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THE EUROPEAN ASSOCIATION OF

NEUROONCOLOGY

EDITORIALWolfgang Grisold

GRANT BESTOWALFirst Recipient of the New EANO Award:Kathy Oliver

REVIEW ARTICLESManagement of Gliomas: Relevance of MolecularMarkers for Clinical PracticeMichael Weller

Advances in Technology in Radiation OncologyMehmet Ufuk Abacioglu

Spectrum of Side Effects of Anticonvulsants inPatients with Brain TumoursChrista P Bénit, Charles J Vecht

Chemotherapy and PolyneuropathiesWolfgang Grisold, Stefan Oberndorfer,Anthony J Windebank

The Chemotherapy-Induced Peripheral NeuropathyOutcome Measures Standardization (CI-Perinoms)Study: An Answer to the Unsettled Question of Drug-Related Neuropathy Assessment in Cancer PatientsGuido Cavaletti on behalf of the CI-PERINOMS Study Group

COLUMNSEducation

Case Reports

Nurses

Patient Issues

Event Calendar

Congress Reports

National Reports

Ongoing TrialsHotspots in Neuro-Oncology

SNO News

www.kup.at/journals/eano/index.html

Volume 2 (2012) // Issue 1 // e-ISSN 2224-3453

Member of the

2 EUR ASSOC NEUROONCOL MAG 2012; 2 (1)

Table ofContent

EDITORIAL

Wolfgang Grisold 4

GRANT BESTOWAL

First Recipient of the New EANO Award: Kathy Oliver 5

REVIEW ARTICLES

Management of Gliomas: Relevance of Molecular Markers for Clinical Practice 6

Michael Weller

Advances in Technology in Radiation Oncology 11

Mehmet Ufuk Abacioglu

Spectrum of Side Effects of Anticonvulsants in Patients with Brain Tumours 15

Christa P Bénit, Charles J Vecht

Chemotherapy and Polyneuropathies 25

Wolfgang Grisold, Stefan Oberndorfer, Anthony J Windebank

The Chemotherapy-Induced Peripheral Neuropathy Outcome MeasuresStandardization (CI-Perinoms) Study: An Answer to the Unsettled Questionof Drug-Related Neuropathy Assessment in Cancer Patients 37

Guido Cavaletti on behalf of the CI-PERINOMS Study Group

Publisher’s Office:Krause & Pachernegg GmbHVerlag für Medizin und Wirtschaft3003 Gablitz, Mozartgasse 10, AustriaTel. +43/2231/61258-0, Fax +43/2231/61258-10

Policy:The European Association of NeuroOncologyMagazine welcomes submission of clinically andoriginal papers, reviews etc in the fields of neuro-logy, neurosurgery, medical oncology, radiotherapy,pediatric neurooncology, neuropathology, neuro-radiology, neuroimaging, nursing, patient issues, etc.

Disclaimer:Authors, editors, and the publisher do not acceptresponsibility for any loss or damage arising fromactions or decisions based on information con-tained in this publication: ultimate responsibilityfor the treatment of patients and interpretation ofpublished material lies with the medical practi-tioner. Statements and opinions expressed in arti-cles herein are those of the authors and not neces-sarily those of the editors or publisher. Great careis devoted to the compilation of the articles. Evenso, however, errors in data processing cannotalways be avoided. In view of this and becausedevelopments in medical science advance veryquickly, it is recommended that the reader con-ducts his own independent inquiries and/or re-search as regards the stated diagnostic methods,measurements of medication etc. The editors andpublisher disclaim any responsibility or liabilityfor the correctness of such material and do not

guarantee, warrant or endorse any product orservice advertised in this publication nor do theyguarantee any claim made by the manufacturerof such product or service. The use of generaldescriptive names, trade names, trademarks etcin this publication even if not specifically identi-fied, does not imply that these names are notprotected by the relevant laws and regulations.

Conflict of interest, ethical approval:A conflict-of-interest statement must be com-pleted for each author of each submitted article.All original research involving human subjectsmust be accompanied by evidence of prior ethicscommittee approval. Authors must supply evi-dence of informed consent of research partici-pants (patients).

Copyright:© Krause und Pachernegg GmbH. All rightsreserved. No part of this publication may be re-produced or transmitted in any form or by anymeans, electronic or mechanic, including photo-copy, recording, or any information storage andretrieval system, without written permission fromKrause und Pachernegg.

Use of texts and files:For personal, non-commercial use and infor-mation only. Not to be reproduced without per-mission of Krause & Pachernegg GmbH.The European Association of NeuroOncologyMagazine is an open-access journal without com-mercial funding.

IMPRINT

European Association ofNeuroOncology Magazine

ISSN-Online: e-ISSN 2224-3453

Official Organ of the European Associationof Neurooncology

Editor-in-Chief:Wolfgang Grisold, MDDepartment of NeurologySozialmedizinisches Zentrum Süd –Kaiser-Franz-Josef-Spital1100 Vienna, Kundratstraße 3, AustriaTel. +43/1/60191-2001, Fax +43/1/60191-2009e-mail: [email protected]

Managing Editor:Riccardo Soffietti, MDDivision of Neuro-OncologyDepartment of NeuroscienceUniversity and San Giovanni Battista Hospital10126 Turin, Via Cherasco 15, ItalyTel. +39/(0)11/633-4904, Fax +39/011/696-3487e-mail: [email protected]

Responsible for the content.Please send queries to:European Association of Neurooncology5170 AE Kaatsheuvel, PO Box 219, BelgiumTel. +31/416/540037, Fax +31/848/398070e-mail: [email protected]

EUR ASSOC NEUROONCOL MAG 2012; 2 (1) 3

COLUMNS

Education

Report on a Completed EANO Research Fellowship 41Matthias Preusser

Report of the EANO Educational Visit to Austria 2010 43Eefje Sizoo

Case Reports

Case Report: A 52-Year-Old HIV-Seropositive Patient with Hodgkin’s Disease 45Khê Hoang-Xuan, Karima Mokhtari, Laurent Capelle

Rare Cerebellar Tumour in a Young Adult Bulging into the Fourth Ventricle 46Karl Rössler, Rolf Buslei, Michael Buchfelder

Nurses and Health-Related Groups

Neuro-oncology Nursing in Europe 48Hanneke Zwinkels

Patient Issues

What You Don’t Know Won’t Hurt You ... 50Kathy Oliver

Event Calendar 52

National ReportsNational Societies: Joint Meeting AINO and ANOCEF 53Roberta Rudà, Marc Sanson

National Societies: Dutch Society for Neuro-Oncology (LWNO) 54Jaap Reijneveld, Roelien Enting

Ongoing Trials

Interview with Dr James Perry about the NCIC-CTG Elderly Glioblastoma Trial 55Ufuk Abacioglu

Hotspots in Neuro-Oncology 57Michael Weller

SNO News 58J Charles Haynes

Instructions for Authors 59

Front Page: Kathy Oliver and Wolfgang Grisold. Reprinted with kind permission from ECCO, p. 5

Editor-in-ChiefWolfgang Grisold

Section EditorsCase reports:Stefan OberndorferGuidelines:Riccardo SoffiettiNurses:Hanneke Zwinkels

Editorial BoardStefan OberndorferKhe Hoang XuanMichael WellerWolfgang WickUfuk Abacioglu (radiotherapy)Lorenzo Bello (neurosurgery)Olivier Chinot (medical oncology)

Patient issues:Kathy OliverOngoing trials:Ufuk AbaciogluHotspots in Neuro-Oncology:Michael Weller

Managing EditorRiccardo Soffietti

J. M. Kros (neuropathology)Giorgio Perilongo(pediatric neuro-oncology)Marion Smits(neuro-radiology)Hanneke Zwinkels (nurses)Kathy Oliver (patient issues)

EANO MAGAZINE

Table ofContent


President’s Column

EditorialW

olfg

ang

Gri

sold

, MD

Dear EANO members and readers of the magazine,

This is the second edition of the EANO Neuro-Oncology Magazine and we are glad to say that thestatistics of the first issue are promising. The overall hits in the first 3 months amounted to 2045,the main articles were downloaded about 200 times each as PDFs, and the absolute leading articlewas the paper by Kathy Oliver on patient advocacy. This teaches us a lesson as the awareness ofpatients and carers is large, and the EANO Magazine may have a potential role in the issues ofpatients and carers.

Issue 1/2011 contained several important articles such as the EANO guidelines for the diagnosisof glial tumours, technical advances in glioma therapy, tolerability of chemotherapy in the elderly,and the issue of central nervous neurotoxicity in cancer treatment, which is important in oncology.Issue 1/2012 follows along this path and provides articles on molecular markers as well as 2 arti-cles on peripheral neurotoxicity, which is important in the treatment of cancer patients.

These are topics occurring in daily practice, written by experts and of high practical value, andthis is the intention of the EANO Neuro-Oncology Magazine – to provide educational resources inthe field of neuro-oncology.

In September 2012, the next EANO congress will take place in Marseille. The programme andscientific committees have developed an attractive programme, which will feature developments indiagnosis and treatment. The popular educational day will have an attractive programme and alsocontributions of scientific and translational background. There will be enough space for free topicsand posters and I cordially invite you to participate actively in the scientific programme. It isimportant for the neuro-oncological community, as well for the authors of scientific papers, topresent and discuss results, findings, and observations. As announced previously, we will alsohave several travel grants for young neuro-oncologists to facilitate attendance since it is one ofthe missions of the EANO to promote the attendance of young researchers and clinicians.

At the last EANO meeting in Maastricht we arranged an interesting session on neuro-oncologyin former Eastern Europe and in North Africa, and it was interesting to learn from the participantshow neuro-oncology is practiced. It seems that much work is done, but the interdisciplinaryapproach towards neuro-oncologic patients will still need some time to grow. At the World Congressof Neurology in Marakech (http://www.wfneurology.org/), there was much interest in neuro-oncology resulting in a main topic and a teaching course. A few weeks later, the Tunisian Societyof Neurology dedicated their yearly meeting to neuro-oncology, which is a great initiative. Aspreviously in Maastricht a meeting will take place in Marseille for national societies of neuro-oncology and we will encourage countries to develop interdisciplinary national societies.

The position of neuro-oncology in Europe also varies from country to country. The intentionis to establish a multidisciplinary joint committee for neuro-oncology within the UEMS(http://www.uems.net), which would allow equal access from all participating fields, such asneurosurgery, neurology, radiotherapy, general oncology, pathology, and probably also rehabi-litation. The negotiations at the UEMS level are supported by the European Board of Neurology(http://www.uems-neuroboard.org/ebn), which has officially applied for such a status.

Within oncology, and presumably neuro-oncology, the concept of rehabilitation (“cancer rehabi-litation”) is developing and will be an important addition to medical and surgical treatment. Inparticular in neuro-oncological patients, rehabilitation not only of sensory and motor functions, butof cognitive problems is becoming increasingly important and will add to the improved and holisticcare of patients.

