Volume 2 (2017) Issue 2ISSN 2518-6507

World Federation of Neuro-Oncology Societies

magazineNeurology bull Neurosurgery bull Medical Oncology bull Radiotherapy bull Paediatric Neuro-Oncology bull Neuropathology bull Neuroradiology bull Neuroimaging bull Nursing bull Patient Issues

EditorialWolfgang Wick EA (Nino) Chiocca

Pediatric Ependymomas A Plea for International CooperationDidier Frappaz

Unsolved Problems in the Medical Treatment of Gliomas PCV or PCCarmen Balatildena Anna Maria Lopez-Andres Anna Estival Eva Montaneacute

Radiation Therapy for Intracranial Meningiomas Current Results andControversial IssuesGiuseppe Minniti Claudia Scaringi Federico Bianciardi

Central Nervous System Disease in Langerhans Cell HistiocytosisA Case Report and Review of the LiteratureAlessia Pellerino Luca Bertero Riccardo Soffi etti

Management of Brain Metastasis Burning Questions to theRadiation OncologistRoberta Rudagrave

European Reference Networks (ERNs) A New Initiative toIncrease Collaborative Cross-Border Approaches to TreatingBrain Tumor PatientsKathy Oliver

Brain MetastasesmdashA Growing Nursing ConcernIngela Oberg

Hotspots in Neuro-Oncology 2017Partick Wen

Hotspots in Neuro-Oncology Practice 20162017Susan M Chang

ANOCEF (French Speaking Association for Neuro-Oncology)Khecirc Hoang-Xuan

5th Quadrennial Meeting of the World Federation ofNeuro-Oncology SocietiesPatrick Roth David A Reardon Ryo Nishikawa Michael Weller

The EANO Youngsters InitiativeAnna Sophie Berghoff

World Federation of Neuro-Oncology Societies

Editors Michael Weller Zurich Switzerland E Antonio Chiocca President SNO

Managing Editor Roberta Rudagrave Torino Italy

SNO Editor Nicholas Butowski San Francisco USA

Editorial Board

S ebastian Brandner London United Kingdom

Oumlz Buumlge Istanbul Turkey

Chas Haynes Houston USA

Filip de Vos Utrecht Netherlands

Francois Ducray Lyon France

Samy El Badawy Cairo Egypt

Anca Grosu Freiburg Germany

Andreas Hottinger Lausanne Switzerland

Chae-Yong Kim Seoul Korea

Florence Lefranc Bruxelles Belgium

Marcos Maldaun Sao Paulo Brazil

Roberta Rudagrave Torino Italy

Gupta Tejpal Mumbai India

Yun-fei Xia Guangzhou China

magazine

copy 2017 Published by The World Federation of Neuro-Oncology Societies This is an Open Access publication distributed under the terms of the Creative Commons Attribution License (httpcreativecommonsorglicensesby40) which permits unrestricted reuse distribution and reproduction in any medium provided the original work is properly cited

Editorial

Dear colleagues

Dear friends of InternationalNeuro-oncology

Dear members of WFNOS

It was a pleasure and privilege to wel-come almost 1000 of you to this 5thWorld Meeting of Neuro-oncologySocieties Zurich was a great placewe spent lively and scientifically re-warding hours in the pleasant lecturehall and owe our thanks to the localorganizing team headed by MichaelWeller and our colleagues fromEANO as well as the staff of theVienna Medical Academy

The topics of our recent issue reflectburning issues in neuro-oncologyOur magazine reviews on an optimaltreatment of an alkylator-based regi-men recent developments in menin-gioma as well as pediatric gliomaand metastases provide insight intoan immunotherapy concept forrecurrent PCNSL

This issue of the magazine featuresour French neuro-oncology col-leagues from ANOCEF Having alook at their achievements we mayneed to remind ourselves thatWFNOS was not only initiated by 3large neuro-oncology societiesmdashSNO ASNO and EANOmdashbut hostsseveral national neuro-oncologysocieties

The new board of EANO haslaunched a young neuro-oncologistsrsquoinitiative Anna Berghoff from Viennawho leads this initiative with CarinaThome from Heidelberg explainsbackground and may trigger applica-tions from many of our younger read-ers With the utmost important topicKathy Oliver from the InternationalBrain Tumor Alliance explains back-ground for a new initiative of theEuropean Union The EuropeanReferences Networks (ERNs) areplanned to increase collaborativecross-border approaches to

treating brain tumor patients with afocus on underserved areas inEurope

Please have a look at the exciting sci-entific and practical news fromneuro-oncology practice The editorsshare their hotspots to prioritizereading

On behalf of EANO I would like tovery much welcome Young-Kil Hongas the new WFNOS president SNOand EANO have passed on the torchto ASNO and look forward to thepreparations for the next WorldMeeting in Seoul in 2021

With warm regards

Wolfgang Wick

President of EANO

41

Volume 2 Issue 2 Editorial

World Federation of Neuro-Oncology Societies

Editors Michael Weller Zurich Switzerland E Antonio Chiocca President SNO

Managing Editor Roberta Rudagrave Torino Italy

SNO Editor Nicholas Butowski San Francisco USA

Editorial Board

S ebastian Brandner London United Kingdom

Oumlz Buumlge Istanbul Turkey

Chas Haynes Houston USA

Filip de Vos Utrecht Netherlands

Francois Ducray Lyon France

Samy El Badawy Cairo Egypt

Anca Grosu Freiburg Germany

Andreas Hottinger Lausanne Switzerland

Chae-Yong Kim Seoul Korea

Florence Lefranc Bruxelles Belgium

Marcos Maldaun Sao Paulo Brazil

Roberta Rudagrave Torino Italy

Gupta Tejpal Mumbai India

Yun-fei Xia Guangzhou China

magazine

copy 2017 Published by The World Federation of Neuro-Oncology Societies This is an Open Access publication distributed under the terms of the Creative Commons Attribution License (httpcreativecommonsorglicensesby40) which permits unrestricted reuse distribution and reproduction in any medium provided the original work is properly cited

