Hypofractionation vs Conventional Radiation Therapy for Newly Diagnosed Diffuse Intrinsic Pontine Glioma: A Matched-Cohort Analysis

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1 Iteratioal Joural of Radiatio Ocology biology physics Cliical Ivestigatio: Cetral Nervous System Tumor Hypofractioatio vs Covetioal Radiatio Therapy for Newly Diagosed Diffuse Itrisic Potie Glioma: A Matched-Cohort Aalysis Geert O. Jasses, MD,* Marc H. Jase, MD, { Selmer J. Lauwers, BSc,* Peter J. Nowak, PhD,** Foppe R. Oldeburger, MD, yy Eric Bouffet, MD, zz Frak Sara, MD, xx Kari Kamphuis-va Ulze, MD, y Erik J. va Lidert, PhD, z Jolada H. Schievig, MD, x Tom Boterberg, PhD, kk Gertja J. Kaspers, PhD, { Paul N. Spa, PhD,* Johaes H. Kaaders, PhD,* Corrie E. Giddig, PhD, k ad Darre Hargrave, MD {{ Departmets of *Radiatio Ocology, y Radiology, z Neurosurgery, x Neurology, ad k Pediatric Ocology, Radboud Uiversity Nijmege Medical Cetre, Nijmege; { Pediatric Ocology/Hematology, VU Uiversity Medical Ceter, Amsterdam; **Departmet of Radiatio Ocology, Erasmus Medical Cetre, Rotterdam; yy Departmet of Radiatio Ocology, Academic Medical Cetre, Amsterdam, The Netherlads; zz Departmet of Hematology/Ocology, The Hospital for Sick Childre, Uiversity of Toroto, Toroto, Caada; xx Departmet of Pediatric Ocology, The Royal Marsde NHS Foudatio Trust, Sutto, UK; kk Departmet of Radiatio Ocology, Ghet Uiversity Hospital, Ghet, Belgium; ad {{ Departmet of Ocology, Great Ormod Street Hospital, Lodo, UK Received Feb 1, 2012, ad i revised form Mar 16, Accepted for publicatio Apr 5, 2012 Summary Despite covetioal radiatio therapy (30 fractios i 6 weeks), most childre with diffuse itrisic potie glioma will die withi 1 year after diagosis. To reduce patiet burde, we ivestigated the role of hypofractioatio radiatio therapy (13 or 16 fractios i 3 to 4 weeks). A 1:1 matched-cohort aalysis demostrates a similar Purpose: Despite covetioal radiatio therapy, 54 Gy i sigle doses of 1.8 Gy (54/1.8 Gy) over 6 weeks, most childre with diffuse itrisic potie glioma (DIPG) will die withi 1 year after diagosis. To reduce patiet burde, we ivestigated the role of hypofractioatio radiatio therapy give over 3 to 4 weeks. A 1:1 matched-cohort aalysis with covetioal radiatio therapy was performed to assess respose ad survival. Methods ad Materials: Twety-seve childre, aged 3 to 14, were treated accordig to 1 of 2 hypofractioatio regimes over 3 to 4 weeks (39/3 Gy, Z16 or 44.8/2.8 Gy, Z11). All patiets had symptoms for 3 moths, 2 sigs of the eurologic triad (craial erve deficit, ataxia, log tract sigs), ad characteristic features of DIPG o magetic resoace imagig. Twety-seve patiets fulfillig the same diagostic criteria ad receivig at least 50/1.8 to 2.0 Gy were eligible for the matched-cohort aalysis. Results: With hypofractioatio radiatio therapy, the overall survival at 6, 9, ad 12 moths was 74%, 44%, ad 22%, respectively. Progressio-free survival at 3, 6, ad 9 moths was 77%, 43%, ad 12%, respectively. Temporary discotiuatio of steroids was observed i 21 of 27 (78%) patiets. No sigificat differece i media overall survival (9.0 vs 9.4 moths; Reprit requests to: Geert O. Jasses, MD, Radboud Uiversity Nijmege Medical Cetre, Departmet of Radiatio Ocology, Postbox 9101, 6500 HB Nijmege, The Netherlads. Tel: (þ31) ; Fax: (þ31) ; g.jasses@rther.umc.l The results of this study are preseted at the 15th Iteratioal Symposium of Pediatric Neuro-Ocology (ISPNO), Toroto, Jue 24-27, Coflict of iterest: oe. It J Radiatio Ocol Biol Phys, Vol. 85, No. 2, pp. 315e320, /$ - see frot matter Ó 2013 Elsevier Ic. All rights reserved. doi: /j.ijrobp

