CME.TheOncologist.com. ABSTRACT The management of brain tumors in very young children remains a challenge for neuro-oncologists in large part because of the greater vulnerability of the developing brain to treatment-related toxicity. Nearly three decades of infant brain tumor clinical trials have led to significant progress in the delineation of prognostic factors and improvements in outcome. Innovative strategies that employ high-dose chemotherapy, intrathecal chemotherapy, modified focal irradiation, or combinations of these have been used to delay or avoid the use of conventional craniospinal irradiation in order to minimize the risk for deleterious neurocognitive impairment in survivors. However, it is difficult to evaluate the impact of such approaches on intellectual and functional outcome, and results to date are limited. This review covers the most recent therapeutic advances for the most common histological subtypes of malignant infant brain tumors: medulloblastoma, supratentorial primitive neuroectodermal tumor, ependymoma, atypical teratoid rhabdoid tumor, choroid plexus carcinoma, and high-grade glioma. Survival and neurocognitive outcome are emphasized. The Oncologist 2009;14: Correspondence: Lucie Lafay-Cousin, M.D., M.Sc., Alberta Children s Hospital, Pediatric Oncology, 2888 Shaganappi Trail NW, Calgary, Alberta, T3B 6A8, Canada. Telephone: ; Fax: ; lucie.lafay-cousin@albertahealthservice.ca or luciecou@hotmail.com Received August 27, 2008; accepted for publication February 16, 2009; first published online in The Oncologist Express on April 2, AlphaMed Press /2009/$30.00/0 doi: /theoncologist The Oncologist 2009;14:

2 434 Malignant CNS Tumors in Infancy INTRODUCTION Young children with brain tumors constitute a very challenging group of patients in many aspects. They typically have a poorer outcome than older children with the same diagnoses [1, 2]. In the past, less aggressive attempts to cure infants may have explained this difference. However, the intrinsic biology of infant tumors may differ from that of their counterparts in older children. For example, histologic variants of medulloblastoma (MB) and certain molecular characteristics of that disease occur with greater frequency in infants [3, 4]. High-grade glioma (HGG) in infants might have a different biological profile from similar tumors in older children that helps explain the higher rates of cure [5]. These data suggest that brain tumors in infants may not be the same disease as in later childhood. Aside from possible differences in tumor biology, the inherent high susceptibility of developing brains in very young children to treatment-induced neurotoxicity creates a major treatment challenge [6, 7]. Although surgery, perioperative conditions, and chemotherapy may each have an impact on neurocognitive outcome, the use of conventional craniospinal irradiation (CSI) in very young children is known to be most strongly associated with significant adverse late effects that include growth impairment, endocrine deficits, and, most importantly, deleterious neurocognitive effects [6 12]. These late effects have driven efforts to defer, or omit entirely, the use of traditional cranial or craniospinal radiation therapy and to the use of innovative chemotherapy and modified radiation. Although 25% 30% of brain tumors occur in children 36 months of age [13, 14], the absolute number of patients affected is low. This has made collaborative studies essential for improving our understanding of the behavior of brain tumors and the effects of treatment, and to then adjust our treatment strategies for affected children. These new treatment approaches have aimed simultaneously at improving the chances of survival and diminishing the risks of poor intellectual outcome. Through the conduct over nearly three decades of clinical trials focused on brain tumors in infants, significant progress has been made in understanding tumor behavior, in the delineation of prognostic factors, and in increasing survival rates. Even so, chances of survival are still lower for infants than for older children. Furthermore, evaluations of the impact of new therapeutic strategies on intellectual development, essential for the validation of these new approaches, remain limited. This review outlines the recent therapeutic advances in the most frequent malignant infant brain tumors: MB, supratentorial primitive neuroectodermal tumor (spnet), ependymoma (EP), atypical teratoid rhabdoid tumor (ATRT), choroid plexus carcinoma (CPC), and HGG. We describe the current status of survival and neurocognitive outcomes that should help in the design of the next generation of infant brain tumor protocols. Because of the dynamic nature of infant neuro-oncology, some of the references contain data presented only in abstract form. The results reflect emerging data, but they must be confirmed through larger studies and in-depth analyses. DEFINING AN INFANT POPULATION Literally, the term infant refers to a child up to 24 months of age that has not yet acquired speech. Throughout pediatric neuro-oncology literature, however, the term infant refers to populations of children not consistently defined by age or skill acquisition, but to children who are at higher risk for significant neurocognitive impairment related to conventional radiation therapy. The age cutoff for infants was initially set at 36 months based on existing knowledge of brain tumor maturation [15]. As adverse late effects of therapy were more widely recognized over the ensuing years, the definition of infant for inclusion on baby brain clinical trials was extended up to 5 and even 10 years of age [16, 17]. Though the inclusion of children from such a broad range of ages is well-intentioned, the results of these studies are more difficult to interpret because of the dynamic nature of brain maturation in the first several years of life. EPIDEMIOLOGY Following a step-like increase in the number of new cases of central nervous system (CNS) tumors in the mid 1980s that was explained by better detection, reporting, or both, the current incidence rate of CNS tumors in children has stabilized [18]. From U.S. Surveillance, Epidemiology, and End Results data covering 1990 to 1995, the incidences of all CNS tumors per 100,000 boys and girls 15 years of age were 3.27 and 2.68, respectively [19]. A similar incidence of 2.99 cases per 100,000 children between birth and 14 years of age was reported by the European Automated Childhood Cancer Information System project [14]. An increase of 1.7% per year in the incidence rate was noted from 1978 to Thirty-six percent of this large cohort of patients was 5 years of age. More recently, Keene et al. [20] reported results of a population-based Canadian study. Between 1990 and 2005, 579 children 36 months of age were diagnosed with a brain tumor, yielding a mean yearly incidence rate of 3.21 per 100,000 children 3 years of age. Thirty percent of cases were astrocytoma, 16% MB, 12.6% EP, 4.4% spnet, and 4.6% ATRT. This distribution of