Editorial

Dear colleagues

Dear friends of InternationalNeuro-oncology

Dear members of WFNOS

It was a pleasure and privilege to wel-come almost 1000 of you to this 5thWorld Meeting of Neuro-oncologySocieties Zurich was a great placewe spent lively and scientifically re-warding hours in the pleasant lecturehall and owe our thanks to the localorganizing team headed by MichaelWeller and our colleagues fromEANO as well as the staff of theVienna Medical Academy

The topics of our recent issue reflectburning issues in neuro-oncologyOur magazine reviews on an optimaltreatment of an alkylator-based regi-men recent developments in menin-gioma as well as pediatric gliomaand metastases provide insight intoan immunotherapy concept forrecurrent PCNSL

This issue of the magazine featuresour French neuro-oncology col-leagues from ANOCEF Having alook at their achievements we mayneed to remind ourselves thatWFNOS was not only initiated by 3large neuro-oncology societiesmdashSNO ASNO and EANOmdashbut hostsseveral national neuro-oncologysocieties

The new board of EANO haslaunched a young neuro-oncologistsrsquoinitiative Anna Berghoff from Viennawho leads this initiative with CarinaThome from Heidelberg explainsbackground and may trigger applica-tions from many of our younger read-ers With the utmost important topicKathy Oliver from the InternationalBrain Tumor Alliance explains back-ground for a new initiative of theEuropean Union The EuropeanReferences Networks (ERNs) areplanned to increase collaborativecross-border approaches to

treating brain tumor patients with afocus on underserved areas inEurope

Please have a look at the exciting sci-entific and practical news fromneuro-oncology practice The editorsshare their hotspots to prioritizereading

On behalf of EANO I would like tovery much welcome Young-Kil Hongas the new WFNOS president SNOand EANO have passed on the torchto ASNO and look forward to thepreparations for the next WorldMeeting in Seoul in 2021

With warm regards

Wolfgang Wick

President of EANO

41

Volume 2 Issue 2 Editorial

Editorial

Dear colleagues

Dear friends of InternationalNeuro-oncology

Dear members of WFNOS

It was a pleasure and privilege to wel-come almost 1000 of you to this 5thWorld Meeting of Neuro-oncologySocieties Zurich was a great placewe spent lively and scientifically re-warding hours in the pleasant lecturehall and owe our thanks to the localorganizing team headed by MichaelWeller and our colleagues fromEANO as well as the staff of theVienna Medical Academy

The topics of our recent issue reflectburning issues in neuro-oncologyOur magazine reviews on an optimaltreatment of an alkylator-based regi-men recent developments in menin-gioma as well as pediatric gliomaand metastases provide insight intoan immunotherapy concept forrecurrent PCNSL

This issue of the magazine featuresour French neuro-oncology col-leagues from ANOCEF Having alook at their achievements we mayneed to remind ourselves thatWFNOS was not only initiated by 3large neuro-oncology societiesmdashSNO ASNO and EANOmdashbut hostsseveral national neuro-oncologysocieties

The new board of EANO haslaunched a young neuro-oncologistsrsquoinitiative Anna Berghoff from Viennawho leads this initiative with CarinaThome from Heidelberg explainsbackground and may trigger applica-tions from many of our younger read-ers With the utmost important topicKathy Oliver from the InternationalBrain Tumor Alliance explains back-ground for a new initiative of theEuropean Union The EuropeanReferences Networks (ERNs) areplanned to increase collaborativecross-border approaches to

treating brain tumor patients with afocus on underserved areas inEurope

Please have a look at the exciting sci-entific and practical news fromneuro-oncology practice The editorsshare their hotspots to prioritizereading

On behalf of EANO I would like tovery much welcome Young-Kil Hongas the new WFNOS president SNOand EANO have passed on the torchto ASNO and look forward to thepreparations for the next WorldMeeting in Seoul in 2021

With warm regards

Wolfgang Wick

President of EANO

41

Volume 2 Issue 2 Editorial

Editorial

Dear Members and Colleagues ofSNO EANO ASNO and WFNOS

I thank you for the opportunity andprivilege to provide you with a sum-mary of SNOrsquos accomplishmentsover this past year I would like torecognize the leadership of ourofficers our vice-president TerriArmstrong and our treasurerGelareh Zadeh I also would like torecognize the work of the membersof our Executive Council and of ourBoard of Directors

We have just returned from a greatmeeting in Zurich for WFNOS 2017The weather for the most part con-tributed to a great meeting but moreimportantly the quality and excite-ment of the talks and presentationswere the highlights of the meetingTogether with our colleagues fromour sister societies we were happyto see so many participants from allcorners of the globe This family ofpractitioners in the sciences and clin-ical practice of neuro-oncology showan unbeatable spirit of creativity andquest for knowledge that bodes wellfor each member society The collab-orations that come out from these

meetings are bound to provide thenext set of impressive results to bepresented in future years Thesemeetings also make one aware thatour patients only benefit from thesharing of knowledge and experi-ence thus ensuring that any patienthas access to very similar care re-gardless of where he or she is seenIn spite of this it is clear that muchmore has to be done on this front forsome of the neediest parts of ourworld

SNO would like to recognize andthank the leadership of EANO and inparticular Michael Weller for thismeeting In addition to the venues forthe talks the social programs wereexcellent and well attended The ban-quet dinner on top of a mountainpeak surrounded by clouds madeone feel the spirit of Switzerland