2 316 Jasses et al. Iteratioal Joural of Radiatio Ocology Biology Physics overall survival rate with a hypofractioatio regime compared with a covetioal radiatio therapy regime. Outside cliical trials, this low-burde regime could be cosidered as a alterative to protracted regimes. PZ.84) ad time to progressio (5.0 vs 7.6 moths; PZ.24) was observed betwee hypofractioatio vs covetioal radiatio therapy, respectively. Coclusios: For patiets with ewly diagosed DIPG, a hypofractioatio regime, give over 3 to 4 weeks, offers equal overall survival with less treatmet burde compared with a covetioal regime of 6 weeks. Ó 2013 Elsevier Ic. Itroductio Despite exhaustive cliical research to improve outcome, survival i childre ad adolescets with diffuse itrisic potie glioma (DIPG) has remaied uchaged over the past 3 decades (1). For a patiet with ewly diagosed DIPG, the curret stadard treatmet cosists of covetioally fractioated exteral beam radiatio therapy up to a dose of 54 Gy i 30 fractios of 1.8 Gy over 6 weeks (1, 2). This usually results i a trasitory improvemet of eurologic sigs ad symptoms; however, most patiets will die withi 1 year after diagosis because of tumor progressio withi the irradiated area. Ulike ew protocols attemptig to improve outcome by itesified regimes, associated with icreased toxicity, umerous outpatiet visits, ad prologed hospital stays, we aimed to reduce treatmet burde by offerig a hypofractioatio radiatio therapy schedule for patiets with ewly diagosed DIPG (1, 3, 4). We recetly demostrated the feasibility ad compliace of 39 Gy give i 13 fractios of 3.0 Gy over 3 weeks (4). Although the umber of patiets was limited to 9, the media overall survival of 8.6 moths was withi the rage of 7 to 14 moths published i 2 recet critical reviews (1, 3). Especially for childre with poor compliace ad performace status or parets who refuse a more itesive regime, the hypofractioatio regime may reduce the burde of treatmet without compromisig survival. We report the results i a large group of patiets with ewly diagosed DIPG treated by 2 hypofractioatio regimes: 39 Gy i 13 fractios or 44.8 Gy i 16 fractios. A 1:1 matched-cohort aalysis was performed, icludig patiets with similar diagostic features, receivig a covetioally fractioated radiatio therapy dose of at least 50 Gy i 6 weeks. Methods ad Materials Eligibility Newly diagosed patiets with the cliical ad radiologic suspicio of DIPG ad treated by a hypofractioatio regime were eligible for this multiceter retrospective aalysis. All patiets, aged 3 to 21, were required to have had symptoms for less tha 3 moths ad at least 2 fidigs of the eurologic triad: craial erve deficits, ataxia, or log tract sigs. No performace status criteria were used. The availability of preradiatio therapy magetic resoace imagig (MRI) cotaiig at least T1 images ad T2 images ad gadoliium admiistratio was ecessary for review. Patiets i this aalysis had to meet all major ad at least 2 mior radiologic criteria for DIPG. The major criteria are the appearace of a poorly margiated tumor with mass effect occupyig more tha 50% of the axial diameter of the pos, hypoitesity o T1 images, ad hyperitesity o T2 images (5). Mior radiologic criteria iclude ecasemet of the basilar artery, extesio ito the mesecephalo ad/or medulla oblogata ad/or cerebellar peducle, ad cotrast ehacemet (focal rig, peripheral, spotty, or focal patchy) with or without ecrosis (5, 6). Childre with a history of eurofibromatosis were excluded because they belog to a subgroup expected to have a more favorable progosis (7). I case of doubt, a biopsy was performed to cofirm high-grade glioma. As a matchig cohort, we radomly selected patiets from 6 differet istitutes with idetical cliical ad radiologic features who were receivig a covetioal fractioated radiatio therapy dose of at least 50/1.8 to 2.0 Gy o the potie tumor. No systemic treatmet other tha steroids was allowed i the eoadjuvat, cocomitat, or adjuvat settig of both cohorts. I case of progressio after radiatio therapy, the use of systemic therapy was permitted i both cohorts. Radiatio therapy Two hypofractioatio regimes were ivestigated. The first regime, used at the Radboud Uiversity Medical Cetre Nijmege ad Academic Medical Ceter Amsterdam, delivered 39 Gy i 13 