pediatric cns tumors: current treatment and future directions

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Review 10.1586/14737175.7.8.1029 © 2007 Future Drugs Ltd ISSN 1473-7175 1029 www.future-drugs.com Pediatric CNS tumors: current treatment and future directions Darren R Hargrave and Stergios Zacharoulis Author for correspondence Pediatric Oncology Unit, Royal Marsden Hospital, Downs Road, Sutton, Surrey, SM2 5PT, UK Tel.: +44 208 661 3329 Fax: +44 208 661 3617 [email protected] KEYWORDS: astrocytoma, chemotherapy, child, ependymoma, glioma, infant, medulloblastoma, monoclonal antibody, radiotherapy, tyrosine kinase Pediatric CNS tumors are the most common solid tumor of childhood and are the leading cause of cancer-related death in this age group. Improving prognosis is not the only challenge facing physicians managing these young patients as it is vital to consider the quality of survival. Current management strategies rely on surgery, radiotherapy and conventional cytotoxic chemotherapy, and although ongoing clinical trials continue to refine these treatments, newer approaches are required. This article will discuss current treatment standards for the most common pediatric CNS tumors: astrocytomas (low- and high-grade glioma), ependymoma and primitive neuroectodermal tumors (medulloblastoma), as well as future biological-based novel therapies. Expert Rev. Neurotherapeutics 7(8), 1029–1042 (2007) Tumors of the CNS are the most common malignancy, after leukemia, during childhood, representing 20% of cancers. They are the lead- ing cause of cancer-related death and have the greatest morbidity of any tumor type. CNS tumors perfectly illustrate the dilemma of the pediatric oncologist in seeking to improve sur- vival whilst wishing to avoid or diminish toxicity (both acute and late) [1]. After a rise in incidence during the late 1980s, data from the USA appears to show that rates are stabilizing [2]. Data from over 5000 childhood CNS tumors from 1980 to 1999 was reported by the German Childhood Cancer Registry, with an estimated incidence of 2.6 (2.8 males/2.4 females) per 100,000 children (<15 years) [3]. Other national registry estimates for a similar time period include: 1.7 (Hong Kong), 2.7 (UK), 3.2 (USA) and 4.1 (Sweden). Age stratified incidence was shown as 2.7 (<1 year), 3.1 (1–4 years), 2.7 (5–9 years) and 2.0 (10–14 years) per 100,000 children. With the rapidly increasing knowledge of the molecular biology of the developing CNS and associated tumors, the production of bet- ter and less toxic therapies for children and adolescents with brain and spinal cord tumors is a distinct reality. This review will outline the current optimal therapy for the main CNS tumor types: astrocytomas (low- and high-grade glioma), ependymoma and primitive neuro- ectodermal tumors (medulloblastoma) in child- hood and adolescence and suggest the future direction of therapy, particularly in relation to emerging new agents. Astrocytomas Astrocytomas (the term glioma is often used interchangeably but glioma is not a pathological term) are the most frequent childhood CNS tumor, representing approximately 40–50% of all childhood tumors. They are classified into low-grade (WHO grade I and II) and high- grade (WHO grade III and IV) tumors [4]. The clinical behavior of astrocytomas corresponds to the histological grade, with low-grade tumors being less aggressive and more responsive to treatment than higher, more malignant lesions. Low-grade astrocytomas in children differ from those in adults in that they very rarely undergo malignant transformation. However, in the rare cases where this does occur it appears there are similar genetic changes involved [5]. High-grade astrocytomas are malignant tumors and consist of the grade III astrocytomas (anaplastic astro- cytoma [AA]) and grade IV astrocytomas (glioblastoma [GBM]). Unlike adults, children relatively frequently develop malignant glioma within the brainstem and this is one of the most aggressive tumors seen in childhood. CONTENTS Astrocytomas Ependymomas Primitive neuroectodermal tumors Infants with malignant brain tumors: current status & future directions Expert commentary Five-year view Conflict of interest Key issues References Affiliations For reprint orders, please contact [email protected]

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10.1586/14737175.7.8.1029 © 2007 Future Drugs Ltd ISSN 1473-7175 1029www.future-drugs.com

Pediatric CNS tumors: current treatment and future directionsDarren R Hargrave† and Stergios Zacharoulis

†Author for correspondencePediatric Oncology Unit, Royal Marsden Hospital, Downs Road, Sutton, Surrey,SM2 5PT, UKTel.: +44 208 661 3329Fax: +44 208 661 [email protected]

KEYWORDS: astrocytoma, chemotherapy, child, ependymoma, glioma, infant, medulloblastoma, monoclonal antibody, radiotherapy, tyrosine kinase

Pediatric CNS tumors are the most common solid tumor of childhood and are the leading cause of cancer-related death in this age group. Improving prognosis is not the only challenge facing physicians managing these young patients as it is vital to consider the quality of survival. Current management strategies rely on surgery, radiotherapy and conventional cytotoxic chemotherapy, and although ongoing clinical trials continue to refine these treatments, newer approaches are required. This article will discuss current treatment standards for the most common pediatric CNS tumors: astrocytomas (low- and high-grade glioma), ependymoma and primitive neuroectodermal tumors (medulloblastoma), as well as future biological-based novel therapies.

Expert Rev. Neurotherapeutics 7(8), 1029–1042 (2007)

Tumors of the CNS are the most commonmalignancy, after leukemia, during childhood,representing 20% of cancers. They are the lead-ing cause of cancer-related death and have thegreatest morbidity of any tumor type. CNStumors perfectly illustrate the dilemma of thepediatric oncologist in seeking to improve sur-vival whilst wishing to avoid or diminish toxicity(both acute and late) [1].

After a rise in incidence during the late1980s, data from the USA appears to show thatrates are stabilizing [2]. Data from over 5000childhood CNS tumors from 1980 to 1999was reported by the German Childhood CancerRegistry, with an estimated incidence of 2.6(2.8 males/2.4 females) per 100,000 children(<15 years) [3]. Other national registry estimatesfor a similar time period include: 1.7 (HongKong), 2.7 (UK), 3.2 (USA) and 4.1 (Sweden).Age stratified incidence was shown as 2.7(<1 year), 3.1 (1–4 years), 2.7 (5–9 years) and2.0 (10–14 years) per 100,000 children.

With the rapidly increasing knowledge ofthe molecular biology of the developing CNSand associated tumors, the production of bet-ter and less toxic therapies for children andadolescents with brain and spinal cord tumorsis a distinct reality. This review will outline thecurrent optimal therapy for the main CNStumor types: astrocytomas (low- and high-grade

glioma), ependymoma and primitive neuro-ectodermal tumors (medulloblastoma) in child-hood and adolescence and suggest the futuredirection of therapy, particularly in relation toemerging new agents.