3 Lafay-Cousin, Strother 435 brain tumor types was in general agreement with previous reports of that age group [21, 22]. TUMOR LOCATION AND TIME TO PRESENTATION Brain tumors in infants tend to localize more frequently in the supratentorial compartment, especially in the first year of life. Infratentorial tumors become more common by approximately 36 months of age but then, at the end of the second decade of life, supratentorial tumors again predominate. Halperin et al. [23] reported a median duration of presenting symptoms of 4 weeks in children 3 years of age with MB; in older children, the corresponding figure was 8 weeks. A higher rate of high-stage disease was found in patients 36 months of age compared with those aged 36 months (47% versus 36%, respectively). These data suggested an inverse correlation between high-stage disease and duration of symptoms. Young children with aggressive MB are more likely to be diagnosed earlier than older children despite their inability to verbalize symptoms. However, these findings might not be applied to other tumor types. For example, in a series of infants with EP, Comi et al. [24] described a duration of symptoms of days in children aged 0 23 months, whereas infants 24 months old were diagnosed at a median time of 34 days. HISTORICAL BACKGROUND Before the introduction of chemotherapy for infant brain tumors, only 20% of children were estimated to survive [2, 25]. The reluctance to use conventional craniospinal radiation, effective in older children, contributed to this poor outcome but also led to alternative strategies wherein chemotherapy was used to delay radiation. The landmark experience of Van Eys et al. [26], later updated by Ater et al. [27], was the first to demonstrate long-term survival in a small cohort of patients with MB and EP without the use of radiation therapy. Based on these promising results, the Pediatric Oncology Group (POG) conducted the first multicenter trial of primary adjuvant chemotherapy for children 36 months old diagnosed with malignant brain tumors. The duration of chemotherapy was based on age, and radiation therapy was deferred until the age of 3 years [28]. Chemotherapy sensitivity of malignant CNS tumors was demonstrated, and 5-year progression-free survival (PFS) and overall survival (OS) rates of 30% 4.9% and 39.4% 3.9%, respectively, were achieved [5]. The highest rates of progressive disease or relapse were observed in the first 6 months of chemotherapy. An unintended result of the study that resulted from parental refusal of radiation therapy was the observation again that some infants with malignant CNS tumors could be cured without the use of radiation therapy. A similar approach of prolonged chemotherapy was undertaken at the same time by the Children s Cancer Group (CCG), but with a different chemotherapy combination called 8 in 1 [29, 30]. Objective response rates of 28% were seen in patients with MB and EP. Both studies of chemotherapy resulted in higher survival rates than seen historically with surgery alone. In the second generation of baby brain protocols led in North America, the effect of dose-intensified chemotherapy was studied. No significant survival advantages were demonstrated with this approach. In the CCG 9921 study, however, radiation therapy was only used in cases of tumor progression or relapse. OS was similar to previous studies, but, remarkably, 58% of patients alive 5 years after study entry had not received radiation therapy [31]. The effort to achieve cure without radiation therapy was strengthened. Subsequently, several clinical trial consortia investigated the possibility of avoiding radiation therapy altogether. Prolonged postoperative conventionally dosed chemotherapy was studied by the French Society of Pediatric Oncology (SFOP), the Australian and New Zealand Children s Cancer Study Group, and the Children s Oncology Group (COG, formed through the merger of POG and CCG). In these trials, different combinations and schedules of chemotherapy were used, but radiation therapy was reserved only for children with progressive disease or with persistent residual disease [31 33]. The German Society of Pediatric Oncology and Hematology (GPOH) used a new strategy in their HIT-SKK protocol of systemic high-dose methotrexate and intraventricular methotrexate to replace radiation [34]. The Head Start approach to treatment, pioneered by Finlay et al., used myeloablative chemotherapy with autologous stem cell rescue to replace radiation therapy [35]. At the other end of the therapeutic spectrum, some investigators maintained radiation therapy as primary treatment of infant brain tumors, but modified the dose or field in order to diminish neurotoxicity [36, 37]. The results of these various approaches have been published in the last decade (Table 1). Although most of the trials were designed for young children with all types of malignant tumors, results have differed according to diagnoses, implicitly suggesting that all infant brain tumors are not the same and announcing the need for tumor-specific approaches. The concept of risk-based strategy has also emerged from these results. Despite limited numbers of patients, upcoming studies are now designed for specific tumors, risk groups, or both. The following sections highlight, by tumor type, the results of recent important clinical trials.