Last but not least we have to continue our efforts in palliative and supportive care in patients withneuro-oncological diseases, and efforts are made to include glioma into the upcoming guidelinesfor palliative care of the European Federation of Neurological Societies (http://www.efns.org).The EFNS initiative on e-learning (ebrain) contains a chapter on end-of-life aspects in glioma patientsand can be useful for teaching purposes.

Wishing you a successful 2012 and looking forward to meet you in Marseille,

Wolfgang Grisold, MDPresident of the EANO

EUR ASSOC OF NEUROONCOL MAG 2012; 2 (1)

Molecular Markers in Gliomas

5

First Recipient of the New EANO Award:Kathy Oliver

Thank you so much for the very great honour of this award.

In accepting this very generous award, I must pay tribute tothe people who inspire us all to keep researching, to keeptreating, to keep advocating, and to keep raising awareness ofthe terrible challenges of brain tumours. Those people are thebrain tumour patients themselves.

Until the harsh realities of a brain tumour diagnosis directlytouch your life, it is impossible to imagine what this journeywill be like or where it will take you.

My son, Colin, was diagnosed at age 24 with a low-gradeglioma and, as many of you know, he died 4 weeks ago fromhis brain tumour which had by then progressed to a glioblas-toma multiforme. He passed away shortly after his 32nd birth-day.

Colin continued to work full-time, live independently, andride his beloved mountain bike up until 5 weeks before hedied at home in the arms of his family. He refused to let hisbrain tumour define his life.

But his journey and that of so many other brain tumour pa-tients whom I’ve met from around the world have certainlydefined the work I’ve done on behalf of the InternationalBrain Tumour Alliance over the last half dozen years.

And there is so much work to be done for brain tumour pa-tients: in research labs, in the clinic, in the political and regu-latory arenas, and in the wider general public.

I frequently say to people that every morning we should all beasking ourselves: “What can we do for brain tumour patientstoday?” And every evening we should ask: “Have we doneenough?”

I believe we also have to look very closely at quality-of-lifeissues for brain tumour patients, at the whole area of informa-tion provision, and also at palliative and end-of-life care.

Having just had my first personal experience of palliative careand end-of-life care with Colin, I can only say that the com-passion and support which was provided to us by our pallia-tive care team gave us enormous comfort and confidence.

I know that certainly not all families have access to this levelof support but I believe that we must do all that we can to pro-vide palliative and end-of-life care to brain tumour patientsand their families that is as comprehensive, as sensitive, and aswidely available as possible.

Colin kept a journal during his brain tumour journey and Iwould like to share one of the entries from it with you. I hopeyou derive as much inspiration from his words as I have, andthat hearing them will further inspire your crucial and con-tinuing work for brain tumour patients. The entry is fromJune 6, 2004, the day before Colin’s awake craniotomy andafter signing his informed consent for the operation.

“I myself have signed papers today mentioning the word“death” numerous times ... The great unknown, or death, doesnot scare me. In fact, I welcome the challenge of fightingagainst it. To be able to stand tall and confront it is the mostexciting thing that one can do ... This [challenge] is the realthing ... Bring it on. I am ready to fight and win ...”

On September 25, 2011, Kathy Oliver was awarded the first EANO Award for her efforts as the co-director of theInternational Brain Tumour Alliance (IBTA, www.theibta.org), an organisation dedicated to the support of braintumour patients. The award was presented by the president of the EANO, Wolfgang Grisold. The EANO Magazinepresents excerpts from her speech.

Kathy Oliver and Wolfgang Grisold. Reprinted with kind permission from ECCO.

6 EUR ASSOC OF NEUROONCOL MAG 2012; 2 (1)


Management of Gliomas: Relevance of MolecularMarkers for Clinical Practice

Michael Weller

Received on August 21, 2011; accepted on September 19, 2011; Pre-PublishingOnline on November 3, 2011

From the Department of Neurology, University Hospital Zurich, SwitzerlandCorrespondence to: Michael Weller, MD, Department of Neurology,University Hospital Zurich, CH-8091 Zurich, Frauenklinikstrasse 26;e-mail: [email protected]

Abstract: The histological subtyping and thegrading of gliomas in the World Health Organiza-tion classification of brain tumours was origi-nally designed mainly to provide clinicians withguidance as to the natural course of disease andthe necessity of further treatment beyond sur-gery. The profound prognostic impact of thispathological grading has been confirmed overthe last decades in numerous retrospectiveanalyses. Yet, it has also become clear that tu-mours virtually identical by morphology may havevery different outcomes and that molecular markersmay aid in deriving more detailed prognostic in-formation. The 1p/19q co-deletion in oligoden-droglial tumours became paradigmatic in this re-

Introduction

The current World Health Organization (WHO) Classificationof Tumours of the Nervous System allows for a histomorpho-logical subtyping of brain tumours and a grading into WHOgrades I–IV according to the expected degree of malignancy[1]. One major goal of the WHO classification was to provideclinicians with guidance as to the natural course of diseaseand the indication to withhold or offer further treatment be-yond surgery, specifically radiotherapy or chemotherapy. Theprofound prognostic impact of the pathological grading af-forded by the WHO classification has been confirmed overthe last decades in numerous retrospective analyses. Yet, thesestudies as well as prospective interventional trials have alsoshown that tumours identical by morphological criteria mayhave highly different outcomes and that molecular markersmay aid in deriving more detailed prognostic information up-front. Numerous such molecular markers in the field ofglioma have been explored, many without attracting enduringattention. Some, however, continue to raise interest overyears, such as p53 mutations, epidermal growth factor recep-tor (EGFR) mutations, and the 1p/19q co-deletion, otherssuch as O6-methylguanylmethyltransferase (MGMT) promo-ter methylation and mutations of isocitrate dehydrogenase(IDH) 1 and B-Raf, are subject of ongoing studies and contro-versies (Table 1, Figure 1). Moreover, powerful high-through-put analyses, which also led to the identification of IDH as amutational target [3], are likely to yield novel diagnostic andprognostic information in the very near future. The article athand summarizes and extends previous reviews on the devel-

gard: patients with 1p/19q-deleted tumours de-rive much more benefit from radiotherapy orchemotherapy than patients with tumours lack-ing this aberration. Thus, the 1p/19q status doesnot help to select among different genotoxictreatments. The first molecular marker attributeda predictive power specifically for benefit fromalkylating agent chemotherapy was promotermethylation of the O6-methylguanylmethyltrans-ferase gene. However, it now seems that thispredictive effect may be limited to glioblastomaand that implementation of the according test inclinical practice is a major challenge. The identi-fication of isocitrate dehydrogenase mutationsas typical changes restricted to certain types of

gliomas and the rapid development of commonmutation-specific antibodies has provided a ma-jor advance in subclassifying gliomas, but not re-sulted in novel treatment strategies yet. A spe-cific type of epidermal growth factor receptormutation, EGFRvIII, has emerged as a target forvaccination. Ongoing high-throughput analysesare likely to yield novel candidate biomarkers indue course, suggesting that molecular neuropa-thology will have an increasing impact in clinicalneurooncology very soon. Eur Assoc of NeuroOncol Mag 2012; 2 (1): 6–10.

Key words: MRI, DTI-FT, fMRI, neuronavigation,brain mapping, glioma

opment of molecular markers for the differential diagnosisand stratified management of gliomas [2, 4–7]. The potentialvalue of molecular markers includes, but is not limited– to aid in the differential diagnosis of brain tumours that are

at times difficult to distinguish– to allow prognostication within tumour entities– to allow prediction of response or lack of response to a spe-

cific type of treatment.

Notably the distinction between prognostic and predictivemolecular factors is not consistently made in the literature andhas given rise to controversies and misconceptions, eg, thefalse assumption that patients with 1p/19q-co-deleted oli-godendrogliomas should be treated with chemotherapy orchemotherapy plus radiotherapy rather than radiotherapyalone (see below).

p53

The tumour suppressor protein (TP) 53 acts mainly as a tran-scription factor that controls the transcription of several genesinvolved in cell cycle arrest, DNA repair, senescence, andapoptosis, eg, p21 or bax. Mutations of the p53 gene or effec-tors of the p53 pathway are among the most common molecu-lar aberrations in human cancers. Among gliomas, p53 muta-tions are relatively common in WHO grade-II and -III tu-mours and, accordingly, also in secondary glioblastomas, thatis, glioblastomas progressing from previously lower-gradegliomas. In contrast, p53 mutations are relatively rare inglioblastoma.

Since p53 controls DNA damage response pathways and isthought to promote either DNA repair and survival or irrevers-ible growth arrest, traditional views held that the p53 statusshould correlate with responses to radiotherapy or DNA-dam-aging agent chemotherapy. While this can be nicely modelledin cell culture models and p53 knockout mice, such an asso-



7

ciation could never be demonstrated in large prospectiveclinical trials, neither in gliomas nor in other tumours. In con-temporary studies from the German Glioma Network, the p53status was neither associated with progression-free survival inpatients with WHO grade-II gliomas managed with surgeryalone [8] and neither with progression-free or overall survivalof glioblastoma patients treated with radiotherapy plus con-comitant and adjuvant temozolomide [9]. Possibly furthermolecular changes resulting from the loss of the p53 check-point control make tumours too heterogeneous to allow pre-diction of their behaviour in response to genotoxic stress.Moreover, the p53 pathway can be disabled at multiple lev-els other than p53 itself, accordingly, p53-signalling altera-tions may be present in 87 % of all glioblastoma patientswhereas the p53 mutation rate is only 15–30 % [10]. Ac-cordingly, at present there is no need to know the p53 statusfor any clinical decision-making in the glioma field. Thereare at least 2 scenarios where this may change: (1) mutantp53 proteins exhibiting immunogenic epitopes could be ex-plored as targets for immunotherapy and (2) p53-mimeticdrugs which induce conformational changes and therebytranscriptional activation of mutant p53 variants could be as-sessed in subgroups of glioma patients carrying appropriatemutations.