SNO continues to thrive in terms ofits impact its membership its abilityto provide exciting annual meetingsand its educational content Wewould be very excited if we couldmatch the success of WFNOS 2017with our SNO 2017 meeting in SanFrancisco Under the leadership of

our scientific program chairs (DrsManish Aghi Vinay Puduvalli andFrank Furnari) the theme for the SNO2017 meeting will be the CANCERMOONSHOT initiatives which havebeen announced by the NIHNCI andsupported in a rare spirit of biparti-sanship by the US CongressKeynote speeches provided by DrJennifer Doudna from UC Berkeleywidely regarded as one of the maininventors of the CrisprCAs9 geneticediting technology and by Dr CarloCroce from Ohio State Universitywill certainly be the feather in the capfor additional exciting oral presenta-tions We thus hope that as manymembers of WFNOS societies attendand visit San Francisco

Finally SNO wishes to provide ournext WFNOS President and host ofthe next WFNOS meeting in SeoulDr Young-Kil Hong our most heart-felt congratulations and wishes for agreat meeting in 2021

Respectfully yours

EA (Nino) Chiocca MD PhD

42

Volume 2 Issue 2 Editorial

PediatricEpendymomasA Plea forInternationalCooperation

Didier FrappazCorrespondence to Didier Frappaz Neurooncologie Pediatrique et Adulte Centre LeonBerard et IHOP 28 Rue Laennec 69008 France

43

AbstractEpendymomas account for 10 of brain tumors inchildren and are thus the third most commonpediatric tumor of the central nervous system (CNS)They may arise from ependymal cells that are spreadalong the entire neuraxis More than 90 ofependymomas occurring in children are locatedintracranially with two-thirds in the infratentorial andone third in the supratentorial regions More than halfof pediatric ependymomas occur in children youngerthan 5 years of age Males are more often affectedwith a sex ratio of 21 There are no environmentalfactors described up to now However some predis-posing factors are described patients with Turcot orGorlin syndrome may develop intracranial ependy-momas and those with neurofibromatosis type 2may develop spinal ependymomas

For the SIOPEpendymoma groupEpendymomas are located in or close to the ventricularsystem though intraparenchymal tumors are describedThese plastic tumors tend to infiltrate the surroundingregions in the posterior fossa extension into the cerebel-lopontine angle through the foramina of Luschka andor toward the cervical region through the foramen ofMagendie is a typical feature of an ependymoma ratherthan that of a medulloblastoma This explains why thecomplete removal is sometimes difficult and should beattempted only by skilled pediatric neurosurgeonsMagnetic resonance imaging usually shows a decreasedT1-weighted signal intensity with gadolinium enhance-ment that may or may not be heterogeneous and a het-erogeneous T2-weighted hyperintensity Cysticcomponents may be seen in supratentorial tumorsEpendymomas are localized at time of diagnosis in morethan 90 of cases The initial staging should include aspinal MRI (if feasible preoperatively) and a CSF cyto-logical study prior to therapy Ependymoma tends torecur locally though with improved local therapy thisbecomes less true Staging should thus be repeated attime of relapse

Ependymomas were divided by the World HealthOrganization (WHO) 2007 classification into 3 histology-based grades whatever their site of origin1 WHO grade Itumors included myxopapillary ependymomas typicallylocated in the spine and subependymomas mostlylocated intracranially They occur predominantly in adultsand are usually associated with favorable patient out-comes though spinal myxopapillary spinal tumors of chil-dren have a tendency to recur and disseminate muchmore than their adult counterpart2 The majority of epen-dymomas are WHO grade II (classic) and grade III (ana-plastic) tumors Classic WHO grade II ependymomasmay show a papillary clear cell or tanicytic phenotypeWHO grade III (anaplastic) ependymomas are defined bya high mitotic count microvascular proliferation andtumor necrosis Differential diagnoses include neurocy-toma and metastasis of a papillary adenocarcinoma Ofnote ependymoblastomas are not ependymal tumorsthough they were included in the past in some series ofependymomas thus blurring the results The reproduci-bility of this classification has been questioned and itsvalue to determine event-free survival and overall survivalwas a matter of debate especially in younger children3

Moreover this classification did not take into account thesite A better understanding of the cell of origin was pro-vided by genome-wide DNA methylation profiling4 Thisinnovative technology has suggested that the cell of ori-gin of supratentorial tumors differs from that of infratento-rial and spinal tumors Ependymoma can be subdividedinto at least 9 subgroups with etiological clinical demo-graphic prognostic and molecular specificities Each

Pediatric Ependymomas A Plea for International Cooperation Volume 2 Issue 2

44

AbstractEpendymomas account for 10 of brain tumors inchildren and are thus the third most commonpediatric tumor of the central nervous system (CNS)They may arise from ependymal cells that are spreadalong the entire neuraxis More than 90 ofependymomas occurring in children are locatedintracranially with two-thirds in the infratentorial andone third in the supratentorial regions More than halfof pediatric ependymomas occur in children youngerthan 5 years of age Males are more often affectedwith a sex ratio of 21 There are no environmentalfactors described up to now However some predis-posing factors are described patients with Turcot orGorlin syndrome may develop intracranial ependy-momas and those with neurofibromatosis type 2may develop spinal ependymomas

For the SIOPEpendymoma groupEpendymomas are located in or close to the ventricularsystem though intraparenchymal tumors are describedThese plastic tumors tend to infiltrate the surroundingregions in the posterior fossa extension into the cerebel-lopontine angle through the foramina of Luschka andor toward the cervical region through the foramen ofMagendie is a typical feature of an ependymoma ratherthan that of a medulloblastoma This explains why thecomplete removal is sometimes difficult and should beattempted only by skilled pediatric neurosurgeonsMagnetic resonance imaging usually shows a decreasedT1-weighted signal intensity with gadolinium enhance-ment that may or may not be heterogeneous and a het-erogeneous T2-weighted hyperintensity Cysticcomponents may be seen in supratentorial tumorsEpendymomas are localized at time of diagnosis in morethan 90 of cases The initial staging should include aspinal MRI (if feasible preoperatively) and a CSF cyto-logical study prior to therapy Ependymoma tends torecur locally though with improved local therapy thisbecomes less true Staging should thus be repeated attime of relapse

Ependymomas were divided by the World HealthOrganization (WHO) 2007 classification into 3 histology-based grades whatever their site of origin1 WHO grade Itumors included myxopapillary ependymomas typicallylocated in the spine and subependymomas mostlylocated intracranially They occur predominantly in adultsand are usually associated with favorable patient out-comes though spinal myxopapillary spinal tumors of chil-dren have a tendency to recur and disseminate muchmore than their adult counterpart2 The majority of epen-dymomas are WHO grade II (classic) and grade III (ana-plastic) tumors Classic WHO grade II ependymomasmay show a papillary clear cell or tanicytic phenotypeWHO grade III (anaplastic) ependymomas are defined bya high mitotic count microvascular proliferation andtumor necrosis Differential diagnoses include neurocy-toma and metastasis of a papillary adenocarcinoma Ofnote ependymoblastomas are not ependymal tumorsthough they were included in the past in some series ofependymomas thus blurring the results The reproduci-bility of this classification has been questioned and itsvalue to determine event-free survival and overall survivalwas a matter of debate especially in younger children3

Moreover this classification did not take into account thesite A better understanding of the cell of origin was pro-vided by genome-wide DNA methylation profiling4 Thisinnovative technology has suggested that the cell of ori-gin of supratentorial tumors differs from that of infratento-rial and spinal tumors Ependymoma can be subdividedinto at least 9 subgroups with etiological clinical demo-graphic prognostic and molecular specificities Each

Pediatric Ependymomas A Plea for International Cooperation Volume 2 Issue 2

44

anatomical zone may be divided into 3 subpopulationsspine (SP) posterior fossa (PF) and supratentorial region(ST) WHO grade I subependymoma (SE) is named ST-SE PF-SE and SP-SE according to its site and occurs inadults only The 2 remaining spinal subgroups match thehistopathological classification of WHO grade I myxopa-pillary ependymoma (SP-MPE) and WHO grade IIIIIependymoma (SP-EPN) The 2 remaining subgroups inthe posterior fossa are called PF-EPN-A and PF-EPN-BPF-EPN-A tumors are seen mostly in infants and youngchildren they show an aggressive behavior with a highrecurrence rate and poor clinical outcome In contrastPF-EPN-B tumors are found mainly in adolescents andyoung adults and are associated with a better prognosisThe 2 remaining subgroups in the supratentorial regionare called ST-EPNndashv-rel avian reticuloendotheliosis viraloncogene homolog A (RELA) and ST-EPNndashYes-associ-ated protein 1 (YAP1) The former is characterized byfusions between a gene with unknown functionC11orf95 and the nuclear factor-kappaB effector RELAThe ST-EPN-RELA subgroup is more frequent (75) andoccurs in children and adults It may have more aggres-sive behavior though this is not clear as clear-cell epen-dymomas with branching capillaries carry this fusiongene and have a good prognosis5 The 2016 WHO classi-fication of central nervous system tumors recognizes thesupratentorial molecular variant ST-EPN-RELA as aseparate pathological disease entity6 The ST-EPN-YAP1is characterized by recurrent fusions to the oncogeneYAP1 and is diagnosed mainly in childhood

Multivariate survival analyses suggest that molecularsubgrouping may become in the close future a majorprognostic factor that will be used to tailor therapeuticoptions according to initial prognostic data Howeverthese data are currently based on retrospective analysisof heterogeneous series and though numbers are hugethis requires prospective validation The EuropeanEpendymoma Biology Consortium program ldquoBiomarkersof Ependymomas in Children and Adolescentsrdquo(BIOMECA) attached to the SIOP Ependymoma II proto-col is intended to prospectively validate these prognosticfactors in a prospective randomized series of patientsApart from molecular subgrouping it will aim at confirm-ing the universally recognized 1q gain7 as a major prog-nostic factor and validating other factors such astenascin C in posterior fossa tumors

TreatmentThe removal of ependymoma is crucial For children withraised intracranial pressure due to a posterior fossatumor shunting is the initial step It may be obtained viaventriculo-cisternostomy or ventriculo-peritoneal shunt orexternal drainage Complete removal remains the majorprognostic factor in most series8ndash10 It may be achieved inone or several steps with similar outcome11 though

increased risk of sequelae12 This explains why the proce-dures of the SIOP Ependymoma II protocol which is cur-rently running includes a central review of initial andpostsurgical imaging with central surgical advice for asecond look when feasible either by the initial or by amore skilled surgeon These advices are organized na-tionally Though both PF-EPN-A and PF-EPN-B tumorsbenefit from gross total resection the impact of resectionmay not be equivalent survival rates are uniformly poorfor incompletely resected PF-EPN-A even after comple-tion of radiation therapy while a subset of patients withgross totally resected PF-EPN-B tumors do not recureven in the absence of radiotherapy13

The standard of postoperative care in localized ependy-moma is to deliver local radiation therapy when feasible Adose of 594 Gy is delivered in most cases10 though in theyoungest children and in those who underwent severalsurgeries andor have poor neurological status this doseshould be decreased to 54 Gy in order to avoid majorsequelae including radionecrosis Radiation margins de-pend on the accuracy of the immobilizing device but areusually on gross total volume with a clinical total volume of05 cm and a planning target volume of 03 to 05 cm3Iterative general anesthesia may be required in the young-est children and requires a dedicated radiotherapy and an-esthetic team hypnosis may be an alternative The role ofproton therapy especially in the youngest children is stillunder investigation14 With the systematic use of focal radi-ation a 7-year progression-free survival rate of 77 maybe achieved The role of postradiation chemotherapy isexplored in older children with complete removal through arandomization versus observation half of the children willreceive a 15-week alternating cycle of vincristine etopo-side and cyclophosphamide with vincristine cisplatin inthe SIOP Ependymoma II study A similar randomization isproposed on the other side of the Atlantic by theChildrenrsquos Oncology Group ACNS0831 protocol For thosechildren who have an inoperable residue the role of an8 Gy radiotherapy boost on top of the standard radiation8

and the addition of pre- and postchemotherapy are cur-rently being explored in the SIOP Ependymoma II protocol

For infants since the late 1990s the fear of neuropsycho-logical sequelae due to radiation delivery on a developingbrain has led to the design of chemotherapy-only pro-grams15 Their goal is to avoid or at least delay the deliv-ery of radiation Several series have been published16ndash18

Based on the best results of the literature a 41 five-year relapse-free survival may be expected17 Histonedeacetylase inhibitors have been shown to be effective indecreasing proliferation in vitro and in vivo19 Their clinicalutility is currently being explored by randomization on topof chemotherapy in the infant stratum of the SIOPEpendymoma II study

Finally a registry is opened for those children under 21that may not enter into one of the randomizations All chil-dren will benefit from biological investigations organizedby the BIOMECA program

Volume 2 Issue 2 Pediatric Ependymomas A Plea for International Cooperation

45

At time of relapse the role of surgery should be high-lighted Irradiation of the infants who received first-lineexclusive chemotherapy is part of the discussion withparents the delay obtained by chemotherapy may ormay not appear sufficient to avoid neurological seque-lae Reirradiation of children previously irradiated isencouraged20 The extent of the fields (focal reirradiationandor craniospinal irradiation) remains a matter of de-bate Further profiling chemotherapy and innovativetreatment should all be discussed in a multidisciplinarysetting Phase II chemotherapy studies have shown alow response rate21 To date anti-angiogenic drugs22

tyrosine kinase23 or gamma secretase24 inhibitors haveshown modest efficacy An elegant in vitro test hasunexpectedly suggested that 5-fluorouracil may beactive in some subgroups of ependymoma25

However it did not translate into a meaningful clinicalactivity26

Ependymal tumors are a biologically heterogeneous dis-ease Future therapy will probably take into account thisheterogeneity though current protocols are intended tovalidate definitively the concept of molecular subgroup-ing Participation in international cooperative trials isencouraged and particularly the collection of fresh frozensamples to perform innovative research As surgery is themain prognostic factor referral of difficult cases to speci-alized teams is encouraged The future will tell whetherpostradiation chemotherapy has a role in older childrenand whether the concept of histone deacetylation mayadd to chemotherapy in the youngest patients Profilingof tumors at the time of relapse is warranted both tounderstand the pathways of resistance and to proposeinnovative strategies

References

1 Louis DN Ohgaki H Wiestler OD Cavenee WK Burger PC JouvetA et al The 2007 WHO classification of tumours of the central ner-vous system Acta Neuropathol 200711497ndash109 doi101007s00401-007-0243-4

2 Fassett DR Pingree J Kestle JRW The high incidence of tumor dis-semination in myxopapillary ependymoma in pediatric patientsReport of five cases and review of the literature J Neurosurg200510259ndash64 doi103171ped200510210059

3 Ellison DW Kocak M Figarella-Branger D Felice G Catherine GPietsch T et al Histopathological grading of pediatric ependy-moma reproducibility and clinical relevance in European trialcohorts vol 10 Dept of Pathology St Jude Childrenrsquos ResearchHospital Memphis USA DavidEllisonstjudeorg 2011

4 Pajtler KW Witt H Sill M Jones DTW Hovestadt V Kratochwil Fet al Molecular classification of ependymal tumors across all CNScompartments histopathological grades and age groups CancerCell 201527728ndash743 doi101016jccell201504002

5 Figarella-Branger D Lechapt-Zalcman E Tabouret E Junger S dePaula AM Bouvier C et al Supratentorial clear cell ependymomaswith branching capillaries demonstrate characteristic clinicopatho-logical features and pathological activation of nuclear factor-kappaB signaling Neuro Oncol 2016 doi101093neuoncnow025

6 Louis DN Perry A Reifenberger G von Deimling A Figarella-Branger D Cavenee WK et al The 2016 World Health Organizationclassification of tumors of the central nervous system a summary

Acta Neuropathol 2016131803ndash820 doi101007s00401-016-1545-1

7 Mendrzyk F Korshunov A Benner A Toedt G Pfister SRadlwimmer B et al Identification of gains on 1q and epidermalgrowth factor receptor overexpression as independent prognosticmarkers in intracranial ependymoma Clin Cancer Res2006122070ndash2079 doi1011581078-0432CCR-05-2363

8 Massimino M Miceli R Giangaspero F Boschetti L Modena PAntonelli M et al Final results of the second prospective AIEOPprotocol for pediatric intracranial ependymoma Neuro Oncol 2016doi101093neuoncnow108

9 Massimino M Gandola L Giangaspero F Sandri A Valagussa PPerilongo G et al Hyperfractionated radiotherapy and chemother-apy for childhood ependymoma final results of the first prospectiveAIEOP (Associazione Italiana di Ematologia-Oncologia Pediatrica)study vol 58 2004 doi101016jijrobp200308030