daily fractios of 3.0 Gy 4 times a week (overall treatmet time: 3 weeks). The secod regime, used at Erasmus Medical Cetre i Rotterdam, applied 44.8 Gy i 16 fractios of 2.8 Gy 4 times a week (overall treatmet time: 4 weeks). I the matchig cohort, patiets received a media total dose of 54 Gy i 30 daily fractios of 1.8 Gy 5 times a week (overall treatmet time: 6 weeks). The majority of the patiets i both cohorts were treated by 2 opposig lateral photo beams. The cliical target volume icluded the tumor as defied by the T2-weighted MR images with a margi of 1.5 to 2.0 cm. The margis were adjusted for boy structures ad tetorium. A additioal margi betwee 0.3 cm ad 0.5 cm was added to create the plaig target volume. Assessmet of respose A baselie eurologic ad geeral cliical examiatio, performed by a pediatric eurologist or a experieced pediatric ocologist, was available for all patiets. Durig radiatio therapy, re-evaluatio by the radiatio ocologist ad/or pediatric ocologist was performed routiely. I the group of patiets treated with hypofractioatio, the use of steroids ad the Radiatio Therapy Ocology Group grade 3 ad 4 ski, ear, ad cetral ervous system toxicity was scored. Because repeated MR imagig was ot routiely performed durig follow-up, disease

3 Volume 85 Number Hypofractioated radiatio therapy for DIPG 317 progressio was defied as a cliical (eurologic) deterioratio with eed for steroid reuse or dose escalatio. Edpoits The primary edpoit was overall survival, measured from diagosis to the date of death. The secodary edpoit was time to progressio, defied as the time to cliical (eurologic) deterioratio with eed for steroid dose escalatio, measured from diagosis. Data were cesored at the last cotrol visit. Statistical aalysis Statistical aalyses were performed with SPSS Overall survival ad time to progressio were calculated with the Kapla- Meier method, ad all aalyses were based o a itetio-to-treat policy. The differeces betwee the Kapla-Meier curves were calculated with the log-rak test. The c 2 test ad Ma-Whitey U test were used to compare patiet, tumor, ad treatmet characteristics, ad the Kruskal-Wallis test was used to compare overall treatmet times i both cohorts. Results Patiet groups ad treatmet Betwee December 2002 ad August 2010, 27 patiets from 3 ceters i the Netherlads were treated with a hypofractioatio regime. All patiets receivig the 13 3 Gy regime met the iclusio criteria prospectively. The patiets treated with the Gy regime fulfilled the striget iclusio criteria o a retrospective basis. Twety-seve of 35 patiets from 6 ceters i the Uited Kigdom, Caada, the Netherlads ad Belgium were used as a matched-pair cohort. The group of patiets receivig covetioal radiatio therapy was treated betwee July 1993 ad October The baselie patiet ad tumor characteristics are show i Table 1. Although all the striget iclusio criteria are respected, a slight imbalace (fewer log tract sigs ad less extesio ito the cerebellar peducle) i favor of the covetioal regime is observed. The treatmet characteristics are listed i Table 2. Radiatio therapy was started withi 2 weeks from diagosis i 20 of 27 (74%; media, 7 days; rage, 0 to 40 days) childre of the hypofractioatio group ad i 14 of 27 (52%; media, 14 days; rage, Table 1 Patiet ad tumor characteristics Hypofractioatio RT Covetioal RT Characteristic P value No. of patiets Sex.14* M F Age (y) Media y Rage Duratio of symptoms.57* <1 mo mo mo Neurologic triad Craial erve deficit Ataxia * Log tract sigs * No. of patiets with complete triad * Radiology Mass effect i the pos Poorly margiated T1 hypoitesity, T2 hyperitesity >50% of axial diameter pos ivolved >67% of axial diameter pos ivolved * Ecasemet of basilar artery * Extesio ito mesecephalo, medulla * Extesio ito cerebellar peducle * Cotrast ehacemet * Pathology-prove glioma.35* WHO grade WHO grade Abbreviatios: RT Z radiatio therapy; WHO Z World Health Orgaizatio. * c 2 test. y Ma-Whitey U test.