4 436 Malignant CNS Tumors in Infancy Table 1. Results of multicenter trials for infant medulloblastoma Study n CT RT Baby POG1 [28] CCG 9921 [31] BB SFOP [32] HIT-SKK92 [34] Head Start I and II [45] Head Start II [17] 62 Conventional Delayed adjuvant CSI 92 Conventional Delayed adjuvant for residual disease or salvage MB MB is the most common malignant brain tumor in infants and best demonstrates the substantial gains made in the delineation and application of prognostic factors to treatment approaches [21]. The extent of initial tumor resection is a key prognostic and risk stratification factor for older children with MB [38]. For infants, the data are inconsistent. In the first baby-pog study, the 5-year OS rate was 66% for patients whose tumors were gross totally resected, compared with 32% for those whose tumors were less than completely resected [28]. Gross total resection (GTR) did not reach significance in the contemporary CCG study, or did so only for the subset of patients with nonmetastatic disease [31, 33, 39]. MB presents with disseminated disease in 28% 55% of infants, rates which are higher than those in older children [8, 23, 38]. Metastatic status in young children by itself has not consistently been found to be of significant prognostic value [8, 28, 31]. More recent studies, however, have combined metastatic status and extent of tumor resection and described significant differences in survival. In the SFOP study, 79 patients received postoperative chemotherapy, irrespective of the extent of resection [32]. Radiation was not part of the initial therapy but was restricted to use at the time of progression or relapse as part of salvage therapy. Based on early imaging, three groups with significantly different 5-Yr EFS/PFS ( SE) 5-Yr OS ( SE) 31.8% ( 8.3%) 39.7 % ( 6.9%) 32% ( 5%) 43% ( 5%) 79 Conventional Salvage R0M0, 29%; R1M0, 6%; M, 13% 43 Conventional with HD MTX intraventricular MTX 21 M0 Induction CT (HDC&SCR) 1 21 M Induction CT with HD MTX (HDC&SCR) 1 None 58% ( 9%); R0M0, 82% ( 9%); R1M0, 50% ( 13%); M, 33% ( 14%) R0M0, 73%; R1M0, 41%; M, 13% 66% ( 7%); R0M0, 93% ( 6%); R1M0, 56% ( 14%); M, 38% ( 15%) Salvage 52% ( 11%) 70% ( 10%) 6 yrs old or residual disease 49% a 60% a P9934 [37] 78 M0 Conventional Early adjuvant 58% ( 6%) a 66% ( 6%) a focal a At 3 years. Abbreviations: BB, baby brain; CCG, Children s Cancer Group; CSI, craniospinal irradiation; CT, chemotherapy; EFS, event-free survival; HD MTX, high-dose methotrexate; HDC&SCR, high-dose chemotherapy and stem cell rescue; M, metastatic; OS, overall survival; PFS, progression-free survival; POG, Pediatric Oncology Group; R0M0, complete resection, nonmetastatic; R1M0, residual disease, nonmetastatic; SE, standard error; SFOP, French Society of Pediatric Oncology. outcomes were defined based on resection (defined by postoperative imaging and surgical report) and metastases: R0M0 (no residual disease, no metastasis), R1M0 (radiological residual disease alone), and RXM (presence of metastasis). The 5-year PFS rates were 29%, 6%, and 13% in these three subgroups, respectively. With salvage therapy that used high-dose chemotherapy and stem cell rescue followed by focal radiation, the 5-year OS rates were, respectively, 73%, 41%, and 13%. The risk for relapse in the R1M0 and RXM groups was significantly higher than that for the R0M0 patients (p.024). Though the number of patients in each subset was relatively low, this strategy identified prognostic groups and allowed the avoidance of radiation in one third of the R0M0 patients. For those 13 nonirradiated children who underwent neuropsychological evaluation, the mean IQ was preserved at 91 when measured at a mean of 23 months after diagnosis. Although the salvage therapy was ineffective for patients who presented with metastatic disease, it did cure half of the patients with nonmetastatic disease whose disease later progressed or relapsed. In the salvaged patients, however, the mean IQ was only 72 at a mean time of 62 months after initial diagnosis. In the German HIT-SKK study of infants with malignant CNS tumors, patients received postoperative chemotherapy that included systemic high-dose methotrexate (5 g/m 2 ) and repeated intraventricular injections of methotrex-

5 Lafay-Cousin, Strother ate (36 doses of 2 mg each). Treatment was ended if patients were in complete remission after 6 months of chemotherapy. In that study, 43 patients were infants 36 months of age with MB. They were categorized in three groups after initial operation: those with complete resection of disease and no metastases, those with residual disease without macroscopic metastases, and those with macroscopic metastatic disease (M2 and M3) regardless of initial tumor resection. The three groups had PFS (OS) rates of 82% (93%), 50% (56%), and 33% (38%), respectively [34]. The results of that study are the best reported to date for infants with nonmetastatic MB and are even more remarkable for two reasons: the duration of chemotherapy was considerably shorter than in historical series and the treatment included significant doses of methotrexate, a known neurotoxic agent [40 42]. Nineteen of 23 assessable HIT-SKK patients had magnetic resonance imaging evidence of leukoencephalopathy without clinically evident symptoms. The neurocognitive performance of these children was significantly lower than that of a control group of healthy children, but significantly higher than that of children in earlier trials who had received radiation therapy [34]. There was also a trend toward a higher performance status in children who received only systemic methotrexate as compared with children who received both systemic and intraventricular methotrexate. This treatment approach and its neurocognitive sequelae need to be studied in higher numbers of patients. Another finding of the HIT-SKK study was the prognostic significance of desmoplastic histology. The 5-year PFS rate for the 20 patients with desmoplastic MB was 85% ( 8%), compared with 34% ( 10%) in the 23 patients with classical MB histology [34]. A recent international metaanalysis of 270 children 5 years of age with MB confirmed desmoplastic histology as a strong independent prognostic factor for patients with either localized or metastatic tumors [43]. However, throughout the literature, the frequency of desmoplastic MB varies up to a high of 46%, suggesting a need for robust and common criteria for the