AstrocytomasAstrocytomas (the term glioma is often usedinterchangeably but glioma is not a pathologicalterm) are the most frequent childhood CNStumor, representing approximately 40–50% ofall childhood tumors. They are classified intolow-grade (WHO grade I and II) and high-grade (WHO grade III and IV) tumors [4]. Theclinical behavior of astrocytomas corresponds tothe histological grade, with low-grade tumorsbeing less aggressive and more responsive totreatment than higher, more malignant lesions.Low-grade astrocytomas in children differ fromthose in adults in that they very rarely undergomalignant transformation. However, in the rarecases where this does occur it appears there aresimilar genetic changes involved [5]. High-gradeastrocytomas are malignant tumors and consistof the grade III astrocytomas (anaplastic astro-cytoma [AA]) and grade IV astrocytomas(glioblastoma [GBM]). Unlike adults, childrenrelatively frequently develop malignant gliomawithin the brainstem and this is one of the mostaggressive tumors seen in childhood.

CONTENTS

Astrocytomas

Ependymomas

Primitive neuroectodermal tumors

Infants with malignant brain tumors: current status & future directions

Expert commentary

Five-year view

Conflict of interest

Key issues

References

Affiliations

For reprint orders, please contact [email protected]

Hargrave & Zacharoulis

1030 Expert Rev. Neurotherapeutics 7(8), (2007)

A number of genetic predisposition syndromes can lead toastrocytoma development. The condition neurofibromatosistype 1 (NF-1) is the most common and up to 15% of sufferersdevelop gliomas, usually low grade [6]. Li Fraumeni, a cancerpredisposition syndrome, can lead to astrocytoma formation asa result of the initial germline p53 mutation and subsequentaccumulation of oncogenic abnormalities.

Low-grade gliomaCurrent treatment

For low-grade gliomas (LGGs), surgery is the principal therapeu-tic modality if the tumor can be easily resected without undueneurological deficit. Survival rates of 90% at 10 years are reportedfor those with more than 90% resection [7]. Postsurgery, observa-tion is safe if the child is asymptomatic, with follow-up studiesreporting that approximately 50% of incompletely resectedtumors do not progress over a 5-year period [7]. In midline loca-tions, such as the optic pathway or hypothalamus, it is usually notpossible to completely remove the tumor without significant neu-rological sequelae. The choice of adjuvant therapy depends on theage of the child, location of the tumor and the presence of anypredisposing conditions such as NF-1. In children with NF-1, anobservation strategy may be warranted owing to an indolentcourse in many patients with more than 50% not progressing [8].External-beam radiotherapy is the most effective adjuvant ther-apy, at least in preventing progression, in the majority of cases.Survival rates are reported in excess of 90% for overall survival(OS) and 60–85% progression-free survival (PFS) [9–11]. How-ever, it is often deferred, particularly in young children and thosewith NF-1, owing to possible late side effects such as learning dis-abilities, vasculopathy [12,13], including ‘moyamoya’ syndrome,neuroendocrine deficits [9] and secondary tumor formation [14,15].By reserving radiotherapy for older ages (>10 years) and utilizingstereotactic conformal techniques, it is hoped that long-term sideeffects will be reduced [16,17]. In young children (<10 years) withsporadic tumors and NF-1 children who require treatment,chemotherapy is preferred as the first-line therapy. Historically, itwas believed that chemotherapy would not be effective for theseslow growing tumors. However, the combination of vincristineand carboplatin, first described in the early 1990s, is nowregarded as standard [18]. Various schedules using this combina-tion have demonstrated significant responses (objective and sta-ble disease) of approximately 80–90%; although this does notnecessarily translate into durable PFS, with the USA Children’sCancer Group (CCG) [19] reporting a 68% PFS at 3 years, andthe European Consortium group reporting a 48% PFS at 5-yearsfollow-up [20]. To try and improve PFS the addition of etoposide(European Consortium) and temozolomide (US group) to thestandard vincristine and carboplatin regimen are currently beinginvestigated in respective clinical trials.

Future directions

Although OS is good for LGGs of childhood, approximately50% of patients will have tumor progression requiring furthertherapy. Current options at relapse/progression include further

cytotoxic-based chemotherapy regimens or radiotherapy, both ofwhich carry significant possible side effects. The possibility of atherapy with a low side-effect profile that can be easily adminis-tered over a long period is highly desirable for LGG of child-hood. New treatments that may fulfil these criteria include: low-dose metronomic chemotherapy, specific angiogenesis inhibitorsand targeted tyrosine kinase inhibitors.

So-called metronomic chemotherapy aims to administer lowdoses of cytotoxic chemotherapy over extended periods [21]. It ispostulated that this type of scheduling exploits not only con-ventional cytotoxicity but also has a sustained antiangiogeniceffect. This is thought to occur by several mechanisms includ-ing: induction of the endogenous inhibitor of angiogenesis,thrombospondin 1, and an intrinsic sensitivity of activatedendothelial cells to certain low-dose chemotherapy; this mayalso apply to circulating endothelial progenitor cells [22–25].This leads to inhibition of tumor angiogenesis and vasculo-genesis, leading to a reduction in tumor neovascularization inthe absence of side effects.

Several chemotherapeutics, but not all, are capable of provid-ing this antiangiogenic effect when administered metronomi-cally. For example, vinblastine has been proven to providepotent antiangiogensis in vitro in low doses by inhibiting themicrotubular function of the tumor endothelial cells. Lafay-Cousin et al. reported the results of a pilot study of mono-therapy with weekly vinblastine for LGG in nine children [26].Vinblastine toxicity was moderate and readily manageable.None of the nine patients had disease progression on therapy.MRI evaluation of tumor size from diagnosis to the end of vin-blastine treatment showed one complete response, one partialresponse, five objective effects and two stable diseases.

In a study of 14 children, Chamberlain et al. demonstratedthat low-dose oral etoposide administered over a 21-day cyclewith a 1-week break has activity in recurrent LGGs [27]. Fivepatients had tumor responses, three had disease stabilizationand six had progressive disease. Similarly, temozolomide hasbeen found to provide antiangiogenic effects in vitro in rela-tively low doses [28]. The protracted use of temozolomide(42-day regimen [75 mg/m2 daily] repeated every 56 days)against LGGs has been reported to be active and less toxic thanthe standard 5-day regimen (150–200 mg/m2 daily) repeatedevery 28 days [29,30].

The fact that metronomic chemotherapy regimens appear tohave activity against relapsed LGG suggests that specific inhibi-tors of angiogenesis could be valid agents in childhood LGG.Development of tumor vasculature and especially new bloodvessel formation is essential for tumor growth. The angiogenicprocess is initiated when the dynamic balance between pro-angiogenic factors and angiogenesis inhibitors is disruptedtowards the angiogenic state. One of the most important angio-genic factors is VEGF. Microvessel density and VEGF immu-noreactvity have been found to correlate with prognosis inLGGs [31]. Several other angiogenic factors targeted by drugscurrently in adult Phase I/II trials participate in the LGG biologysuch as basic FGF, matrix metalloproteinases and PDGF [32,33].

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An initial clinical trial of the specific VEGF receptor (VEGFR)inhibitor bevacizumab (Avastin®) is ongoing in pediatric braintumors and Phase I clinical trials of several small moleculeVEGFR inhibitors are currently being planned. These willhave the advantage of oral continuous administration.

The possible combination of low-dose metronomic chemo-therapy with specific angiogenesis inhibitors is an attractive reg-imen for childhood brain tumors, including LGG. Kieran et al.reported the feasibility of such a regimen [34]. During this study20 pediatric patients were treated with continuous oral thalido-mide and celecoxib with alternating oral etoposide and cyclo-phosphamide every 21 days for a planned duration of 6 monthsusing antiangiogenic doses of all four drugs. Therapy was welltolerated in this heavily pretreated population. A total of 16%of patients showed a radiographic partial response. One of theresponders was a patient with optic pathway glioma.

As previously mentioned, PDGF plays a role in angiogenesisand it is known that this family of growth factors (both ligandand receptors) have been found to be expressed in all grades ofglial tumors. In vitro data suggest that the development of auto-crine stimulatory loops is an early event in oncogenic transfor-mation [35–37]. Tumor growth can be inhibited by PDGF recep-tor (PDGFR) kinase inhibition. Imatinib mesylate (Glivec®), apotent PDGF pathway inhibitor, is being evaluated in clinicalstudies in malignant gliomas as a single agent and in combina-tion with other agents with some promising activity [38,39].Imatinib has been reported to have resulted in a marked regres-sion of a pilocytic astrocytoma in a case report and, althoughthe patient’s tumor did not express PDGFR, in a panel of 20other pilocytic astrocytomas tested, PDGFR was detected intumor vasculature, and not in the tumor cells [40]. This suggeststhat perhaps imatinib acts as an angiogenesis inhibitor byblocking PDGF in the vasculature and by other unidentifiedpathways. Again, the possible combination of metronomicchemotherapy in combination with imatinib is currently beingconsidered for study in relapsed LGG.

High-grade gliomaCurrent treatment

High-grade astrocytomas, as in adults, remain a difficult thera-peutic challenge. The standard conventional therapy of surgi-cal resection followed by irradiation only very rarely results insurvival in GBM with a historic 20% survival with AA [41,42].Surgery, unlike in adults, appears to be of prognostic sign-ificance with a benefit of near total resection (>90%) in chil-dren, particularly in AA [43]. This emphasizes the need for spe-cialist pediatric neurosurgical teams who utilize sophisticatedneuroimaging and neuronavigation techniques to assist maxi-mal safe resection. Apart from in infants (<3 years), focalradiotherapy is used as first-line adjuvant therapy. Unlikeadults, the benefit of chemotherapy in pediatric high-gradeglioma was confirmed in the 1980s. The first randomizedPhase III trial for children was undertaken by the CCG ofNorth America [41]. The CCG 943 demonstrated a survivaladvantage for the use of adjuvant chemotherapy with lomustine

(CCNU), vincristine and prednisone, in addition to irradiationcompared with radiotherapy alone (48 vs 18% 5-year PFS).Following this, many cytotoxic agents have been studied in sin-gle agent Phase II trials including: etoposide, cyclophospha-mide, ifosfamide, irinotecan, platinum compounds, procar-bazine and topotecan. These have demonstrated only modestefficacy as monotherapy, and many subsequent studies havelooked at various multiagent combinations with some limitedsuccess often in low-risk patients, for example AAs with a grossmacroscopic resection [44].

The publication of the results of the European Organizationfor Research and Treatment of Cancer (EORTC) randomizedstudy of concomitant temozolomide and radiotherapy inadult GBM patients by Stupp et al. has led to a new standardof care [45]. In this study, patients with newly diagnosed, histo-logically confirmed glioblastoma were randomly assigned toreceive radiotherapy alone or radiotherapy plus continuousdaily temozolomide (75 mg/m2/day from the first to the lastday of radiotherapy), followed by six cycles of adjuvant temo-zolomide (150–200 mg/m2/day for 5 days during each 28-daycycle). A total of 573 patients demonstrated a median survivalof 14.6 months with radiotherapy plus temozolomide and12.1 months with radiotherapy alone. The 2-year survival ratewas 26.5% in the study arm and 10.4% with radiotherapyalone. Of particular interest was the correlative biologicalstudy reported by Hegi et al., which indicated that the key topredicting which patients will gain from temozolomide was agene called MGMT, which is involved in DNA repair, and itsrespective methylation status in the patient’s tumor [46]. If theMGMT promoter is methylated, the MGMT gene is silencedand this means that no MGMT repair enzyme will be pro-duced, thus preventing correction of faults in the DNA. Ofthe 573 patients in the EORTC study, biopsies from 206glioblastoma patients had been tested successfully with 45%having a methylated MGMT promoter. There was a 46% sur-vival rate at 2 years for the 46 patients in the group who had amethylated MGMT promoter (silent MGMT gene) but forthe 60 patients with nonmethylated promoter (active MGMTgene) status the 2-year survival rate was only 13.8%, a statisti-cally highly significant difference. Previous Phase I studiesconducted by the UK Children’s Cancer Study Group(CCSG) and the American CCG had already indicated activ-ity in malignant glioma, but a follow-up UK Phase II study inmalignant glioma (including brainstem glioma [BSG]) usingadjuvant temozolomide at a dose of 200 mg/m2/day for 5 dayswas disappointing with a response rate of only 12% [47–49].Despite this, there has been continued interest in this agentwith both combination studies, for example cisplatin plustemozolomide (European study recently closed to accrual), orin differing schedules, such as concomitant temozolomidewith radiotherapy (i.e., the EORTC regimen). The US Chil-dren’s Oncology Group (COG) group has completed a non-randomized study in pediatric malignant glioma using theEORTC regimen, and preliminary results indicate similar PFSresults in childhood GBM to those in comparable adult

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patients; however, this does not represent a significant advancewhen compared with pediatric historical controls. The resultsof an associated biological study looking at MGMT status andoutcome in children are awaited. Therefore, this schedule hasnow become a standard for malignant glioma in both adultsand children, but with most patients still dying form their dis-ease within 2 years there is much scope for improvement inthese aggressive tumors.

The classical diffuse intrinsic BSG that occurs in childhoodhas a very poor prognosis with a median survival of approxi-mately 9 months [50]. Surgery is not possible other than biopsy(which is not routinely undertaken), with conventional radio-therapy (50–54 Gy in 30 fractions) being the standard treat-ment. This essentially palliative therapy benefits up to 70% ofpatients but does not lead to a durable response in the vastmajority. Extensive investigations of dose, schedule and combi-nation with potential radiosensitizers has shown no additionalbenefit. No chemotherapeutic agent has shown significantactivity in high-grade BSGs [50].