4 318 Jasses et al. Iteratioal Joural of Radiatio Ocology Biology Physics Table 2 Treatmet characteristics Hypofractioatio RT Characteristic Covetioal RT P value No. of patiets Radiatio therapy dose prescribed 39.0/3.0 Gy /2.8 Gy / Gy Radiatio therapy dose give 39.0/3.0 Gy /2.8 Gy / Gy Time from diagosis.02* to start of radiatio therapy Days Media Overall treatmet <.01 y time Days Media Abbreviatio: RT Z radiatio therapy. * Ma-Whitey U test. y Kruskal-Wallis test. 3 to 54 days) childre of the covetioally fractioated group. I the hypofractioatio group, 11 of 27 patiets received chemotherapy (temozolomide, Z11) after documeted progressio. I the covetioal radiatio therapy group, 9 of 27 patiets received chemotherapy (temozolomide, Z3; etoposide, Z2; imotuzumab, Z1; thalidomide þ etoposide þ cyclophosphamide, Z1; fotemustie, Z1; tamoxife, Z1) for documeted progressio. At the ed of follow-up, 26 of 27 patiets had died i the hypofractioatio group. I 25 patiets, death was due to local disease progressio. Oe patiet died of a cetral ervous system ifectio after prove tumor progressio show o MRI. At the time of this aalysis 1 patiet is still alive, 2.4 years from diagosis, without disease progressio. I the covetioal group, all patiets died of disease progressio. Efficacy I the hypofractioatio cohort, the media overall survival was 9.0 moths (95% CI, moths) (Fig. 1A). The overall survival at 6, 9, ad 12 moths was 74%, 44%, ad 22%, respectively. The media time to progressio was 5.0 moths (95% CI, moths), as illustrated i Fig. 1B. Progressiofree survival at 3, 6, ad 9 moths was 77%, 43%, ad 12%. I the hypofractioatio group, all patiets received steroids at the begiig of ad durig radiatio therapy. I 21 of 27 (78%) patiets, the use of steroids could be temporarily discotiued. No sigificat differece i media overall survival was observed betwee hypofractioatio ad covetioal radiatio therapy: 9.0 moths vs 9.4 moths, respectively (PZ.84) (Fig. 2A). There was o sigificat differece i media time to progressio betwee hypofractioatio ad covetioal radiatio therapy: 5.0 moths vs 7.6 moths, respectively (PZ.24) (Fig. 2B). Fig. 1. Overall survival (A) ad time to progressio (B) for patiets with ewly diagosed diffuse itrisic potie glioma after hypofractioatio radiatio therapy (39/3.0 Gy or 44.8/2.8 Gy, 4 fractios/week). I subgroup aalysis, o sigificat differece i overall survival or time to progressio was observed with 44.8/2.8 Gy compared with 39.0/3.0 Gy (Fig. 3). Toxicity ad compliace to radiatio therapy Both hypofractioatio regimes were well tolerated. A statistically sigificat differece i media overall treatmet time was observed i favor of the hypofractioatio regimes: 20 days (rage, 16 to 22 days) for the 39/3.0 Gy regime, 24 days (rage, 7 to 34 days) for the 44.8 Gy regime vs 41 days for the covetioally fractioated regimes (rage, 30 to 50 days) (Table 2) (P<.01). I the hypofractioatio regime, 1 treatmet iterruptio was eeded after 2 fractios because of brai edema, ucotrollable by

5 Volume 85 Number Hypofractioated radiatio therapy for DIPG 319 Fig. 2. Overall survival (A) ad time to progressio (B) for patiets with ewly diagosed diffuse itrisic potie glioma after hypofractioatio radiatio therapy matched to a group receivig covetioal radiatio therapy. steroids. The treatmet was resumed after 4 days. Radiatio therapy was iterrupted after 5 fractios i 1 patiet because of progressive disease durig treatmet. I the covetioal group, 2 patiets did ot receive a total dose of 50 Gy because of disease progressio after 22 ad 26 fractios. All childre i the hypofractioatio group experieced fait to moderate erythema of the ski followed by dry desquamatio. A miority had moist desquamatio cofied to the ski folds of the auricle. No grade 3 or 4 acute toxicity from radiatio therapy was recorded. Two childre experieced recurret cetral ervous system ifectios caused by bacterial coloizatio of a vetricular-peritoeal drai, put i place for obstructive hydrocephalus. Discussio The results of this matched-cohort aalysis reveal a similar overall survival with a hypofractioatio regime (13 or 16 fractios i 3 to 4 weeks) compared with a covetioal radiatio therapy regime (30 fractios i 6 weeks) for patiets with ewly diagosed DIPG. A osigificat differece i media time to progressio was observed i favor of the covetioal radiatio therapy regime. Accordig to Hargrave et al (1), the overall