definition of desmoplasia [32, 34, 44 46]. The Head Start regimens used multiple cycles of induction chemotherapy, second operations for resection of residual disease, and consolidation high-dose chemotherapy followed by autologous stem cell rescue. Radiation therapy was reserved for recurrent disease. In these studies, the 5-year OS rate for all patients 3 years of age with MB was 52% ( 11%), and 71% of the survivors of nonmetastatic disease were not irradiated [45]. A limitation to this approach was the high toxic mortality rate of 19%. In Head Start II, patients with metastatic MB received the chemotherapy regimen of Head Start I augmented with high-dose methotrexate. CSI at a dose of 23.4 Gy was used for children 6 years old and for those with evidence of residual disease at completion of induction treatment. Twenty-one patients 10 years of age with metastatic MB were enrolled [17]. Of these, 16 were 5 years old at diagnosis. Eightyone percent of the patients achieved a complete response to therapy. The 3-year event-free survival (EFS) and OS rates were 49% and 60%, respectively. Ten of the 16 patients 5 years of age were alive at the time of reporting, and six of these (four of whom were 3 years old) were never irradiated. The toxic mortality rate in this study was only 5.4%. Although the age group was wider than in other infant studies, the survival rate may be one of the highest for high-risk patients. Again, the combined use of methotrexate and radiation therapy, albeit in a limited number of patients, raises the concern of neurocognitive development in surviving patients [47]. Neuropsychological data from this cohort are not yet available. Based on the promising results of the Head Start approach, the COG has initiated a trial for infants with metastatic MB that randomizes patients to induction chemotherapy with or without high-dose methotrexate, followed by tandem courses of high-dose chemotherapy with autologous stem cell rescue. Given the deleterious effect of conventional CSI on the developing brain of very young children but its proven efficacy to control MB, some investigators have explored the benefit of reduced-dose CSI in this vulnerable population. Goldwein et al. [36, 48] reported their single-institution experience of chemotherapy plus 18 Gy CSI, with a posterior fossa boost to 50.4 Gy, in 10 children 5 years of age with nonmetastatic MB. The actuarial survival rate after 6 years was 70% ( 20%), with sustained IQ scores in the normal range on longitudinal assessments. More recently, Dufour et al. [49] reported their preliminary results of a pilot study of five sequential courses of high-dose chemotherapy and stem cell rescue followed by age-adapted CSI, using doses in the range of Gy in a cohort of 34 patients 7 years of age with metastatic MB. The OS rate at 30 months was 50%, with substantial but manageable toxicity. Longer follow-up is warranted to assess the long-term quality of life and neurocognitive function of the survivors. Based on the hypothesis that focal radiation as used in the SFOP approach to salvage therapy contributed to local control of MB [50, 51], a phase III study (P9934) for infants with nonmetastatic MB was recently completed by the COG [37]. Patients in this study received 4 months of preradiation standard-dose multiagent chemotherapy and were then to undergo a second attempt at resection of residual disease. They were treated with conformal radiation therapy to the posterior fossa followed by an additional 8 months of chemotherapy. The study, which closed in 2006, accrued 78 patients. Preliminary analyses show 3-year EFS

6 438 Malignant CNS Tumors in Infancy and OS rates of 58% ( 6%) and 77% ( 6%), respectively, for the patients whose tumors were completely resected at diagnosis. Patterns of recurrence appeared to be related to the timing of radiation therapy. Six of the eight patients whose disease progressed prior to radiation did so with involvement of the primary site only. In all the 18 patients whose tumors progressed after the administration of focal radiation, none had recurrence in the areas that received at least 12 Gy of radiation. These observations are preliminary but provocative. Should they be confirmed in later analyses, there may be rationale to study the inclusion of relatively lower doses of CSI in MB treatment schedules. The P9934 study also included a functional evaluation of the patients via a telephone-based parent interview (the Functional Independence Measure for Children [WeeFIM]), a developmental questionnaire (Ages and Stages Questionnaire [ASQ]), and formal neuropsychological testing [52]. Compliance with the telephone-based interview was 100%; this rate compared very favorably with the 46% compliance rate for formal neuropsychological testing at 2 years. The results of the WeeFIM and ASQ were reported to closely mirror the result of conventional neuropsychological assessment. This result provides support for further assessment of a new method of evaluating the longterm impact of treatment on function of survivors and for filling the enormous void in long-term follow-up data on survivors of MB during infancy. Future Directions Results of studies from around the world highlight several points: the outcome of therapy is influenced by the degree of initial tumor resection and by the presence or absence of metastatic disease, some infants with MB can be cured without radiation therapy, and radiation therapy restricted to the posterior fossa may improve local disease control without causing the negative impact on neurocognitive function that has been associated with CSI. The studies are limited individually by low numbers of patients enrolled and collectively by inconsistencies in the patients ages. No one strategy can yet be considered definitively superior for nonmetastatic MB when considering both survival and neurocognitive preservation. To overcome these limitations, the COG, SFOP, GPOH, and United Kingdom Children s Cancer Study Group (UKCCSG) are collaborating on the development of a clinical trial for infants with nonmetastatic MB that will study the impacts of desmoplastic histology, high-dose chemotherapy, and intraventricular methotrexate on survival and neurocognitive outcome. Given the poorer prognosis for patients with either nonmetastatic, classic histology MB or metastatic MB, treatment intensification through the use of high-dose chemotherapy with stem cell rescue, with or without focal radiation or reduced-dose CSI, is being explored. In these patients, achievement of the simultaneous goals of higher survival rates and acceptable neurocognitive function in survivors will be extremely challenging. Preservation of intellectual and functional outcome has been the prime motivation for infant brain strategies since the 1980s. Regrettably, meaningful long-term follow-up data from these studies are missing. International cooperative efforts will require prior consensus on common and realistic methods for evaluating the neurocognitive and functional status of survivors. To be successful and to overcome linguistic and cultural barriers, these tests will need to be simple, sensitive, and reproducible [46]. Once survival rates have been consistently raised, the quality of neurocognitive and overall function of survivors might become the primary objective of future studies. Finally, the recent identification of molecular markers such as Trk-C, c-myc mrna, and -catenin in archived MB samples offers the potential to use biologic factors to refine disease risk and treatment stratification of infants with MB [53 56]. The next generation of infant MB protocols should include molecular biology components to provide prospective age-based validation of these factors and to uncover currently unknown markers of disease behavior that might be targeted in future treatment approaches. SPNET spnets are a heterogeneous group of highly malignant neoplasms comprising 3% 5% of all pediatric brain tumors [57]. In clinical trials for infants with CNS tumors, however, patients with spnets comprise up to 16% of those enrolled [31]. Although spnets are histologically indistinguishable from infratentorial MB, there is growing evidence that spnets have a distinct molecular profile from MB [58]. The prognosis of spnet patients has been worse than in MB patients despite identical therapies [59, 60]. spnets are typically separated into two groups: cerebral and pineal PNETs. In older children, pineal PNET, or pineoblastoma, carries a better prognosis than cerebral PNET. This does not appear to be true for infants [61 63]. Young children with spnets treated with chemotherapy alone fare very poorly, with a median time to progression of 6 months. In the SFOP study, the 2-year PFS rate was only 4%, whereas in the CCG study, the 4-year PFS rate was 16% [16, 31, 64]. Despite the belief that infant spnets may be less responsive to chemotherapy than spnets in older children, the use of high-dose chemotherapy with peripheral stem cell support has generated encouraging results. In the Head Start studies, the 5-year EFS and OS rates for 43 patients were, respectively, 39% and 49% [65]. Radiation

7 Lafay-Cousin, Strother 439 therapy was avoided in 60% of the survivors, however. Although radiotherapy is clearly part of the treatment strategy in older children with spnets, it appears a less acceptable option in younger children given the location, the usually large size of these tumors, and, therefore, the expected deleterious effects of even focal radiation of 54 Gy [66]. Even so, tumor control may be superior when radiation therapy is used. From the German HIT-SKK87 and HIT-SKK92 experiences, Timmerman et al. [67] reported a 3-year PFS rate of 24.1% in children who received radiation, compared with only 6.7% for those who did not. Based on their results, they argued that omission of radiation jeopardized survival and suggested that radiation be delayed for a maximum of 6 months, even in very young children. Whether the modest gain in survival is justified by the expected neurocognitive function in survivors is debatable. However, the interpretation of these data is limited by the low number of patients treated and the absence of analysis by intent-totreat. Any meaningful conclusion for a survival advantage, including an analysis of the quality of survival, achieved through the use of radiation would need to be demonstrated in a larger study [68]. EP EP is the third most common pediatric CNS tumor. Approximately 50% occur before the age of 5 years [69]. In the younger age group, an infratentorial location is more common. Extent of resection is the most important prognostic factor for localized EP and local disease control is the biggest therapeutic challenge [70, 71]. Despite recent neurosurgical advances, the achievement of a GTR of tumor remains a significant surgical challenge, because of the usual extension of infratentorial tumor to the cerebellarpontine angle and adherence to the brainstem. The effectiveness of using chemotherapy to treat EP remains a matter of controversy. Direct evaluation of the response of EP to several chemotherapy agents has failed to demonstrate significant chemosensitivity [72]. However, given the redundant concern of radiation-related neurotoxicity in young children, several trials of postoperative chemotherapy have been undertaken with different aims. Within the cohort of the first POG trial for infants were 48 children with EP [28]. Nearly half of the 25 evaluable patients showed a partial or complete response to two courses of cyclophosphamide and vincristine. The 5-year PFS rate was 27% ( 8.2%) [71]. Conclusions of the study emphasized the importance of maximal surgical resection and a delay in radiation therapy of 1 year from diagnosis. In contrast to the POG experience, no patients in the SFOP study of adjuvant chemotherapy for children 5 years of age with EP had a 50% decrease in the size of their tumors following chemotherapy [73]. The 4-year PFS and OS rates in this study were 22% and 59%, respectively, and the radiation-free survival rate was 23%. Results similar to these were observed in the CCG 9921 study (5-year EFS rate of 32% 6%) and in the German HIT-SKK87 and HIT- SKK92 studies (3-year PFS rate, 27.3%) [31, 74]. The use of high-dose chemotherapy with stem cell rescue in the Head Start trials, promising for patients with MB, produced disappointing results (5-year EFS rate of 12%) [75]. Collectively, the benefit of chemotherapy, either at standard or high doses, could not be clearly defined from these studies. The results of the UKCCSG/International Society of Pediatric Oncology (SIOP) study reported by Grundy et al. [76] provide a provocative contrast to these experiences. In that trial, primary postoperative chemotherapy included high-dose methotrexate, and radiation therapy was prescribed only for