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A multi-disciplinary consensus statementconcerning surgical approaches to low-grade,high-grade astrocytomas and diffuse intrinsicpontine gliomas in childhood (CPN Paris2011) using the Delphi method

David A. Walker, JoFen Liu, Mark Kieran, Nada Jabado, Susan Picton, Roger Packer,and Christian St. Rose (on behalf of the CPN Paris 2011 Conference ConsensusGroup)

Children’s Brain Tumour Research Centre, University of Nottingham, Queen’s Medical Centre, Nottingham,

United Kingdom (D.A.W., J.L.); Dana-Farber Cancer Institute, Boston, Massachusetts (J.L., M.K.); McGill

University Health Centre, Montreal Children’s Hospital Research Institute, Montreal, Quebec, Canada (N.J.);

Regional Paediatric Oncology Unit, St James’s University Hospital, Leeds, United Kingdom (S.P.); Children’s

National Medical Centre, Washington, DC(R.P.); and Service de Neurochirurgie, Hopital Necker-Enfants

Malades, Paris, France (C.R.)

Astrocytic tumors account for 42% of childhood braintumors, arising in all anatomical regions and associatedwith neurofibromatosis type 1 (NF1) in 15%.Anatomical site determines the degree and risk of resect-ability; the more complete resection, the better the sur-vival rates. New biological markers and modernradiotherapy techniques are altering the risk assessmentsof clinical decisions for tumor resection and biopsy. Theincreasingly distinct pediatric neuro-oncology multidis-ciplinary team (PNMDT) is developing a distinct evi-dence base.

A multidisciplinary consensus conference on pediatricneurosurgery was held in February 2011, where 92invited participants reviewed evidence for clinicalmanagement of hypothalamic chiasmatic glioma(HCLGG), diffuse intrinsic pontine glioma (DIPG),and high-grade glioma (HGG). Twenty-seven statementswere drafted and subjected to online Delphi consensusvoting by participants, seeking .70% agreement from.60% of respondents; where ,70% consensus

occurred, the statement was modified and resubmittedfor voting.Twenty-seven statements meeting consensus criteria

are reported. For HCLGG, statements describingoverall therapeutic purpose and indications for biopsy,observation, or treatment aimed at limiting the risk ofvisual damage and the need for on-going clinical trialswere made. Primary surgical resection was notrecommended. For DIPG, biopsy was recommended toascertain biological characteristics to enhance under-standing and targeting of treatments, especially in clini-cal trials. For HGG, biopsy is essential, the WorldHealth Organization classification was recommended;selection of surgical strategy to achieve gross total resec-tion in a single or multistep process should be discussedwith the PNMDT and integrated with trials based drugstrategies for adjuvant therapies.

Keywords: low-grade astrocytoma.

Astrocytic tumors account for 42.3% of braintumors in the childhood age range.1 The over-whelming majority are low-grade pilocytic histol-

ogy (grade1), with ,7% occurring as fibrillary (grade 2)tumors and 20% as high-grade tumors (malignantgliomas and diffuse intrinsic pontine glioma); oligoden-droglial tumors are very rare. The association between

Corresponding author:David A.Walker, BMBS, Professor of Paediatric

Oncology, Children’s Brain Tumour Research Centre, University of

Nottingham, Queen’s Medical Centre, Nottingham NG7 2UH, UK

([email protected]).

Received August 14, 2012; accepted December 4, 2012.

Neuro-Oncology 15(4):462–468, 2013.doi:10.1093/neuonc/nos330 NEURO-ONCOLOGY

# The Author(s) 2013. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.All rights reserved. For permissions, please e-mail: [email protected].

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neurofibromatosis type 1 (NF1), particularly in low-grade astrocytoma (15%), and the impact of thisgenetic predisposition on the clinical presentation,natural history, and response to treatment are majorfactors in determining treatment approaches withrespect to surgery, radiotherapy, and selection of drugs.