survival of 9 moths with hypofractioatio radiatio therapy i this study is withi the rage of 8 to 11 moths observed i studies usig more striget iclusio criteria ad is better tha the 7.6 moths overall survival observed i a recet hypofractioatio study reported by Negretti et al (8). The outcome i our cohort cofirms the results of our previous pilot study o hypofractioatio (4). Similar outcome results, eve i the presece of a imbalace of Fig. 3. Overall survival (A) ad time to progressio (B) after 39/3.0 Gy vs 44.8/2.8 Gy for patiets with ewly diagosed diffuse itrisic potie glioma. eurologic symptoms i favor of the covetioal regime, further support the efficacy of hypofractioated radiatio therapy for DIPG. After decades of several types of itesive regimes i cliical trials, this is the first time a low-burde protocol has demostrated similar outcome compared with covetioal radiatio therapy i a larger group of patiets fulfillig several striget iclusio criteria (1, 3, 4). Hargrave et al clearly demostrated that the rage i media overall survival shifted from 7 to 16 moths toward 8 to 11 moths whe the cliical ad radiologic eligibility criteria were specified ad respected (1). The combiatio of short symptom duratio (3 moths), a miimum of 2 sigs of the eurologic triad, the presece of predefied MRI characteristics, ad a biopsy result positive for high-grade glioma i case of doubt (22%) eabled us to avoid higher fractio doses to the ormal brai for a potetially idolet or curative disease course i all but 1 patiet (4%). A iterestig fidig is the differece (although osigificat) i time to progressio of 5.0 vs 7.6 moths i favor of the covetioally fractioated regime. A reasoable explaatio for this ca be obtaied by comparig tumor ad treatmetrelated characteristics ad the use of MRI. Although all patiets i both cohorts met the striget iclusio criteria, a higher icidece of log tract sigs ad tumor extesio ito the cerebellar peducle was observed i the hypofractioatio group. Both features potetially cotribute to a earlier detectio of eurologic deterioratio. Compared with the covetioal regime, radiotherapy i the hypofractioatio cohort started 1 week ad eded 3 weeks earlier. This meas that a correctio of 4 weeks should be

6 320 Jasses et al. Iteratioal Joural of Radiatio Ocology Biology Physics used to evaluate the real cotributio of the radiotherapy regime i terms of delayig disease progressio, iasmuch as it is ow calculated from the time of diagosis. Repeated MRI was ot routiely performed durig follow-up i the hypofractioatio cohort. Disease progressio was defied as a cliical (eurologic) deterioratio with eed for steroid reuse or dose escalatio. Progressio accordig to this defiitio might be differet from that accordig to a cliical-radiologic defiitio, particularly because of the lack of clear-cut MRI criteria for disease progressio i braistem tumors (1). Whe all the potetial subjective factors i this rapidly progressive disease are cosidered, it is clear that overall survival seems to provide the most reliable iformatio i the absece of stadardized ad validated criteria for disease progressio (1). The mai reaso why we treat patiets 4 days per week istead of 5 is patiet burde. Takig ito accout all radiatio therapyrelated publicatios o DIPG, it is ulikely that a differece i overall treatmet time of 3 to 4 days will ifluece the fial outcome (1). It is uclear whether or ot 5 fractios of 2.8 to 3.0 Gy per week could result i a higher icidece of treatmet iterruptios (eg, braistem edema) despite systematic steroid use. I the absece of ay differece i overall survival time betwee 13 fractios of 3 Gy ad 16 fractios of 2.8 Gy, the lower dose ad shorter regime ca be defeded. The selectio of the lowest radiatio dose with equal effect may become particularly iterestig, especially i the cotext of reirradiatio at the time of progressio. For a disease with a course like DIPG, this approach ca be justified ad ca offer potetial optios for future reirradiatio trials. I 6 highly selected patiets, prelimiary experiece of reirradiatio of the braistem, after a iitial dose of 54 to 55.8 Gy, still demostrated some improvemet of symptoms with miimal toxicity with a dose of 18 to 20 Gy i 2.0-Gy fractios (9). As we embark o the log-awaited molecular era for pediatric DIPG, it is probable that may ew studies combiig 1 or more small molecules with covetioal radiatio therapy will be