recurrent or progressive disease. Tumor response to chemotherapy was not reported. For patients with nonmetastatic disease, the 5-year OS rate was 63.4%. Fifty (62%) of the 80 patients with nonmetastatic disease ultimately had progressive disease. Of these, 34 received radiation, for a cumulative rate of freedom from radiation therapy of 42%. Based on their results, the authors suggested that chemotherapy had an important role in the management of infants with EP. The authors acknowledged, however, that for children 18 months of age, the balance of burden associated with treatment probably shifted to conformal radiation [77]. Given the limited benefit of chemotherapy for infants with EP, investigators at St. Jude Children s Research Hospital developed a conformal radiation therapy (CRT)-based strategy for children aged 12 months with EP [78, 79]. Children received CRT to the tumor bed at a dose of 59.4 Gy; those 18 months of age were treated with 54 Gy. The 3-year PFS rate for the 48 children 3 years of age was 69.5% ( 8.6%). Neurocognitive function was evaluated before and after treatment with CRT. Younger children had significantly lower IQs at the initiation of CRT than older children (89 versus 98) but showed improvement over time to within normal ranges. To date, this approach is associated with the best of both survival and short-term neurocognitive outcome. The COG recently completed a study of CRT for children aged 1 year with EP that was based on these data. For those children whose tumors were incompletely resected at diagnosis, adjuvant chemotherapy was studied for its potential to facilitate complete tumor resection in a second operation. Results of this and future studies may help to clarify the role of chemotherapy in the treatment of EP. Results of recently completed studies will shape those of the future. If chemotherapy is found to facilitate complete resection of tumor in a second operation, then studies

8 440 Malignant CNS Tumors in Infancy will examine different combinations of therapy with the hope of finding one that is maximally effective and minimally toxic. Further modifications of radiation therapy or postradiation chemotherapy may be studied as well. Finally, biologic data might identify potential targets for new agents in patients with recurrent or unresectable disease. ATRT Intracranial ATRT is a rare and relatively new entity, first described in the late 1980s [80, 81]. Cytogenetic abnormalities at chromosome 22q11, involving the tumor suppressor gene INI1/hSNF5, can be detected in up to 75% 80% of ATRTs [82, 83]. Before the increased recognition of this distinct tumor entity and prior to the wide availability of immunohistochemical staining for INI1, these tumors were often misdiagnosed as PNETs, MB, or choroid plexus lesions. The true incidence of CNS ATRT is not well known, but approximately 200 cases have been reported in the literature to date [84, 85]. CNS ATRT is a tumor of early childhood, with nearly two thirds of cases diagnosed before the age of 3 years [86]. Sixty percent occur in the posterior fossa. These tumors behave aggressively and carry a dismal prognosis. The optimal therapy for children with ATRT is not presently known. Data are primarily in the form of case reports, limited institutional series, the unique CNS ATRT registry, and the recently published Head Start experience [86 91]. GTR of tumor appears to be the one potentially significant prognostic factor in these published data [87, 92]. The ability to resect disease is influenced by the tumor s tendency to be quite large and invasive at presentation. CNS ATRT is a chemotherapy-sensitive tumor, in particular to platinum and alkylators [86, 93]. Adjuvant chemotherapy has been proposed to facilitate second-look surgery to achieve GTR [94]. Overall, however, conventionally dosed chemotherapy has failed to raise the chance of survival to an acceptable level. These poor results have led to the use of more intensive chemotherapy regimens and to the study of intrathecal therapy. Based on case reports and a small pilot study following the Intergroup Rhabdomyosarcoma III protocol [89, 90, 95], a multi-institutional phase II study (Dana Farber Cancer Institute ) of multiagent intrathecal and systemic chemotherapy with age- and risk-adapted radiation was recently reported by Chi et al. [96]. Chemotherapy response was seen in 62% of 22 treated patients. Seventeen patients received radiation therapy, delivered conformally in 12 patients. The 2-year EFS and OS rates were, respectively, 48% 13% and 67% 10%. The median OS duration had not been reached. The GHOP recently reported their preliminary results of a pilot study that used systemic anthracycline-based chemotherapy, intraventricular chemotherapy, and focal radiation in 19 patients [97]. The survival rate was 79%, with a median survival time of 50 months (range, 38 63). Compared with historic series, high rates of survival were achieved with these approaches, though associated toxicities were not fully appreciable given the short follow-up. As a method to potentially avoid radiation therapy in children with ATRT, a possible role for systemic high-dose methotrexate has been suggested in very limited data from Head Start II: three patients were alive and radiation free at 42, 54, and 67 months from diagnosis [88]. As for all infants with malignant brain tumors, the use of radiotherapy in young children with ATRT remains controversial [85]. From institutional and registry data, one can infer higher rates of disease control and survival associated with the use of radiation. In these reports, however, radiation therapy is much more likely to be given to children 3 years of age [86, 87]. These data and those from the National Cancer Institute ATRT workshop are the basis for the recommendation that involved-field radiation be included in ATRT therapy [93]. The COG has just opened a trial for children of all ages with ATRT. In that study, maximum surgical resection will be attempted, followed by induction chemotherapy that includes high-dose methotrexate. Focal radiation therapy will be employed either before or after three courses of high-dose chemotherapy and autologous stem cell rescue, depending on patient age and disease status at diagnosis. Because the study does not randomize therapy, it will not be able to compare treatment with and without radiation. Nonetheless, as it will be the first study of