The low-grade tumors characteristically are clusteredanatomically to midline supratentorial structures in39%, including hypothalamus, optic chiasm andnerves, ventricular system, and other midline structures;the cerebellum in 32%; the cerebral cortex in 13.1%; thebrainstem in 10%; and the spinal cord in 4.5%.2

Anatomical distribution of highgrade tumors is marked-ly different with cortical tumors, accounting for 63%,midline supratentorial structures for 28%, and brain-stem for 11%.3 Anatomical site determines resectability,which, in turn, when complete, is associated with bettersurvival outcomes in both low-grade and high-gradetumors. Brainstem tumors are now considered to besafe targets for either stereotactic or open biopsy, withmodern techniques in specialist pediatric centers.Refinement of surgical approaches to the hypothalamictumors has highlighted the potential for surgical resec-tion in low-grade tumors in selected cases.

International clinical trials have highlighted the im-portance of age as a major factor interacting withtumor behavior (progression risk) in low-grade tumorsand tumor biology in high-grade tumors. Recent re-search identifying new biological markers of tumor clas-sification and new druggable targets for trials hasprovided an opportunity to explore novel approachesto therapy. Modern radiotherapy techniques, withtheir enhanced capacity to limit the volume of normalbrain irradiated, are reducing the risk of radiationbrain injury. The experience of applying this new knowl-edge and refined treatment techniques is altering clinicalrisk assessments surrounding decisions regarding tumorresection and biopsy. Multidisciplinary pediatric neuro-oncology teams are becoming more clearly distinguishedfrom the adult neuro-oncology teams as the evidencebase for practice in childhood develops further.

For these reasons, author C.S.R. initiated an interna-tional consensus meeting to review current evidence,underpinning surgical practice in these tumors. Themeeting involved 92 selected clinical and scientific spe-cialists. The aim was to review the evidence forchanges in surgical practice in astrocytomas of child-hood and to establish a new consensus on surgicalapproaches to these tumors when managed within thecontext of a pediatric multidisciplinary neuro-oncologyteam.

Methods

Consensus Process

The second Consensus Conference on Pediatric Neuro-surgery was held in Paris, France, on 11–12 February2011 (CPN2011). During the meeting, 92 participants

reviewed the evidence for clinical management and out-comes in hypothalamic chiasmatic low-grade glioma(HCLGG), diffuse intrinsic pontine glioma (DIPG),and high-grade glioma (HGG) with the intention of in-forming consensus discussions with a designated panelthat took place at the end of each session.

The panel subsequently drafted 27 statements basedon the workshop discussion for consideration using theDelphi consensus methodology by the meeting’s partici-pants with use of e-mail for distribution and aweb-basedsurvey tool for responses. Participants were asked to rateeach statement as “I don’t support the statement,” “Iwould support the statement with modification,” or “Isupport the statement.” A comments section was also in-cluded for each statement to permit suggested modifica-tions. A statement was accepted if .70% of votes werein support from .60% of the attendees in each round ofvoting.

Fig. 1 shows the consensus process. The firstquestionnaire was sent on 03 March 2011. All 92CPN2011 participants were invited via e-mail, butonly 85 e-mail addresses were valid. Among those, 58replied, for a response rate of !68%. Twenty-two of27 questions achieved .70% support. The 5 unsuccess-ful statements were then revised after discussion with theconsensus of panel members, and the invitation of thesecond round was sent on 18 May 2011. The responserate was 81% (47 of 58) in the second round, and allrevised statements gained .70% support. Five partici-pants who did not respond in the first round approachedus in the second round and completed the question-naires. They were asked to review the 22 statementsfrom round 1 and the 5 revised statements in round 2 to-gether, and their votes were included in the analysis(Fig. 1). A total of 52 health care professionals complet-ed both rounds of the survey; the dropout rate was38.8% overall. Final statements for the t3 types of pedi-atric brain tumors are discussed below.

Consensus Statements

HCLGG

(1) Overall therapeutic purpose.

(a) The overall aim of therapy in childhood andadolescent HCLGG is to gain time by con-trolling tumor progression and to preservefunction.

(b) Multidisciplinary discussion should be themethod adopted for all patients’ diagnosticassessments and clinical decision-making.

(2) Anatomical staging.

A revised anatomy-based staging system based on thecurrent imaging techniques should be developed toassist standardized, surgical assessment of hypothalamicchiasmatic tumors that includes criteria to predict risk ofseverity of bilateral visual loss, surgical resectability,tumoral vascularity, tumor size, genetic status, and ageat assessment. The modified Dodge PLAN classification

Walker et al.: A multi-disciplinary consensus statement concerning surgical approaches using the Delphi method

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was designed to predict visual risk.4 Development of arevision of this classification with additional surgicaland clinical factors is proposed.

(3) Combined histopathological and biological/genetic classification.

Rapid developments in this field means that combinedhistopathological and biological assessment of tumorscan be imminently anticipated as an essential require-ment of future clinical trials.

(4) Tumor biopsy: at diagnosis,

(a) Typical intrinsic optic pathway tumors in as-sociation with NF1 do not require biopsy atthe time of diagnosis.

(b) For typical intrinsic optic pathway tumors inassociation with NF1, it is acceptable toperform a biopsy after multidisciplinarydiscussion by a specialist pediatric neuro-oncology team (including a pediatric neuro-surgeon) before offering a clinical interven-tion when they are being managed in aclinical trial that involves a relevant biologi-cal stratification or question.

(5) Tumor biopsy: before nonsurgical treatment insporadic tumor

(a) NF1-negative/sporadic:It is acceptable to perform a biopsy aftermultidisciplinary discussion by a specialistpediatric neuro-oncology team (including apediatric neurosurgeon) before offeringnonsurgical treatment (chemotherapy or

biological therapy) in a clinical trial thatinvolves a relevant biological stratificationor question.

(b) NF1-positive:At the planning of nonsurgical treatment(biological therapy, chemotherapy, orradiotherapy), multidisciplinary discussionshould recommend biopsy of tumors withany atypical features and justify any decisionnot to biopsy such tumors at this stage.

(6) Initiating nonsurgical treatment because ofthreat to vision at diagnosis:

(a) Threat to vision is high if there is clear evi-dence of visual deterioration in the historybefore diagnosis.

(b) Threat to vision is high if there is clinical ev-idence of bilateral vision loss, as judged byvisual acuity or visual fields.

(c) Bilateral optic atrophy is evidence of bilat-eral visual loss but is also indicative of irre-versible optic nerve damage.

(d) In a child with unilateral visual loss, asjudged by reduced visual acuity, visualfields, or presence of optic atrophy, and inthe absence of a clear history of visual dete-rioration, who can reliably cooperate withdetailed vision testing, can be observedclosely (every 1-2 months) for evidence ofcontinued visual change before initiatingnonsurgical treatment (chemotherapy andbiologic therapy).

Fig. 1. Delphi consensus process.


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(7) Primary tumor resection/debulking:

(a) Attempted primary resection of HCLGG isnot the current recommended standard ofcare.

(b) Multidisciplinary discussion identifies somepatients with characteristics (e.g., cystictumors, large tumors, and exophytic or hy-pothalamic tumors) when early surgicaldebulking is possible with acceptable risk.The proposed anatomical classification willbe designed to assist with selection of thesecases.

(c) In view of the risk or early postoperativetumor regrowth, close observation with 2monthly scans for at least 6 months is rec-ommended to select patients for follow-upnonsurgical therapy to control subsequentrecurrence.

(8) Clinical trials:

(a) The selection and testing of surgical andnonsurgical treatments requires an active in-ternational trials program, including pa-tients with newly diagnosed cases andpatients requiring second- and third-line orsubsequent therapies.

These trials will specify criteria for selecting treatmentmodalities according to anatomical stage, geneticstatus, age, and symptomatology to increasingly stand-ardize indications for treatment.

DIPG

(9) Typical DIPG:

Biopsy of a typical DIPG (defined by a short history andtypical imaging findings) is justified when the patient ispart of an ethically approved clinical study in whichthe tissue obtained will be used to investigate orinform the role of biological markers after treatment se-lection or molecular tumor grading.

(10) Atypical pontine region tumors:

(a) Biopsy by an experienced pediatric neuro-surgeon is indicated to confirm the diagnosisand guide therapy.

(b) An atypical pontine region tumor would beconsidered separately from classic DIPGfor therapy or research purposes.

HGG

(11) Surgical biopsy in HGG is necessary:

(a) to ensure comprehensive diagnosis,

(b) for ethically approved clinical and biologicalresearch, and

(c) to help understand why conventional thera-pies are effective in a subset of patients andare not in others.

(12) Decision making:

(a) A multidisciplinary team approach is favoredfor the management of hemispheric and thalam-ic tumors, suspicious of HGGs.

(b) Multidisciplinary preoperative discussionwould help determine whether gross total resec-tion can be achieved without major morbidity.

(c) If initial gross total resection cannot beachieved safely, a stepwise approach withinitial biopsy or subtotal resection, followed bytrials-based chemotherapy to improve resectabil-ity (reduce vascularity or tumor volume), thenreconsideration of further surgery, is the pre-ferred strategy.

(13) Pathology classification:

The World Health Organization neuropathology classi-fication is the current international standard. Researchaimed at exploring alternative neuropathology classifi-cation should be promoted.

Discussion

Previous reports of consensus meetings in the field areminimal,5,6 although the use of consensus methodolo-gies for creating clinical guidelines is well described inthe literature. This meeting was initiated to review evi-dence justifying a review of surgical practice in pediatricneuro-oncology by inviting established experts to reviewevidence and promote consensus discussions with thehelp of an expert panel. The draft statements, generatedby discussion during the conference, were submitted forsubsequent consensus voting and refinement by the con-ference participants with use of web-based question-naires, under the supervision of the expert panel, whodiscussed results of voting and suggested amendmentsto statements after reviewing feedback.7–9 Preset con-sensus rate of 70% and response rate of .60% meantthat agreement was measurable and representative.

This method for reaching consensus by structuredpresentation of evidence discussions, drafting of state-ments, and subsequent rounds of voting seeking consen-sus is an established method for clinical guidelinedevelopment, which is based on a number of assump-tions about decision-making in groups. It assumes thatsafety lies in numbers, as opposed to individual decision-making, because several people are less likely to arrive atthe wrong conclusion. It lends authority to the productof the process, especially if the individuals are estab-lished experts in the field. The use of reasoned argumentin a group promotes a situation in which assumptionsare challenged and participants are forced to justifyviews, thereby enhancing rationality. The organizationand structure of the process enhances control, and itsformality enhances scientific credibility. It is for thesereasons that the Delphi method was suggested andadopted for this process by the expert group and the par-ticipants consented to the subsequent voting process atthe end of the conference discussions. The potential lim-itations are determined by the structure and



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organization of the process and the constitution of theparticipants and expert group. These aspects have beendescribed in this article.

An attempt to seek additional consensus frommembers of a subsequent Societe Internationaled’Oncologie Pediatrique (Europe) Brain TumorCommittee meeting group in Liverpool in 2011 did notgenerate sufficient response rate from participants forthe votes to be included; furthermore, their lack of in-volvement of the majority in the discussions at theParis Conference undermined their contribution as in-formed participants, despite their special interest statusas SIOPE Brain Tumor Committee members.

The meeting was structured to consider the needs ofHCLGG, DIPG, and HGG.

HCLGGs are subcategorized by their associationwith NF1 in up to 30%, their age at presentation, andtheir threat to vision or other neurological functions.These factors have been used to select patients, eitherfor observation, attempted resection, or adjuvant non-surgical therapy in clinical trials. The NF1-associatedtumors are often multifocal, involving the opticnerve(s) chiasm and/or posterior optic radiations; theirgrowth involves the optic nerves in the pathways inti-mately. They almost never present in persons ,1 yearof age. In contrast, sporadic HCLGGs frequentlypresent during infancy (age, ,1 year) with largetumors. Sporadic HCLGGs are commonly smallerwhen presenting later in childhood (age, .18 months).Their anatomical location threatens the visual pathwayby compression and/or invasion and threatens other ad-jacent structures similarly. Their tendency to progressreduces as the children grow older. It is common fortumor growth to arrest later in childhood, leaving signif-icant residual tumor. Life is threatened by rapidlygrowing, large tumors during infancy; hydrocephaluscan be a complicating factor; and vision is threatenedat all ages. They are chronically relapsing tumors witha tendency to burnout into a static state. It is for thesereasons that the consensus states that the overallpurpose is “to gain time by controlling tumor progres-sion,” justifying clinical strategies aimed at minimizingharm and containing tumor progression. Such approach-es have been established in recent trials. The consensusstatements therefore recognize the need for a precaution-ary, multidisciplinary strategy directed at the overalltherapeutic purpose (statements 1a and b).

Surgical consideration of risks for vision, endocrinefunctions, homeostasis, emotion, memory, and centralneuronal connections must be considered. The anatom-ical relationships of the structures were considered indetail, as well as the association with NF1. A review ofthe consensus regarding selection of cases for biopsy,particularly within the framework of clinical trials,based on these factors and current techniques, was dis-cussed and refined (statements 4a and b, 5a and b).

The detailed discussion of visual threat was informedprimarily by a pediatric oncologist expert in the consentprocess with such patients. The professional group notrepresented was pediatric ophthalmology. Althoughthis may be a weakness of the group’s constitution in

this area, the current clinical practice is that ophthalmol-ogists assist with diagnosis and visual assessment but arenot directly involved in nonsurgical treatment consent orsight-saving operative interventions directed at thetumor. Future consensus discussion in this area wouldbe enhanced by involvement of pediatric ophthalmolo-gists to inform the group on the interpretation ofvisual assessment and prediction of visual disability.The strong association with visual threat in HCLGG jus-tified reappraisal of which cases were suitable for imme-diate intervention with nonsurgical treatments andwhich were considered to be suitable for careful observa-tion and deferred treatments (statements 6a–d).

It was agreed that primary attempted surgical resec-tion of HCLGG is not the current recommended stan-dard of care. However, it was also acknowledged thatselected cases were amenable to attempted resection ordebulking with low risk. The risk of visual damagewith such surgery was acknowledged, and it was pro-posed that a modification of the Dodge/PLAN classifica-tion by incorporation of surgical, genetic, and visual riskinto multidisciplinary planning of surgical approacheswould assist with standardized reporting and, therefore,formal evaluation in clinical trials.4 When resectionoccurs in a tumor that is growing, careful follow-upimaging is recommended: 2 monthly scans for6 months (n ! 3), based on a precautionary approachto monitor early progression is recommended (statement2 and 7a–c) (Fig. 2). The requirement for ongoing studythrough trials of multidisciplinary approaches to treatthese tumors in children and young persons wasreinforced and further endorsed as a key consensusstatement (Statement 8).

DIPG

This brainstem tumor is radiologically distinct fromother brain stem tumors and is associated with a partic-ularly poor prognosis, which has shown no signs of im-provement in the past 30 years, despite considerableefforts to test new treatments. A previous neuro-surgicalconsensus5 concluded that biopsy was not indicated,because histological grading did not alter therapy oroutcome. This view has prevailed until recently, whena number of reports on the safety of biopsy using avariety of minimally invasive techniques have been pre-sented and published and the capacity to explore the bi-ological nature of these uniquely located, diffuse tumorshas expanded. This change in clinical view is driven bythe opportunity to include these patients in trials ofnovel therapies. Obtaining tissue samples under such cir-cumstances ensures that the biological observations canbe interpreted in the light of complete information aboutpatient, tumor, treatment, and outcome (statement 9).After consideration of DIPG, the other brainstemtumor types were also considered to require biopsyafter assessment by the pediatric multidisciplinaryneuro-oncology team (statement 10). The selection oftargets for biopsy was not the focus of consensus



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discussion. For HGG at other sites, contrast-enhancingareas are preferentially targeted.

HGG

HGGs include grades 3 (anaplastic astrocytoma) and 4(glioblastoma multiforme [GBM]) gliomas accordingto World Health Organization classification; they con-stitute ,10% of CNS tumors in childhood, classicallyoccurring in cortical regions and basal ganglia. TheWorld Health Organization classification is currentlythe histological classification most commonly applied.Their rarity means that relatively few studies have beencompleted, and frequently, trials have combined grade3 and 4 histologies. Pediatric studies have identifiedchildren’s GBMs, in particular, as being biologically

distinct, being predominantly primary (de novo) GBMrather than secondary GBM, and arising from prior low-grade gliomas (grade 2). Biological differences are alsoseen between adult and paediatric HGGs, with differ-ences in epidermal growth factor, platelet-derivedgrowth factor, IDH-1, and CDKN2A being the most sig-nificant. Characteristic chromosomal abnormalities arealso reported with different frequencies between child-hood and adult tumors, specifically 1q gain being morecommon and chromosome 7 gain and 10q loss beingless common in children.

Developments in imaging characterization can nowgroup these tumors using MR perfusion, which mea-sures relative blood volume in areas of brain andtumor; higher grade tumors have increased vascularity.MR spectroscopic profiles are also characteristic in par-ticular tumor types; diffusion-weighted MR can grade

Fig. 2. Modified Dodge classification of optic pathway tumors, identifying anatomical sites, hypothalamic involvement, metastasis and NF

status.



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the level of cellularity, and diffusion tensor imagingmay assess tumor infiltration of the surrounding brain.These advances in biological and anatomical characteri-zation of HGGs are contributing to more comprehen-sive, preoperative characterization of these tumors,influencing the surgical risk assessment of resectability.These new factors require histological correlation, withWorld Health Organization classification as the pre-ferred system, justifying biopsy for both clinicalmanagement and clinical trials and in the persistentneed to validate emerging technologies (statements 11and 13). When neurological risks are high, it wasagreed that cases be selected through multidisciplinaryassessment for a staged approach combining surgerywith chemotherapy in sequence, to enhance complete re-section rates and minimize neurological risks. The selec-tion of chemotherapy would depend on either currentbest practice based on evidence or a trial of novel treat-ment for which the patient is formally eligible (statement12a–c).

Conclusions

These consensus statements have been reported to act asa basis for further advancing clinical practice in pediatricneuro-oncology and represent a quantified, contemporary

statement of representative opinion by a meeting of in-ternational clinical leaders in the field.

Acknowledgments

We thank all CPN2011 consensus survey participants,in particular those who completed both rounds of thesurveys:

Antoinette Schouten Van Meeteren, Alice Carvalho,An Van Damme, Bart Depreitere, Bengt Gustavsson,Bernt J Due Tonnessen, Anne Isabelle Bertozzi-Salamon,Angela Brentrup, Charles Raybaud, Chris Jones,Christelle Dufour, Christian Dorfer, Christian Sainte-Rose, Conor Malluci, Darren Hargrave, David Walker,Dannis Van Vuurden, Emilie De Carli, Eric Bouffet,Frank Van Calenbergh, Didier Frappaz, PaoloFrassanito, James Goodrich, Heidi Baechli, JacquesGrill, Jessica Ternier, Johan Cappelen, John Caird,Josue Pereira, Laurent Riffaud, Marc Baroncini, MarionWalker, Mark Kieran, Memet Ozek, Nada Jabado,Karsten Nysom, Pascale Varlet, John Goodden, PatriciaBertolini, Giorgio Perilongo, Philippe Mercier, RichardGrundy, Rolf Dieter Kortmann, Roger Packer, StefanPfister, Shlomi Constantini, Spyros Sgouros, StefanHolm, Thomas Czech, Thomas Merchant, ToreStokland, Vita Ridola, and Peter Vandertop.

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