Future directions

The molecular biology of adult malignant astrocytomas areincreasingly being defined, however, whether the same path-ways are involved in childhood and brainstem tumors is still tobe elucidated. The importance of abnormalities of thep53/MDM2/p21 pathway as an early event is well known, asreported in studies of adult high-grade gliomas. In childhood,multi-institutional studies have confirmed that p53 overexpres-sion and mutation correlates independently with an adverseoutcome and appear to vary with age [51,52]. The followinggenetic abnormalities are all important in the tumorogenesis ofadult malignant gliomas: amplification of the EGF receptor(EGFR) and PDGFR, abnormalities of the p16/p15/CDK4/CDK6/RB pathway and deletion of the PTEN gene. The liter-ature suggests significant differences between pediatric andadult groups [53–57], but more work is required. Based on theknowledge of the molecular abnormalities in pediatric high-grade glioma, preclinical evaluation and initial results fromadult clinical trials, a number of novel targeted therapies areeither being studied or will be studied in the near future inchildhood malignant glioma [58].

The EGFR is one such target that is being actively studied.Most GBM in adults express the EGFR. A total of 30–50% ofGBM, mainly de novo GBM, have amplification of the EGFRgene [59–61]. There is a close correlation between EGFR amplifi-cation and EGFR overexpression. Several types of EGFR genemutations have been reported in glioblastomas, with the mostcommon mutant being the truncated EGFRvIII, which can befound in 45% of EGFR-amplified GBM patients and in 8.5%patients without amplification. This mutant variant does notrecognize EGF or TGF, and is constitutively (ligand independ-ently) activated and thus escapes normal regulation. EGFRvIIIenhances cell proliferation through the PI3K/AKT pathway [62].A multivariate analysis demonstrated that EGFR amplificationwas an independent, significant, unfavorable, predictor of OS

in all patients, and EGFRvIII overexpression in the presence ofEGFR amplification was the strongest indicator of a poor sur-vival prognosis [63]. Thus, in patients with GBM, the tumorsnot only demonstrate EGFR amplification, but the mutatedEGFR is often constitutively stimulated as evidenced by thedownstream proteins being activated. EGFR expression hasbeen reported in childhood brain tumors. Compared withmalignant glioma in adults, EGFR gene amplification appearsto occur less frequently in childhood gliomas [64]. Bredel et al.observed elevated immunoreactivity for EGFR in 80% of aseries of 27 pediatric high-grade non-BSGs, only two of thesecases had gene amplification [65]. Moreover, gene-expressionprofiling in 13 childhood astrocytomas identified the over-expression of the EGFR/FKBP12/HIF-2a pathway as animportant promoter of angiogenesis in malignant childhoodhigh-grade gliomas [66]. EGFR was amplified and overexpressedin one of nine grade III and two of seven grade IV diffuselyinfiltrative pediatric BSGs [67].

Two pediatric studies, which included brain tumors, havebeen completed using the small molecule EGFR inhibitorgefitinib (Iressa®) [68]. A US Phase I study in relapsed solidtumors administered gefitinib orally once daily and enrolled25 patients [69]. Dose-limiting toxicity was rash in two patientstreated and elevated transaminases in one patient with a maxi-mum tolerated dose of 400 mg/m2/day. The most frequentnondose-limiting toxicities were grade 1 or 2 dry skin, anemia,diarrhea, nausea and vomiting. Of the four brain tumorpatients in the study, two of the three with BSG exhibited dis-ease stabilization. However, one patient with an ependymomasuffered an intratumoral hemorrhage (ITH) and this led toclosure of the study to further CNS patients. A further USstudy of children with newly diagnosed BSG and incompletelyresected supratentorial malignant gliomas studied gefitinib incombination with radiotherapy [68]. A total of 33 patients wereentered (20 BSG and 13 supratentorial malignant gliomas[STMG]). There were five instances of symptomatic ITHnoted (two BSG and three STMG) and no responses noted. Asubsequent paper suggested that ITH in BSG may be as highas 20% irrespective of treatment modality and, therefore, it isstill unclear if these hemorrhages were related to the studydrug [70]. Further studies of another small molecule EGFRinhibitor, erlotinib (Tarceva®), are ongoing both in Europeand the USA in children with brain tumors. An alternativeway of targeting EGFR is through the use of monoclonal anti-bodies, and a German Phase II study has produced veryencouraging results in BSG using nimotuzumab, a humanizedmonoclonal anti-EGFR antibody [71]. Pediatric patients withrelapsed malignant glioma or BSG received an induction ther-apy including a weekly short infusion of 150 mg/m2 nimotu-zumab for 6 weeks, and a subsequent consolidation therapy offour infusions in a 3-week interval. A total of 34 patients aged5.0–17.4 years (median 10.9 years) were enrolled in this study.According to the Response Evaluation Criteria in SolidTumors (RECIST) criteria, 12 of 34 patients showed response(one partial response and 11 stable disease) with, surprisingly,

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nine of 14 BSG patients having stable disease or response.Eight patients continued with the consolidation therapy, withthree showing a partial response at week 21. No severe sideeffects related to the study medication were observed. APhase III study is now planned. Of course, EGFR can be usedto target delivery of other anticancer therapies, such as boronneutron capture therapy, cytotoxic agents, radioligands andimmunotherapy [72–75].

As previously described, PDGFR is a potential target in allgrades of astrocytoma, and a recently published Phase I study ofimatanib explored its use in relapsed malignant glioma andnewly diagnosed BSG in combination with radiotherapy [76]. Inthe BSG stratum, imatinib was initially administered twice dailyduring irradiation, but because of a possible association withITH was subsequently started 2 weeks after irradiation. Theprotocol was also amended to exclude children with prior hem-orrhage. In total, 16 patients experienced ITH (eight patientswere symptomatic). It was concluded that imatinib mayincrease the risk of ITH, but again the high rate of spontaneoushemorrhage was noted.

Recent results in adult GBM with bevacizumab in combina-tion with irinotecan in relapsed patients have increased theinterest in antiangiogenesis therapy in malignant glioma. Stark-Vance et al. initially reported that, among 21 patients withrecurrent malignant glioma treated with bevacizumab plus iri-notecan, one patient achieved a complete response, eightachieved partial responses and 11 achieved stable disease [77].Overall, the regimen was reported as well tolerated, althoughtwo deaths occurred on treatment, including one patient withan intracranial hemorrhage and one patient with bowel perfora-tion. These impressive results were followed up by a Phase IIstudy, which has recently been published [78]. Patients receivedbevacizumab and irinotecan every 2 weeks of a 6-week cycle.Bevacizumab was administered at 10 mg/kg. Patients not tak-ing enzyme-inducing antiepileptic drugs received 125 mg/m2.A total of 32 patients were assessed (23 with grade IV gliomaand nine with grade III glioma), and radiographic responseswere noted in 63% (20 of 32) of patients (14 of 23 grade IVpatients and six of nine grade III patients). The median PFSwas 23 weeks for all patients. The 6-month PFS probabilitywas 38% and the 6-month OS probability was 72%. No CNShemorrhages occurred, but three patients developed deepvenous thromboses or pulmonary emboli, and one patient hadan arterial ischemic stroke. A possible explanation of theseencouraging results comes from a recent report that suggeststhat cancer stem cells rely on a close interaction with endo-thelial cells in brain tumor models (medulloblastoma and gli-oma) [79]. The possibility that cancer stem cells not only exist asan entity in malignant brain tumors but also need to be tar-geted by therapies has received increasing interest [80,81]. Itappears that cancer stem cells may rely on a perivascular nichemicroenvironment and that antiangiogenic agents such as beva-cizumab can target these stem cells by attacking this niche andpossibly augment responses to conventional therapy by removingthese self-renewing cells.

These impressive results have led to an ongoing US study inrelapsed pediatric malignant glioma. Further evaluations withcombinations including temozolomide are planned. Whetherthe same results can be replicated using small molecule-basedtyrosine kinase inhibitors of VEGFR, such as AZD2171, willbe answered by ongoing studies. Other antiangiogenic agents,such as cilengitide (targets integrins that are responsible forattachment of endothelial cells to the extracellular matrix) andRevlimid® (a potent analogue of thalidomide), are currently inPhase I pediatric brain tumor trials [82].

Further potential targets that are not yet in the clinic buthave demonstrated preclinical efficacy include: targeting thePI3K pathway by direct inhibitors, possibly in combinationwith mTOR inhibitors, or overcoming MGMT-based temo-zolomide resistance by inhibiting base excision repair, forexample PARP-1 inhibitors or methoxyamine [83–93].

EpendymomasCurrent treatmentsEpendymomas usually arise in paraventricular locations. Theyrepresent 8% of all pediatric primary brain tumors and 25% ofall spinal cord tumors. Intracranial ependymomas most fre-quently arise in the first decade of life, with spinal lesions pre-senting later. The majority of ependymomas in the brain occur inthe posterior fossa. There are three WHO grades of ependy-moma: grade I (myxopapillary), grade II (cellular, papillary, clearcell and tancytic) and the malignant grade III anaplastic ependy-moma. The anaplastic phenotype consists of raised mitotic activ-ity, microvascular proliferation and necrosis. A major goal thatremains to be achieved is reduction of the variability betweenneuropathologists in assigning anaplastic grading; the incidencevaries between 7 and 89% with discordance rates of 69%between local and central review [94,95]. Ependymomas tend torecur locally, often many years later. Approximately 10% oftumors disseminate throughout the neuroaxis. Therefore, bothbrain and spinal MRI are mandatory at diagnosis, and cerebro-spinal fluid (CSF) cytology should be obtained after a negativespinal MRI as disseminated disease will need consideration ofcraniospinal therapy. Surgery alone can cure ependymoma ifcomplete in a minority of patients, but adjuvant therapy shouldbe considered according to the age of the child [96]. The mostimportant prognostic factor, from multiple studies, is the extentof surgical resection with a gross total (>90%) resection impartinga better prognosis [95,97]. More aggressive surgical approaches arebeing taken but these come with the possibility of increased mor-bidity (e.g., bulbar palsy requiring tracheostomy/gastrostomy).Second-look surgery after adjuvant chemotherapy/radiotherapyhas emerged as an important concept in ependymoma.

Radiotherapy, except in very young children, is the standardadjuvant therapy after surgery. The 5-year event-free survival(EFS) in completely resected tumors varies between 50 and 70%compared with 0–30% in incompletely resected tumors. Theneed for craniospinal radiotherapy to prevent spinal seeding hasbeen refuted by several studies as local failure is the main reasonfor relapse in nondisseminated cases [98,99]. Recently, the use of

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1034 Expert Rev. Neurotherapeutics 7(8), (2007)

conformal radiotherapy has been shown to achieve high rates ofdisease control in pediatric patients with ependymoma andresults in stable neurocognitive outcomes [100].

The following chemotherapy agents have been studied in Phase IIstudies: aziridinylbenzoquinone, carboplatin, cisplatin, etoposide,idarubicin, ifosfamide, irinotecan, PCNU, temozolomide, thi-otepa and topotecan [101]. These single agent studies in relapsedpatients have shown very modest response rates and there is a con-tinued need to identify anticancer drugs with activity. The abilityto study new agents in chemotherapy naive patients means thatwindow Phase II studies prior to second-look surgery have beenexplored. Multiagent therapy has also been disappointing in olderpatients, with the US CCG study group demonstrating no benefitof CCNU, prednisone and vincristine when added to cranio-spinal radiotherapy with a survival rate of 37% at 10 years [102]. Aregimen alternating vincristine–carboplatin with etoposide–ifosfa-mide after irradiation resulted in an EFS of 74% at 5 years, whichappeared to be improved compared with historical controls [103].No benefit of using high-dose chemotherapy with stem cell rescuehas been shown including busulphan–thiotepa, thiotepa–carbopl-atin–etoposide and cyclophosphamide–melphalan combinations[104,105]. The European and American cancer groups are studyingcombination chemotherapy and its ability to facilitate thefrequency of complete resection by second-look surgery.

Future directionsAgain the knowledge of the molecular biology of ependymomais the key to developing effective novel agents, but progress hasbeen somewhat limited compared with other brain tumors. Thegenetics of ependymomas has been evaluated with chromosomaldeletions on 6q, 17 and 22 and gain of 1q being consistentlyreported, however, the prognostic power of these abnormalitiesis complex [106–109]. The ErbB receptor signaling pathwayappears to correlate with an aggressive phenotype in ependy-moma and as such may be a potential therapeutic target; ongo-ing studies with erlotonib (Europe) and lapatanib (USA) areinvestigating this [110]. Perhaps one of the most interestingdevelopments has been studies suggesting that radial glial cells arecandidate cells of origin for possible ependymoma cancer stemcells [111,112]. If one accepts the cancer stem cell hypothesis, it isobviously essential that new agents target these self-renewingcells otherwise treatment is very likely to fail owing to the abilityto self populate from a very small number of surviving stemcells. Possible ways of targeting these cancer stem cells includeattacking their protected environments (e.g., antiangiogenesis)or ensuring that the pathways that support their aberrant selfrenewal are disabled. One possible target is inhibition of theNOTCH pathway, which has been shown to deplete stem-likecells and block engraftment in embryonal tumor models [113].

Primitive neuroectodermal tumorsCurrent treatmentMedulloblastoma is the most common malignant CNS tumorand accounts for 20% of all childhood brain and spinal cordtumors. These embryonal tumors are now classified as primitive

neuroectodermal tumors (PNET) with the term medulloblast-oma being reserved for PNETs arising in the posterior fossa. Pin-eal region tumors are named pineoblastomas and those in thecerebral hemispheres are termed supratentorial primitive neuro-ectodermal tumors (SPNETs). The incidence of CSF seeding atdiagnosis ranges from 10 to 40%, but the risk is significant andfull MRI of the brain and spine is mandatory along with post-operative citrate synthase cytology. In approximately 5% of cases,dissemination outside of the CNS occurs [114]. As PNETs aremorphologically similar irrespective of location, there was con-siderable debate as to whether medulloblastomas and SPNETsarise from a common cell type. Gene expression profiling datashows a high correlation of several genes encoding transcriptionfactors specific for cerebellar granule cells found in medulloblast-omas but not other CNS PNETs [115]. The WHO classificationrecognizes several distinct subtypes: classical, desmoplastic, largecell anaplastic, medullomyoblastoma and melanotic medullo-blastoma. The large cell anaplastic variant has an adverse progno-sis as confirmed by two large studies, and even in the absence oflarge cell morphology it appears that anaplasia imparts a worseprognosis compared with the classical histological type [116,117].

Treatment starts with surgical resection, which aims to bemaximal but avoiding significant morbidity as studies have con-firmed that in nondisseminated PNET a 90% or more resectionimproves prognosis but this does not have to be complete. Theaddition of craniospinal radiotherapy has been the standardadjuvant therapy for decades. Craniospinal radiotherapy, with adose of 54–55 Gy to the primary tumor and 34–36 Gy to thewhole neuroaxis, has consistently resulted in a 5-year survivalrate of 60–70%. Whole neuroaxis irradiation has been regardedas essential owing to the propensity of PNETs to disseminate,but this leads to the risk of endocrine, growth and cognitive def-icits. Risk factors for late effects include: young age, dose andvolume of radiotherapy. Therefore, much effort has been putinto studying the reduction in the dose of craniospinal radio-therapy in standard-risk tumors and to try and avoid, delay orreduce irradiation in infants.

The role of chemotherapy was initially confirmed in high-risk patients when combined with full dose craniospinal radio-therapy (metastatic disease or large residual local disease)[118,119]. The advantage of chemotherapy in poor or high-risktumors was further documented by a US group using a combi-nation of CCNU, cisplatin and vincristine (the so-calledPacker regime), and the results of a following multi-institu-tional study confirmed these findings with an EFS of 67% at5 years [120]. The European group, the International Society ofPaediatric Oncology, demonstrated with the results of theirrandomized PNET III the benefit of neoadjuvant chemo-therapy when added to radiotherapy for standard-risk (non-metastatic, small or no residual) tumors [121]. The addition offour courses of chemotherapy (including carboplatin, cyclo-phosphamide, etoposide and vincristine) led to a PFS at5 years of 74% compared with 60% in radiotherapy alone.However, it is the Packer regime that has been subsequentlyused in low/standard-risk medulloblastoma in combination

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with reduced dose (23.4 Gy) craniospinal radiotherapy [122]

and is now regarded as standard therapy. The CCG 9892nonrandomized study reported a 5-year EFS of 79%, this is atleast comparable with historical controls using full-dosecraniospinal radiotherapy [123]. Most standard/low-riskmedulloblastoma studies use this regimen along with reduceddose craniospinal radiotherapy. The current US study aims toreduce radiotherapy in standard-risk patients further by inves-tigating in a Phase III randomized study the feasibility ofreducing the dose of craniospinal radiation by 25% (18 Gy),and also decreasing the volume of the tumor boost in childrenaged 3–7 years by intensification of the adjuvant chemo-therapy regimen. In Europe, the recently closed PNET IVstudy investigated the use of differing schedules of radio-therapy in standard-risk medulloblastoma, randomizingbetween reduced-dose conventional once daily craniospinalradiotherapy and a hyperfractionated (twice daily) schedule.In high-risk tumors, the main priority is not reduction of lateeffects as in standard-risk medulloblastoma, but improvementof OS. High-risk PNETs (incompletely resected, metastaticmedulloblastoma and SPNET) have poor survival rates rang-ing between 30 and 50% at 5 years. Using the cisplatin,CCNU and vincristine regimen with full-dose radiotherapyresulted in a 67% 5-year survival. In the PNET III study,preirradiation chemotherapy resulted in a 5-year EFS of 46%,but pineal tumors had a better outcome (76 vs 37%) thannonpineal sites [124]. Current studies are exploring: hyper-fractionated accelerated radiotherapy (HART), high-dosechemotherapy with or without stem cell rescue and concomi-tant chemo-radiotherapy in high-risk PNETs [125]. The com-bination of both intensive chemotherapy and HART hasgiven encouraging preliminary results in an Italian groupstudy, with a 3-year EFS of 78% in metastatic medulloblast-oma. The combination of HART and cisplatin, CCNU andvincristine chemotherapy is the basis of the current UKCCSG high-risk medulloblastoma and SPNET protocols.

Future directionsKnowledge of the molecular biology of PNETs will directfuture therapy in two ways. First, by identifying new potentialtargets for novel agents and, second, by better identifying riskgroups and allowing escalation or reduction of current thera-pies to both improve survival and decrease long-term sideeffects. This knowledge has been helped by studying a numberof genetic predisposition syndromes that can give rise tomedulloblastoma development. The Gorlin (nevoid basal cellcarcinoma) syndrome is characterized by multiple basal cellcarcinomas, jaw cysts, skeletal abnormalities, palmar pits andmental retardation. A minority of sufferers (4%) develop thedesmoplastic type of medulloblastoma, usually during the first3 years of life. This autosomal dominant condition is knownto be due to mutations of the PTCH gene on chromosome9q22.3. The gene product is known to act as a receptor for thesonic hedgehog (SHH) family of proteins, which in turn acton the transcription factor Gli. Germline mutations of other

members of the SHH pathway have been discovered and thesealso predispose to medulloblastoma [126]. Recent preclinicalstudies have shown, in a mouse model of medulloblastoma,the ability of a small molecule inhibitor of the SHH pathway,HhAntag, to block the function of Smoothened in mice withmedulloblastoma and to inhibit SHH [127]. This resulted insuppression of several genes highly expressed in medulloblast-oma, inhibition of cell proliferation, an increase in cell deathand, at the highest dose, complete eradication of tumors.Long-term treatment with HhAntag prolonged medulloblast-oma-free survival. These findings support the development ofSHH antagonists for the treatment of medulloblastoma.

An association with colorectal polyps and primary braintumors, known as Turcot syndrome, can predispose to eitherglioblastoma or medulloblastoma. This is actually two dis-tinct genetic conditions associated with familial adenomatouspolyposis (mutation of the APC gene) and hereditary non-polyposis colorectal carcinoma syndrome (mutation in mis-match repair genes), the latter predisposing to medulloblast-oma, usually in adolescence. Familial adenomatous polyposiscan give rise to glioblastoma during late adolescence. Thegermline mutations of APC in patients with Turcot syn-drome, as well as somatic mutations of APC, β-catenin andaxin in sporadic medulloblastomas, have shown the impor-tance of Wnt signaling in the pathogenesis of medullo-blastoma and its possible identification as a target for treat-ment [128–133]. In addition, nuclear accumulation of theβ-catenin protein, which is associated with activation of theWnt/Wg signaling pathway, appears to be a marker of favora-ble outcome in medulloblastoma [134]. Other molecular mark-ers include: gene amplification of c-MYC (8q24), which hasbeen associated with aggressive disease and a poor outcome,whilst high mRNA expression of the NGF receptor TrkCappears to correlate with a favorable prognosis [135,136]. TheErbB family of tyrosine kinases are important in cerebellardevelopment and high expression of ErbB2 and ErbB4 inmedulloblastoma cells appears to result in a significantlyworse prognosis [137,138]. The possibility of targeting ErbBfamily receptors is being explored in Europe (Tarceva®) andthe USA (lapatanib) using small molecule tyrosine kinaseinhibitors. Further targets have been identified by gene-expression profiling with clusters of genes characterized thatare able to distinguish between good- and poor-outcometumors. One example is the NOTCH pathway and specificinhibitors are being explored in preclinical trials [139].

Infants with malignant brain tumors: current status & future directionsInfants with malignant brain tumors have commanded muchattention over the past few decades owing to their poor OS. Itis not clear whether the biological behavior of malignant braintumors in this age group or the fact that irradiation cannot beused accounts for these differences in prognosis. Craniospinalirradiation in very young children is associated with signifi-cant sequelae including intellectual impairment, growth delay

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and endocrinologic abnormalities. Delay or avoidance of irra-diation has been the main principle on which most of the‘baby brain’ protocols have been formulated for all malignantbrain tumors at this age group. For example, in the early1980s, in the Baby Pediatric Oncology Group (POG) I study,children under the age of 3 years newly diagnosed with malig-nant brain tumors received chemotherapy including twocycles of cyclophopshamide and vincristine followed by a cycleof cisplatin and etoposide. The three-cycle program wasrepeated for 1 year in children between 24 and 36 months andin children less than 24 months of age. At the end of therapymost children received irradiation as prescribed in the study.In this trial, the most common tumors were medulloblasto-mas. A total of 62 children were treated with postoperativechemotherapy and delayed craniospinal irradiation performedafter the age of 3 years. The 5-year PFS was 31% and the5-year OS was 39%. The delay in radiation of 1 or 2 years hadno impact on survival [140].

A total of 46 children aged less than 18 months have beeninvolved in the CCG study of postoperative chemotherapywith an eight drugs in 1 day regimen and proposed delayedirradiation. The 3-year PFS was 22% (30% for those withgross total resection and no metastasis), but most the patientswho had prolonged survivals did not receive irradiation follow-ing completion of chemotherapy [141]. The Baby Brain FrenchSociety for Pediatric Oncology (BB-SFOP) protocol usedalternating cycles of carboplatin and procarbazine, etoposideand cisplatin and vincristine and cyclophosphamide over16 months. No irradiation was given in patients unless theyrelapsed. In case of local progressive or recurrent disease, therecommended salvage treatment was high-dose busulfan andthiotepa with autologous stem cell support, followed by irradi-ation limited to the site of disease at the time of progression.The 5-year survival rates for patients with completely resected,residual tumors and disseminated disease were 73, 41 and13%, respectively [142].

More recently, in a study by Rutkowski et al., young childrenwith medulloblastoma were treated with a regimen includingboth intraventricular and intrathecal methotrexate [143]. The5-year survival rates for patients with completely resectedtumors, residual tumors and disseminated disease were 56, 33and 38%, respectively. The conclusion of these trials was thatconventional chemotherapy alone can be used to cure chil-dren with nonmetastatic medulloblastoma who have grosstotal resection, but is not sufficient for treatment of thosewith metastatic or incompletely resected medulloblastoma.Chi et al. reported the preliminary results of a study usinginduction chemotherapy with an intravenous methotrexateinduction regimen followed by high doses of thiotepa, carbo-platin and etoposide with hematopoietic stem cell rescue;among the 21 patients enrolled, there were 17 completeresponses (81%) [144]. The 3-year EFS and OS were 49 and60%, respectively. Similar high-dose chemotherapy strategiesare currently being investigated for young children withdisseminated medulloblastoma.

Ependymomas represent the second most common braintumor in young children and metastatic disease is rare. A totalof 48 children less than 3 years with intracranial ependy-momas entered the Baby POG I study. The 31 patients whowere less than 24 months at diagnosis received 2 years ofchemotherapy followed by irradiation, whereas the 17 patientsaged 24–36 months received chemotherapy for 1 year beforeirradiation. Unlike children with medulloblastomas, in whomfailures occurred early, children with ependymomas developprogressive disease over several years. The 5-year PFS and OSrates were 25 and 40.5%, respectively, for the whole popula-tion. Furthermore, there was a significant difference in PFSaccording to the age at diagnosis, as 5-year PFS was 12.7% forchildren less than 24 months who had received 2 years ofchemotherapy, and 54.8% in the 24–36-month-old patientswho received only 1 year of chemotherapy before radiotherapy.It was concluded that delaying irradiation adversely affectedsurvival [140]. Subsequent studies using chemotherapy to avoidor delay irradiation did not significantly improve the outcomeof young infants with ependymoma. The 3-year PFS of the15 infants with malignant ependymomas who received theeight drugs in 1-day regimen according to the CCG protocolwas 22% [141]. A total of 23 children were included in the ini-tial report of the BB-SFOP protocol to receive the 16-monthpostoperative chemotherapy without irradiation. In the eventof relapse or progression, salvage treatment consisted of a sec-ond surgical procedure followed by local irradiation with orwithout second-line chemotherapy. The 4-year PFS and OSrates were 22 and 59%, respectively. A total of 23% of patientswere still alive at 4 years without the use of irradiation duringthis study [145]. High-dose chemotherapy with hematopoieticstem cell rescue have failed to provide outcome benefits ininfants with ependymoma [105,146].

As discussed previously, preliminary data by Merchant et al.supported the use of conformal irradiation in young childrenwith ependymoma [100]. A total of 88 children (median age:2.85 years [15 were <8 months]) received 54–53 Gy to thegross tumor volume and a margin of 10 mm. The 3-year PFSwas 74.7%. The cumulative incidence of local failure at3 years was 14.8%, and the early neurocognitive assessment ofthese children did not reveal any deterioration. Currently, theuse of conformal irradiation in very young children is beinginvestigated by the COG.

Unlike ependymomas and medulloblastomas, high-gradegliomas in very young children have slightly better outcomecompared with older children and adults. A total of 18 high-grade glioma children entered the Baby POG I protocol (sixwith glioblastomas multiforme, nine with unclassified malig-nant gliomas and three with AAs). Of the 18 children, 13 wereyounger than 12 months at diagnosis. PFS and OS rates at5 years were 43 and 50%, respectively. No failures occurredafter 2 years and four patients among the survivors havereceived no irradiation [140]. Dufour et al. reported similarfindings using the BB-SFOP protocol with a total of 21patients treated. Median age at diagnosis was 23 months [147].

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Histology was classified as grade III in 13 and grade IV in eightpatients. Of the 13 children with a residual tumor, chemotherapyinduced two partial responses, one minor response and one stabledisease with no recurrent disease. The 5-year PFS was 35% and5-year OS was 59%, with a median follow-up of 5.2 years.

In summary, it appears that the different histopathologicmalignant tumors have a different course and prognosis ininfants compared with older children, possibly due to differencesin the intrinsic biology. As we move into the future, specificinfant protocols for each tumor type are being developed that arebased on a combination of clinical and molecular risk stratifica-tion. International collaboration will be required to gain suffi-cient patient numbers to study these rare subgroups of tumors.Whilst new conformal radiotherapy techniques, which avoidsevere late effects and dose intensive high-dose chemotherapystrategies, are currently being studied, new targeted therapiesbased on the knowledge of the unique biology of infant tumorsneed to be developed.

Expert commentaryThe challenges for pediatric neuro-oncology are twofold: toimprove the survival of patients with aggressive tumor types,such as malignant glioma, high-risk PNET and recurrentependymoma, and to decrease the treatment-related toxicity inthose patients with tumors with a good prognosis (i.e., LGGand standard-risk medulloblastoma). This can be achieved intwo ways: first, by improving the current use of standard treat-ment modalities by the use of state of the art neurosurgical andradiation techniques, and by better prognostication and stratifi-cation of treatment regimens by the introduction of molecularbiology classifiers; and, second, by the development of newmolecular-targeted therapies that may provide alternatives toconventional cytotoxic-based chemotherapy.

However, a note of caution should be given in that early evi-dence would suggest that molecular-based therapies are notwithout significant acute toxicity, for example, ITH and pulmo-nitis are associated with the use of EGFR inhibitors, and hemo-rrhage, thrombosis and gastric perforation with VEGFR inhibi-tors. Plus, the pathways that may be targeted are physiologicallyimportant and often involved in development, for example theangiogenesis pathway is involved in bone growth, and theNOTCH and Wnt pathway in embryonal development. There-fore, care must be taken to design studies that will detect possi-ble sequelae related to the inhibition of these physiological func-tions, particularly if used in a chronic setting and eventually inyoung patients with a possible long-term survival.

Pharmaceutical firms now have large research and develop-ment pipelines of small molecule inhibitors and monoclonalantibodies, many of which represent possible theoretical targetsfor pediatric brain tumors. However, the vast majority of thesedrugs have been developed for the most common adult cancers,such as breast, colorectal and lung cancer. Specific pediatric tar-gets are not a high priority for most pharmaceutical companiesowing to the rarity of these tumors, but it is essential that theseare not ignored. How to select and prioritize these agents for

study in pediatric tumors is increasingly important. For this rea-son, robust science should underpin the identification and vali-dation of possible molecular targets and the use of preclinicalmodels needs to be optimized. Clinical trial designs will need toaccount for the fact that many novel agents are not cytotoxicbut cytostatic and, if used as monotherapies, monitoring oftumor regression by conventional imaging will not recognizeactivity. Therefore, the inclusion of pharmacodynamic endpoints, both direct, such as tumor biopsy, and surrogate, forexample functional imaging or blood-based biomarkers, areessential in assessing these novel therapies.

Five-year viewInitially, the challenges are as already mentioned: the optimiza-tion of current treatment regimens and the identification, vali-dation and early clinical testing of the various novel therapies. Itis likely that, in the near future, Phase III trials in medullo-blastoma will use a combination of clinical, pathological andmolecular classifiers to stratify patients to risk groups enablingthe strategic reduction or escalation of treatment for childrenwith this tumor. Increasingly conformal, stereotactic radiother-apy is employed to reduce the late effects of irradiation on thedeveloping brain and will become standard. More and morenovel therapies for the treatment of pediatric brain tumors areand will be studied in the next 2–3 years, both in the preclinicalsetting and in Phase I/II trials.

However, over the next 5 years the difficulty of how to incor-porate these different classes of molecular-targeted therapiesinto front-line therapies will be an increasing challenge. Thepossibility of combining biological modifiers and not onlyimproving existing therapies, such as radiotherapy and chemo-therapy, exist, but undesirable interactions could occur. There-fore, preclinical models need to be used to try and addressissues such as scheduling of combinations and the study of pos-sible additive, synergistic and antagonistic effects at an earlystage. This particularly applies to the possible targeting of mul-tiple pathways, which may be required to achieve significanttumor control, but could also lead to increased toxicity in nor-mal cells. It is essential to try and ensure a therapeutic indexbetween the effects on cancer cells and normal tissue by attack-ing differentially expressed targets. This therapeutic index mustbe established as early as possible, ideally in the preclinicalphase, to improve both the success rate of detecting effectivetolerable new agents and avoid unnecessary costs, both finan-cially and, more importantly, to patients. Another challengeover the next 5 years will be how to assess the cost–effectivenessof novel expensive therapies that demonstrate patient benefit inthe setting of limited healthcare spending.

The next 5 years appears to be promising for pediatric braintumors and a new era of biologically driven and increasinglyindividualized cancer therapy is becoming a distinct possibility.

Conflict of interestDr Hargrave has worked as a consultant for both Schering-Plough and Genentech.

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1038 Expert Rev. Neurotherapeutics 7(8), (2007)

Key issues

• Pediatric CNS tumors are the most common solid tumor of childhood and a major cause of cancer-related death.

• A critical balance between survival and morbidity from late effects has to be made in each individual case.

• Significant progress has already been made in the management of low-grade astocytomas, localized ependymomas and medulloblastoma.

• Survival rates for malignant gliomas and high-risk primitive neuroectodermal tumors (PNETs) remain disappointing and new strategies are needed.

• CNS tumors occurring in infants and young children require different treatment strategies to avoid unacceptable late effects such as growth, neurocognitive and neuroendocrine deficits.

• Future directions for astrocytomas include: optimizing current chemotherapy and radiotherapy strategies in low-grade lesions and exploring novel biologically targeted therapies in malignant astrocytomas.

• For PNETs the development of combined clinical, pathological and molecular risk stratification will allow the de-escalation of treatment in very low-risk tumors and identification of very high-risk tumors where novel therapeutic strategies can be applied in first-line therapy.

• For ependymomas, which are usually localized, the results of modern conformal-based radiotherapy has been very encouraging, both in terms of survival and late effects even at young ages.

• The future for pediatric CNS tumors will be based on using the knowledge of the molecular biology of these tumors to design individualized treatment protocols and develop new targeted therapies.

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Affiliations

• Darren R Hargrave, MB ChB, MRCP, FRCPCH

Consultant Pediatric Oncologist in Drug Development, Pediatric Oncology Unit, Royal Marsden Hospital, Downs Road, Sutton, Surrey, SM2 5PT, UKTel.: +44 208 661 3329Fax: +44 208 661 [email protected]

• Stergios Zacharoulis, MD

Consultant Pediatric Oncologist, Pediatric Oncology Unit, Royal Marsden Hospital, Downs Road, Sutton, Surrey, SM2 5PT, UKTel.: +44 208 661 3329Fax: +44 208 661 [email protected]