tested i the ext decade to come (10-12). Although it is clear that we should ecourage the developmet of such ew agets, it is our experiece that a sigificat proportio of parets ad patiets, whe properly iformed, may prefer the optio of a low-burde radiatio therapy regime with emphasis o quality of life. Hypofractioatio radiatio therapy offers a treatmet course that is completed i 3 to 4 weeks. Assumig a media overall survival time of 9 moths, the child ad his or her parets will have to sped oly 10% of the remaiig survival time for i-hospital treatmet. Protracted regimes usig covetioal fractioatio double the radiatio therapy overall treatmet time, ad whe systemic combiatios are used i additio to radiatio, childre may sped more tha half of the remaiig survival time uder treatmet (1, 3, 13, 14). This is the reaso for us to start a phase II prospective trial o hypofractioatio with emphasis o quality of life. Ideally, a radomized oiferiority study should be the method of choice to cofirm our results. However, whe covetioal radiatio therapy provides the well-kow palliatio of 8.5 moths, the ratioale becomes practically very difficult, especially i a rare tumor type ad a myriad of other cliical trials (1, 2, 10, 11, 13). Whe outcome is cofirmed i a prospective trial, the curret hypofractioatio regime ca serve as a potetial base for combied treatmet approaches i future trials. However, if ucertaity exists about the potetial radiosesitizig effects of ovel agets, a cautious approach is recommeded, because with a higher dose per fractio the radiosesitizig effect ca be larger, with the cosequece of icreased risk of toxicity. It is clear that such combiatios ca be tested oly i the cotext of well-desiged trials with emphasis o the precise moitorig of toxicity. Coclusio The results of this matched-cohort aalysis demostrate a similar overall survival rate with a hypofractioatio regime (13 or 16 fractios i 3 to 4 weeks) compared with a covetioal radiatio therapy regime (30 fractios i 6 weeks) for patiets with ewly diagosed DIPG. Outside cliical trials, this low-burde regime could be cosidered as a good alterative to protracted regimes. Refereces 1. Hargrave D, Bartels U, Bouffet E. Diffuse braistem glioma i childre: critical review of cliical trials. Lacet Ocol 2006;7: Doaldso SS, Laigham F, Fisher PG. Advaces towards a uderstadig of braistem gliomas. J Cli Ocol 2006;24: Jase MH, va Vuurde DG, Vadertop WP, et al. Diffuse itrisic potie gliomas: a systematic update o cliical trials ad biology. Cacer Treat Rev 2012;38: Jasses GO, Giddig CE, va Lidert EJ, et al. The role of hypofractioatio radiotherapy for diffuse itrisic braistem glioma i childre: a pilot study. It J Radiat Ocol Biol Phys 2009;73: Zimmerma RA. Neuroimagig of primary braistem gliomas: diagosis ad course. Pediatr Neurosurg 1996;25: Guillamo JS, Doz F, Delattre JY. Brai stem gliomas. Curr Opi Neurol 2001;14: Ullrich NJ, Raja AI, Iros MB, et al. Braistem lesios i eurofibromatosis type I. Neurosurgery 2007;61: Negretti L, Bouchireb K, Levy-Piedbois C, et al. Hypofractioated radiotherapy i the treatmet of diffuse itrisic potie glioma i childre: a sigle istitutio s experiece. J Neuroocol 2011;104: Fotailla HP, Piix CC, Ketoe LM, et al. Palliative reirradiatio for progressive diffuse itrisic potie glioma. Am J Cli Ocol 2012;35: Hawkis CE, Bartels U, Bouffet E. Molecular geetic approaches ad potetial ew therapeutic strategies for pediatric diffuse itrisic glioma. J Cli Ocol 2011;29: Bartels U, Hawkis CE, Vezia G, et al. Proceedigs of the diffuse itrisic potie glioma Toroto Thik Tak: advacig basic ad traslatioal research ad cooperatio i DIPG. J Neuroocol 2011; 105: Zarghooi M, Bartels U, Lee E, et al. Whole-geome profilig of pediatric diffuse itrisic potie gliomas highlights platelet-derived growth factor receptor alpha ad poly (ADP-ribose) polymerase as potetial therapeutic targets. J Cli Ocol 2010;28: Madell LR, Kadota R, Freema C, et al. There is o role for hyperfractioated radiotherapy i the maagemet of childre with ewly diagosed diffuse itrisic braistem tumors: results of a pediatric ocology group phase III trial comparig covetioal vs. hyperfractioated radiotherapy. It J Radiat Ocol Biol Phys 1999;43: Bouffet E, Raqui M, Doz F, et al. Radiotherapy followed by highdose busulfa ad thiotepa: a prospective assessmet of high-dose chemotherapy i childre with diffuse potie gliomas. Cacer 2000;88: