ISSN 2518-6507 Volume 2 (2017) Issue 1 World Federation of ...€¦ · EANO Meeting 2016 in...

Volume 2 (2017) Issue 1ISSN 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

Editorial WFNOS MagazineWolfgang Wick Nino Chiocca

Boron Neutron Capture Therapy for Malignant Brain TumorsShin-Ichi Miyatake Shinji Kawabata Ryo Hiramatsu Toshihiko KuroiwaMinoru Suzuki Natsuko Kondo Hiroki Tanaka and Koji Ono

Viral Induction of GliomasChristoph Steininger

Bevacizumab in GlioblastomaRicky Chen Nicholas Butowski

It is Not Just About Biology and Drugs Roger Henriksson

InterviewChristine Marosi

Determinants of long-term survival in glioblastomamdashEORTC 1419Michael Weller

Hotspots in Neuro-OncologyRiccardo Soffi etti

GreetingsKathy Oliver

Erratum


Editors Michael Weller Zurich Switzerland E Antonio Chiocca President SNO

Managing Editors Christine Marosi Vienna Austria 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 WFNOS Magazine

Dear colleagues and friends inneuro-oncology

It is a great pleasure to welcome youto the WFNO Meeting Year 2017With great expectations we are look-ing forward to a splendid world meet-ing in Zurich in early May

Please allow a brief review of theEANO Meeting 2016 in MannheimHeidelberg We have experienced acouple of nice sunny late autumndays in the Rosengarten conferencevenue The meeting has attractedcolleagues from all over the worldand despite a somewhat lower num-ber of attendees has been specifi-cally visited by our younger fellowsMore than one quarter of all partici-pants were PhD students youngPhDs or residents early in their ca-reers In addition EANO was proud

to have launched the Young EANOinitiative at this meeting

In the present magazine you will finda fine selection of specialistsrsquo reviewson the current standard of practice inthe use of bevacizumab Further bio-chemically targeted radiotherapynamely boron neutron capture ther-apy has been evaluated for use inpractice by Dr Miatake fromTaktsuki We would like to draw yourspecial attention to a politically im-portant topic that concerns all neuro-oncology societies that is inequalityof access to treatment socialinequalities and impact on outcomefor cancer patients The article byRoger Henriksson board member ofEANO and host of the EANO Meeting2018 in Stockholm provides a differ-ential view on precision therapy He

lays out that precision medicine isnot only about genes or drugs butshows that patient care largely de-pends also on individual and societalsocial factors We should all try tobridge gaps within our outreachareas and should certainly be pre-pared to draw our attention not onlyto the latest scientific developmentsbut also to improving care for allbrain tumor patients

With best regards andjoyful reading

Wolfgang WickEANO President

Nino ChioccaSNO President

1

Volume 2 Issue 1 Editorial

Boron NeutronCapture Therapyfor MalignantBrain Tumors

Shin-Ichi Miyatake MD PhD12

Shinji Kawabata MD PhD2

Ryo Hiramatsu MD PhD2

Toshihiko Kuroiwa MD PhD2

Minoru Suzuki MD PhD3

Natsuko Kondo MD PhD3

Hiroki Tanaka PhD3 andKoji Ono MD PhD3

1Cancer Center2Department of Neurosurgery Osaka MedicalCollege Takatsuki Japan3Particle Radiation Oncology Research Center KyotoUniversity Research Reactor Institute Kumatori Japan

Corresponding Author

Dr Shin-Ichi Miyatake Cancer Center OsakaMedical College 2-7 Daigaku-Machi Takatsuki Osaka569-8686 Japan Phonethorn81-72-683-1221 Faxthorn81-72-683-4064 Email neu070osaka-medacjp

Acknowledgment This work is partly supported by Osaka Medical College Internal Research Grant

2

AbstractBoron neutron capture therapy (BNCT) is abiochemically targeted radiotherapy based on thenuclear capture and fission reactions that occurwhen nonradioactive boron-10 (10B) which is a con-stituent of natural elemental boron is irradiated withlow-energy thermal neutrons to yield high linear en-ergy transfer alpha particles and recoiling lithium-7nuclei Therefore BNCT enables the application of ahigh dose of particle radiation selectively to tumorcells in which 10B has been accumulated We ap-plied BNCT using nuclear reactors for 167 cases ofmalignant brain tumors including recurrent andnewly diagnosed malignant gliomas and recurrenthigh-grade meningiomas from January 2002 to May2014 Here we introduce the principle and the clini-cal results of our BNCT for the above-mentionedmalignant brain tumors and describe a novel diag-nostic tool fluoride-labeled boronophenylalaninepositron emission tomography

Finally we discuss the recent development ofaccelerators producing epithermal neutron beamsThis development reported here for the first timecould provide an alternative to the current use ofnuclear reactors as a neutron source and couldallow BNCT to be performed in a hospital setting

Keywords boron neutron capture therapymalignant glioma glioblastoma high-grademeningioma positron emission tomography

Introduction andPrinciple of BNCTIn theory boron neutron capture therapy (BNCT) pro-vides a way to selectively destroy malignant cellswhile sparing normal cells BNCT requires 2 compo-nents a neutron and a boron-carrier Sir JamesChadwick discovered the neutron in 1932 and wasawarded the 1935 Nobel Prize in Physics for his dis-covery1 A mere 4 years later Locher introduced theconcept of BNCT2 BNCT is based on the nuclearcapture and fission reactions that occur when boron-10 (10B) which is a nonradioactive constituent of nat-ural elemental boron is irradiated with low-energythermal neutrons to yield high linear energy transfer(LET) alpha particles (4He) and recoiling lithium-7 (7Li)nuclei

In order for BNCT to be successful a sufficient amount of10B must be selectively delivered to the tumor cells(20 lgg weight or109 atomscell) with good contrastof accumulation to surrounding normal cells and a suffi-cient number of thermal neutrons must be absorbed bythe tumor cells to sustain lethal damage from the10B(n a)7Li capture reaction Since the high LET particleshave limited path lengths in tissue (5ndash9 lm) thedestructive effects of high LET particles are limited toboron-containing cells

The principle of BNCT is shown in Figure 1 In thisfigure malignant gliomas in the brain are the pre-sumed target One characteristic of this type of tumoris that it infiltrates the surrounding normal brain andthus care should be taken that the tumor cells selec-tively accumulate the 10B atoms rather than the nor-mal cells This selective accumulation is achieved bythe nature of the 10B-containing compounds them-selves and is discussed in detail in the next sectionAfter the 10B-containing compounds are accumulatedin the tumor cells the tumor cells are irradiated withnonhazardous low-energy thermal neutrons Duringthis process it is not necessary to aim the neutron ir-radiation exclusively at the tumor cells High LET par-ticles will destroy only 10B-containing cells andpreserve the normal surrounding cells as shown inFigure 1

Since BNCT is primarily a biochemically rather thana physically targeted type of radiation treatment thepotential exists to destroy tumor cells dispersed innormal brain tissue if sufficient amounts of 10B andthermal neutrons are delivered to the target volumeas described above In this article we will provide anupdate on BNCT specifically as it relates to thetreatment of recurrent gliomas and recurrent high-grade meningiomas based on our experiences Wewill also introduce the concept of accelerator-basedBNCT

Volume 2 Issue 1 Review of BNCT

3

Selective Accumulationof Boron Compoundsand PET ImagingThere are only 2 boron delivery agents in clinical use thepolyhedral boron anion sodium mercaptoundecahydro-closo-dodecaborate (Na2B12H11SH) commonly knownas sodium borocaptate (BSH)3 and the boron-containingamino acid (L)-4-dihydroxyborylphenylalanine known asboronophenylalanine (BPA)4

Each of these compounds reaches or accumulates in dif-ferent subpopulations of tumor cells in a different fash-ion5 BSH is not delivered into the normal brain throughthe bloodndashbrain barrier and thus the concentration of thiscompound in tumor tissue is related to both the tumorvasculature and its concentration in the blood BPA accu-mulates preferentially in the actively proliferating subpop-ulation via the augmented expression of amino acid

transporters on tumor cells However some of this com-pound inevitably accumulates in normal tissue

The selective destruction of glioblastoma (GBM) cells inthe presence of normal cells represents an even greaterchallenge than malignancies at other anatomic sitessince high-grade gliomas are highly infiltrative into thenormal brain histologically complex and heterogeneousin their cellular composition

To ensure the selective accumulation of BPA and tomake a dose simulation prior to neutron irradiation weused 18F-BPAndashpositron emission tomography (PET) Thisreadily provided us with accurate information on the BPAaccumulation and distribution before neutron irradiation(ie without craniotomy)6ndash8 A representative 18F-BPA-PETimage is depicted in Figure 2 The lesion-to-normal brain(LN) ratio of the enhanced tumor was 78 in this caseNote that even the periphery of the main massmdashthat isthe infiltrative portion of the tumor without contrastenhancementmdashshowed BPA uptake These results wereused to estimate the LN ratio of BPA uptake which inturn was used for the dose planning The PET image

Figure 1 The principle of boron neutron capture therapy

BNCT is a binary approach a boron-10 (10B)ndashlabeled compound is administered that delivers high concentrations of 10B to the targettumor relative to surrounding normal tissues This is followed by irradiation with thermal neutrons or epithermal neutrons that becomethermalized at depth in tissues The short range (5ndash9 lm) of high LET alpha and 7Li particles released from the 10B(n a)7Li neutroncapture reaction realizes tumor-selective killing without damage to adjacent normal brain tissue

Review of BNCT Volume 2 Issue 1

4

provides clear evidence of tumor cellndashselective destruc-tion by BNCT using BPA

BNCT for RecurrentMalignant GliomasInitially we applied BNCT for recurrent malignant gliomasIn the clinical setting either BPA alone or in combinationwith BSH has generally been used for BNCT of recurrentmalignant gliomas On neuroimages marked early shrink-age of the enhanced lesions or perifocal edema was evi-dent in these initial studies910 More than 50 of thecontrast-enhanced volumes disappeared in 8 of the initial12 patients during the follow-up period10 To overcomethe weak points of BNCT as performed in the 1950s andto improve the clinical results we used an epithermalneutron beam instead of a thermal neutron beam sincethe neutron flux by the latter was often insufficient

especially in the deeper parts of the brain In addition weused BSH and BPA simultaneously a method reportedelsewhere as modified BNCT10

Figure 3 shows representative MRI changes in a case ofrecurrent malignant glioma treated by BNCT using BPAas the sole boron compound The original histological di-agnosis was anaplastic oligoastrocytoma and the massrecurred after chemo-irradiation using standard chemora-diotherapy consisting of X-ray treatment (XRT) and temo-zolomide (TMZ) BNCT was applied for this patientaccording to our recent protocol for recurrent malignantgliomas and meningiomas11 Briefly only BPA was ad-ministered over a 2-h period (200 mgkgh) just prior toand during the neutron irradiation (100 mgkgh) Basedon the PET-based simulation described above we chosea neutron irradiation time that would keep the peak braindose below 120 Gy-Eq (Gray-equivalent) Here Gy-Eqcorresponds to the biologically equivalent X-ray dose thatwould have equivalent effects on tumors and on the nor-mal brain Figure 3 shows the marked shrinkage of themass this patient survived more than 4 years after BNCT

Figure 2 Contrast-enhanced T1-weighted MRI of a representative glioblastoma patient and 18F-labeled BPA-PET image after initialdebulking surgery

The patients received 18F-BPA-PET to assess the distribution of BPA and to estimate the boron concentration in tumors before BNCTwithout direct determination of boron concentration in the tumor (A) Gadolinium-enhanced T1-weighted MRI (B) F-BPA-PET image Allimages were obtained after initial debulking surgery and prior to BNCT The lesion-to-normal brain (LN) ratio of the enhanced tumorwas 78 in this case Note that even the periphery of the main mass that is the infiltrative portion of the tumor and non-enhanced areashowed BPA uptake The LN ratio of BPA uptake was estimated from this study and was then used for the dose planning 18F-BPA-PET provided an accurate estimate of the accumulation and distribution of BPA as previously reported3637


5

Next we assessed the survival benefit of treating recur-rent malignant gliomas by BNCT12 Unfortunately how-ever no standard treatment has yet been established forrecurrent malignant gliomas Therefore it was difficult toevaluate the survival benefit of BNCT for recurrent malig-nant gliomas To address this problem we evaluated thesurvival benefit in patients classified into 2 groups low-and high-risk recurrent malignant gliomas by adoptingthe recursive partitioning analysis (RPA) classification forrecurrent malignant glioma advocated by Carson et alThis classification system which was presented in a2007 article in the Journal of Clinical Oncology wasbased on the results of 10 recent protocols of phase I andII trials applied by the New Approaches to Brain TumorTherapy CNS Consortium for recurrent malignant gli-oma13 When we published our initial results of BNCT forrecurrent malignant glioma the survival data were ana-lyzed using 22 consecutive cases of recurrent malignantgliomas treated by BNCT from 2002 to 2007 Here cases

without GBM based on initial histology and with KPS70 were assigned to RPA class 3 while those withGBM based on initial histology age50 and steroid usewere classified as RPA class 7 The median survival times(MSTs) after BNCT for all patients and for glioblastoma ason-study histology at recurrence were 108 months(nfrac14 22 95 CI 73ndash128 mo) and 96 months (nfrac14 1995 CI 69ndash114 mo) in our series respectively TheMST for high-risk RPA classes (class 3thorn 7) was 91months (nfrac14 11 95 CI 44ndash110 mo) By contrast theoriginal data of Carson et al showed that the MST of thesame RPA classes was only 44 months (nfrac14 129 95CI 36ndash54 mo) BNCT showed a marked survival benefitfor recurrent malignant glioma especially in the high-riskgroup12 Moreover the median target volume on contrastMRI in our series was 42 mL which is too large for treat-ment by stereotactic radiosurgery In the Journal ofNeuro-Oncology in 2009 we published data on 22 casesof recurrent malignant glioma treated by BNCT20 among

Figure 3 Representative MRI changes in a case of recurrent malignant glioma treated by BNCT

The patient underwent a craniotomy and the histological analysis indicated anaplastic oligoastrocytoma She received chemo-irradiation with several chemotherapeutic regimens including procarbazinelomustinevincristine and TMZ Unfortunately the massrecurred with aggravation of the left hemiparesis RPA classification for recurrent malignant gliomas was judged as class 3 andtherefore the estimated median survival time at recurrence was 38 months The MRI prior to BNCT showed irregularly enhanced massinfiltrates from the right frontal and temporal lobes into the basal ganglia Two months after BNCT the mass shrunk rapidly Shesurvived more than 4 years after BNCT


6

these 22 cases we lost 5 10 1 and 3 cases due to localtumor progression CSF dissemination a combination ofboth and uncontrollable brain radiation necrosis (BRN)respectively

The biggest drawback of BNCT for recurrent malignantgliomas is the occurrence of BRN and symptomaticpseudoprogression (PsPD) Recurrent malignant gliomacases generally receive nearly 60 Gy XRT prior to reirradi-ation by BNCT Even with tumor-selective particle

radiation BNCT BRN and symptomatic PsPD may de-velop because nonselective gamma-ray and nitrogen-neutron reaction and BPA uptake in normal tissue are in-evitable Occasionally BRN causes severe neurologicaldeficits and sometimes endangers the patientrsquos life Thekey molecule in this pathology is vascular endothelialgrowth factor (VEGF) Bevacizumab an anti-VEGF anti-body has been used recently for the treatment of symp-tomatic BRN1415 We have used bevacizumab in an

Figure 4 A representative case of brain radiation necrosis caused by BNCT and treated with bevacizumab successfully

The right parietal GBM recurred after standard chemoradiotherapy The F-BPA-PET image showed marked tracer uptake in the rightparietal region with a 38 LN ratio of the tracer indicating that the lesion was a recurrent GBM The patient was treated with BNCTPeriodic MRIs showed gradual enlargement of both the enhanced lesion and perifocal edema whereas F-BPA-PET showed a gradualdecrease of the tracer uptake The final LN ratio 13 months after BNCT was 23 This LN ratio and the simultaneous MRI suggestedthat the lesion was brain radiation necrosis The patient was not able to continue his work as a cook and we decided to beginintravenous bevacizumab treatment biweekly (5 mgkg) After 4 treatments MRI showed marked improvement in the perifocal edemaand left hemiparesis The patient is now doing well and has resumed his work as a cook 57 months after the BNCT without tumorprogression or recurrence of the radiation necrosis

A A0 and A00 gadolinium (Gd)-enhanced T1-weighted and fluid attenuated inversion recovery (FLAIR) MRI and F-BPA-PET imagingtaken just prior to BNCT B B0 and B00 Gd-enhanced T1-weighted and FLAIR MRI and F-BPA-PET imaging taken 13 months afterBNCT From B00 we judged that this worsening on MRI represented brain radiation necrosis C C0 Gd-enhanced T1-weighted andFLAIR MRI taken 15 months after BNCT and 2 months after the initiation of bevacizumab treatment D D0 Gd-enhanced T1-weightedand FLAIR MRI taken 57 months after BNCT with bevacizumab treatments


7

attempt to control the symptomatic BRN and the symp-tomatic PsPD encountered after BNCT for recurrent ma-lignant gliomas with promising results16ndash18 ThereforeBNCT with the combination of bevacizumab should im-prove the quality of life and prolong the survival of recur-rent malignant glioma patients In Figure 4 we introducea representative case of BRN caused by BNCT and suc-cessfully treated with bevacizumab

BNCT for NewlyDiagnosed MalignantGliomasHatanaka and his colleagues reported a good result ofBNCT for newly diagnosed malignant gliomas between

1987 and 199419 However Laramore et al20 analyzed thesurvival data of a subset of 12 patients who had beentreated by Hatanaka et al and concluded that therewere no differences in their survival times comparedwith the Radiation Therapy Oncology Group RPAclassifications21

Several clinical studies of BNCT for newly diagnosed ma-lignant gliomas22ndash25 were reported in the first decade ofthe 2000s in Europe and the USA In each of these stud-ies the MST was approximately 13 months Althoughthese survival times were similar to those obtained withsurgery followed by XRT no firm conclusions can bemade as to whether the clinical results of BNCT areequivalent or superior to those of XRT

On the other hand after confirming the effectiveness ofBNCT for recurrent malignant glioma we applied BNCTfor newly diagnosed malignant gliomas most of whichwere GBM We have carried out several clinical studies in

Figure 5 Representative treatment effects of BNCT on high-grade meningioma

A 25-year-old woman who had a history of repetitive recurrence of rhabdoid meningioma (World Health Organization grade III) even afterseveral surgeries and stereotactic radiosurgeries Serial contrast-enhanced axial coronal and sagittal MR images demonstrated that a rightfrontal tumor which had rapidly regrown after the last Gamma Knife surgery was reduced gradually in the 4 months after BNCT Prior toBNCT she manifested left hemiparesis and could mobilize only with a wheelchair whereas she began to walk a week after BNCT

Row A 1 week prior to BNCT row B 2 weeks after BNCT row C 4 months after BNCT


8

which BPA alone or in combination with BSH was admin-istered for treatment of patients with primary surgicallyresected malignant glioma26 In patients with newly diag-nosed GBMs favorable responses were seen usingBNCT with BPA and BSH either with or without an XRTboost especially in high-risk groups The MST of patientstreated with this regimen (BNCT with an X-ray boost) was235 months compared with 156 months (95 CI122ndash239 mo) after diagnosis for patients who hadsurgery followed by BNCT alone This was significantlylonger than the MST of 103 months for the historical con-trols (nfrac14 27) at Osaka Medical College who had under-gone surgical resection followed by XRT andchemotherapy with nitrosourea (mainly ACNU)27 Notethat for these cases TMZ was not used

Similarly Yamamoto et al reported improved survival bycombining BNCT with a photon boost28 Based onthese experiences we recently completed a multicenterphase II Japanese clinical trial to evaluate BNCT incombination with TMZ and an XRT boost (Osaka-TRIBRAIN 0902 NCT00974987) for newly diagnosedGBM We are currently opening the results of thisclinical trial and hope to report on our findings in thenear future

BNCT for High-gradeMeningiomasThe management of high-grade meningioma especiallymalignant meningioma is very difficult In a large series ofpatients with this disease the 5-year recurrence rate ofhigh-grade meningioma was reported as 78ndash8429

The MST of patients has been reported as 689 yearslate mortality due to recurrence after the initial surgeryhas been reported at 6930 Although some treatmentsfor recurrent high-grade meningioma have been reportedincluding chemotherapeutic regimens no standard treat-ment has yet been established31

Since 2005 we have applied BNCT for cases of high-grade meningioma recurrent after or refractory to any in-tensive treatment modality3233 To date we have treated32 consecutive cases of high-grade meningiomas withBNCT Twenty cases were followed up for more than 4years and the MSTs after BNCT and diagnosis were 141(95 CI 86ndash404) and 457 months (95 CI 324ndash707)respectively11 A representative case is shown in Figure 5Like the case shown in this figure all cases responded

Figure 6 A cyclotron-based accelerator for neutron generation and a schematic drawing of an irradiation room including a berylliumtarget collimator and irradiation bed or chair

Courtesy of Sumitomo Heavy Industries Ltd The size of the cyclotron itself is very compact at 3030 1724 1620 meters


9

well to BNCT and showed good shrinkage of the massafter BNCT

However many cases were lost even after BNCT Out of20 cases of high-grade meningioma treated by BNCT welost 13 cases 2 from local tumor progression with radia-tion necrosis 1 from simple local tumor progression 4from systemic metastasis 1 from intracranial distant re-currence outside the irradiation field 3 from CSF dissemi-nation and 2 from other diseases11 These problemsmust be overcome

From Reactor toAcceleratorBefore 2012 all BNCT clinical irradiations were carriedout at nuclear reactor neutron sources As describedabove BNCT is very effective for malignant gliomas andhigh-grade meningiomas The biggest restriction ofBNCT for universal and standard use as radiation therapynot only for malignant brain tumors but also for malignan-cies at other organs is the use of nuclear reactors Morethan 8 such facilities have been constructed for clinicaluse in the USA Argentina Europe and Asia Howevernuclear reactors require a vast amount of land and verylarge structures In addition they run the risk of contami-nation by radioactivity In the disastrous 2011 Tohokuearthquake and tsunami in northern Japan one of the 2nuclear reactors that could be used for BNCT was lost Inaddition as this manuscript is being prepared anotherKyoto University Research Reactor has been orderedclosed since the beginning of June 2014 for a thoroughcheck and maintenance

Another potential source of neutrons are the accelerator-based neutron generators currently being developed inhospital settings Accelerator sources are expected to bemuch easier to license in a hospital setting than nuclearreactors Proponents of accelerator-based neutron sour-ces also believe that they could be more compact andless expensive than comparable reactor sources

For practical use a small accelerator-based neutronsource has been produced in Japan by Sumitomo HeavyIndustries in which a cyclotron is used to generate theprotons (cyclotron-based epithermal neutron source)3435

Figure 6 presents a photograph and a schematic drawingof this cyclotron-based epithermal neutron source sys-tem We have finished a phase I clinical trial for patientswith recurrent malignant gliomas that was the first in theworld to use a cyclotron-based epithermal neutronsource system This was followed by a trial in patientswith recurrent head and neck cancers We are now start-ing a phase II clinical trial for recurrent GBM using acyclotron-based epithermal neutron source Hopefully allnuclear reactors currently in use for clinical BNCT will bereplaced with accelerator-based neutron sources in thenext decade

Differences BetweenBNCT and OtherParticle RadiationModalitiesFinally we should consider the differences between BNCTand other particles such as protons and carbon As we havediscussed BNCT is cell-selective high LET particle radia-tion Thus it is especially efficacious for tumors with an infil-trative nature irrespective of X-ray sensitivity However thereal absorbed dose is still uncertain because the compoundbiological effectiveness is only a putative value In additionthe neutron penetration is limited in depth Finally BPA up-take depends on the biological activity of the target tumorTherefore we do not recommend that BNCT be used forskull base chordomas and so on In contrast protons andcarbon have the merit of achieving a very precise irradiationfield by referencing the Bragg peak However they are notappropriate for tumors with an infiltrative nature In the fu-ture we should apply these highly sophisticated radiationmodalities in a case-specific manner depending on the tar-get tumor characteristics and location

Conflicts of InterestDisclosureThere is no conflict of interest to disclose for any of theauthors

References

1 Chadwick J The existence of a neutron Proc Roy Soc London1932 136692ndash708

2 Locher G Biological effects and therapeutic possibilities of neu-trons American Journal of Roentgenology 1936 361ndash13

3 Soloway AH Tjarks W Barnum BA et al The chemistry of neutroncapture therapy Chem Rev 1998 98(4)1515ndash1562

4 Mishima Y Ichihashi M Tsuji M et al Treatment of malignant mela-noma by selective thermal neutron capture therapy usingmelanoma-seeking compound Journal Invest Dermatol 1989 92(5Suppl)321Sndash325S

5 Ono K Masunaga SI Kinashi Y et al Radiobiological evidence sug-gesting heterogeneous microdistribution of boron compounds in tu-mors its relation to quiescent cell population and tumor cure inneutron capture therapy Int J Radiat Oncol Biol Phys 199634(5)1081ndash1086

6 Imahori Y Ueda S Ohmori Y et al Positron emission tomography-based boron neutron capture therapy using boronophenylalaninefor high-grade gliomas part I Clin Cancer Res 19984(8)1825ndash1832

7 Imahori Y Ueda S Ohmori Y et al Positron emission tomography-based boron neutron capture therapy using boronophenylalaninefor high-grade gliomas part II Clin Cancer Res 19984(8)1833ndash1841


10

8 Takahashi Y Imahori Y Mineura K Prognostic and therapeutic indica-tor of fluoroboronophenylalanine positron emission tomography in pa-tients with gliomas Clin Cancer Res 2003 9(16 Pt 1)5888ndash5895

9 Kawabata S Miyatake S Kajimoto Y et al The early successfultreatment of glioblastoma patients with modified boron neutron cap-ture therapy Report of two cases J Neurooncol 200365(2)159ndash165

10 Miyatake S Kawabata S Kajimoto Y et al Modified boron neutroncapture therapy for malignant gliomas performed using epithermalneutron and two boron compounds with different accumulationmechanisms an efficacy study based on findings on neuroimagesJ Neurosurg 2005 103(6)1000ndash1009

11 Kawabata S Hiramatsu R Kuroiwa T Ono K Miyatake SI Boronneutron capture therapy for recurrent high-grade meningiomasJ Neurosurg 2013

12 Miyatake S Kawabata S Yokoyama K et al Survival benefit of bo-ron neutron capture therapy for recurrent malignant gliomasJ Neurooncol 2009 91(2)199ndash206

13 Carson KA Grossman SA Fisher JD Shaw EG Prognostic factorsfor survival in adult patients with recurrent glioma enrolled onto thenew approaches to brain tumor therapy CNS consortium phase Iand II clinical trials J Clin Oncol 2007 25(18)2601ndash2606

14 Furuse M Kawabata S Kuroiwa T Miyatake S Repeated treat-ments with bevacizumab for recurrent radiation necrosis in patientswith malignant brain tumors a report of 2 cases J Neurooncol2011 102(3)471ndash475

15 Levin VA Bidaut L Hou P et al Randomized double-blind placebo-con-trolled trial of bevacizumab therapy for radiation necrosis of the centralnervous system Int J Radiat Oncol Biol Phys 2011 79(5)1487ndash1495

16 Furuse M Nonoguchi N Kuroiwa T et al A prospective multicentresingle-arm clinical trial of bevacizumab for patients with surgicallyuntreatable symptomatic brain radiation necrosisdaggerNeurooncol Pract 2016 3(4)272ndash280

17 Miyatake S Furuse M Kawabata S et al Bevacizumab treatment ofsymptomatic pseudoprogression after boron neutron capture ther-apy for recurrent malignant gliomas Report of 2 cases NeuroOncol 2013 15(6)650ndash655

18 Miyatake S Kawabata S Hiramatsu R Furuse M Kuroiwa T SuzukiM Boron neutron capture therapy with bevacizumab may prolongthe survival of recurrent malignant glioma patients four casesRadiat Oncol 2014 96

19 Nakagawa Y Hatanaka H Boron neutron capture therapy Clinicalbrain tumor studies J Neurooncol 1997 33(1ndash2)105ndash115

20 Laramore GE Spence AM Boron neutron capture therapy (BNCT)for high-grade gliomas of the brain a cautionary note Int J RadiatOncol Biol Phys 1996 36(1)241ndash246

21 Curran WJ Jr Scott CB Horton J et al Recursive partitioning analysisof prognostic factors in three Radiation Therapy Oncology Group ma-lignant glioma trials J Natl Cancer Inst 1993 85(9)704ndash710

22 Busse PM Harling OK Palmer MR et al A critical examination ofthe results from the Harvard-MIT NCT program phase I clinical trial

of neutron capture therapy for intracranial disease J Neurooncol2003 62(1ndash2)111ndash121

23 Diaz AZ Assessment of the results from the phase III boron neutroncapture therapy trials at the Brookhaven National Laboratory from aclinicianrsquos point of view J Neurooncol 2003 62(1ndash2)101ndash109

24 Henriksson R Capala J Michanek A et al Boron neutron capturetherapy (BNCT) for glioblastoma multiforme A phase II study evalu-ating a prolonged high-dose of boronophenylalanine (BPA)Radiother Oncol 2008 in press

25 Joensuu H Kankaanranta L Seppala T et al Boron neutron capturetherapy of brain tumors clinical trials at the finnish facility using bor-onophenylalanine J Neurooncol 2003 62(1ndash2)123ndash134

26 Kawabata S Miyatake S Kuroiwa T et al Boron neutron capturetherapy for newly diagnosed glioblastoma J Radiat Res (Tokyo)2009 50(1)51ndash60

27 Kawabata S Miyatake S Hiramatsu R et al Phase II clinical studyof boron neutron capture therapy combined with X-ray radiother-apytemozolomide in patients with newly diagnosed glioblastomamultiformemdashstudy design and current status report Appl RadiatIsot 2011 69(12)1796ndash1799

28 Yamamoto T Nakai K Kageji T et al Boron neutron capture therapyfor newly diagnosed glioblastoma Radiother Oncol 200991(1)80ndash84

29 Jaaskelainen J Haltia M Servo A Atypical and anaplastic meningio-mas radiology surgery radiotherapy and outcome Surg Neurol1986 25(3)233ndash242

30 Palma L Celli P Franco C Cervoni L Cantore G Long-term prog-nosis for atypical and malignant meningiomas a study of 71 surgicalcases J Neurosurg 1997 86(5)793ndash800

31 Chamberlain MC The role of chemotherapy and targeted therapy inthe treatment of intracranial meningioma Curr Opin Oncol 201224(6)666ndash671

32 Miyatake S Tamura Y Kawabata S Iida K Kuroiwa T Ono K Boronneutron capture therapy for malignant tumors related to meningio-mas Neurosurgery 2007 61(1)82ndash90 discussion 90ndash81

33 Tamura Y Miyatake S Nonoguchi N et al Boron neutroncapture therapy for recurrent malignant meningioma Case reportJ Neurosurg 2006 105(6)898ndash903

34 Tanaka H Sakurai Y Suzuki M et al Experimental verification ofbeam characteristics for cyclotron-based epithermal neutron source(C-BENS) Appl Radiat Isot 2011 69(12)1642ndash1645

35 Tanaka H Sakurai Y Suzuki M et al Evaluation of thermal neutronirradiation field using a cyclotron-based neutron source for alphaautoradiography Appl Radiat Isot 2014 88153ndash156

36 Imahori Y Ueda S Ohmori Y et al Fluorine-18-labeled fluoroboro-nophenylalanine PET in patients with glioma J Nucl Med 199839(2)325ndash333

37 Miyashita M Miyatake S Imahori Y et al Evaluation of fluoride-labeled boronophenylalanine-PET imaging for the study of radiationeffects in patients with glioblastomas J Neurooncol 200889(2)239ndash246


11

Viral Inductionof Gliomas

Christoph SteiningerDepartment of Medicine I Medical University ofVienna

12

Infectious diseases arefrequently linked withhuman cancerCancer is diagnosed in13 million people annuallyworldwide Infections with bacteria fungi viruses andparasites account for16 of all new cases of cancerevery year The microbes most commonly associatedwith human neoplasm are Helicobacter pylori humanpapilloma viruses hepatitis B and C viruses Epstein-Barrvirus and Kaposi sarcoma herpes virus with a relativecontribution to all cases of 32 30 30 5 and2 respectively The importance of infectious diseasesfor the occurrence of human cancer varies considerablyamong geographic regions and socioeconomic groupsThe institution of large screening programs for cervicalcancer in Western countries for example greatly reducedthe rates of this papilloma virusndashassociated cancer longbefore the development of effective vaccines for the pre-vention of the infection Similarly treatment and particu-larly prevention of hepatitis B virus infection with use ofeffective vaccines and stringent hygiene measures re-duced dramatically the rates of liver cancer in Westerncountries In contrast these infectious diseases are stillvery common causes for human cancer in developingcountries Current knowledge on the association betweenmicrobes and cancer very likely reflects only the tip of aniceberg Multiple new microbes and particularly virusesare discovered every year with the progress in detectionmethods and some of these novel microbes have beenassociated with human cancer such as Merkel cell poly-omavirus (MCPyV) which was named after an aggressiveskin cancer

Gliomas are commonbrain tumorsPrimary brain tumors are cancers that originate in thebrain and develop from glial cells Glial cells provide thestructural backbone of the brain and support the functionof the neurons (nerve cells) which are responsible forthought sensation muscle control and coordinationThe term ldquogliomardquo sums this large and diverse group ofcommon brain tumors which in their microscopic ap-pearance are similar to healthy brain cells (ie astrocytesoligodendrocytes and ependymal cells) For each ofthese different types of gliomas there are cancer typesthat span a broad spectrum of biological aggressivenessAccordingly these brain tumors also differ significantly intheir biological properties prognoses and treatmentapproaches Patients diagnosed with malignant gliomashave to face an aggressive cancer accompanied by in-creasing neurological deficits which also impact their

quality of life including particularly epileptic seizures theside effects of high-dose corticosteroids and thrombo-embolic complications

The role of viruses inthe evolution of gliomasThe origin of these brain tumors however is not clearThe role of infectious pathogens in the evolution of glio-mas has been discussed for decades particularly in viewof the development of effective antimicrobial treatmentsand vaccines against a diversity of bacteria and virusesIdentification of a causal link between microbe and braintumor would potentially open whole new avenues to theprevention and treatment of this disease One of the mostcommonly implicated microbes is human cytomegalovi-rus (CMV) which is a herpes virus that chronically infects40ndash100 of the general population Following primaryinfection CMV remains latently and is dormant for thelifetime of its host in a diversity of human cells The symp-toms may be significant during primary infection (sub-sumed as infectious mononucleosis) but resolvepermanently thereafter Infected individuals may only ex-perience symptoms in the course of reactivations in thepresence of significant immunocompromise such as insolid-organ transplantation

Association ofcytomegalovirus withgliomasCMV was linked to gliomas for the first time in 2002 in astudy by Cobbs and colleagues who demonstrated thepresence of CMV in tumor cells but not adjacent tissuesDetection of viral particles was possible in several differ-ent types of gliomas and with different virus detectionmethods but not in the brains of patients without neuro-logical disease Several follow-up studies further con-firmed this finding by testing glioma samples of patientsfrom other geographic regions and glioma cells after iso-lation from other tissue by culture and with the use ofother detection methods Recent studies could evenshow that the CMV particles detected were from differentstrains of viruses which made it further unlikely that acontamination of samples with CMV during collection orin the laboratory may have caused these positive resultsThe presence of CMV in tissue samples could be corre-lated with a poorer outcome of the glioma Finally treat-ment of glioma cells and animals with gliomas with theantiviral drug cidofovir resulted in an improved survivalHence antiviral treatment of patients with gliomas

Volume 2 Issue 1 Viral Induction of Gliomas

13

appeared to be a whole new and highly effective thera-peutic option

Nevertheless several other studies raised questions withregard to these positive findings Our group could repro-duce the antitumor effect of cidofovir on glioma cells butonly at concentrations of the antiviral drug that may notbe achieved in humans because of toxic side effects(Figure 1) Re-analysis of a successful clinical study onthe effectiveness of another antiviral drug (valganciclovir)in the treatment of gliomas suggested a significant statis-tical miscalculation of results (immortality bias)Screening of glioma tissues for the presence of CMV withthe same methods yielded uniformly negative results in

the hands of other research groups Testing of gliomasamples with use of modern metagenomic methods thatallow the detection of all viral nucleic acids also yieldednegative results

In summary the jury on a causal link of CMV infectionwith the evolution of gliomas is still out Multiple lines ofevidence suggest involvement of CMV infection butstudy results could not be confirmed by many other re-search groups Accordingly antiviral treatment of pa-tients with gliomas appears to be premature given theincomplete evidence for a significant benefit and the con-siderable potential side effect associated with thesecompounds

Figure 1 Effect of cidofovir on glioblastoma cells in vitro Dose-response curves after 72 hours of drug exposure with the indicatedconcentrations of cidofovir were evaluated by MTT assay Assay was performed in triplicate in the indicated glioblastoma cell lines(Lotsch D Steininger C Berger W unpublished data) MTT frac14 3-(45-dimethylthiazol-2-yl)-25-diphenyltetrazolium bromide

Viral Induction of Gliomas Volume 2 Issue 1

14

Bevacizumab inGlioblastoma

Ricky Chen MD NicholasButowski MD

Division of Neuro-Oncology Department ofNeurological Surgery University of California SanFrancisco

15

IntroductionThe use of bevacizumab in glioblastoma (GBM) is a narra-tive filled with promise and disappointment which revealsthe remarkable challenges confronting advancement inthis disease Despite decades of research GBM remains abaleful diagnosis with a dismal prognosis After maximalsurgical resection treatment with radiotherapy plus con-comitant and adjuvant temozolomide chemotherapy is thestandard of care median overall survival (OS) for thosetreated with this standard therapy is no more than 20months[1] Optune or tumor treating field therapy a novelantimitotic device that works through the generation of al-ternating electric fields recently gained approval based ona large randomized trial that concluded it was a safe andeffective adjunct therapy conferring an added survivalbenefit of 48 months over current standard of care[12]

Regardless of treatment GBM invariably recurs causingprogressive neurologic decline and death for most within1ndash2 years with less than 10 of patients surviving be-yond 3 years[3] Patients with disease recurrence face ameager landscape of known effective therapeutic op-tions For some patients with surgically resectable recur-rent tumor reoperation prior to systemic treatment isundertaken with the logic that ensuing treatments may bemore effective with reduction in bulky disease Howeverin many patients reoperation is precluded by risk of injuryto eloquent areas of the brain or rendered impracticalwhen only a small portion of the tumor can be removedlimiting any potential benefit Systemic therapy with otheralkylating agents such as nitrosoureas has only modestbenefit when used at recurrence Also in the recurrentsetting tumor treating field therapy may be as efficaciousas the other commonly used therapies[4]

Bevacizumab a humanized monoclonal antibody that in-hibits vascular endothelial growth factor A (VEGF-A) and hasdemonstrated clinical antitumor activity in other human tu-mors is also approved for use in recurrent GBM[6]bevacizumabrsquos use is based on the fact that VEGF-A is akey regulator of tumor-associated angiogenesis in GBMthat GBMs are highly vascularized tumors and that angio-genesis is a histological hallmark of its diagnosis In fact thesprouting of serpiginous and abnormal new vessels lays outan important mechanism for tumor proliferation and mainte-nance as well as potential spread along perivascular space-s[5] This article briefly reviews the history of bevacizumabuse in glioblastoma and potential future directions

Bevacizumab forrecurrent glioblastomaIn 2008 2 phase II open-label trials were published exam-ining the use of bevacizumab in recurrent glioblastomaboth alone and in combination with irinotecan chemo-therapy The National Cancer Institute study by Kreisl et

al[6] evaluated single-agent bevacizumab at a dose of10 mgkg every 2 weeks in recurrent GBM The trial metits primary endpoint with a 6-month progression-freesurvival (PFS) of 29 which compared favorably withhistorical controls As a secondary endpoint the trialshowed that 35 or 71 of patients had an objective ra-diographic response (by modified Macdonald or WorldHealth Organization [WHO] radiographic criteria respec-tively) Approximately half of patients had reduction ofcerebral edema with improvement of neurological symp-toms and more than half were able to significantly re-duce their corticosteroid dose as a result of therapy Theauthors thus concluded that single-agent bevacizumabhas significant clinical activity in recurrent glioblastomaSimilarly in the BRAIN study by Friedman et al[7] single-agent use of bevacizumab at the same dose and sched-ule was associated with a favorable 6-month PFS of426 compared with historical controls with an objec-tive radiographic response rate of 282 (by WHO radio-graphic criteria) and a trend in decreasing steroid dosesthough this was not rigorously studied As a result of thepromise of these phase II studies neither of whichshowed a survival benefit the FDA granted acceleratedapproval to bevacizumab for the treatment of recurrentglioblastoma anticipating confirmation of efficacy inphase III randomized controlled trials

However clinical efficacy of bevacizumab in these initialtrials was largely based on dramatic radiographic reduc-tion in contrast enhancement and the ability ofbevacizumab to keep gadolinium extravasation low as ameasure of prolonged PFS Although the BRAIN studydid take into account new areas of non-enhancing T2fluid attenuated inversion recovery (FLAIR) lesions to indi-cate progressive disease until the advent of theResponse Assessment for Neuro-Oncology (RANO) crite-ria in 2010 prior radiographic assessment in clinical trialsdid not uniformly evaluate T2FLAIR quantitatively andqualitatively or stipulate durability of responses to be sus-tained for greater than 4 weeks Given the vascular mecha-nism of VEGF inhibition the dramatic notably rapidreduction of contrast enhancement in a large proportion ofpatients raised questions of a likely ldquopseudo-responserdquowhere transient reduction of gadolinium extravasation andalteration of vessel permeability mediated by VEGF inhibi-tion could produce a false impression of tumor reduction

Given the accelerated approval by the FDA based onlargely uncontrolled trials many later trials also failed toincorporate a control arm to compare bevacizumab treat-ment versus therapy without bevacizumab In 2014 theBELOB trial[8] was published and cast doubt upon the bi-ological activity of bevacizumab in gliomas This phase IIopen-label randomized study was initially designed with2 treatment arms bevacizumab alone and bevacizumabplus lomustine However a third arm for control withlomustine alone was added after the EuropeanRegulatory Agency rejected the use of bevacizumab forrecurrent glioblastoma To overcome confounding effectsof potential pseudoresponse the authors avoided

Bevacizumab in Glioblastom Volume 2 Issue 1

16

focusing on PFS which was generally seen as altered bythe gadolinium-restricting effects of anti-angiogenicagents acting to modify vascular permeability Insteadthey measured OS at a time point of 9 months as thestudyrsquos primary end point Furthermore this was one ofthe first trials to employ the new RANO criteria to assessprogression which among other stipulations requiresthat any response (whether partial or complete) be sus-tained for at least 4 weeks and counts any significant in-crease in non-enhancing T2FLAIR lesions that cannot beattributed to any cause other than tumor as indicative ofprogression These modifications became crucial in theera of bevacizumab where researchers were concernedabout the steroid-like effects of pseudoresponse beingmisrepresented as stable or treatment-responsive dis-ease while tumors progressed undetected

In BELOB the groups were noncomparative and thusnot powered to assess differences in survival betweenthe groups Rather each grouprsquos performance was mea-sured against predetermined criteria to determinewhether that therapy or combination was worthy of fur-ther study in a phase III trial Of the treatment groupsonly the combination treatment with bevacizumab andlomustine met the criteria with 63 (combining bothtreatment doses of lomustine) OS at 9 months to warrantfurther study whereas single-agent bevacizumab wasdecidedly inactive clinically with an OS of only 38 at 9months Single-agent lomustine was not much betterwith 43 OS at 9 months though possibly affected by avery limited number of doses received The same storywas seen with regard to median OS as well as OS at 12months Interestingly bevacizumab alone had a moder-ate objective response rate (ORR) of 38 whereaslomustine had a low ORR of 5 though single-agenttreatment with either resulted in very similar PFS and OSThis speaks to the ability of RANO to filter out pseudores-ponse rather than a meaningful difference in PFS

After the results of BELOB showed that bevacizumab usedalone likely has little if any clinical activity against recurrentglioblastoma the window remained open for the possibilityof combining bevacizumab with other agents such as tradi-tional cytotoxic agents Despite the hope for possible effi-cacy of combined lomustine and bevacizumab in BELOBthe follow-up randomized phase III trial by the EuropeanOrganisation for Research and Treatment of CancerEORTC 26101[9] showed that the addition of bevacizumabproduced no additional OS benefit to lomustine alone Thusthe promise of bevacizumab in recurrent glioblastomawhich gained accelerated approval has been unfulfilled

Bevacizumab for newlydiagnosed glioblastomaThe question of whether bevacizumab has efficacy innewly diagnosed patients with glioblastoma was an-swered by 2 large phase III double-blind randomized

studies with a combined total of 1500 patients[1011] whowere randomized to maintenance therapy with eitherbevacizumab or placebo in addition to standard of careradiation plus temozolomide In both the AVAglio andRadiation Therapy Oncology Group (RTOG)-0825 stud-ies bevacizumab did not confer an OS benefit comparedwith the standard of care although crossover in the trialswas not negligible PFS and radiographic response ratewere increased with bevacizumab treatment although thePFS advantage only reached prespecified statistical sig-nificance in the AVAglio study Furthermore there was di-vergence between the 2 studies of a possible impact onquality of life (QoL) with AVAglio suggesting a prolongedstable health-related QoL whereas RTOG-0825 observedsome reduction in particular domains of overall QoL whileother domains remained stable Although post-hoc analy-sis of AVAglio did identify a potential survival benefit in theproneural IDH1 wild-type subgroup of GBM the lack ofstandardized testing for genetic subtypes in the study andthe ad hoc nature of this finding leave the community lessthan convinced The clear conclusion was thatbevacizumab does not improve OS in patients with glio-blastomas whether new or recurrent Although use of thedrug may hold some benefit for PFS in the ldquorightrdquo patientsconsistent with a steroid-like improvement in vasogenicedema it is unclear whether this translates to a significantclinical benefit with a reliable preservation of QoL

What happens at tumorprogression afterbevacizumabtreatmentThe dramatic and relatively immediate reduction in radio-graphic enhancement typically seen in GBM patientstreated with bevacizumab has long suggested that theimpact of the drug on tumor was more related to changesin vessel permeability rather than cytoreductionHowever the actual reasons why bevacizumab and anti-angiogenic treatments have failed to improve OS in glio-blastomas remains an area of investigation Correlativestudies[12] among clinical radiographic and histopatho-logical cases have shown that tumor progression afterprolonged bevacizumab use alters tumor biology andproduces a distinctive phenotype that is invasive in theabsence of angiogenesis In such studies researchersidentified cases of clinical progression with increase inmass-like T2FLAIR hyperintensity in high-grade gliomatumors undergoing bevacizumab treatment without con-comitant increase in enhancement and found recurrenttumor on pathology However despite highly cellular his-tology microvascular proliferation had reduced withbevacizumab treatment compared with profuse vascular

Volume 2 Issue 1 Bevacizumab in Glioblastom

17

proliferation noted upon prior diagnostic pathology InGBM areas of necrosis caused by rampant tumor prolifer-ation and consequent hypoxia are intimately linked to andcharacteristically appear in proximity to vascular prolifera-tion as tumor neo-angiogenesis brings forth aberrant ves-sels to satisfy the great need for oxygen and nutrients tosustain an ambitious rate of growth Yet after bevacizumab-induced ldquonormalizationrdquo of the vasculature studies notenew areas of necrosis in the recurrent or progressive tumordevoid of any vascular proliferation In xenograft modelssimilarly treated with bevacizumab this atypical infiltrativenon-enhancing FLAIR pattern of progression appeared withinvasion along the perivascular spaces of normally existingvessels associated with elevated insulin-like growth factorbinding protein 2 and matrix metalloproteinase 2 potentialmediators of tumor evasion of VEGF inhibition[12] a patternnot similarly appreciated in the controls

Prolonged anti-angiogenic therapy to infiltrative tumorprogression may create selective pressures from hypoxiaand nutrient deprivation that may induce the mechanismsof escape from anti-VEGF therapy (1) hypoxia generatedfrom prolonged inhibition of angiogenesis in this recalci-trant tumor could enable an alternate pathway of angio-genesis separate from the VEGF pathway includingactivation of fibroblast growth factor (FGF) platelet derivedgrowth factor (PDGF) and other endothelial growth factorsto partially reconstitute needed vasculature to sustain tu-mor growth (2) the added metabolic stress on the tumorinduces alternate nonvascular mechanisms of proliferationand spread via neuropil invasion as suggested by thepathological findings in the above study (3) the tumor in-vades along the perivascular spaces of otherwise normalmicrovessels which it adapts as a scaffold for diffuse inva-sion This latter phenomenon dubbedldquoautovascularizationrdquo has been widely discussed in recentyears and is now well supported in preclinical models aswell as clinical samples from human GBM patients Inwork by Baker et al[13] the co-immunolabeling of antibod-ies to vimentin and von Willebrand factor in human GBMbiopsied tissues proves the existence of neoplastic cells inthe perivascular space and ldquosubstantiates perivascular tis-sue invasion as a clinically relevant mechanism of humanmalignant brain tumor growthrdquo The authors argue that theperivascular space of normal microvessels can be an idealscaffold for invasion by virtue of the fact that it is the placeof entry for oxygen and nutrients and the basement mem-brane is rich in highly glycosylated matrix proteins that cansupport cell adhesion and migration as well as stimulatepro-survival pathwaysmdashand for these reasons the perivas-cular space is also often co-opted in the invasive progres-sion of other peripheral cancers

The search forcombinatorial therapiesTrials of numerous other anti-angiogenic therapies inGBM have been thoroughly reviewed in the literature[14]

and found to be unsuccessful including trials of afliber-cept and cedirinib as well as other tyrosine kinase inhibi-tors such as sunitinib and pazopanib among othersStrategies that involve angiogenic pathways outside ofVEGF including thalidomide (which inhibits FGF as wellas VEGF) and celingitide (an inhibitor of integrins impli-cated in activated endothelial cells of gliomas) also haveresulted in disappointment Due to these failures and thatof single-agent bevacizumab to improve OS in GBMthere has been interest in combination strategies withbevacizumab Despite the disappointing clinical findingsmany still hold to the fact that vascular proliferation re-mains the rate limiting step to cancer growth and inva-sion Thus one of the most promising combinatorialapproaches involves pairing bevacizumab with apathway-independent anti-angiogenic attack on tumorco-opted microvasculature VB-111 is a novel viral genetherapy that specifically targets endothelial cells withinthe tumor angiogenic microenvironment for apoptotic celldeath It does so via a nonreplicable adenovirus vector toinfectively transfer an episomal element in vascular cellsthat is preferentially expressed in the right environmentOnly in the angiogenic and hypoxic proliferative climateof tumor-related microvasculature is the signal activatedby recognition of a modified murine promoter of precur-sor protein of endothelin-1 which then expresses a hu-man pro-apoptotic transgene that is a chimera of Fas andtumor necrosis factorndashreceptor 1 (TNF-R1) into the cellmembrane Apoptosis is induced by activation of Fasonly in the setting of TNF-R1 binding by TNF-alpha(which is upregulated in tumor and downregulated in nor-mal tissues) leading to selective apoptosis of angiogenicblood vessels[15] Preclinical studies have found that VB-111 successfully reduced tumor-related capillary densityand extended survival in several GBM xenograft lines[16]A multicenter phase II trial of VB-111 added tobevacizumab in recurrent GBM found a strong signal ofpreliminary efficacy whereby the median OS was nearlydoubled (to 15 mo) compared with historical controls re-ceiving bevacizumab alone (8 mo in the BELOBbevacizumab arm)[17] A subsequent phase III random-ized controlled trial is hoping to confirm efficacy of com-bined VB-111 with bevacizumab over bevacizumab alone(NCT 02511405)

Outside anti-angiogenic therapies other therapies havebeen investigated in combination with bevacizumab inGBM Combination treatment with cytotoxic chemothera-pies such as irinotecan lomustine and temozolomidehave been rigorously explored in trials[79ndash11] with the ra-tionale being that they represent an important but differ-ent mechanism of action and because vascularnormalization by bevacizumab may allow for improveddelivery of these agents to areas of tumor Thus far therehave been no efficacious regimens identified Other com-bination therapies are continuing to be exploredVorinostat is a small-molecule histone deacetylase inhibi-tor that crosses the bloodndashbrain barrier and has preclini-cal antitumor activity but also promotes anti-angiogenic


18

effects[18] including downregulation of VEGF FGF andhypoxia inducible factor 1a and therefore may have utilityin combination with bevacizumab [19]

The Src family of kinases (SFKs) are implicated in thegeneration of increased tumor invasiveness after bevaci-zumab treatment and activate epidermal growth factor re-ceptor PDGF receptor and integrins key pathways ofglioma migration and proliferation Future clinical studiesare supported by preclinical work with xenograft GBMmodels which demonstrate that SFKs are activated afterbevacizumab treatment dasatinib a broad spectrum po-tent inhibitor of all SFKs effectively blocked the increasedtumor invasiveness associated with bevacizumab resis-tance[20] and may be used in trials Ongoing clinical trialsare also poised to test the combination of bevacizumabwith tumor-treating field therapy one of the few otherFDA-approved therapies for patients with GBM in the re-current[4] as well as the newly diagnosed[12] setting[2122] It utilizes a novel mechanism of alternating electricfields to disrupt tumor microtubule polymerization duringmitosis and cause aneuploidy and apoptosis It remainsto be seen whether the addition of bevacizumab couldenhance efficacy of this novel therapy (NCT01894061)

We now know that angiogenesis can facilitate tumor im-mune evasion and anti-VEGF therapies have also beenshown in preclinical studies to increase tumor permeabil-ity to activated T cells rendering the tumor more vulnera-ble to immune attack[14] Rindopepimut a targetedvaccine for the GBM epitope epidermal growth factor re-ceptor variant III conjugated with keyhole limpet hemocy-anin has shown promise in a phase II double-blindrandomized controlled trial in combination withbevacizumab In this ReACT study[23] of 73bevacizumab-naıve patients with recurrent GBM bothPFS and OS were favorably prolonged in the dual ther-apy arm versus bevacizumab plus no-vaccine withoutsignificant toxicity On the last update 25 of patientstreated with rindopepimut plus bevacizumab were stillalive at 2 years compared with none in the controlgroup Unfortunately in a large phase III trial[24] involv-ing patients newly diagnosed with GBM the use ofsingle-agent rindopepimut added to standard of caremaintenance temozolomide offered no survival benefitcompared with vaccine-free controls In this case thecontrol group had matched median OS of 20 monthswhich was surprisingly better than prior matched histor-ical controls Notably compared with the earlierReACT bevacizumab combination therapy was notevaluated in this study and the treatment group wasnewly diagnosed rather than recurrent GBM Thusthere has been no subsequent work to confirm or refutethe preliminary efficacy of combining rindopepimut withbevacizumab in recurrent GBM as previously seen withfurther studies Given the disappointment of the phaseIII trial enthusiasm for future trials using rindopepimuthas waned However other vaccine trials are under wayto explore the ability of bevacizumab to enhance immu-nogenicity in GBM such as the ongoing phase II study

of the heat shock protein vaccine HSPP-96(NCT01814813)

Lastly there has been interest in injection of bevacizumabintra-arterially after bloodndashbrain barrier disruption to con-centrate the dose to the tumor compared with intravenousinfusion which has been studied in small phase II stud-ies[2526] although larger phase II or phase III confirma-tory studies are needed to clarify efficacy (NCT02285959)

Toward imagingprediction of treatmentresponse or failureTo date there have been no established biomarkers topredict response to bevacizumab Howeverbevacizumab investigations in GBM have not only stimu-lated development of standardized imaging criteria tobetter evaluate treatment response but also promptedinvestigations of novel imaging modalities in hopes offinding a predictive model for true prolonged response(efficacy) or early detection of treatment failure in subsetsof patients For example an exploratory analysis usingPET imaging with a MET tracer (11C-methyl-L-methio-nine) an amino acid metabolite that rapidly accumulatesin tumor cells despite an intact bloodndashbrain barrier (unlikethe false harbinger of reduced enhancement with vascu-lar normalization by bevacizumab) has shown a greaterpotential to rule out false positives and identify true re-sponders at 8 weeks from the starting bevacizumab ther-apy when paired with traditional MRI than MRI alone[27]Others have tried to leverage other innate properties ofMRI to detect recurrence sooner than traditional methodsOne study used quantitative maps of increased T1 prolon-gation times to detect slight increases in permeability ofwater (which is a smaller and more penetrable moleculethan standard contrast agents) and hence detect subtlebloodndashbrain barrier disruption associated with tumor re-currence before it becomes visible on conventional imag-ing[28] Similarly promising investigations include MRI-PET imaging[29] and radiomic profiling[30] of numerousquantifiable imaging features in an attempt to isolate animaging biomarker indicative of bevacizumab efficacy

The promise reducedbut hope remainsThe failure of bevacizumab to improve OS in newly diag-nosed or recurrent GBM is a disappointment for patientsand physicians who battle this implacable disease tosome the benefit in PFS and QoL remains controversialHowever a core tenet of GBM biology is that a rate limit-ing step of tumor growth and spread must involve


19

angiogenesis and the field of neuro-oncology continuesthe search for an effective anti-angiogenic strategy to haltthe relentless growth and rampant recurrence of diseaseAt this juncture the promise of bevacizumab althoughsubstantially reduced is not extinguished follow-up ex-amination of imaging prediction of responders and com-binatorial therapies including a burgeoning pipeline inconjunction with vaccines still offers reason for hope

References

1 Stupp R Idbaih A Steinberg DM Read W Toms S Barnett G et alLTBK-01 prospective multi-center phase III trial of tumor treatingfields together with temozolomide compared to temozolomide alonein patients with newly diagnosed glioblastoma Neuro-Oncology201618i1ndashi1

2 Stupp R Taillibert S Kanner AA Kesari S Steinberg DM Toms SAet al Maintenance therapy with tumor-treating fields plus temozolo-mide vs temozolomide alone for glioblastoma JAMA20153142535ndash9

3 Stupp R Hegi ME Mason WP van den Bent MJ Taphoorn MJJanzer RC et al Articles Effects of radiotherapy with concomitantand adjuvant temozolomide versus radiotherapy alone on survival inglioblastoma in a randomised phase III study 5-year analysis of theEORTC-NCIC trial Lancet Oncol 200910459ndash66

4 Stupp R Wong ET Kanner AA Steinberg D Engelhard H HeideckeV et al NovoTTF-100A versus physicianrsquos choice chemotherapy inrecurrent glioblastoma a randomised phase III trial of a novel treat-ment modality Eur J Cancer 2012482192ndash202

5 McConnell HL Kersch CN Woltjer RL Neuwelt EA The translationalsignificance of the neurovascular unit a mini-review J Biol Chem2016jbcR116760215ndash8

6 Kreisl TN Kim L Moore K Duic P Royce C Stroud I et al Phase IItrial of single-agent bevacizumab followed by bevacizumab plus iri-notecan at tumor progression in recurrent glioblastoma J ClinOncol 200927740ndash5

7 Friedman HS Prados MD Wen PY Mikkelsen T Schiff D Abrey LEet al Bevacizumab alone and in combination with irinotecan in re-current glioblastoma J Clin Oncol 2009274733ndash40

8 Taal WT Oosterkamp HMO Walenkamp A et al Single-agent beva-cizumab or lomustine versus a combination of bevacizumab pluslomustine in patients with recurrent glioblastoma (BELOB trial) arandomised controlled phase 2 trial Lancet Oncol 2014151ndash11

9 Wick W Brandes AA Gorlia T Bendszus M Sahm F EORTC 26101phase III trial exploring the combination of bevacizumab and lomus-tine in patients with first progression of a glioblastoma [Internet] JClin Oncol 2016 Available from httpmeetinglibraryascoorgcontent169696-176

10 Gilbert MR Dignam JJ Armstrong TS Wefel JS Blumenthal DTVogelbaum MA et al A randomized trial of bevacizumab for newlydiagnosed glioblastoma N Engl J Med 2014370699ndash708

11 Chinot OL Wick W Mason W Henriksson R Saran F Nishikawa Ret al Bevacizumab plus radiotherapyndashtemozolomide for newly diag-nosed glioblastoma N Engl J Med 2014370709ndash22

12 de Groot JF Fuller G Kumar AJ Piao Y Eterovic K Ji Y et alTumor invasion after treatment of glioblastoma with bevacizumabradiographic and pathologic correlation in humans and mice Neuro-Oncology 201012233ndash42

13 Baker GJ Yadav VN Motsch S Koschmann C Calinescu A-AMineharu Y et al Mechanisms of glioma formation iterative perivas-cular glioma growth and invasion leads to tumor progression VEGF-independent vascularization and resistance to antiangiogenic ther-apy Neoplasia 201416543ndash61

14 Weathers S-P de Groot J VEGF manipulation in glioblastomaOncology (Williston Park NY) 201529720ndash7

15 Triozzi PL Borden EC VB-111 for cancer Exp Opin Biol Ther2011111669ndash76

16 Gruslova A Cavazos DA Miller JR Breitbart E Cohen YC Bangio Let al VB-111 a novel anti-vascular therapeutic for glioblastoma mul-tiforme J Neurooncol 2015124365ndash72

17 Brenner A Cohen Y Vredenburgh J Peters K Nayak L BlumenthalD et al 2901 Phase 2 study of VB- an anti-cancer gene therapy asmonotherapy followed by combination of VB-111 with bevacizu-mab in patients with recurrent glioblastoma Eur J Cancer201551S584

18 Ghiaseddin A Reardon DA Massey W Mannerino A Phase II studyof bevacizumab and vorinostat for recurrent glioblastoma ASCOAnnual Meeting 2015

19 Huveldt D Lewis-Tuffin LJ Carlson BL Schroeder MA Rodriguez FGiannini C et al Targeting Src family kinases inhibits bevacizumab-induced glioma cell invasion PLoS One 20138e56505ndash10


21 Stupp R Hegi ME Mason WP van den Bent MJ Taphoorn MJJanzer RC et al Effects of radiotherapy with concomitant and adju-vant temozolomide versus radiotherapy alone on survival in glioblas-toma in a randomised phase III study 5-year analysis of the EORTC-NCIC trial Lancet Oncol 200910459ndash66


23 Reardon DA Desjardins A Schuster J Tran DD Fink KL NaborsLB et al IMCT-08ReACT long-term survival from a randomizedphase II study of rindopepimut (CDX-110) plus bevacizumab in re-lapsed glioblastoma Neuro-Oncology [Internet] 201517v109ndash9Available from httpneuro-oncologyoxfordjournalsorgcontent17suppl_5v1091fullpdfthornhtml

24 Weller M Butowski N Tran D Recht L Lim M Hirte H et al ATIM-03 ACT IV an international double-blind phase 3 trial of rindopepi-mut in newly diagnosed EGFRvIII-expressing glioblastoma Neuro-Oncology 201618vi17ndash8

25 Chakraborty S Filippi CG Burkhardt J-K Fralin S Ray A Wong Tet al Durability of single dose intra-arterial bevacizumab after bloodbrain barrier disruption for recurrent glioblastoma J Exp Ther Oncol201611261ndash7

26 Burkhardt J-K Riina H Shin BJ Christos P Kesavabhotla KHofstetter CP et al Intra-arterial delivery of bevacizumab afterblood-brain barrier disruption for the treatment of recurrent glioblas-toma progression-free survival and overall survival WorldNeurosurg 201277130ndash4

27 Beppu T Terasaki K Sasaki T Sato Y Tomabechi M Kato K et alMRI and 11C-methyl-L-methionine PET differentiate bevacizumabtrue responders after initiating therapy for recurrent glioblastomaClin Nuclear Med 201641852ndash7

28 Lescher S Jurcoane A Veit A Beuroahr O Deichmann R Hattingen EQuantitative T1 and T2 mapping in recurrent glioblastomas underbevacizumab earlier detection of tumor progression compared toconventional MRI Neuroradiology 20145711ndash20

29 Bennett IE Early perfusion MRI predicts survival outcome in patientswith recurrent glioblastoma treated with bevacizumab and carbopla-tin J Neurooncol 201600ndash0

30 Kickingereder P Go tz M Muschelli J Wick A Neuberger UShinohara RT et al Large-scale radiomic profiling of recurrent glio-blastoma identifies an imaging predictor for stratifying anti-angiogenic treatment response Clin Cancer Res 2016225765ndash71


20

It is Not JustAbout Biologyand Drugs

Roger Henriksson MD PhDProfessor and Chief Physician

Regional Cancer Center Stockholm Gotland andthe Department of Radiation Sciences amp OncologyUniversity of Umea Sweden

21

The survival in cancer has been gradually improving dur-ing the last decades The proportion of patients survivingbeyond 5 years has increased for all cancer diseases in-cluding even those tumors that still have a dismal progno-sis exemplified in the figure below by the situation inStockholm county Sweden

Furthermore the quality of life aspects even in the con-text of short life such as when treating high-grade gli-oma have attracted an increased awareness The overallpattern is therefore positive but at the same time thereare unacceptable variations among different tumor typescountries regions and not least various socioeconomicgroups

Place of Residence andSocioeconomicsAssociations among place of residence level of educa-tion socioeconomic factors and cancer incidence andmortality are well documented and supported by

scientific evidence Population-based data from for ex-ample the Swedish Board of Health and health boards inthe USA and UK show differences in attending cancerscreening cancer incidence and survival There is evi-dence of inequalities at all stages of the patient pathwayfrom information provision and treatment through to palli-ative care It is estimated that at least 10 of all deathsfrom cancer can be attributed to inequalities It is obviousthat some groups who do not have access to informationoptimal resources and services required do not take fulladvantage of these improvements in health Even in themanagement of brain tumors variations related to in-equality have been reported Some of these studiesdemonstrate a strong association between highersocioeconomic status and higher risk of glioma On theother hand in spite of improvement in the overall survivalof patients with high-grade glioma this improvement hasbeen reported to be confined to younger patients and hasbeen most prominent among patients living in high-income districts Similar results are seen in SwedenHowever it has to be emphasized that the knowledge inthese aspects about brain tumors especially for out-come are extremely limited and therefore the ultimate

It is Not Just About Biology and Drugs Volume 2 Issue 1

22

challenge with inequalities must also be more of a focusin neuro-oncology

Lifestyle factors have been found to have an impactupon cancer incidence and mortality and show evidenceof differential levels between socioeconomic populationsThe Swedish authorities and Cancer Research UK areamong those who estimate that around one third to halfof all cancers could be prevented by changes in lifestyleDifferential levels of exposure or engagement in riskyhealth behaviors are the most significant cause ofinequalities in the likelihood of developing cancerAssociations between lifestyle factors and the incidenceand outcome in the treatment of brain tumors includingglioma are still controversial

Tobacco causes9 out of 10 cases of lung cancer aswell as many other cancers Smoking is one of the maincauses of variations in illness and death between thepoor and the wealthy Inequalities in smoking rates there-fore impact cancer rates in different countries and patientpopulation communities No conclusive studies haveshown a correlation between brain tumors and smoking

Almost a third of all cancer deaths have been linked todiet including the risk of cancers in the gastrointestinaltract but an association has also been shown for othercancer types The variations in food consumption be-tween more and less affluent groups are linked to theavailability and cost of food and knowledge of healthyeating The result is that higher-income families tend toconsume healthier versions of most foods compared withlower-income families Moreover people with lower in-comes and lower education levels are less likely to meetgovernment guidelines for healthy eating The link of dietto brain tumors needs to be studied further

A lack of physical activity increases the risk of a numberof cancers and inactive lifestyle is estimated to accountfor around 5 of all cancer deaths Low levels of physicalactivity combined with a poor diet can also lead to obe-sity which is thought to increase cancer risk Adult obe-sity is strongly related to social class Men involved inmanual employment tend to be more active than those innonmanual jobs mainly due to the physical nature of theiroccupations At the same time participation in physicalactivity outside of work is strongly related to householdincome with those in higher-income households morelikely to participate The beneficial effects of physical ac-tivity have also been proposed for patients suffering frombrain tumors Exercise behavior was shown to be astrong independent predictor of survival that provides in-cremental prognostic value to performance status as wellas traditional markers of prognosis in malignant recurrentglioma It has also been shown that there is a decreasedrisk of brain tumor mortality from running and walkingThe recommendations of physical activity above are stillrather generic and additional research is of importanceto develop optimal tools for promoting physical rehabilita-tion in patients suffering from brain tumors Neverthelessthere is a strong belief that the importance of exercise for

cancer patients in general must also be valid for brain tu-mor survivors

A lot of data support that patients with the same cancerat the same stage of development on many occasionsdo not receive the same type of cancer treatment Thisseems also true for brain tumors However inequalities incancer treatment are difficult to identify given the optionsavailable to people according to the type of cancer diag-nosed in them the stage of disease at diagnosis the waythe disease develops and not least the increased pres-ence of comorbidities among those living in deprivedareas and the extent to which other health and lifestylefactors (eg poor diet tobacco use) render people lessphysically able to face or survive cancer treatment Thiscould at least partially explain why there are mixed find-ings regarding correlation between socioeconomic orsociodemographic factors and cancer treatmentFurthermore access to services is often worse for thoseliving in rural areas due to a lack of infrastructure whichcan lead to poorer outcomes for these communitiesThese factors could pose particular problems for older ordisabled individuals who as a result have been found tobe diagnosed at a later cancer stage

Perceptions of CancerRisk and TreatmentPossibilitiesWealthier populations seem more likely to have knowl-edge of cancer risk factors (smoking sunlight etc) com-pared with those at the other end of the socioeconomicscale Early diagnosis of cancer is a critical factor whichdetermines the types of treatment available to an individ-ual and his or her chances of survival Awareness of can-cer symptoms is a crucial factor in early diagnosis aspeople who recognize that their symptoms may be seri-ous are more likely to visit a health care provider For allthe main risk factors the wealthier an individual the morelikely he or she is to be aware of their link to cancer com-pared with people from the most deprived groups andcommunities People from disadvantaged groups canface difficulties in communicating with health profes-sionals Among disadvantaged groups there is evidenceof misunderstanding and more or less fear about cancerThis could result in people being reluctant to seek healthcare People from deprived groups are the most likely todelay seeking medical advice and are therefore morelikely to present at health services (and be diagnosed)when their cancer is at a more advanced stage For thosewith mental health problems the assumptions made byhealth professionals may make it more difficult to getpossible cancer symptoms recognized At the same timecommunication difficulties make incorrect diagnosis orunmet needs for this group more likely

Volume 2 Issue 1 It is Not Just About Biology and Drugs

23

The relationship between inequalities and cancer is com-plex and multifaceted Certain types of cancermdashsuch aslung mouth and esophagusmdashare more likely to be diag-nosed in the most deprived groups For other types ofcancermdashsuch as breast and prostatemdashdeath rates arehigher among the most deprived despite the fact that in-cidence rates are lower There is a substantial amount ofevidence relating to the impact that a range of socioeco-nomic and sociodemographic factors have upon uptakeof cancer services (from screening through to palliativecare) which ultimately lead to decreased survival

A Local InitiativeIn view of the above the Regional Cancer CenterStockholm Gotland has initiated a project in a multicul-tural and multilingual county of Stockholm The goal is toincrease knowledge about cancer and prevention in thiscommunity focusing on lifestyle and self-care A mainpart of this project is to arrange and conduct public infor-mation activities to raise awareness about cancer andcancer prevention Many of these activities are arrangedin collaboration with multicultural organizations that areactive in the community Our experience so far is thatthese information activities bring us closer to populationswe usually do not reach with other health campaignsChallenges encountered in the project include issues re-

lated to language barriers health literacy and differentcultural andor religious attitudes about cancer We haveaddressed the issue of language barriers by having localinterpreters at our meetings and translating the printed in-formation materials into 8 different languages Besides anexcellent collaboration between local and regional stake-holders the active participation of nonndashhealth care pro-fessionals and patient representatives at all levels hasbeen a driving factor for the success of the project Thepeer advisors are in a unique position to reach popula-tions who may be unfamiliar with the Swedish health caresystem and may have a low level of health literacy Thefact that the project manager is a cancer survivor has alsobeen important for the projectrsquos legitimacy

It is Not Just AboutBiologyThe knowledge and awareness of inequalities is in gen-eral low Therefore it is important also in neuro-oncologyto consider whom we reach with our diagnostic and treat-ment efforts Even the most promising cancer treatmentadvances are only as good as our ability to deliver themto patients


24

InterviewChristine Marosichristinemarosimeduniwienacat

25

Driving provides us with individual mobility and a sensa-tion of liberty despite all the reservations one could haveon environment the lack of parking space and trafficjams For most patients with brain tumors losing theauthorization to drive a car is a major impact on theirself-esteem and quality of life We asked the membersof our editorial board to answer a question that everyone

involved in the care of brain tumor patients has beenasked many times

ldquoAm I allowed to driverdquo

The depth of the regulations greatly differs from country tocountry

Editorial Board Member Q1 Does the justice systemof your country provideexplicit laws regulating theauthorization of driving acar after the diagnosis of abrain tumor or is this topicincluded in laws regulatingdriving for patients with epi-leptic seizures

Q2 Are patients withrecurrent brain tumorsand without seizuresallowed to drive

Q3 Do you think thatpatients drive after youhave told them that theyshould not

In Italy the laws regulatingauthorization of a drivinglicense after a diagnosis ofbrain tumor are included inthe laws regarding patientswith epileptic seizures ingeneral In this regard thelaw differentiates betweenldquofirst or unique unprovokedseizurerdquo and ldquoepilepsyrdquodefined by ldquotwo or moreseizures in a time interval ofless than 5 yearsrdquo In the firstcase the patient is declaredfit to drive after a time inter-val of 6 months seizure free

In Italy there is no differ-ence between newlydiagnosed and recurrentbrain tumors patientswith recurrent diseasewithout seizures areallowed to drive in theabsence of significantfunctional disabilities

Yes this could be true inparticular for young ldquofitrdquopatients or when drivingis important for keeping ajob

In case of epilepsy thepatient is authorized to driveafter a period of one yearwithout seizures In eithercase patients are monitoredby a medical committee untilthey have at least 5 yearswithout seizures in theabsence of antiepilepticdrugs

Continued

Interview Volume 2 Issue 1

26

Continued

In Switzerland the situationof driving and seizure is cur-rently hotly debated as acommission of the SwissLeague against Epilepsyreleased new guidelinesabout ldquothe authorization ofdriving following a seizurerdquoin 2015 These guidelinescall for a very strict limitationof a 6-month ban on drivingfor any person who suffereda first unprovoked seizureand 12 months in case ofepilepsy (Commission de lacirculation routiere de laLscE Directives actualiseesde la Commission de la cir-culation routiere de la LigueSuisse contre lrsquoEpilepsie(LScE) Epilepsie et capacitea conduire un vehicule BullMed Sui 200687 6 219ndash221) These periods can beshortened in certain situa-tions (including in case offocal seizures) but can alsobe extended notably in caseof the ldquopresence of progres-sive lesionsrdquo Although notspecifically mentioned braintumors must probably beincluded in the latter situa-tion Moreover this panelrecommends that patients athigh risk (defined asgt40of risk of seizure in the com-ing year) should also be pro-hibited from driving even inthe absence ofseizureThese guidelineshave been discussedintensely and prompted sev-eral reactions from both epi-leptologists and neuro-oncologists as it is felt thatthey are much too restrictivecompared with the globalrisks involved A compara-tive analysis of accidents inthe USA suggested that therisks are well below this limitof 40 (Winston GP JaiserSR Western driving regula-tions for unprovoked first

No specific guidelines areprovided for this situationin Switzerland In myopinion it is important toevaluate the global situa-tion of the patient notonly regarding risk ofseizure but also the neu-ropsychological situationand potential limitationslinked to visual fielddefects

Yes probably

Continued

Volume 2 Issue 1 Interview

27

Continued

seizures and epilepsySeizure 201221(5)371ndash376) Moreover the risk of arecurrent seizure is maximalin the first 3 months (MarsonA Jacoby A Johnson A KimL Gamble C Chadwick DMedical Research CouncilMESS Study GroupImmediate versus deferredantiepileptic drug treatmentfor early epilepsy and singleseizures a randomised con-trolled trial Lancet2005365(9476) 2007ndash2013)

You must tell the Driver andVehicle Licensing Agency[DVLA] if you have a braintumor You must also speakto your doctor who mighttell you to surrender yourlicenseYou can be fined upto pound1000 if you donrsquot tellDVLA about a medical con-dition that affects your driv-ing You may be prosecutedif yoursquore involved in an acci-dent as a result

Patients whose licenseswere suspended canreapply for the reinstate-ment of the licensehttpswwwgovukreapply-driving-licence-medical-condition

I cannot comment on thisas I do not see patients Iam a neuropathologist

Car or motorcycle licenseFill in form B1 and send it toDVLA The address is on theform

Bus coach or lorry licenseFill in form B1V and send it toDVLA The address is on theform httpswwwgovuk

brain-tumour-and-driving httpswwwgovukgov

ernmentpublicationsb1-online-confidential-medical-information

It appears that it is regulatedspecifically for brain tumors

Continued


28

Continued

In the Netherlands accordingto statutory provision 111section 4 130 ndash132 and 134of the Road Traffic Bill of1994 people with braintumors (including brain meta-stasis) are not qualified auto-matically to drive a vehicle Inthe case of people with braintumors the prognosis andany functional impairmentsare the criteria for fitness todrive In contrast to peoplewith cerebrovascular diseasethe Fitness CriteriaRegulation 2001 is based onthe risk of recurrence and therisk of other disorders as wellas any functional impair-ments The proposal is likelyto result in more patients withtumors or cerebrovasculardisease being assessed as fitto drive on group 1 drivinglicenses (cars and motor-cycles) in the case of group 2licenses (heavy goodsvehicles) it is generally some-what more ldquostringentrdquo thanthe current rules Drivinglicense holders should beobliged to notify the author-ities if they contract a disorderthat could affect their fitnessto drive The maximum ageup to which driving licensesremain valid without a furthermedical checkup should bereduced from 70 to 60

Judged on their fitness todrive patients with braintumors are allowed todrive after the CentralBureau for Distribution ofDriving Licenses hasbeen sent a specializedreport In case of visualdisturbance extra condi-tions need to be met Ifmotor or cognitive dis-turbance is mentioned inthis specialized report ayearly driving test is nec-essary to evaluate the fit-ness to drive If a stableclinical condition exists inthe absence of functionaldisabilities a drivinglicense for the maximalduration of 5 years can beissued

Yes but in limited casessuch as fit patients with-out clear disabilities andwith a limited social net-work Although at time ofdiagnosis we stress theimportance not to drivewithout renewal of thedriving license we tendto believe there is somelevel of noncompliancedue to the limiting effectin personal freedom andmovement

The laws in the US differ perstatemdashthough all center onseizure rather than tumor

Yes Yes

Continued


29

Continued

There is no specific law orregulations for patients withbrain tumors And more forepilepsy patients there isalso no specific regulationsHowever a few months agothere was a traffic accidentcaused by a driver who wasan epilepsy patient so weare now discussing making alaw regarding driving a carby a brain tumor patient orepilepsy patient

Yes If the patient has nodeficit (motor weaknessor decreased cognitivefunction) as well as noseizure he or she isallowed to drive Actuallythere is no rule or regula-tion for them

Yes I do They may dothat

The topic is included in lawsregulating driving forpatients with different medi-cal conditions that can affectdriving (sensorimotor deficitvisual deficit visual field def-icit and epileptic seizures)no specific law for braintumor patients In my experi-ence in France brain tumorpatients who are seizure freefor 6 months are in mostcases allowed to drive againby the medical experts whodecide this point

Yes if the neurologicalstatus is ok

Probably yes but I wouldnot say that this is themajority

The justice system allowsthe patientrsquos physician todecide it He should write acertificate of condition todrive to the drive departmentphysician allowing or notdriving and for how longRegulations for brain tumorpatients are the same forthose with epileptic seizures

Yes if they have no otherclinical condition thatprohibits it

Absolutely and unfortu-nately They used to saythat was a neighborhoodof easy driving andfamilies complain butallow it

Continued


30

Continued

Unfortunately our justicesystem does not specifybrain tumors It requires ageneral health certificatebut not a detailed one

Again it is not specified inthe law but it alwayscomes from the treatingphysician

I think some will do

I donrsquot know The patients with recur-rent brain tumor and with-out seizures are allowedto drive

Yes I think that patientsstill drive

In India there is no explicitlaw regulating the authoriza-tion of driving after beingdiagnosed with a braintumor However all drivinglicense applicants have to fillin a form which specificallyasks ldquoDo you have epi-lepsyrdquo If a person answersin the affirmative he or sheis denied a driving licenseUnfortunately most peo-ple do not necessarilyreveal their medical historyof seizures andor use ofanticonvulsant medicationwhen applying for such alicense

There are no laws regulat-ing authorization of driv-ing by patients with braintumors (either newly diag-nosed or recurrent)Given the existing laws inIndia (as clarified above)if the patient has not hada seizure he would beallowed to drive

Yes but this varies fromindividual to individualMany of our patients fromthe lower socioeconomicstrata of society do notdrive simply becausethey do not have accessto a vehicle (car or bike)Among the middle-income and higherincome strata a propor-tion of patients do con-tinue to drive even afterthey have been specifi-cally asked to stop driv-ing However a largemajority do not drive afterunderstanding the

Continued


31

Continued

The Indian EpilepsyAssociation has been cam-paigning for amendment tothe Motor Vehicles Actsuch that epileptics canobtain driving licenses asin other countries (seizurefree for some periods oftime generally 1ndash2 years)

implications (endangeringtheir lives as well as neg-atively impacting publicsafety in case of a seizureepisode while driving)

This topic is included in lawsregulating driving after epi-lepsy A treated patient with-out crises can driveHowever a patient with sec-ondary epilepsy has to wait1 year without any crisisbefore obtaining the greenlight to drive

Yes Yes


32

Determinants of long-term survival inglioblastomamdashEORTC 1419Study chair

Michael Weller MD

Department of Neurology and Brain Tumor Center University Hospital andUniversity of Zurich Frauenklinikstrasse 26 8091 Zurich SwitzerlandMichaelWelleruszch

Glioblastomas represent almost 50of malignant brain tumors in adults andbelong to the most lethal cancer typesdue to their highly infiltrative naturewith approximately half of all affectedpatients dying within the first year of di-agnosis despite a multimodal thera-peutic approach including surgeryradiotherapy and chemotherapyHowever a small percentage of 5 ofall glioblastoma patients survive for 5years and more and are referred to aslong-term survivors Still the group oflong-term survivors is heterogeneousand the determinants of this survivalbenefit are not fully understood so far

Identifying and understanding poten-tial clinical biological and lifestyle-related factors of this long-term sur-vival is the aim of a large comprehen-sive multicenter study that will beconducted in more than 30 sitesworldwide with the support of theBrain Tumor Fundersrsquo Collaborativeand under the lead of the Brain TumorGroup of the European Organisationfor Research and Treatment of Cancer(EORTC) and the Brain Tumor Centerat the University Hospital Zurich Overa period of 2 years extensive clinicaldata of more than 400 confirmed glio-blastoma patients with a survival ofmore than 5 years from first diagnosisare recorded in a central databaseMoreover quality-of-lifendashrelated dataincluding extensive neurocognitive as-sessments are collected to allow for abetter understanding of the implica-tions of the disease as well as the ther-apies in affected patients Formolecular analyses tumor tissue andblood samples are collected centrally

in a large biobank to study genetic fea-tures of glioblastoma in long-term sur-vivors and the results will becompared with a preexisting datasetof glioblastoma patients with shortersurvival Immunological studies areperformed in parallel to potentially es-tablish a specific immunological long-term survivor profile Moreover tumorgrowth patterns and development ofthe tumors will be investigated byanalysis of all neuroimaging studiesavailable from the selected patientswith different imaging tools

Considering the rareness of long-term survival in this disease only amulticenter approach involving asmany clinical neuro-oncological sitesas possible allows for a sufficientnumber of collected patients togather meaningful results Additionalassociated sites have therefore beenauthorized for patient registration andcontribute to the increasing numberof enrolled long-term survivors

The information gained with this studymay contribute and benefit for im-proved survival in all glioblastoma pa-tients in the future and may helpdevelop better treatment strategies ingeneral as well as improve quality of life

EORTC 1419 is open to patientregistration

Questions concerning the protocol orparticipation can be addressed toCaroline Happold(CarolineHappolduszch) Emilie LeRhun (emilielerhunchru-lillefr) TinaVerschuere (tinaverschuereeortcbe) or Michael Weller(MichaelWelleruszch) St

udy

syno

psis

33

Volume 2 Issue 1 Study synopsis

Hotspots in Neuro-Oncology

Riccardo SoffiettiDepartment of Neuro-Oncology UniversityHospital Turin Italy

34

1 Novel METTIE2VEGFR2 inhibitor altiratinib inhibitstumor growth and invasiveness in bevacizumab-resistant glioblastoma mouse models

Piao Y et al Neuro Oncol 2016 Sep18(9)1230ndash1241

Glioblastoma highly expresses the proto-oncogene METin the setting of resistance to bevacizumab MET engage-ment by hepatocyte growth factor (HGF) results in recep-tor dimerization and autophosphorylation mediatingtumor growth invasion and metastasis Evasive revascu-larization and the recruitment of macrophages expressingtunica interna endothelial cell kinase 2 (TIE2) are also trig-gered by antindashvascular endothelial growth factor (VEGF)therapy

The authors investigated the activity of altiratinib (a novelinhibitor of METTIE2VEGF receptor 2) against humanglioblastoma stem cell lines in vitro and in vivo usingxenograft mouse models The biological activity of altirati-nib was assessed in vitro by testing the expression ofHGF-stimulated MET phosphorylation as well as cell via-bility after altiratinib treatment Tumor volume stem celland mesenchymal marker levels microvessel densityand TIE2-expressing monocyte infiltration were evaluatedin vivo following treatment with a comparison with con-trol bevacizumab alone bevacizumab combined withaltiratinib or altiratinib alone

In vitro HGF-stimulated MET phosphorylation was com-pletely suppressed by altiratinib and altiratinib markedlyinhibited cell viability in several glioblastoma stem celllines More importantly in multiple xenograft mouse mod-els altiratinib combined with bevacizumab dramaticallyreduced tumor volume invasiveness mesenchymalmarker expression microvessel density and TIE2-expressing monocyte infiltration compared with bevaci-zumab alone Furthermore in the xenograft model altira-tinib combined with bevacizumab significantly prolongedsurvival compared with bevacizumab alone Togetherthese data suggest that altiratinib may suppress tumorgrowth invasiveness angiogenesis and myeloid cellinfiltration in glioblastoma Thus altiratinib administeredalone or in combination with bevacizumab may overcomeresistance to bevacizumab and prolong survival inpatients with glioblastoma

2 Primary CNS lymphoma at first relapseprogres-sion characteristics management and outcome of256 patients from the French LOC network

Langner-Lemercier S et al Neuro Oncol 2016Sep18(9)1297ndash1303

The treatment of relapsedrefractory (RR) primary CNSlymphoma (PCNSL) is poorly defined because random-ized trials and large studies are lacking The aim of thisstudy was to analyze the characteristics managementand outcome of RR PCNSL patients after first-line ther-apy in a nationwide cohort The authors analyzed RRPCNSL patients following first-line treatment who hadbeen prospectively registered in the database of the

French network for oculocerebral lymphoma (LOC)between 2011 and 2014

Among 563 PCNSL patients treated with first-line therapy256 patients with relapsed (nfrac14 93 165) or refractory(nfrac14 163 290) disease were found Patients who wereasymptomatic at relapseprogression (255) mostlydiagnosed on routine follow-up neuroimaging tended tohave a better outcome Patients who received salvagetherapy followed by consolidation (mostly intensivechemotherapy plus autologous hematopoietic stem celltransplantation [ICT thorn AHSCT]) experienced prolongedsurvival compared with those who did not receive sal-vage or consolidation therapy Independent prognosticfactors at first relapseprogression were KPS 70 ver-sus KPS lt70 sensitivity to first-line therapy (relapsed vsrefractory disease) duration of first remission (progres-sion-free survival [PFS] 1 y vslt 1 y) and managementat relapseprogression (palliative care vs salvagetherapy)

In conclusion patients who relapsed early after first-linetherapy (ie PFSlt1 y) had a poor outcome comparableto that of refractory patients Conversely patients experi-encing late relapses (PFS1 y) andor undergoing con-solidation with ICTthorn AHSCT experienced prolongedsurvival

3 Upfront bevacizumab may extend survival for glio-blastoma patients who do not receive second-linetherapy an exploratory analysis of AVAglio

Chinot OL et al Neuro Oncol 2016 Sep18(9)1313ndash1318

In this post-hoc exploratory analysis the authors exam-ined outcomes for patients enrolled in the AVAglio trial offront-line bevacizumab or placebo plus radiotherapytemozolomide who received only a single line of therapyPatients with newly diagnosed glioblastoma receivedprotocol-defined treatment until progressive disease(PD) Co-primary endpoints were investigator-assessedprogression-free survival (PFS) and overall survival (OS)After confirmed PD patients were treated at the investi-gatorsrsquo discretion PFSOS were assessed in patientswith a PFS event who did not receive post-PD therapy(Group 1) and patients with a PFS event who receivedpost-PD therapy plus patients who did not have a PFSevent at the final data cutoff (Group 2) KaplanndashMeiermethodology was used A multivariate Cox proportionalhazards model for known prognostic variables wasgenerated

Baseline characteristics were balanced In patients with aPFS event who did not receive post-PD therapy (Group 1nfrac14 225 [244 of the intent-to-treat population]) theaddition of bevacizumab to radiotherapytemozolomideresulted in a 36-month extension in both median PFS(hazard ratio [HR] 062 Pfrac14 0016) and median OS (HR067 Pfrac14 0102) Multivariate analyses supported this OSbenefit (HR 066) In the remaining patients (Group 2nfrac14 696) a 52-month PFS extension was observed in

Volume 2 Issue 1 Hotspots in Neuro-Oncology

35

bevacizumab-treated patients (HR 061 Plt 0001)while OS was comparable between the treatment arms(HR 088 Pfrac14 1502) No significant differences in safetywere observed between the 2 groups

In conclusion this exploratory analysis suggests that theaddition of bevacizumab to standard glioblastoma treat-ment prolongs PFS and OS for patients with PD whoreceive only one line of therapy Unfortunately theseresults will not affect the indications of bevacizumab(patients relapsed after the Stupp protocol)

4 Long-term analysis of the NOA-04 randomizedphase III trial of sequential radiochemotherapy ofanaplastic glioma with PCV or temozolomide

Wick W et al Neuro Oncol 2016 Nov18(11)1529ndash1537

Optimal treatment and precise classification for anaplas-tic glioma are needed The objective for long-term follow-up of German NOA-04 was to optimize the treatmentsequence for patients with anaplastic gliomas Patientswere randomized 211 to receive the standard radiother-apy (RT) (arm A) procarbazine lomustine and vincristine(PCV) (arm B1) or temozolomide (TMZ) (arm B2) Resultsshowed that primary endpoint was time-to-treatment-failure (TTF) defined as progression after 2 lines of ther-apy or any time before if no further therapy was adminis-tered Exploratory analyses examined associations ofmolecular marker status with TTF progression-freesurvival (PFS) and overall survival (OS)

At 95 years (95 CI 86ndash102) no difference betweenarms A versus B1B2 was observed in median TTF (46 y[34ndash51] vs 44 y [33ndash53]) PFS (25 y [13ndash35] vs 27 y[19ndash32]) and OS (8 y [55ndash103] vs 65 y [54ndash83])Oligodendroglial versus astrocytic histologymdashbut moreso the subgroups according to cytosine-phosphate-guanine island methylator phenotype (CIMP) and 1p19qcodeletion statusmdashrevealed a strong prognostic value ofCIMP(pos) with (CIMP(codel)) versus without 1p19qcodeletion (CIMP(non-codel)) versus CIMP(neg)) but nodifferential efficacy of RT versus chemotherapy for any ofthe endpoints PFS was better for PCV- than for TMZ-treated patients with CIMP(codel) tumors (HR B1 vs B2039 [017ndash092] Pfrac14 031) In CIMP(neg) tumors hyper-methylation of the O6-DNA methylguanine-methyl-transferase promoter provided a risk reduction for PFSwith chemotherapy

In conclusion there is no differential activity of primarychemotherapy versus RT in any subgroup of anaplasticglioma Molecular diagnosis for prediction of outcomeseems superior to conventional histology

5 Neurocognitive function varies by IDH1 geneticmutation status in patients with malignant gliomaprior to surgical resection

Wefel JS et al Neuro Oncol 2016 Dec18(12)1656ndash1663

Patients with malignant gliomas present with variation inneurocognitive function (NCF) not attributable to lesionsize or location alone A potential contributor is the rate at

which tumors grow or ldquolesion momentumrdquo Isocitratedehydrogenase 1 wild type (IDH1-WT) tumors are moreproliferative and aggressive than IDH1 mutant (IDH1-M)tumors The authors hypothesized that patients with

IDH1-WT would exhibit worse NCF than patients withIDH1-M tumors Comprehensive NCF testing wascompleted in 119 patients with malignant glioma prior tosurgical resection IDH1 status was determined withimmunohistochemistry and sequencing Rates of impair-ment and mean test performances were compared byIDH1

NCF impairment was significantly more frequent in pa-tients with IDH1-WT tumors in terms of memory process-ing speed visuoconstruction language executivefunctioning and manual dexterity Mean performances ofpatients with IDH1-WT were also significantly lower thanthose with IDH1-M tumors on measures of learning andmemory processing speed language executive func-tioning and dexterity Lesion volume was not statisticallydifferent between IDH1-WT and IDH1-M tumors Tumorand lesion volumes on T1-weighted and fluid attenuatedinversion recovery MRI were significantly associated withmost NCF tests in patients with IDH1-WT but only signifi-cantly associated with a single measure in patients withIDH1-M tumors

In conclusion patients with IDH1-WT show reduced NCFcompared with those with IDH1-M malignant gliomasLesion volume is inversely associated with NCF for pa-tients with IDH1-WT but not IDH1-M tumors These find-ings are consistent with the hypothesis that patients withIDH1-WT tumors present with more severe NCF impair-ment due to greater lesion momentum which mayimpede compensatory neuroplasticity and cerebralreorganization

6 Clinical parameters outweigh diffusion- andperfusion-derived MRI parameters in predictingsurvival in newly diagnosed glioblastoma

Burth S et al Neuro Oncol 2016 Dec18(12)1673ndash1679

The purpose of this study was to determine the relevanceof clinical data apparent diffusion coefficient (ADC) andrelative cerebral blood volume (rCBV) from dynamic sus-ceptibility contrast (DSC) perfusion and the volume trans-fer constant from dynamic contrast-enhanced (DCE)perfusion for predicting overall survival (OS) andprogression-free survival (PFS) in newly diagnosed treat-ment-naıve glioblastoma patients Preoperative MRscans including standardized contrast-enhanced T1(cT1) T2 fluid attenuated inversion recovery (FLAIR)ADC DSC and DCE of 125 patients with subsequenthistopathologically confirmed glioblastoma were per-formed on a 3 Tesla MRI scanner ADC DSC and DCEparameters were analyzed in semiautomatically seg-mented tumor volumes on cT1 and hyperintense signalchanges on T2 FLAIR Univariate and multivariate Cox re-gression analyses including age sex extent of resection

Hotspots in Neuro-Oncology Volume 2 Issue 1

36

(EOR) and KPS were performed to assess the influenceof each parameter on OS and PFS

Univariate Cox regression analysis demonstrated a sig-nificant association of age KPS and EOR with PFS andof age KPS EOR lower ADC and higher rCBV with OSMultivariate analysis showed independent significance ofmale sex KPS EOR and increased rCBV contrast en-hancement for PFS and of age sex KPS and EOR for

OS The conclusion was that MRI parameters help topredict OS in a univariate Cox regression analysis andincreased rCBV contrast enhancement is associated withshorter PFS in the multivariable model

In summary these findings suggest that the relevance ofMRI parameters is outperformed by clinical parameters ina multivariable analysis which limits their prognosticvalue for survival prediction at the time of initial diagnosis


37

Greetings

We all have high hopes that 2017 willbring good news of promising thera-peutic advances in the treatment ofbrain and CNS tumors A number ofrecent developments have beenencouraging In 2016 these includedan update by the World HealthOrganization of its classificationsystem for brain tumors which nowfocuses on molecular profilestogether with traditional histopathol-ogy to reclassify tumor entities Thiswill lead in 2017 and beyond tomore accurate diagnoses and betterstratification in clinical trials as wellas more appropriate personalized

treatments for brain tumor patientsSome of the examples that signifyreasons to be optimistic for the futureinclude immunotherapeuticapproaches further study intobiomarkers and liquid biopsies theuse of innovative devices efforts toimprove drug delivery and a moreprominent focus on quality of lifeissues for brain tumor patients Braintumor patient advocacy is alsomaking great strides as we forge newand exciting collaborations with thescientific community and arebecoming much more activelyinvolved in providing the patient voice

in the research and development ofnew treatments and supportive carePatient advocates are also playing anincreasingly important role in policyand regulatory work We hope thatwith all of these developments andothers we will see some significantadvances in brain tumor treatment inthe near future

Kathy OliverChair and Co-Director

International Brain Tumour Alliance(IBTA)

PO Box 244Tadworth SurreyKT20 5WQUnited Kingdom

38

Volume 2 Issue 1 Greetings

ErratumIn the article ldquoIntroduction of the Korean Society for Neuro-Oncology (KSNO)rdquo in volume 1 issue 3 of World Federationof Neuro-Oncology Societies Magazine the editors would like to correct the author name credited to this article asfollows

Yun Hwan Jung MD PhD

President Korean Society for Neuro-Oncology

Professor Department of Internal Medicine

Chungnam National University Medical Center

Jeong Hoon Kim and Chul-Kee Park are chair and secretary of Scientific Committee of KSNO respectively The editorsapologize for the oversight

39


Editors Michael Weller Zurich Switzerland E Antonio Chiocca President SNO

Managing Editors Christine Marosi Vienna Austria 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











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Michael Weller MD









udy

syno

psis

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Greetings







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27

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29

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31

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Michael Weller MD









udy

syno

psis

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Greetings







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32


Michael Weller MD









udy

syno

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Greetings







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29

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30

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32


Michael Weller MD









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syno

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Greetings







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28

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29

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30

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32


Michael Weller MD









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syno

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Greetings







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32


Michael Weller MD









udy

syno

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Greetings







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32


Michael Weller MD









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syno

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Greetings







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Michael Weller MD









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syno

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29

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30

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32


Michael Weller MD









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syno

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27

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Yes Yes

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29

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30

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31

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Yes Yes


32


Michael Weller MD









udy

syno

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33




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References









10

































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29

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30

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31

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32


Michael Weller MD









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syno

psis

33




34

















35



















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Greetings







38








39

































11



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29

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32


Michael Weller MD









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syno

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34

















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32


Michael Weller MD









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32


Michael Weller MD









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syno

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33




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32


Michael Weller MD









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syno

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33




34

















35



















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Greetings







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39




15









16








17







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19


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20




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Continued


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27

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28

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29

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30

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31

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32


Michael Weller MD









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syno

psis

33




34

















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16








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28

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29

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30

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32


Michael Weller MD









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syno

psis

33




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35



















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29

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30

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32


Michael Weller MD









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syno

psis

33




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35



















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37

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39







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Continued


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Yes Yes

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29

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30

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32


Michael Weller MD









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syno

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33




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29

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30

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32


Michael Weller MD









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syno

psis

33




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39


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20




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29

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32


Michael Weller MD









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syno

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33




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38








39




21






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29

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32


Michael Weller MD









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syno

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33




34

















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37

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39






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32


Michael Weller MD









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syno

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33




34

















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36






37

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38








39










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29

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32


Michael Weller MD









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syno

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33




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32


Michael Weller MD









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syno

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33




34

















35



















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37

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38








39


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28

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29

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30

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32


Michael Weller MD









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syno

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33




34

















35



















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37

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29

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32


Michael Weller MD









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syno

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33




34

















35



















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37

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39

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29

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32


Michael Weller MD









udy

syno

psis

33




34

















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37

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38








39

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29

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32


Michael Weller MD









udy

syno

psis

33




34

















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37

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38








39

Continued





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29

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30

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31

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32


Michael Weller MD









udy

syno

psis

33




34

















35



















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37

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38








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30

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32


Michael Weller MD









udy

syno

psis

33




34

















35



















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37

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39

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31

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32


Michael Weller MD









udy

syno

psis

33




34

















35



















36






37

Greetings







38








39

Continued




Yes Yes


32


Michael Weller MD









udy

syno

psis

33




34

















35



















36






37

Greetings







38








39


Michael Weller MD









udy

syno

psis

33




34

















35



















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38








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38








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Greetings







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ISSN 2518-6507 Volume 2 (2017) Issue 1 World Federation of ...€¦ · EANO Meeting 2016 in...

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