10 Merchant TE Mulhern RK Krasin MJ Kun LE Williams T Li C et alPreliminary results from a phase II trial of conformal radiation therapyand evaluation of radiation-related CNS effects for pediatric patientswith localized ependymoma vol 22 2004 doi101200JCO200411142

11 Massimino M Solero CL Garre ML Biassoni V Cama A Genitori Let al Second-look surgery for ependymoma the Italian experienceJ Neurosurg Pediatr 20118246ndash250 doi10317120116PEDS1142

12 Morris EB Li C Khan RB Sanford RA Boop F Pinlac R et alEvolution of neurological impairment in pediatric infratentorialependymoma patients J Neurooncol 200994391ndash398doi101007s11060-009-9866-8

13 Ramaswamy V Hielscher T Mack SC Lassaletta A Lin T PajtlerKW et al Therapeutic impact of cytoreductive surgery and irradi-ation of posterior fossa ependymoma in the molecular era a retro-spective multicohort analysis J Clin Oncol 2016342468ndash2477doi101200JCO2015657825

14 Macdonald SM Sethi R Lavally B Yeap BY Marcus KJ Caruso Pet al Proton radiotherapy for pediatric central nervous system epen-dymoma clinical outcomes for 70 patients Neuro Oncol2013151552ndash1559 doi101093neuoncnot121

15 Duffner PK Horowitz ME Krischer JP Burger PC Cohen MESanford RA et al The treatment of malignant brain tumors in infantsand very young children an update of the Pediatric Oncology Groupexperience vol 1 1999

16 Garvin JH Selch MT Holmes E Berger MS Finlay JL Flannery Aet al Phase II study of pre-irradiation chemotherapy for childhoodintracranial ependymoma Childrenrsquos Cancer Group protocol 9942a report from the Childrenrsquos Oncology Group Pediatr Blood Cancer2012591183ndash1189 doi101002pbc24274

17 Grundy RG Wilne SA Weston CL Robinson K Lashford LSIronside J et al Primary postoperative chemotherapy withoutradiotherapy for intracranial ependymoma in children the UKCCSGSIOP prospective study vol 8 2007 doi101016S1470-2045(07)70208-5

18 Massimino M Gandola L Barra S Giangaspero F Casali CPotepan P et al Infant ependymoma in a 10-year AIEOP(Associazione Italiana Ematologia Oncologia Pediatrica) experiencewith omitted or deferred radiotherapy Int J Radiat Oncol Biol Phys201180807ndash814 doi101016jijrobp201002048

19 Milde T Kleber S Korshunov A Witt H Hielscher T Koch P et al Anovel human high-risk ependymoma stem cell model reveals thedifferentiation-inducing potential of the histone deacetylase inhibitorvorinostat Acta Neuropathol 2011122637ndash650 doi101007s00401-011-0866-3

20 Bouffet E Hawkins CE Ballourah W Taylor MD Bartels UKSchoenhoff N et al Survival benefit for pediatric patients with recur-rent ependymoma treated with reirradiation Int J Radiat Oncol BiolPhys 2012831541ndash1548 doi101016jijrobp201110039

Pediatric Ependymomas A Plea for International Cooperation Volume 2 Issue 2

46

21 Bouffet E Foreman N Chemotherapy for intracranial ependymo-mas Childs Nerv Syst 199915563ndash570 doi101007s003810050544

22 Gururangan S Chi SN Young Poussaint T Onar-Thomas AGilbertson RJ Vajapeyam S et al Lack of efficacy of bevacizumabplus irinotecan in children with recurrent malignant glioma and dif-fuse brainstem glioma a Pediatric Brain Tumor Consortium studyvol 28 2010 doi101200JCO2009268789

23 DeWire M Fouladi M Turner DC Wetmore C Hawkins C Jacobs Cet al An open-label two-stage phase II study of bevacizumab andlapatinib in children with recurrent or refractory ependymoma aCollaborative Ependymoma Research Network study (CERN) JNeurooncol 2015 doi101007s11060-015-1764-7

24 Fouladi M Stewart CF Olson J Wagner LM Onar-Thomas AKocak M et al Phase I trial of MK-0752 in children with refrac-tory CNS malignancies a pediatric brain tumor consortiumstudy J Clin Oncol 2011293529ndash3534 doi101200JCO2011357806

25 Atkinson JM Shelat AA Carcaboso AM Kranenburg TA Arnold LABoulos N et al An integrated in vitro and in vivo high-throughputscreen identifies treatment leads for ependymoma Cancer Cell201120384ndash399 doi101016jccr201108013

26 Wright KD Daryani VM Turner DC Onar-Thomas A Boulos N OrrBA et al Phase I study of 5-fluorouracil in children and young adultswith recurrent ependymoma Neuro Oncol 2015171620ndash1627doi101093neuoncnov181

Volume 2 Issue 2 Pediatric Ependymomas A Plea for International Cooperation

47

UnsolvedProblems in theMedical Treatmentof Gliomas PCVor PC

Carmen Bala~na1 Anna MariaLopez-Andres2 Anna Estival1

Eva Montane3

1Medical Oncology Catalan Institute of OncologyBadalona (ICO) Barcelona Spain2Fundacio Institut Investigacio Germans Trias iPujol (IGTP) Clinical Pharmacology ServiceHospital Universitari Germans Trias i Pujol3Department of Pharmacology Therapeutics andToxicology Universitat Autonoma de Barcelonaand Clinical Pharmacology Service BadalonaBarcelona Spain

Correspondence to Carmen Balana CatalanInstitute of Oncology (ICO) Hospital GermansTrias i Pujol Ctra Canyet sn 08916 Badalona(Barcelona) Spain Tel thorn34 93 497 89 25 Faxthorn34 93 497 89 50 Email cbalanaiconcologianet

48

IntroductionThe combination of radiation therapy plus chemotherapywith procarbazine lomustine and vincristine (PCV) is thepostsurgical treatment of choice in high-risk low-gradegliomas and in anaplastic oligodendroglial tumorsbased on results of studies demonstrating the superiorityof adding chemotherapy to treatment with local irradi-ation1ndash3 Interest in adding chemotherapy to the treatmentof oligodendroglial tumors arose from observing objectiveresponses with PCV-like chemotherapy in small series ofpatients with recurrent disease45 Two independent stud-ies one by the European Organisation for Research andTreatment of Cancer (EORTC) and the Medical ResearchCouncil Clinical Trials Group (EORTC 26951)2 and theother by the Radiation Therapy Oncology Group (RTOG9402)1 randomized patients with anaplastic oligodendro-glioma or oligoastrocytoma after surgery to receive treat-ment with PCV plus radiotherapy or radiotherapy aloneThe 2 trials differed slightly in study design chemother-apy dose and number of planned cycles Chemotherapywas prior to irradiation in RTOG 9402 and after radiationin EORTC 26951 the doses of lomustine and procarba-zine (PC) were higher and there was no dose ceiling forvincristine in the RTOG 9402 trial Four cycles wereplanned in the RTOG 9402 trial compared with 6 in theEORTC 26951 trial Despite these differences both trialsdemonstrated that the addition of PCV to radiation ther-apy undoubtedly increased overall survival for patientsharboring the 1p19q codeletion now recognized as trueoligodendroglial tumors according to the recent WorldHealth Organization (WHO) classification for braintumors6 and grade III gliomas with oligodendroglialtumors with mixed morphology without the 1p19qcodeletion but with isocitrate dehydrogenase 1 muta-tions78 These results led to major changes in thestandard treatment of these diseases However it tookmore than 15 years to confirm the benefit of PCV TheEORTC 26951 trial began recruitment in 1996 andrequired 6 years to include 368 patients9 while theRTOG 9402 trial began in 1994 and required 8 years to in-clude 291 patients10 The first reports of effectivenessdate from 2006 and final results were published in 201312

(Table 1)

PCV also produced regressions in low-grade gliomas11

and it was tested as first-line adjuvant treatment in theRTOG 9802 randomized trial which compared radiationversus radiation plus PCV in low-grade gliomas with ahigh risk of relapse This trial initially demonstrated an in-crease in progression-free survival12 and subsequently aclear increase in overall survival in the patients treatedwith radiation plus PCV (133 vs 78 years hazard ratio[HR] for death 059 Pfrac14 0003)3 A total of 251 patientswere included in the trial between 1998 and 2002 andmature results were not published until 20163 It thus took18 years to change the standard of treatment of low-grade gliomas13

PCV has a long trajectory in neuro-oncology dating froma phase II study reported in 197514 and has since beendemonstrated to be an active combination in numerousphase II and several phase III studies15ndash20 PCV was moreactive in anaplastic astrocytoma than in glioblastoma20ndash22

and better results were obtained in tumors with oligo-dendroglial components than in anaplastic astrocy-toma2023 PCV was the control arm in several phase IIItrials in morphologically defined anaplastic tumors 2124ndash27

and in high-grade (III and IV) gliomas2228 in different set-tings Results of randomized clinical trials showed thatPCV was more effective than carmustine (BCNU)21 orlomustineteniposide (CCNUVM26)29 However a retro-spective review of patients treated in the RTOG protocolswith radiotherapy plus either PCV or BCNU found no dif-ferences between the 2 treatments30 Furthermore al-though temozolomide has lower toxicity than PCV it hasnever been shown to be more effective than the PCVcombination272831 (Table 1) Nevertheless temozolo-mide was more effective than procarbazine alone in arandomized phase II trial for patients with relapsedglioblastomas32

After more than 20 years of clinical trials PCV has nowcome into its own as a standard treatment in neuro-oncology Nevertheless over these years there has beenrising concern about the role of vincristine in the PCVregimen Since it is now clear that patients treated withPCV will have long survival the dual objective of preserv-ing quality of life and avoiding unnecessary toxicity hastaken on a more prominent role

Vincristine the BloodndashBrain Barrier andAntitumor ActivityThe bloodndashbrain barrier (BBB) is a physical and biologicalbarrier that protects the brain from pathogens and toxicmolecules and regulates hypometabolic exchanges be-tween the brain and blood to maintain brain homeostasisOnly highly lipophilic molecules can cross the BBB bypassive paracellular diffusion However the BBB is dis-rupted physiologically in restricted zones of the brainclose to the third and the fourth ventricles the circumven-tricular organs and around brain metastases or high-grade primary tumors such as glioblastoma These dis-rupted areas constitute the so-called bloodndashtumor barrier(BTB) where anarchic disorganized and leaky bloodvessels increase permeability and allow the passage ofcertain drugs without lipophilic properties In fact thisphenomenon is the main reason why gadolinium en-hancement reveals the disruption of the BBB in high-grade brain tumors while this disruption seems absent inlow-grade tumors which commonly do not enhance33ndash35

The brain adjacent to tumor (BAT) includes invasive

Volume 2 Issue 2 Unsolved Problems in the Medical Treatment of Gliomas

49

UnsolvedProblems in theMedical Treatmentof Gliomas PCVor PC

Carmen Bala~na1 Anna MariaLopez-Andres2 Anna Estival1

Eva Montane3

1Medical Oncology Catalan Institute of OncologyBadalona (ICO) Barcelona Spain2Fundacio Institut Investigacio Germans Trias iPujol (IGTP) Clinical Pharmacology ServiceHospital Universitari Germans Trias i Pujol3Department of Pharmacology Therapeutics andToxicology Universitat Autonoma de Barcelonaand Clinical Pharmacology Service BadalonaBarcelona Spain

Correspondence to Carmen Balana CatalanInstitute of Oncology (ICO) Hospital GermansTrias i Pujol Ctra Canyet sn 08916 Badalona(Barcelona) Spain Tel thorn34 93 497 89 25 Faxthorn34 93 497 89 50 Email cbalanaiconcologianet

48

IntroductionThe combination of radiation therapy plus chemotherapywith procarbazine lomustine and vincristine (PCV) is thepostsurgical treatment of choice in high-risk low-gradegliomas and in anaplastic oligodendroglial tumorsbased on results of studies demonstrating the superiorityof adding chemotherapy to treatment with local irradi-ation1ndash3 Interest in adding chemotherapy to the treatmentof oligodendroglial tumors arose from observing objectiveresponses with PCV-like chemotherapy in small series ofpatients with recurrent disease45 Two independent stud-ies one by the European Organisation for Research andTreatment of Cancer (EORTC) and the Medical ResearchCouncil Clinical Trials Group (EORTC 26951)2 and theother by the Radiation Therapy Oncology Group (RTOG9402)1 randomized patients with anaplastic oligodendro-glioma or oligoastrocytoma after surgery to receive treat-ment with PCV plus radiotherapy or radiotherapy aloneThe 2 trials differed slightly in study design chemother-apy dose and number of planned cycles Chemotherapywas prior to irradiation in RTOG 9402 and after radiationin EORTC 26951 the doses of lomustine and procarba-zine (PC) were higher and there was no dose ceiling forvincristine in the RTOG 9402 trial Four cycles wereplanned in the RTOG 9402 trial compared with 6 in theEORTC 26951 trial Despite these differences both trialsdemonstrated that the addition of PCV to radiation ther-apy undoubtedly increased overall survival for patientsharboring the 1p19q codeletion now recognized as trueoligodendroglial tumors according to the recent WorldHealth Organization (WHO) classification for braintumors6 and grade III gliomas with oligodendroglialtumors with mixed morphology without the 1p19qcodeletion but with isocitrate dehydrogenase 1 muta-tions78 These results led to major changes in thestandard treatment of these diseases However it tookmore than 15 years to confirm the benefit of PCV TheEORTC 26951 trial began recruitment in 1996 andrequired 6 years to include 368 patients9 while theRTOG 9402 trial began in 1994 and required 8 years to in-clude 291 patients10 The first reports of effectivenessdate from 2006 and final results were published in 201312

(Table 1)

PCV also produced regressions in low-grade gliomas11

and it was tested as first-line adjuvant treatment in theRTOG 9802 randomized trial which compared radiationversus radiation plus PCV in low-grade gliomas with ahigh risk of relapse This trial initially demonstrated an in-crease in progression-free survival12 and subsequently aclear increase in overall survival in the patients treatedwith radiation plus PCV (133 vs 78 years hazard ratio[HR] for death 059 Pfrac14 0003)3 A total of 251 patientswere included in the trial between 1998 and 2002 andmature results were not published until 20163 It thus took18 years to change the standard of treatment of low-grade gliomas13

PCV has a long trajectory in neuro-oncology dating froma phase II study reported in 197514 and has since beendemonstrated to be an active combination in numerousphase II and several phase III studies15ndash20 PCV was moreactive in anaplastic astrocytoma than in glioblastoma20ndash22

and better results were obtained in tumors with oligo-dendroglial components than in anaplastic astrocy-toma2023 PCV was the control arm in several phase IIItrials in morphologically defined anaplastic tumors 2124ndash27

and in high-grade (III and IV) gliomas2228 in different set-tings Results of randomized clinical trials showed thatPCV was more effective than carmustine (BCNU)21 orlomustineteniposide (CCNUVM26)29 However a retro-spective review of patients treated in the RTOG protocolswith radiotherapy plus either PCV or BCNU found no dif-ferences between the 2 treatments30 Furthermore al-though temozolomide has lower toxicity than PCV it hasnever been shown to be more effective than the PCVcombination272831 (Table 1) Nevertheless temozolo-mide was more effective than procarbazine alone in arandomized phase II trial for patients with relapsedglioblastomas32

After more than 20 years of clinical trials PCV has nowcome into its own as a standard treatment in neuro-oncology Nevertheless over these years there has beenrising concern about the role of vincristine in the PCVregimen Since it is now clear that patients treated withPCV will have long survival the dual objective of preserv-ing quality of life and avoiding unnecessary toxicity hastaken on a more prominent role

Vincristine the BloodndashBrain Barrier andAntitumor ActivityThe bloodndashbrain barrier (BBB) is a physical and biologicalbarrier that protects the brain from pathogens and toxicmolecules and regulates hypometabolic exchanges be-tween the brain and blood to maintain brain homeostasisOnly highly lipophilic molecules can cross the BBB bypassive paracellular diffusion However the BBB is dis-rupted physiologically in restricted zones of the brainclose to the third and the fourth ventricles the circumven-tricular organs and around brain metastases or high-grade primary tumors such as glioblastoma These dis-rupted areas constitute the so-called bloodndashtumor barrier(BTB) where anarchic disorganized and leaky bloodvessels increase permeability and allow the passage ofcertain drugs without lipophilic properties In fact thisphenomenon is the main reason why gadolinium en-hancement reveals the disruption of the BBB in high-grade brain tumors while this disruption seems absent inlow-grade tumors which commonly do not enhance33ndash35

The brain adjacent to tumor (BAT) includes invasive

Volume 2 Issue 2 Unsolved Problems in the Medical Treatment of Gliomas

49