this scope dedicated to ATRT, it is hoped that the prescribed therapy will result in rates of survival higher than those historically reported and that hypotheses will be generated for future ATRT studies. Comprehensive and longitudinal neurocognitive and systemic evaluations will be crucial to assess the long-term effects of this strategy, especially for children with supratentorial ATRT. CHOROID PLEXUS TUMORS Choroid plexus tumors (CPTs) are collectively represented by CPC, choroid plexus papilloma (CPP), and an intermediate variant known as atypical plexus papilloma. They are very rare neoplasms, representing 1% of all pediatric CNS tumors. CPCs account for 20% 40% of CPTs and nearly three quarters present in patients 24 months of age [98 101]. Unlike CPPs, which are usually curable with complete surgical resection, CPCs carry a poor prognosis. The role of surgery has been well described and GTR is a key prognostic factor for survival in CPC, whether achieved immediately at diagnosis or through subsequent operation [99, 102]. In a review of 75 cases of pediatric CPC, Fitzpatrick et al. [103] reported a survival rate of 84% for patients with a GTR, compared with 18% for patients

9 Lafay-Cousin, Strother 441 with subtotal resection. Aggressive resection may be very challenging because of the invasive nature and extreme vascularity of CPCs. In order to achieve a GTR, some authors have suggested a staged approach through the use of neoadjuvant chemotherapy following biopsy of disease [98, 101]. For those patients whose tumors are completely resected at diagnosis, the role of adjuvant chemotherapy, radiation therapy, or both remains controversial [100, ]. What does seem clear is a role for adjuvant therapy following subtotal resection; the best modality, chemotherapy or radiation, is not known [103, 106]. The ongoing SIOP 2000 protocol for patients with CPT is a prospective registry and randomized study for children and adults with CPT. The treatment contains maximal surgical resection, and for those with CPC, postoperative chemotherapy and delayed radiation for patients 3 years old. The study aims to compare response rates, survival, and tumor resectability after chemotherapy randomized to carboplatin or cyclophosphamide backbones. Measurement of neurocognitive function is not built into the study. It is known that several factors can contribute to impaired function, including overproduction of cerebrospinal fluid, chronic hydrocephalus, and surgery for the tumor and its complications [ ]. In this context, cumulative neurotoxicity from the addition of adjuvant radiation must be carefully weighed, given the absence of strong evidence of benefit from this modality. An important result of the SIOP 2000 study thus far is demonstration that international collaboration on therapy for a rare tumor is feasible; this may serve as a model for collaboration in other rare tumors. HGG HGGs occur rarely in very young children [111]. They have been reported to bear a more favorable prognosis in infants than in older children despite the lack of radiation used in treatment. OS rates in prospective studies are in the range of 50% 66% [30, ]. As is true with older children, these results need to be interpreted in light of the welldescribed discordance among neuropathologists when diagnosing HGG. In the CCG 945 experience, 40% of the children 6 years of age with HGG had consensus panel review diagnoses other than HGG [115, 116]. The usual review diagnosis was low-grade glioma. Similarly, in the SFOP infant brain tumor studies, wherein postoperative conventional chemotherapy resulted in a 5-year OS rate of 59%, the proportion of children with oligodendroglial tumors, anaplastic and not, was unusually high on central pathology review [112]. In a recently published small series from St. Jude Children s Research Hospital of patients 3 years of age with HGG, the 5-year OS rate was 66.3% [114]. These cases underwent histologic review, and 14 of 16 patients had either anaplastic astrocytoma or glioblastoma multiforme; none of the patients had oligodendroglial tumors. Compared with the French study, the survival rate was similar despite a different balance in histologic diagnoses. In both studies, the use of focal radiation therapy was suggested to be beneficial for control of nonmetastatic recurrent disease. In the St. Jude report, the neurocognitive function of survivors was generally low. Tumor location, degree of resection, and field of radiation therapy all appeared to contribute to intellectual compromise. CONCLUSION Since the initiation in the 1980s of clinical trials for infants with malignant CNS tumors, substantial progress has been made toward improving survival rates, particularly for infants with MB. Parallel progress in preserving long-term neurocognitive function is less evident. A better understanding of the diseases and the identification of prognostic factors have supported the development of risk-based treatment approaches. The use of high-dose chemotherapy and autologous stem cell rescue shows potential for further increasing survival rates. The concurrent use of focal or craniospinal radiation, even at lower than historical doses, may contribute to disease control, but may also contribute to cumulative adverse neurotoxicity. Given the limited number of infants affected with any single diagnosis, an evaluation of these approaches, gains in survival rates, and improvements in quality of life for survivors will only be possible through international collaboration. Assessing neurocognitive and functional outcomes remains a challenge amplified by the need for international consensus on the format of evaluation. These should constitute the ambition of the next generation of therapeutic trials. AUTHOR CONTRIBUTIONS Manuscript writing: Lucie Lafay-Cousin, Douglas Strother Final approval of manuscript: Lucie Lafay-Cousin, Douglas Strother REFERENCES 1 Magnani C, Aareleid T, Viscomi S et al. Variation in survival of children with central nervous system (CNS) malignancies diagnosed in Europe between 1978 and 1992: The EUROCARE study. Eur J Cancer 2001;37: Duffner PK, Cohen ME, Myers MH et al. Survival of children with brain tumors: SEER Program, Neurology 1986;36: Herms JW, Behnke J, Bergmann M et al. Potential prognostic value of C-erbB-2 expression in medulloblastomas in very young children. J Pediatr Hematol Oncol 1997;19: Pan E, Pellarin M, Holmes E et al. Isochromosome 17q is a negative prognostic factor in poor-risk childhood medulloblastoma patients. Clin Cancer Res 2005;11:

10 442 Malignant CNS Tumors in Infancy 5 Duffner PK, Horowitz ME, Krischer JP et al. The treatment of malignant brain tumors in infants and very young children: An update of the Pediatric Oncology Group experience. Neuro Oncol 1999;1: Suc E, Kalifa C, Brauner R et al. Brain tumours under the age of three. The price of survival. A retrospective study of 20 long-term survivors. Acta Neurochir (Wien) 1990;106: Fouladi M, Gilger E, Kocak M et al. Intellectual and functional outcome of children 3 years old or younger who have CNS malignancies. J Clin Oncol 2005;23: Walter AW, Mulhern RK, Gajjar A et al. Survival and neurodevelopmental outcome of young children with medulloblastoma at St Jude Children s Research Hospital. J Clin Oncol 1999;17: Kiltie AE, Lashford LS, Gattamaneni HR. Survival and late effects in medulloblastoma patients treated with craniospinal irradiation under three years old. Med Pediatr Oncol 1997;28: Packer RJ, Gurney JG, Punyko JA et al. Long-term neurologic and neurosensory sequelae in adult survivors of a childhood brain tumor: Childhood cancer survivor study. J Clin Oncol 2003;21: Copeland DR, demoor C, Moore BD 3rd et al. Neurocognitive development of children after a cerebellar tumor in infancy: A longitudinal study. J Clin Oncol 1999;17: Duffner PK, Cohen ME, Voorhess ML et al. Long-term effects of cranial irradiation on endocrine function in children with brain tumors. A prospective study. Cancer 1985;56: Rickert CH, Paulus W. Epidemiology of central nervous system tumors in childhood and adolescence based on the new WHO classification. Childs Nerv Syst 2001;17: Peris-Bonet R, Martínez-García C, Lacour B et al. Childhood central nervous system tumours incidence and survival in Europe ( ): Report from Automated Childhood Cancer Information System project. Eur J Cancer 2006;42: Dobbing J, Sands J. Quantitative growth and development of human brain. Arch Dis Child 1973;48: Marec-Berard P, Jouvet A, Thiesse P et al. Supratentorial embryonal tumors in children under 5 years of age: An SFOP study of treatment with postoperative chemotherapy alone. Med Pediatr Oncol 2002;38: Chi SN, Gardner SL, Levy AS 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: Smith MA, Freidlin B, Ries LA et al. Trends in reported incidence of primary malignant brain tumors in children in the United States. J Natl Cancer Inst 1998;90: Gurney JG, Smith MA, Bunin GR. CNS and miscellaneous intracranial and intraspinal neoplasms. In: Ries L, Smith MA, Gurney JG et al., eds. Cancer Incidence and Survival Among Children and Adolescents: United States SEER Program Bethesda, MD: National Cancer Institute, 1999: Keene D, Lafay-Cousin L, Carret AS et al. The Canadian Pediatric Brain Tumor Consortium national survey of CNS tumors in children under 3 years of age [abstract]. Neuro Oncol 2008;10: Rickert CH. Epidemiological features of brain tumors in the first 3 years of life. Childs Nerv Syst 1998;14: Tomita T, McLone DG. Brain tumors during the first twenty-four months of life. Neurosurgery 1985;17: Halperin EC, Watson DM, George SL. Duration of symptoms prior to diagnosis is related inversely to presenting disease stage in children with medulloblastoma. Cancer 2001;91: Comi AM, Backstrom JW, Burger PC et al. Clinical and neuroradiologic findings in infants with intracranial ependymomas. Pediatric Oncology Group. Pediatr Neurol 1998;18: Kellie SJ. Chemotherapy of central nervous system tumours in infants. Childs Nerv Syst 1999;15: van Eys J, Cangir A, Coody D et al. MOPP regimen as primary chemotherapy for brain tumors in infants. J Neurooncol, 1985;3: Ater JL, van Eys J, Woo SY et al. MOPP chemotherapy without irradiation as primary postsurgical therapy for brain tumors in infants and young children. J Neurooncol 1997;32: Duffner PK, Horowitz ME, Krischer JP et al. Postoperative chemotherapy and delayed radiation in children less than three years of age with malignant brain tumors. N Engl J Med 1993;328: Geyer JR, Zeltzer PM, Boyett JM 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 Children s Cancer Group. J Clin Oncol 1994;12: Geyer JR, Finlay JL, Boyett JM et al. Survival of infants with malignant astrocytomas. A Report from the Children s Cancer Group. Cancer 1995; 75: Geyer JR, Sposto R, Jennings M et al. Multiagent chemotherapy and deferred radiotherapy in infants with malignant brain tumors: A report from the Children s Cancer Group. J Clin Oncol 2005;23: Grill J, Sainte-Rose C, Jouvet A et al. Treatment of medulloblastoma with postoperative chemotherapy alone: An SFOP prospective trial in young children. Lancet Oncol 2005;6: White L, Kellie S, Gray E et al. Postoperative chemotherapy in children less than 4 years of age with malignant brain tumors: Promising initial response to a VETOPEC-based regimen. A Study of the Australian and New Zealand Children s Cancer Study Group (ANZCCSG). J Pediatr Hematol Oncol 1998;20: Rutkowski S, Bode U, Deinlein F et al. Treatment of early childhood medulloblastoma by postoperative chemotherapy alone. N Engl J Med 2005; 352: Mason WP, Grovas A, Halpern S et al. Intensive chemotherapy and bone marrow rescue for young children with newly diagnosed malignant brain tumors. J Clin Oncol 1998;16: Goldwein JW, Radcliffe J, Johnson J et al. Updated results of a pilot study of low dose craniospinal irradiation plus chemotherapy for children under five with cerebellar primitive neuroectodermal tumors (medulloblastoma). Int J Radiat Oncol Biol Phys 1996;34: Ashley D, Merchant T, Zhou T et al. P9934: Systemic chemotherapy, second-look surgery and conformal radiation therapy limited to the posterior fossa and primary site for children 8 months and 3 years with nonmetastatic medulloblastoma: A Children s Oncology Group phase III study [abstract]. Neuro Oncol 2008;10: Zeltzer PM, Boyett JM, Finlay JL et al. Metastasis stage, adjuvant treatment, and residual tumor are prognostic factors for medulloblastoma in children: Conclusions from the Children s Cancer Group 921 randomized phase III study. J Clin Oncol 1999;17: Geyer R, Levy M, Berger MS et al. Infants with medulloblastoma: A single institution review of survival. Neurosurgery 1991;29: ; discussion Riva D, Giorgi C, Nichelli F et al. Intrathecal methotrexate affects cognitive function in children with medulloblastoma. Neurology 2002;59:48 53.