EGFR

Amplification, constitutive activation, or increased expres-sion of the epidermal growth factor receptor (EGFR) genemay promote EGFR-signalling and thereby proliferation, in-vasiveness, and resistance to cell death induction. EGFR am-plification or mutational activation are rare in gliomas oflower WHO grades, but frequent in primary glioblastomasand glioblastoma in elderly patients [9, 10]. EGFR overex-pression has been associated with inferior prognosis in some,but not all studies, and a major prognostic impact in glioblas-toma can be ruled out. Numerous EGFR-targeted agents, in-cluding tyrosine kinase inhibitors such as gefitinib orerlotinib, as well as antibodies have been explored in patientswith newly diagnosed or recurrent glioblastoma, but neverproduced a signal for activity justifying phase-III develop-ment. It has been argued that upfront EGFR status determina-tion to enrich patients likely to respond to EGFR-targetedtreatments might be necessary to improve the outcome ofanti-EGFR trials in glioblastoma. Thus it has been propo-sed that patients with high EGFR expression and low levelsof phosphorylated protein kinase B/Akt respond betterto erlotinib than those with low levels of EGFR expressionand high levels of phosphorylated protein kinase B/Akt[11]. Furthermore, it was reported that the coexpression ofEGFRvIII and phosphatase-and-tensin-homolog-on-chromo-some-ten (PTEN) by glioblastoma cells was associated withresponsiveness to EGFR kinase inhibitors [12]. However, nei-ther of these observations was confirmed in the prospectiverandomized European Organization for Research and Treat-ment of Cancer (EORTC) 26034 trial on erlotinib in recurrentglioblastoma [13]. Since the EGFR status is not strongly prog-nostic and since no EGFR-targeting agents are approved forglioma treatment, currently there is no need for the determina-tion of EGFR mutation or expression status outside a clinicaltrial, and its knowledge will not influence clinical decision-

making. However, a specific type of EGFR mutation,EGFRvIII, which gives rise to a truncated receptor that is ac-tive independent of ligand, produces a neoantigen that mightbe amenable to immunological targeting [14, 15]. Thus thedetection of EGFRvIII might assume relevance at least forinclusion into clinical trials in the next few years.

1p/19q

Combined losses of genetic material from chromosomal arms1p and 19q, now commonly referred to as 1p/19q co-dele-tions, result from an unbalanced translocation which leads tothe loss of one hybrid chromosome and thereby loss of hetero-zygosity (LOH) [16]. These observations early on indicatedthe presence of tumour suppressor genes on 1p or 19q. 1p/19qco-deletions are almost never found in non-glial tumours andare strongly associated with oligodendroglial morphology. InWHO grade-II gliomas, the absence or presence of this bio-marker does not correlate with progression-free survival inpatients treated by surgery alone, but neither with radio-therapy nor chemotherapy [8, 17]. However, they identifyanaplastic glioma patients with a superior outcome independ-ent of whether these patients are treated with radiotherapy orchemotherapy or both [18–20]. In glioblastoma, 1p/19q co-deletions are rare and of unknown biological significance.The higher effectivity of radiotherapy and chemotherapy inoligodendroglioma patients with 1p/19q co-deletions hasgiven rise to the hypothesis that these chromosomal regionsharbour not only tumour suppressor genes but also importantgenes which may determine cellular sensitivity to genotoxicstress or cell death stimuli in general. However, only very re-cently the first convincing candidate genes have been identi-fied. By means of coding exon sequencing, mutations in 2genes hitherto not related to gliomas, the CIC gene, a homo-logue of the drosophila gene capicua) on chromosome 19q,and the FUBP1 gene, which encodes the “far upstream ele-ment (FUSE) binding protein” on chromosome 1p, werefound in a relevant proportion of oligodendroglial tumours[21]. To what extent mutations in CIC or FUBP1 contribute tooligodendrogliomagenesis or the radiochemosensitivity of1p/19q-co-deleted oligodendrogliomas is currently under in-tense investigation.

MGMT

MGMT is a DNA repair enzyme that reverses the alkylation ofDNA induced by alkylating agent chemotherapy, includingnitrosoureas and temozolomide. The MGMT protein is con-sumed during this process by its targeting to the proteasomeand is therefore often classified as a suicide enzyme. An asso-ciation of MGMT expression and the efficacy of alkylatingagent chemotherapy in glioblastoma has been proposed formore than 20 years [5]. However, most studies reporting aprognostic impact of MGMT in glioblastoma examined pro-moter methylation of the MGMT promoter rather than proteinlevels or activity in the tumour cells. In fact, there was gener-ally poor correlation between promoter methylation and lossof protein, and promoter methylation correlated better withoutcome than MGMT protein determination by immuno-chemistry [5, 22]. The reasons for these discrepancies mayhave included poor-quality antibodies or difficulties in distin-



guishing MGMT-expressing tumour from non-tumour hostinfiltrating cells. Alternatively, MGMT promoter methylationmay not always result in loss of protein expression and maysignify a biological feature with significance beyond MGMT,that is, there may be a pattern of gene silencing by methylationthat predicts a better outcome [23]. The MGMT promotermethylation status shows little intratumoural heterogeneity[24] and is preserved at recurrence in most glioblastomas [25,26].

In the context of the pivotal trial that showed the superiority ofconcomitant and adjuvant temozolomide plus radiotherapyover radiotherapy alone [27], MGMT promoter methylationwas strongly associated with the extent of benefit from theaddition of chemotherapy in the experimental arm [28], buthad only minor prognostic impact on progression-free sur-vival in patients treated with radiotherapy alone. This set ofdata is currently the only to demonstrate that MGMT pro-moter methylation is not only an overall prognostic factor, butpredictive for benefit of chemotherapy, if only in glioblas-toma. The strong prognostic role of MGMT promoter me-thylation has recently been confirmed in the RTOG 0525/EORTC/NCCTG Intergroup Study that investigated 3 weekson one week off adjuvant temozolomide dose intensificationin comparison with the standard EORTC/NCIC treatmentschedule. While there was no difference in progression-freeor overall survival, the primary endpoint, between both treat-ment arms, overall survival was 23.2 months in patients withMGMT promoter-methylated tumours as opposed to 16months in patients with unmethylated tumours [29]. ThePCR-based assay used in that trial is being prepared for com-mercial use by MDX Health (Ghent, Belgium).

IDH

Somatic mutations of isocitrate dehydrogenase (IDH) genes 1and 2 have only recently been described, but have already hada major impact in diagnostic neurooncology [3, 7, 30, 31].The IDH1 gene encodes cytosolic NADP+-dependent IDHwhereas the IDH2 gene encodes mitochondrial NADP+-de-pendent IDH. IDH mutations cluster at codon 132 of theIDH1 respectively codon 172 of the IDH2 gene, suggestingthat these mutations afford a gain of function to tumour cells.If merely loss of IDH function was the main mechanism, anytype of mutation resulting in loss of functional enzyme wouldbe tumourigenic. Present concepts include that the mutantIDH variants exhibit an altered substrate specificity which re-sults in the production of a putative oncometabolite, D-2-hydroxyglutarate. While this oncometabolite has been con-sidered a possible biomarker to monitor disease activity inacute myeloid leukaemia, the only other cancer with a rela-tively high rate of IDH mutations, D-2-hydroxyglutarate lev-els may be too low in the serum of glioma patients to be ofdiagnostic value [32].

The IDH mutation rate in astrocytic and oligodendroglialgliomas of grades II and III is in the range of 60–80 % where-as the rate does not exceed 10 % in glioblastomas, indicatinga differential cellular origin of these tumours. Other brain tu-mours such as ependymomas lack IDH mutations. This differ-ential distribution and the development of an antibody-recog-nizing mutant IDH1 R132H protein [33], which accounts for> 90 % of all mutants in gliomas, explains why IDH assess-ment was rapidly introduced into the diagnostic repertoire ofneuropathology in many centres.

Table 1. Molecular markers in glioma: an overview

Biological Method of Clinical relevance

Grade-II Grade-III anaplastic Grade-IVsignificance assessment

gliomas gliomas glioblastoma

p53 Cell cycle check- PCR, sequencing, None None Nonepoint, DNA repair and immuno-

histochemistry

EGFR Proliferation, invasion PCR or immuno- None Suggests possible under- Often overexpressed (40 %),histochemistry grading→ consider reclas- EGFRvIII mutation (25 %)

sification as glioblastoma as a possible target forimmunotherapy

1p/19q Biological role unclear, PCR, FISH Controversial, Prognostically favourable Rare, significance unclearco-deletion of chromo- probably prog- in patients treated withsomal arms 1p and 19q nostically favour- radiotherapy or chemo-linked to oligodendroglial able therapy or bothmorphology

MGMT DNA repair Methylation-specific Controversial Prognostically favourable Predictive for benefit fromPCR in patients treated with alkylating agent chemo-

radiotherapy or chemo- therapytherapy or both

IDH Biological role unclear, PCR or immuno- Prognostically Prognostically favourable Rare, prognosticallypossible link to energy histochemistry favourable in patients treated with favourable, suggestivemetabolism and pro- (IDHR132H) radiotherapy or chemo- of secondary glioblastomaangiogenic pathways therapy or both

B-Raf Cell growth and division PCR Possibly identify- Rare, no significance Rare, no significanceing patients res-ponsive to B-Rafkinase inhibi-tors (?)



9

Figure 1. Molecular markers in glioma. A, 1p/19q co-deletion. Microsatellite-PCR-based analysis of allelic losses of 1p and 19q in an astrocytoma (WHO grade II) (A II) andan anaplastic oligodendroglioma (WHO grade III) (AO III). Losses of both markers are indicated by arrowheads in AO III, but not A II. B, MGMT promoter methylation.Methylation-specific PCR for unmethylated (U) and methylated (M) promoter sequences in 5 glioblastoma samples, including the glioblastoma cell line A172 as a positivecontrol for methylated and peripheral blood cells as a control for unmethylated promoter sequences, as well as water as a negative control (empty). C, IDH mutation. Grade-II oligoastrocytoma, upper panels: HE staining, lower panels: IDH immunostaining, left panels: tumour centre, right panels: infiltration zone (Courtesy: Jörg Felsberg, Düs-seldorf, Germany). Reprinted from [2].

Within glioma entities II–IV, patients with IDH-mutant tu-mours show a longer survival than patients with IDH-wild-type tumours [20, 34, 35]. Yet, the IDH status, like the 1p/19qstatus, does not predict benefit from a specific type of treat-ment, eg, radiotherapy versus chemotherapy [20, 36, 37]. In-terestingly, the survival of glioblastoma patients with IDHmutation is superior to that of anaplastic astrocytoma withoutIDH mutation [38], illustrating that molecular features canprofoundly improve the prognostic power of the current,largely morphological neuropathological assessment.

B-Raf

B-Raf is a member of the Raf kinase family which belongs tothe serin threonine kinases and regulates cell growth and divi-sion via mitogen-activated protein kinase (MAPK) and extra-cellular signal-related kinases (ERK). Duplications of B-Rafare frequent in pilocytic astrocytomas [39, 40]. Since B-Rafmutations are rare in diffuse astrocytic gliomas of WHOgrades II–IV, their absence or presence may aid in the differ-ential diagnosis of pilocytic and higher-grade astrocytomas.An activating point mutation, B-RafV600E, is found in approxi-mately 60–70 % of pleomorphic xanthoastrocytomas and20 % of gangliogliomas, but again very rarely in other typesof glioma [41, 42]. The detection of B-Raf pathway activationmight assume therapeutic relevance since specific inhibitorsof B-Raf, such as PLX-4032, are already explored for efficacyin malignant melanoma. Moreover, less selective multikinaseinhibitors such as sorafenib inhibit B-Raf, too. Finally, inhibi-tors of heat shock protein (HSP) 90, which destabilize mutantB-Raf, may be of interest in this regard.

Is Molecular Neuropathology Readyfor Clinical Use?

Major progress has been made in recent years to supplement themorphological framework of the WHO classification [1] withmolecular markers of diagnostic and prognostic significance (Ta-ble 1, Figure 1). MGMT promoter methylation stands out as amarker where choice of assay and technical standardization haveturned out to be most challenging [5]. EGFR amplification, 1p/19q co-deletion, IDH mutation, and B-Raf alterations are charac-teristic of specific tumours whereas MGMT promoter methyla-tion is not. 1p/19q co-deletion, IDH mutation, and MGMT pro-moter methylation are strongly prognostic in anaplastic gliomas.Importantly, these 3 favourable markers may not be independ-ent, eg, the 1p/19q co-deletion lost significance upon themultivariate analysis of the NOA-04 trial when MGMT andIDH status were included in the analysis [20]. Only IDH muta-tions are confirmed to be prognostic in grade-II gliomas. Inglioblastoma, IDH mutations indicate the origin from a priorlower-grade lesion, and MGMT promoter methylation is prob-ably both prognostic and predictive for benefit from alkylating-agent chemotherapy. Accordingly, molecular neuropathologyprovides a lot of diagnostic and prognostic information, but isstill largely dispensable for individual clinical decision-mak-ing.

Molecular Markers and ClinicalTrial Design

Molecular markers have been introduced into the design ofclinical trials to enrich patient populations, that is, to define



more homogeneous patient populations which are more likelyto respond to treatment in a uniform manner. This strategy hasbeen employed for MGMT promoter methylation in the CEN-TRIC trial for newly diagnosed glioblastoma, based on theanalysis of a small phase-II trial [43] and, based on robust his-torical data [18, 19], for the 1p/19q co-deletion in the multina-tional CATNON and CODEL trials which are also open inmany European countries. As one of the next steps, it seemsreasonable to exclude glioblastoma patients with IDH muta-tions from future glioblastoma trials. The most convincinguse of molecular marker analysis would be the analysis of theEGFRvIII mutation in glioblastoma as the requirement forinclusion into a vaccination trial targeting specifically thiscommon type of mutation [15].

Outlook

Further areas of biomarker research that are far less advancedin terms of implementation in the clinic include the diagnosticand prognostic use of glioma stem cell markers as well as theidentification of predictive markers for benefit from specifictypes of antiangiogenic treatment. These could include notonly tumour tissue markers but also plasma biomarkers suchas vascular endothelial growth factor (VEGF) family mem-bers or their soluble receptors [44, 45] or vessel structuresamenable to advanced imaging techniques such as integrinsexpressed on the luminal vessel wall [46].

Conflict of Interest

The author has received research grants from MSD, MerckSerono, and Roche and honoraria for lectures or advisoryboards from Magforce, MSD, Merck Serono, and Roche.

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EUR ASSOC NEUROONCOL MAG 2012; 2 (1)

Advances in Technology in Radiation Oncology

11

Advances in Technology in Radiation OncologyMehmet Ufuk Abacioglu

Received on September 18, 2011; accepted after revision on October 31, 2011

From the Department of Radiation Oncology, Neolife Medical Center, Istanbul, TurkeyCorrespondence to: Ufuk Abacioglu, MD, Department of Radiation Oncology,Neolife Medical Center, Yucel Sok # 6, 1. Levent, Besiktas, 34340 Istanbul, Turkey;e-mail: [email protected]

Introduction

For many decades, radiation has been one of the main weap-ons against tumours located in the central nervous system aswell as in many other sites. It has potentially curative and ab-lative effects not only on malignant tumours but also on be-nign tumours and vascular malformations. Beginning with theradium and kilovoltage X-rays, technological developmentshave made radiotherapy an essential component of therapy[1]. While the first revolutionary development were Cobaltmachines and linear accelerators to treat deep-seated tumours,there has been an evolution of computer and imaging tech-nologies over the last 30 years. Transition from 2-D treat-ments to 3-D and nowadays 4-D has been possible with CT,MR, and PET imaging. Irregularly shaped targets can be bet-ter irradiated using 3-D conformal and intensity-modulatedbeams. Stereotactic radiosurgery and radiotherapy have beenwidely adopted in daily practice with the aim of precise andaccurate ablative treatments, making it possible to shortenmany treatments and to improve patient comfort. Image guid-ance during treatment has been an important component forthese highly precise techniques. Orthogonal X-rays, in-roomCT and cone beam CT are examples for right targeting duringtreatment.

This review aims to cover recent technological developmentsof radiotherapy targeting central nervous system (CNS) dis-eases.

Intensity-Modulated Radiotherapy

With the use of CT, 3-dimensional (3-D) visualization of thepatient anatomy has been possible and 3-D-conformal radio-therapy has been widely used in almost any treatment site. Ithas the advantage of improving dose conformity around thetarget and of sparing adjacent normal tissues compared toconventional radiotherapy fields. Intensity-modulated radio-therapy (IMRT) is a more sophisticated method to deliverhighly conformal radiotherapy and its use has been largelycommon especially in head, neck, prostate, and brain tumoursin proximity to critical structures. The basis for IMRT relieson an inverse-planning system, which optimizes delivery of

Abstract: The last decade has shown breathtak-ing developments in radiotherapy. As a local andorgan-preserving method, radiation oncology asa discipline is changing its paradigm to moresophisticated, precise treatments rather than large-field irradiations. A radiation beam is more like a

scalpel in the era of hypofractionated and abla-tive doses. It becomes increasingly possible toescalate the fractional and total doses withoutincreasing toxicity; toxicity may even decrease.While early clinical results with these new tech-nologies are very satisfactory, evidence-based long-

term results are anticipated. Eur Assoc Neuro-oncol Mag 2012; 2 (1): 11–4.

Key words: radiotherapy, radiation oncology,neurooncology, radiosurgery

non-uniform beam fluences from multiple directions to allowthe intended dose to reach the target with maximal sparing ofnormal tissues. The treatment system involves use of multi-leaf collimators that divide each beam into many small beam-lets, which are each modulated such that the overall beam in-tensity patterns achieve the desired target coverage and criti-cal tissue sparing. IMRT treatment for high-grade gliomas hasallowed for improved target conformity without increasingthe integral dose and volume of normal tissue exposed to lowdoses of radiation [2].

Helical tomotherapy, developed by Tomotherapy, Inc, as adedicated rotational IMRT system with a slip-ring rotatinggantry, achieves more efficient delivery by continuous gantryrotation and treatment couch translation (Figure 1). It has theadvantage of spiral IMRT treatments without the problem ofintersecting fields [3].

Linear accelerator vendors have released the capability tovary the angular dose rate by dynamically changing dose rateand/or gantry speed during arc delivery. This new capability,referred to as volumetric-modulated arc therapy (VMAT), haslikely spurred a re-emergence of clinical interest in the use ofarc therapy. An advantage of VMAT is the potential reductionin delivery time compared with IMRT [4]. A 200-cGy fractiondose can be delivered within 1.5–3 min with VMAT [5].Varian with RapidArc and Elekta has the commercially avail-able VMAT softwares being used in their linear accelerators

Figure 1. Novel radiotherapy and radiosurgery platforms: TomoHD Tomotherapy.Image used with permission from Accuray Incorporated.



and treatment planning systems. RapidArc treatment plan-ning and delivery of integrated plans of whole-brain radio-therapy (WBRT) and boosts to multiple brain metastases is arapid and accurate technique that has a higher conformity in-dex than conventional summation of WBRT and radiosurgeryboost [6]. With this technique it is feasible to treat both themacroscopic metastases to a higher dose and the microscopicdisease with a lower prophylactic dose at the same time (Fig-ure 2). Another novel technique is hippocampus sparing dur-ing whole-brain radiotherapy, aiming at the reduction ofneurocognitive complications of whole-brain irradiation [7].It is possible to reduce the median dose for the hippocampusto 5–8 Gy, while other parts of the brain receive 30 Gy.

With the advent of precise radiation techniques, the role ofprophylactic irradiation both in primary brain tumours (likeglioblastoma) or metastases has been questioned. Even in theconcurrent temozolomide era, local in-field recurrences arestill the majority. Recent studies show that a 1-cm clinical tar-get volume expansion to the contrast-enhancing areas mightresult in the same local recurrence rate as a 2–3-cm margin[8]. For patients with a limited number of metastases, radio-surgery alone results in the same overall survival as with theaddition of whole-brain irradiation [9].

The proton beam has a very advantageous physical character.It has a very rapid dose fall-off at the range. However, its de-pendence on a large particle accelerator, which is very expen-sive to build, has prevented the technique from being widelyused. There is ongoing research by several companies to con-struct proton machinery with smaller accelerators, and at an

affordable price to make this highly conformal treatment ac-cessible to larger populations.

Stereotactic Radiosurgery and Hypofrac-tionated Radiotherapy

Since Leksell’s conception of stereotactic radiosurgery, tech-nology has proliferated and radiosurgery has become a stand-ard procedure in the treatment of many benign and malignantCNS pathologies [10]. Radiosurgery relies on 3-D or stere-otactic image localization, thereby enabling co-identificationof a virtual target in the treatment-planning computer with theactual target position for treatment delivery [11]. The firstGamma Knife containing 179 Co-60 sources became opera-tional in Stockholm in 1968. It was redesigned using 201 Co-60 sources arranged in a hemispherical configuration to createa more spherical dose distribution. Treatment is performed bypositioning the patient’s tumour in the centre of the focusedradiation. Models B and C were developed to facilitate reload-ing of the Co-60 sources and patient positioning. The Per-fexion model has 192 Co-60 sources arranged in a cylindricalconfiguration in 5 rings (Figure 3) [12]. The new reposition-ing head frame, “Extend”, facilitates fractionated treatmentsand extends the treatment fields to the cervical and upper neckregions as well.

Cyberknife is a compact X-band linear accelerator mountedon a 6-axis robotic arm (Figure 4) [13]. The multi-axis roboticarm allows the positioning of the linear accelerator in any di-rection and at various surface-to-axis distances. With a com-plex planning process to choose the optimal beam configura-

Figure 2. Whole-brain radiotherapy with integrated boost for multiple metastases. The whole brain receives 30 Gy in 10 fractions, while the boost dose to the macroscopictumours is 50 Gy.



13

tions and beam weights, automated procedures help physi-cians and physicists. Diagnostic X-rays mounted to the ceil-ing enable real-time orthogonal image guidance without theneed for a stereotactic frame. Bony structures or implantedradio-opaque markers allow the localization of the target. Thedynamic tracking software, Synchrony, allows to follow thetarget in moving parts of the body.

In recent years, linac-based radiosurgery manufacturers havealso developed high-technology linear accelerators to specifi-cally deliver radiosurgery more accurately and efficiently[14–16]. All of the linacs currently marketed for radiosurgeryshare common features: higher dose rates, integrated imageguidance, integrated high-resolution multi-leaf collimation,and improved mechanical accuracy [11]. The first examplewas Clinac 600SR by Varian, a dedicated radiosurgery accel-erator with a single 6-MV energy with a 10 × 10 cm maximumfield size [17]. Later on, Varian’s partnership with BrainLabimproved linac-based radiosurgery technology. Besides cir-cular collimators, computer-controlled m3® micro-multileafcollimators (mMLC) with a 3-mm projection at the beamisocentre allowed for beam-shaping and intensity-modulatedradiosurgery. Image guidance on the Novalis systems is per-formed by the fully integrated ExacTrac X-Ray 6D, whichconsists of 2 infrared cameras for patient prepositioning andtracking, 2 floor-mounted X-ray tubes, and 2 ceiling-mountedamorphous silicon flat panel detectors for X-ray image guid-ance. These components allow for computer-assisted infraredand X-ray-based correction and verification of the patient’sposition before and during treatment. Varian has extended theradiosurgery partnership to Trilogy and Novalis TX high-en-ergy linear accelerators which are also equipped with conebeam CT, allowing for the acquisition of soft-tissue imagingfor image guidance. Similarly, both Elekta and Siemens havemarketed radiosurgery linacs featuring higher dose rates,higher accuracy, high-resolution mMLCs, and CBCT for soft-tissue image guidance (Figure 5).

Traditional radiosurgery uses an invasive headring for stereo-tactic localization and minimization of motion during imageacquisition and treatment. Taking into account the disadvan-

tages of frame-based invasive systems, several frameless sys-tems have been developed. They rely on optical and/or imageguidance. Thermoplastic masks are used for immobilization.Extracranial radiosurgery (eg, of the spine) has also become aneffective and more frequently used treatment to increase theeffectiveness of radiation treatment for tumours in close proxi-mity to very critical structures such as the spinal cord.

In recent years, there has been increasing interest in flatteningfilter-free (FFF) linacs [18]. It is possible to expect a reductionin the out-of-field dose due to reduced head scatter and re-sidual electron contamination, which results in a benefit fornormal tissues because of decreased scatter doses [19]. Re-moval of the flattening filter may also provide delivery of thedose up to 4 times faster. Besides its treatment efficiency, ra-diobiological implications of increased dose rates are investi-gated [20]. The first commercially available system is TrueBeamfrom Varian. After integration of the TrueBeam linac with theNovalis ExacTrac imaging and positioning system, a 6-di-mensional couch and high-definition multi-leaf collimatorswere added to further improve the precision of radiosurgeryand SBRT (Figure 6).

As a result of these flexible platforms for any type of radio-therapy, it has been possible to use different fractionation

Figure 3. Novel radiotherapy and radiosurgery platforms: Gamma Knife Perfexion.Courtesy of Elekta.

Figure 4. Novel radiotherapy and radiosurgery platforms: Cyberknife. Image usedwith permission from Accuray Incorporated.

Figure 5. Novel radiotherapy and radiosurgery platforms: Elekta Axesse. Courtesyof Elekta.



regimens from multiple fractions to single-fraction treat-ments. Large tumours in the brain that cannot be irradiated ina single fraction now have the option to be irradiated withhypofractionated treatments. Using the accurate imaging, ithas been possible for some tumours to shorten overall treat-ment time by means of hypofractionation.

Image-Guided Radiotherapy

Detailed anatomical imaging in CNS has been one of the mostimportant milestones for treatment of CNS tumours. Revolu-tionary change has been made by the implementation of 3-di-mensional imaging with soft tissue visualization of the bodyby CT and MR. Modern treatment planning softwares havethe capability of registering and fusing MR and CT imagesets, which significantly enhances the accuracy of target de-lineation [21]. Aminoacid and hypoxia tracers for PET/CT, be-sides new MR techniques like diffusion, perfusion, andspectroscopy, have added metabolic information to the ana-tomical delineation [22]. They are useful for target delineation,dose-painting, and evaluation of disease progression. Althoughrather investigational at the moment, delineation of nerve fibretracts and shape of dose according to this information allow forthe radiation oncologist to decrease the possible complicationsof radiotherapy, just like its use in neuro-oncology [23].

A potential source of inaccuracies in the treatment of patientsrelates to the difficulty in daily repositioning of the patientwithin the immobilization device in exactly the same way[21]. Image-guided radiotherapy (IGRT) is visualization ofthe target and the normal structures just before and duringtreatment and correction of the potential set-up errors. Differ-ent vendors have different on-board imaging (OBI) solutionsfor image guidance. Orthogonally paired X-ray images can becompared to the digitally reconstructed radiographs (DRR)which are created from the simulation CT to check the set-upaccuracy and to correct positioning errors. Cone beam CTs,integrated to the modern linacs, make it possible to image thesoft tissues in-room and correct positioning according to theverification of registered images with the planning CT scan.

For extracranial treatments, respiratory motion is an impor-tant component of intrafractional motion. 4-D CT simulationmakes it possible to have images at different phases of respira-tion and to contour the target and critical structures separately.Gating, active breath control, and tracking are contemporarymethods, both to increase the accuracy of treatment and todecrease the volume and dose applied to critical structures.

Conclusions

Radiotherapy is an important part of the standard of carefor many CNS tumours. Recent technological advanceshave enhanced our targeting accuracy, thereby reducingunnecessary, so far normal tissue doses. New technologieshave also provided the possibility to shorten the fractionaland overall treatment times, which is an improvement re-garding patient comfort and quality of life. Integration ofsystemic and targeted therapies with novel radiotherapytechnologies is investigated for their synergistic interac-tions.


MUA has no conflict of interest to declare.

Figure 6. Novel radiotherapy and radiosurgery platforms: TrueBeam STX with Novalis.Image courtesy of Varian Medical Systems, Inc. All rights reserved.

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12. Regis J, Tamura M, Guillot C, et al. Radio-surgery with the world’s first fully robotizedLeksell Gamma Knife PerfeXion in clinical use:a 200-patient prospective, randomized, control-led comparison with the Gamma Knife 4C. Neu-rosurgery 2009; 64: 346–55.13. Adler JR, Chang SD, Murphy MJ, et al. TheCyberknife: a frameless robotic system for ra-diosurgery. Stereotact Funct Neurosurg 1997;69: 124–8.14. Bayouth JE, Kaiser HS, Smith MC, et al.Image-guided stereotactic radiosurgery using aspecially designed high-dose-rate linac. MedDosim 2007; 32: 134–41.15. Chang Z, Wang Z, Wu QJ, et al. Dosimetriccharacteristics of Novalis Tx system with highdefinition multileaf collimator. Med Phys 2008;35: 4460–3.16. Huntzinger C, Friedman W, Bova F, et al.Trilogy image-guided stereotactic radiosurgery.Med Dosim 2007; 32: 121–33.17. Das IJ, Downes MB, Corn BW, et al. Char-acteristics of a dedicated linear accelerator-based stereotactic radiosurgery-radiotherapyunit. Radiother Oncol 1996; 38: 61–8.18. Hrbacek J, Lang S, Klöck S. Commissioningof photon beams of a flattening filter-free lin-ear accelerator and the accuracy of beammodeling using an anisotropic analytical algo-rithm. Int J Radiat Oncol Biol Phys 2011; 80:1228–37.19. Scorsetti M, Alongi F, Castiglioni S, et al.Feasibility and early clinical assessment ofFlattening Filter Free (FFF) based StereotacticBody Radiotherapy (SBRT) treatments. RadiatOncol 2011; 6: 113.20. Lohse I, Lang S, Hrbacek J, et al. Effect ofhigh dose per pulse flattening filter-free beamson cancer cell survival. Radiother Oncol 2011;101: 226–32.21. Van Meir EG, Hadjipanayis CG, Norden AD,et al. Exciting new advances in neuro-oncolo-gy: The avenue to a cure for malignant glioma.CA Cancer J Clin 2010; 60: 166–93.22. Grosu AL, Weber WA. PET for radiationtreatment planning of brain tumours. RadiotherOncol 2010; 96: 325–7.23. Pantelis E, Papadakis N, Verigos K, et al. In-tegration of functional MRI and white mattertractography in stereotactic radiosurgery clinicalpractice. Int J Radiat Oncol Biol Phys 2010; 78:257–67.


Spectrum of Side Effects of Anticonvulsants in Patients with Brain Tumours

15

Spectrum of Side Effects of Anticonvulsantsin Patients with Brain Tumours

Christa P Bénit, Charles J Vecht

Received on December 30, 2011; accepted on January 8, 2012; Pre-PublishingOnline on January 24, 2012

From the Neuro-oncology Unit, Department of Neurology, Medical Center The Hague,The NetherlandsCorrespondence to: Charles J Vecht, MD, PhD, Neuro-oncology Unit, Depart-ment of Neurology, Medical Center The Hague, POB 432, 2501 CK The Hague,The Netherlands; e-mail: [email protected]

Abstract: Seizures are a common manifestationin patients with brain tumours, and most patientsneed anticonvulsants. Apart from seizure control,the risk of side effects makes the proper choiceof anticonvulsants a major concern. Toxicitiesnot only exist as common side effects, but alsoappear as drug-drug interactions, neurotoxici-ties, and other organ dysfunctions.

One reason for interactions is the use of theclassical anti-epileptic drugs (AED), phenobarbital(PB), phenytoin (PHT), and carbamazepine (CBZ).Large differences in dose regimens with concomi-tant chemotherapy reflect the potency of these ef-fects. Although valproic acid (VPA) can be benefi-cial to prevent tumour growth, it may lead to bonemarrow suppression and other toxicities becauseof its enzyme-inhibiting properties.

Another noteworthy side effect are skin reac-tions, like erythema multiforme, which occa-

sionally develops during radiation. Althoughthis side effect is rare, it can be life-threaten-ing. Many anti-epileptic drugs can have extratoxic effects with existing organ dysfunction,like bone-marrow suppression or liver abnor-malities, this applies particularly for PB, PHT,CBZ, and VPA.

Existing clinical or subclinical signs of braindamage secondary to space-occupying tumouraleffects or the sequelae of previous neurosurgery,radio-, and chemotherapy enhance the chancesof neurotoxicity. Besides, the intake of anticon-vulsants itself and their total number stronglycontribute to cognitive dysfunction. As neuro-cognitive decline interferes with quality of life,such changes may substantially affect daily ac-tivities of patients and their family members.

The multitude of co-therapies applied withbrain tumours contributes to a myriad of side ef-

fects that are almost impossible to unravel, asdrugs and other therapies used can have aggra-vating or counteracting effects on each other.Knowledge of individual anticonvulsants and an-ticipation of toxicity including the recognition ofalready existing co-morbidities all contribute tobetter selection and dosing of anticonvulsants,including the choice of agents that do not inter-act. Although this survey is not aimed atthe proper drug choice, future studies need toshow which anti-epileptic agents or combin-ations would be the best match to achieve effec-tive seizure control together with good tolerabil-ity. Eur Assoc Neurooncol Mag 2012; 2 (1):15–24.

Key words: brain tumour, seizure, anticonvul-sant, drug interaction, toxicity, cognitive dys-function

Introduction

Epilepsy is common in patients with brain tumours, and sei-zures constitute the presenting symptom in 30–50 % of pa-tients with brain tumours [1]. Seizures can also affect patientswith systemic cancer with brain or leptomeningeal metastasesor by organ dysfunction or drug treatment, including chemo-therapy causing metabolic or toxic encephalopathies [2]. Forthese reasons, patients with seizures and cancer often needanticonvulsants; 2/3 of patients with primary brain tumours useAEDs [3]. Unavoidably, this may lead to side effects either asgeneral toxic effects, or more specifically related to the under-lying condition, for example the occurrence of interactionswith concomitantly administered chemotherapeutic agents. Inthis review, we will comment on the general side effects ofanticonvulsants, followed by a more extensive discussion onside effects of anticonvulsants associated with brain tumoursor systemic cancer.

Side effects of anticonvulsants are more common in patientswith brain tumours (20–40 %) than in other types of epilepsyand lead in almost 1/4 to a discontinuation of therapy [4].These effects include cognitive changes, abnormalities re-lated to organ function, interactions with other drugs, mostnotably chemotherapy, and other toxicities particularly asso-ciated with brain tumours.

Seizures in patients with brain tumours can be classified aspartial (simple or complex partial) or symptomatic, with orwithout secondary generalisation. Here we briefly mentionthe main characteristics of anticonvulsants, and Table 1 de-picts an overview of the main mechanisms of action, the meta-bolic pathways involved, their pharmacokinetic propertiesand common toxicities, including idiosyncratic side effectsoccurring in cancer patients.

Phenobarbital (PB) is one of the oldest anticonvulsants andstill in use in many parts of the world. Major drawbacks are itsrelatively strong sedating effect as well as its being a strongenzyme-inducer. Nevertheless, because of its action as a broad-spectrum anticonvulsant, it may still be applied in treatment-resistant seizures. In cancer patients, one should be aware ofcognitive side effects, hepatic dysfunction, skin reactions in-cluding Stevens-Johnson syndrome (SJS), and drug interac-tions.

Phenytoin (PHT) is a first-generation anticonvulsant which isalso employed in status epilepticus. It is a strong enzyme-in-ducer and has been implied in many reports on interactionswith co-administered agents, including chemotherapeuticdrugs (CTD). Besides, it shows non-linear pharmacokineticsand has a relatively small therapeutic window. Today, it ismainly applied by the intravenous route in status epilepticus,and is felt to be less suitable for oral maintenance therapy.Interaction with other drugs and side effects like encepha-lopathy, hepatitis, coagulation defects, and bone marrow hy-poplasia are of concern in patients with brain tumours.

Carbamazepine (CBZ) is a still widely used first-generationanticonvulsant for partial seizures. It is a potent enzyme-in-ducer and can strongly accelerate the metabolism of many

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Table 1. Mechanisms of action of AEDs (in alphabetical order) and pharmacokinetic characteristics. Based on [5–8].

AED Usual Therapeutic Common/important Main mechanism of action Oral bio- Time to Metabolism Vd T1/2 CL Proteindosage range side effects availability peak and excretion (l/kg) (h) (l/kg/h) binding(mg/day) (mg/l) (%) levels (h) (%)

CBZ 400–1600 4–12 Leukopenia, aplastic Blocks voltage-dependent 75–85 4–8 Hepatic epoxidation, 0.8– 5– 0.133 75anaemia, hepatotoxicity, Na+-channels conjugation 2 26hyponatraemia, SJS/TEN

CZP 0.5–4 0.02–0.08 Sedation, cognitive effects, GABA receptor agonist 90 1–4 Hepatic reduction and 1.5– 20– 0.09 86drowsiness acetylation 4.4 80

FBM 1200–3600 30–100 Hepatic disturbance, SJS NMDA and Na+-channel > 90 2–6 Hepatic hydroxylation and 0.75 13– 0.027– 20–25aplastic anaemia, insomnia, conductance conjugation (60 %), renal 30 0.032weight loss excretion (40 %)

GBP 900–3600 2–20 Weight gain, worsening of Blocks Ca+-channels, < 65 2–3 Renal excretion without 0.65– 5–7 0.120– Noneseizures GABA receptor agonist metabolism 1.04 0.130

LCM 200–400 10–20 Dizziness, headache, nausea, Slow inactivation of voltage- > 95 2–4 Hepatic demethylation, 0.6 13 < 15diplopia, blurred vision, cognitive dependent Na+-channels unchanged renal excretion (40 %)dysfunction, skin reactions

LTG 200–600 1–15 Rash, SJS, TEN, DRESS, head- Blocks voltage-dependent > 95 1–3 Hepatic glucuronidation (without 1.0– 12– 0.044– 55ache, blood dyscrasia, ataxia Na+-channels phase-1 reaction), renal excretion 1.3 60 0.084

(10 %)

LEV 1000–3000 3–30 Somnolence, asthenia, Binding to synaptic vesicle > 95 0.6–1.3 Partially hydrolysed in the blood, 0.5– 5–11 0.01 Noneirritabiity psychosis protein 2 (SV2A) 0.7

OXC 900–2400 10–35 Somnolence, headache, Blocks voltage-dependent > 95 4–6 Hydroxylation, glucuronidation 0.3– 8– 38diplopia, SJS, bone marrow Na+-channels 0.8 10suppression, hyponatraemia

PB 30–180 15–40 Rash, hepatotoxicity, impaired GABA receptor agonist, 80–100 1–3 Hepatic oxidation, glucosidation, 0.42– 46– 0.006– 45–60cognition, ataxia, mood change, glutamate antagonist, blocks hydroxylation, conjugation 0.75 136 0.009SJS/TEN voltage-dependent Na+-/Ca+-

channels

PHT 150–400 10–20 Blood dyscrasia, hepatitis, SJS, Blocks voltage-dependent 95 4–12 Hepatic oxidation, hydroxylation, 0.5– 24– 0.003– 85–95gum hyperplasia, lupus-like Na+-channels conjugation 0.8 72 0.02reactions, hirsutism

PGB 150–600 2–8 Somnolence, dizziness, ataxia Binds to Ca+-channels 90 1 No metabolism, renal excretion 6.3 None

TPM 100–500 2–20 Impaired cognition, hepato- Blocks Na+-channels, 81–95 2–4 No metabolism, mainly renal 0.6– 19– 0.022– 9–17toxicity, weight loss, renal GABA receptor agonist, excretion 1.0 25 0.036calculi blocks NMDA receptors

VGB 200–300 0.8–36 Visual field defects (33 %, GABA transaminase inhibitor 80–90 1–2 No metabolism, renal excretion 0.8 6–8 Similar Noneoften irreversible), fatigue, (70 %, unchanged) to GFRdrowsiness

VPA 500–2500 50–100 Hepatotoxicity, thrombo- and Uncertain, may affect GABA > 95 1–10 Hepatic glucuronidation, oxidation, 0.15 8– 0.006– 85–95neutropenia, aplastic anaemia, glutaminergic activity conjugation 15 0.015tremor, weight gain, hair loss,ovarian cystic syndrome

ZON 200–600 20–30 Somnolence, ataxia, dizziness, Blocks Na+- and Ca+- > 95 2–6 Hepatic acetylation, glucuronida- 1.2– 60– 0.015– 40–50renal cuniculi channels tion (20 %), renal excretion (30 %) 1.8 70 0.019

AED: antiepileptic drug; Vd: volume of distribution; T1/2: elimination half-life; Cl: clearance; DRESS: drug reactions with eosinophilia and systemic symptoms; Na+: sodium; NMDA: N-Methyl-D-aspartate; Ca+:calcium; K+: potassium; GFR: glomerular filtration rate; CBZ: carbamazepine; CZP: clonazepam; FBM: felbamate; GBP: gabapentin; LCM: lacosamide; LTG: lamotrigine; LEV: levetiracetam; OXC: oxcarbazepine;PB: phenobarbitone; PHT: phenytoin; PGB: pregabalin; SJS: Stevens-Johnson syndrome; TEN: toxic epidermal necrolysis; TPM: topiramate; VGB: vigabatrin; VPA: valproic acid; ZON: zonisamide.



17

other drugs. Relevant side effects include drug interactions,hepatotoxicity, skin reactions including Stevens-Johnson syn-drome (SJS), leukopenia, bone marrow dyscrasia, and hy-ponatraemia.

Valproic acid (VPA) is a broad-spectrum anticonvulsant forboth generalized and partial epilepsy with rather mild toxic-ity. Recent reports indicate that it may also have anti-tumoureffects in glioblastoma multiforme and other types of cancer,possibly secondary to its action as a histone-deacetylase in-hibitor [9–11]. In children and adults with high serum levels,one should be aware of a disturbed haemostasis; monitoringof liver functions, platelet counts, and coagulation parametersis advisable. The impact of these abnormalities is uncertain asclinical studies have not indicated enhanced bleeding tenden-cies following neurosurgery. Nevertheless, in patients withcancer, one should be aware of drug-drug interactions andside effects including hepatotoxicity, disturbed haemostasis,bone marrow suppression, and skin reactions, ie, rash, SJS, ortoxic epidermal necrolysis (TEN).

Clonazepam (CZP) is a benzodiazepine, and a broad-spec-trum and effective anticonvulsant. Because its use may easilylead to sedation and tolerance, its application is generally re-stricted to the abrogation of acute seizures, in status epilepti-cus, or as a last resort therapy when other antiepileptic drugshave failed.

Lamotrigine (LTG) represents a first-choice anticonvulsantfor symptomatic partial epilepsy. However, although lamo-trigine by itself has only weak inducing and inhibiting activi-ties of the P-450 co-enzyme system of the liver, LTG is sus-ceptible to induction by concomitantly given drugs. A draw-back of lamotrigine is that the initiation of therapy requires along time period of dose increments before therapeutic rangesare reached. One should be aware of side effects in cancerpatients such as skin reactions (SJS, TEN), bone marrow tox-icity, and drug interactions.

Oxcarbazepine (OXC) has a close structural similarity to CBZbut it is better tolerated and shows fewer drug interactions. Inpatients with cancer, one should be aware of hyponatraemia,skin reactions (SJS, TEN), and sometimes bone marrow sup-pression.

Topiramate (TPM) is a second-generation and effective broad-spectrum AED with no obvious drug interactions, although itstolerability is lower than for many of the other newer AEDs.In cancer patients, one should be aware of cognitive dysfunc-tion, hepatic abnormalities, and blood dyscrasia (rare).

Gabapentin (GBP) is one of the second-generation anticon-vulsants, it is generally well-tolerated and shows no interac-tion with other drugs. However, it has a limited efficacy andsometimes a worsening of seizures may happen. In patientswith renal dysfunction, dose adjustment is necessary.

Felbamate (FBM) can lead to serious adverse events, like he-patic abnormalities or aplastic anaemia; its use is mainly re-stricted to intractable types of epilepsy.

Levetiracetam (LEV) has good anti-seizure efficacy, includ-ing in brain tumours [12–15]. Its major advantage is the ab-

sence of interactions with other agents. It is being excreted bythe kidney, and in the presence of renal dysfunction, dose ad-justment is necessary. Side effects include irritability and psy-chosis; blood dyscrasia is rare.

Pregabalin (PGB) is a third-generation anticonvulsant thatdoes not show pharmacokinetic interactions with enzyme-in-ducing or -inhibiting drugs. To date, there is little experiencewith pregabaline as an anticonvulsant, including its applica-tion in brain tumour patients. In patients with renal dysfunc-tion, dose adjustment is necessary.

Lacosamide (LCM) selectively enhances slow sodium chan-nel inactivation. Because of the absence of drug interactions,lacosamide seems a promising AED in cancer. Presently, it isregistered for use as an add-on AED. Side effects include cog-nitive dysfunction and skin reactions.

Zonisamide (ZON) is a broad-spectrum anticonvulsant and ismetabolised by conjugation with glucuronic acid. It does notinhibit or induce hepatic co-enzymes, however, other enzy-me-inducing drugs, like PHT and PHB, can enhance its me-tabolism. Side effects like weight loss and cognitive distur-bances are of concern in patients with brain tumours.

Drug Interactions

Drug interactions are characterized as either pharmacokinetic(when uptake, distribution, metabolism, or excretion is af-fected) or pharmacodynamic (when target organs or receptorsites are affected). Pharmacokinetic drug-drug interaction_occurs when ≥ 2 drugs are administered simultaneously andone drug modifies the metabolism of the other. In this way,serum concentrations of co-administered drugs can becomereduced or elevated, leading to either ineffective therapy ordrug toxicity. The most common interactions between anti-epileptic and cytostatic drugs are of a pharmacokinetic nature,and as a rule may occur when both are being metabolized by acorresponding co-enzyme of the P450 CYP system, by epox-ide oxidation, or by glucuronidation in the liver [16, 17]. Al-though the CYP system consists of approximately 60 differentiso-enzymes, 5 of them (CYPs 3A4, 2D6, 2C9, 2C19, and1A2) are responsible for the metabolism of 95 % of all drugs,of which the CYPs 3A4, 2C9, and 2C19 (Table 2) are particu-larly important in relation to potential interactions of AEDs[19, 20]. An overview of the different groups of chemothera-peutic agents and the interactions they may have with anti-convulsants, most notably with enzyme-inducing AEDs, isgiven in Table 3.

Compromised Activity of CTDs by Enzyme-Inducing AEDs

Alkylating AgentsCyclophosphamide is an alkylating agent and is commonlyadministered in the treatment of malignant lymphomas,leukaemias, neuroblastoma, retinoblastomas, and carcinomasof the ovary, breast, endometrium, and lung, usually in combin-ation with other chemotherapeutic drugs [25]. By itself, cy-clophosphamide is inactive and requires enzymatic bioactiv-



ation in the liver and various CYP iso-enzymes have beendemonstrated to be involved, including 3A4/5 and 2C9/19[25]. PB, PHT, and CBZ can induce the clearance of cyclo-phosphamide via its action on enzyme-inducing iso-enzymes[62]. As a faster metabolism may also lead to an increasedexposure to active metabolites, this combination can also re-sult in toxicity [22]. Lower plasma concentrations of ifosfa-mide have also been observed in combination with PHT,probably due to enhanced activity of CYP2B6 [24].

Busulphan is an alkylating agent that is applied with autolo-gous bone marrow transplantation. Concomitant prescriptionof AEDs is recommended because busulphan gives rise toepileptic seizures. However, administration of PHT may re-sult in reduced steady-state levels of busulphan [63].

Antimitotic CytostaticsVinca alkaloids, including vinblastine, vincristine, andvindesine, are largely metabolized by 3A4/5 iso-enzymes [64,65]. Systemic clearance (Cl) of vincristine is 63 % higher, theelimination half-life (T1/2) 35 % shorter, and the total area-under-the-plasma-concentration-time curve (AUC) 43 % smallerin patients receiving PTH or CBZ, probably as a result of anaccelerated metabolism of vincristine [39].

TaxanesPaclitaxel is widely used in different types of cancer, includ-ing lung, breast, and ovarian carcinoma and acts by stabi-lisation of tubulin polymerization. Its metabolism takes placethrough oxidative metabolism mediated by 3A4/5 and 2C8[66]. In combination with enzyme-inducing AEDs, the maxi-mum tolerated dose (MTD) of paclitaxel is 43–50 % higherand depends to some extent on the way of administration [34,35].

AntimetabolitesMethotrexate is an antimetabolite that acts as a folate antago-nist, it is widely applied in different types of cancer, includingleukaemia, lymphomas, and breast cancer. Methotrexate in-hibits dihydrofolate reductase, leading to reduced synthesis ofDNA, RNA, and proteins [67]. Its elimination is mainly renal,and 80–90 % is unchanged excreted in urine [68]. In a retros-pective study, 40 of 716 children with acute lymphoblasticleukaemia receiving PB, PHT, or CBZ had a lower plasmaclearance of methotrexate and teniposide, together with aworse event-free survival, more haematological and CNS re-lapses, and a shorter survival [26]. In a small retrospectivestudy, blood levels of methotrexate were lower in patients re-ceiving EIAEDs as compared to either the non-EIAED topira-mate or not receiving any anticonvulsant [27]. The exactmechanism of interaction between the AEDs methotrexateand EIAEDs is not known.

Topo-Isomerase InhibitorsEtoposide and teniposide are used in non-small-cell lung car-cinoma (NSCLC) and acute myeloid leukaemia, (non-) Hodg-kin’s lymphoma, acute lymphoblastic leukaemia, and in au-tologous bone marrow transplantation, and are mainly me-tabolized by CYP 3A4 [64]. The Cl of etiposide is about 77 %faster in patients on concomitantly administered EIAEDs[38]. Concomitant use of PB or PTH leads to a 2–3-fold in-crease of Cl of teniposide, which may thus compromise itsefficacy [37].

The camptothecin analogue topotecan is mostly used in re-fractory small-cell lung cancer and ovarian cancer, and co-administration of PHT leads to a 47-% increase of Cl andfewer haematological side effects [69]. For 9-aminocampto-tecin, plasma concentration levels are 3× lower with concomi-

Table 2. Mechanisms of metabolism of AEDs and their effects on the P450 hepatic CYP system. Based on [16, 18].

AED Metabolism Substrate (CYP) Inducer (CYP) Inhibitor (CYP)

CBZ Cytochrome P450 1A2, 2C9, 2C19, 3A4 1A2 (s), 2B6 (s), 2C9 (s), 2C19 (s), 3A4 (s) –3A4 (s)

CZP Cytochrome P450 3A4 – –

FBM Cytochrome P450 2E1 2C19, 3A4 (w) 2C19

GBP Not metabolised – – –

LCM Partial cytochrome P450 2C19 – –

LTG UDPGT glucuronidation – UDGPT (w) –

LEV Non-hepatic hydrolysis – – –

OXC UDPGT glucuronidation, limited – 2C19 (w), 3A4 (w) 2C19 (w)cytochrome P450 metabolism

PB Cytochrome P450 2C9, 2C19, 2E1 1A2 (s), 2B6 (s), 2C8 (s), 2C9/C19 (s), 3A4 (s) –

PHT Cytochrome P450 2C8, 2C9, 2C19 1A2, 2B6 (s), 2C9/19 (s), 3A4 (s) –

PGB Not metabolised – – –

TPM Mainly renal excretion, limited – 2C19 (w), 3A4 (w) 2C19 (w)cytochrome P450 metabolism,UDPGT glucuronidation

VGB Not metabolised – – –

VPA Cytochrome P450, UDPGT 2A6, 2B6, 2C9, 2C19 – 2C9, EH, UDPGTglucuronidation, β-oxidation

ZON Cytochrome P450 2C19, 3A4, 3A5 – –

AEDs: see Table 1; s: strong; w: weak; CYP: cytochrome P450 enzyme; UDPGT: uridine diphosphate glucuronyltransferase



19

tant EIAEDs [28]. Co-medication with EIAEDs results in anincrease in clearance of 27–57 % and a decrease in bioavai-lability of 75 % of irinotecan [28].

Other Cytostatic DrugsIxabepilone is a novel microtubule-targeting agent with anti-tumour activity against ovarian, colon, cervical, gastric, breast,melanoma, NSCLC, and non-Hodgkin’s lymphoma. Togetherwith EIAEDs, the MTD is 41 % and the Cl 50 % higher, prob-ably by induction of 3A4 [70].

Proteinkinase InhibitorsResearch into the development of gliomas and other carcino-mas has improved the understanding of specific cellular, mo-lecular, and genetic mechanisms that lead to cancer growthand progression. To date, many agents can target these path-

ways, including tyrosine-kinase inhibitors and angiogenic in-hibitors. The metabolism of these drugs is often influenced byconcomitant administration of anticonvulsants.

Erlotinib is an inhibitor of the epidermal growth factor re-ceptor (EGFR) and is used in NSCLC, and mainly metabo-lized via the iso-enzymes 3A4, 3A5, and to a lesser extent by1A2 [43]. The MTD for erlotinib is 200 mg/day without en-zyme induction and more than 2–3× higher (450–650 mg/day) together with an EIAED [42, 43].

Another tyrosine-kinase receptor inhibitor is the small mol-ecule gefitinib that is used in NSCLC and is metabolized by3A4, 3A5 co-enzymes, and the non-inducible CYP2D6. Forpatients using an EIAED, the peak dose of gefitinib is –45 %,the AUC –60 % and the MTD 4× higher (1000 mg/d) as com-

Table 3. Interactions between AEDs and CTDs

Table 3a. AED that reduce CTD efficacy

Group CTD Type of CTD AED that reduces CTD Effect Reference

Alkylating agents Busulphan PHT Cl 15 % ↑, AUC 16 % ↓, [21]**T1/2 23 % ↓

Cyclophos- PB, PHT AUC 67 % ↓, biotransformation [22]* [23]*phamide 200–300 % ↑Ifosfamide PHT AUC ↓ (ns), Cl ↑ (ns) [24]*Thiotepa PHT AUC 29 % ↓ [25]*

Antimetabolites Methotrexate PB, PHT, CBZ Cl ↑ (ns), Cpl 90 % ↓ [26]*** [27]*Antimitotic agents 9-Amino- PB, PHT, CBZ Cpl 67 % ↓, MTD 109 % ↑, [28]*** [29]**

camptotecin Cl 122 % ↑Irinotecan PB, PHT, CBZ, PRM, OXC MTD 160–250 % ↑, Cl 61 % ↑ [30]*** [31]*** [32]***Topotecan PHT Cl 47 % ↑ [33]***Paclitaxel EIAEDs (ns) MTD 43–57 % ↑, MTD 50 % ↑, [34]*** [35]*** [36]***

Css 55 % ↓Teniposide PB, PHT Cl 146 % ↑ [37]*Etoposide AEDs (ns) Cl 77 % ↑ [38]*Vincristine PHT, CBZ Cl 63 % ↑, AUC 43 % ↓ [39]**

Proteinkinase inhibitors Bortezomib EIAEDs (ns) MTD 47 % ↑ [40]**Enzastaurin EIAEDs (ns) Cpl 80 % ↓ [41]**Erlotinib EIAEDs (ns) AUC 55 % ↓, MTD 150–333 % ↑ [42]*** [43]**Gefitinib PB, PHT, CBZ, PRM, OXC AUC 60 % ↓, MTD 300 % ↑ [44]**Imatinib PHT, CBZ, PRM, OXC, TPM Cpl 66–68 % ↓, MTD 50 % ↑ [45]*** [46]***Sorafenib EIAEDs (ns) Cpl ↓ [47]**Tipifarnib PB, PHT, CBZ AUC 83 % ↓, MTD 100 % ↑ [48]***Vatalinib PB, PHT, CBZ, PRM, OXC Cl 200 % ↑, Cmax 67 % ↓ [49]**Temsirolimus PB, PHT, CBZ, OXC Cmax 73 % ↓, MTD 47 % ↑, Cpl 33 % ↓ [50]*** [51]**Sirolimus PB, PHT, CBZ, OXC AUC 39 % ↓, MTD 100 % ↑ [52]*** [53]**Everolimus EIAEDs (ns) Lower C (ns) [50]*** [51]**

Table 3b. Increase of toxicity

CTD AED that increases toxicity of CTD Result ReferenceCCNU (Lomustine) VPA Frequency of haematological toxicity 60 % ↑ [9]***AED CTD that increase toxicity of AED Effect ReferencePHT 5-Fluorouracil Cpl (PHT) 170–225 % ↑ [54]* [55]*

Capecitabine Cpl (PHT) 168–171 % ↑ [55]* [56]*Doxifluridrine Cpl (PHT) 400 % [57]*Erlotinib Cpl (PHT) 322–406 % ↑ [58]*Tamoxifen Cpl (PHT) 44 % [59]*

VPA Fotemustine/Cisplatin Frequency of haematological toxicity 300 % ↑ [60]****PHT, PB, CBZ, VPA Procarbazine Frequency of skin hypersensitivity reactions 390 % ↑ [61]****(as combination therapy)CTD: chemotherapeutic drug; AED: antiepileptic drug (abbreviations: see Table 1); Cl: clearance; AUC: area-under-the-concentration-timecurve; T1/2: elimination half-life; ns: not specified; C: concentration; EIAED: enzyme-inducing antiepileptic drug; Cpl: plasma concentration;MTD: maximum tolerated dose; PRM: primidone; TD: tolerated dose; Css: steady-state concentration; Cmax: peak plasma concentration.case report (1–4 patients); ** small series (4–19 patients); *** large series (20–49 patients); **** large prospective series (> 50 patients)



pared to an MTD of 250 mg/day without EIAEDs [44].Imatinib, another selective inhibitor of tyrosine-kinase, is ad-ministered in chronic myeloid leukaemia and with gastro-intestinal stromal tumours, and largely metabolized byCYP3A4 [46]. Mean trough levels of imatinib are 2.9× lowerwith an MTD of 1200 mg/day for patients on EIAEDs as com-pared to 800 mg/day normally [45, 46]. For sorafenib, whichis mostly used in advanced renal cell carcinoma and hepato-cellular carcinoma, the peak concentration (Cmax) is –54 %and the AUC –63 % for patients on EIAEDs [47].

Tipifarnib is currently under investigation, mostly in blood andbreast cancers. A phase-I trial of tipifarnib in patients with re-current glioma using EIAEDs showed that the MTD is 2×higher, and the AUC approximately 2× lower than for patientsnot on EIAEDs. It is unclear to what extent either glucuroni-dation or oxidative metabolism by P450 co-enzymes is respon-sible for this decrease in systemic exposure [48].

Bortezomib is applied in multiple myeloma and in recurrentmantle-cell lymphoma. The use of EIAEDs can lead to an ac-celeration of metabolism requiring 2× higher doses ofbortezomib [40].

In enzastaurin, a VEGFR inhibitor, which is investigated inB-cell lymphoma, chronic lymphatic leukaemia, and solid tu-mours including glioblastoma, simultaneous EIAED useleads to approximately –80 % AUC [41].

Temsirolimus is an ester of the immunosuppressive agentsirolimus and inhibits the mammalian target of rapamycin. Itis mainly used in metastatic renal cell carcinoma and underinvestigation in glioblastoma multiforme. Sirolimus is an im-munosuppressant agent mostly given to transplant patients,and may have anti-tumour activity against malignant gliomas[53]. Both temsirolimus and sirolimus constitute substrates ofiso-enzymes 3A4/5. In one study, the peak concentration oftemsirolimus was –73 % and of sirolimus –47 % and the AUC–50 % with EIAED co-therapy. Grade-3 haematological tox-icity was more commonly seen (20 vs 3 %) in patients on non-EIAEDs [50, 53]. Also, everolimus concentrations are lowerwith concomitant 3A4-inducing AEDs [71].

Increased Toxicity by AEDs or CTDs

Increased toxicity of AEDs may occur when enzyme-inhibit-ing CTDs are concurrently prescribed. Toxicity of PHT hasbeen observed when combined with 5-fluorouracil, tamoxi-fen, capecitabine, erlotinib, or doxifluridine [55, 57–59]. Theunderlying mechanism of these interactions is probably acompetitive inhibition of PTH clearance by 2C9 and 2C19iso-enzymes. The use of the alkylating agent procarbazine incombination with PB, PTH, CBZ, or VPA can lead to hyper-sensitivity reactions of the skin. In a fotemustine-cisplatinregimen, the use of VPA leads to a 4-fold increase of thrombo-penia, neutropenia, or both [60].

Corticosteroids

Glucocorticosteroids are frequently used in patients withbrain tumours and systemic cancer, their administration can

cause drug-drug interactions because of enzyme-inducing ef-fects on the 3A4 iso-enzyme [72]. Vice versa, they are suscep-tible to agents affecting 3A4; PB, PHT, and CBZ enhance theclearance of dexamethasone 2–4× [5, 73, 74]. Hydrocortisoneis metabolized via the hepatic 11-B-hydroxysteroid dehydro-genase system, which is also susceptible to enzyme induction.PB, PHT, and CBZ induce the metabolism of prednisolonewith enhanced clearances of 79 %, 41 % and 77 %, respec-tively, and the metabolism of methylprednisolone more than3.4, 1.5, and 2×, respectively [75]. Vice versa, dexamethasonegiven together with PHT may lead to an increased clearanceof PHT and therefore with a lesser anti-epileptic activity. In-creased seizure frequency has indeed been observed with co-therapy of dexamethasone with 38–50 % lower serum PHTlevels [76–78]. When dexamethasone is discontinued, PHTconcentrations can easily rise to toxic levels [79].

These observations emphasize that it is equally important toapply dose adjustment not only at the time of initiating medi-cation but also when interacting co-therapy is discontinued.However, also increased levels of PHT have been observedwith co-medication of dexamethasone. Apparently, the use ofdexamethasone can lead to unpredictable interactions withPHT, including either enzyme-inducing or -inhibiting effects.

From these observations, one may conclude that simultaneoususe of enzyme-inducing anticonvulsants and corticosteroidsshould rather be avoided, or, when given simultaneously, thatplasma concentrations of anticonvulsants should be monitored.

Idiosyncratic and Skin Reactions

Bone marrow suppression and liver dysfunction can occur asa side effect of a number of individual AEDs, and are morefrequently seen in association with brain tumours than withother co-morbidities [4]. This can be explained by overlap-ping adverse events of CTDs, which are often more pro-nounced with the concomitant use of AEDs. For example,haematotoxicity can be the result of administration of PB,PHT, CBZ, or VPA, but is also common with use of temozolo-mide and other chemotherapeutic agents [80, 81].

Also, severe systemic allergic reactions can occur with the useof a number of AEDs, mainly at the time of initiation oftherapy with PB, PHT, CBZ, OXC, VPA, or LTG [82]. Themost common type of hypersensitivity is skin rash as a sideeffect of AEDs, which can be accompanied by fever, lym-phadenopathy, and, occasionally, by multi-organ abnormali-ties [83]. Its frequency seems higher in patients carrying abrain tumour than in non-tumoural patients with epilepsy [84,85]. More severe allergic reactions are erythema multiformeor the Stevens-Johnson syndrome and toxic epidermal necro-lysis with necrosis and blistering of skin and mucosal mem-branes, which may lead to a potential mortality of up to 40 %[86]. A number of observations strongly suggests an increasedappearance of SJS in patients undergoing cranial irradiationand receiving anticonvulsants, particularly with PB, PHT, orCBZ, often together with co-therapy with glucocorticosteroids[87, 88]. Nevertheless, the appearance of this severe dermato-logical complication is relatively rare. In one retrospectivereview of 289 patients receiving radiotherapy and anticonvul-



21

sants, only 1 patient developed SJS [85]. Recently, the humanleukocyte antigen (HLA) class 1 allele B*1502 was associ-ated with 100 % of patients with CBZ-induced SJS, and onlyin 3 % of CBZ-tolerant and in 8.6 % of controls in an Asianpopulation [89]. PHT and OXZ have been associated with se-vere skin reactions in HLA-B*1502 carriers [90]. In Europe,one has observed that the HLA-A*3101 allele increases therisk of developing a CBZ-induced hypersensitivity from 5 %to 26 % [91]. By screening patients on specific HLA allelesbefore prescribing anticonvulsants these sometimes life-threatening skin reactions can possibly be prevented [92].

Cognition

Besides pharmacokinetic effects, antiepileptic drugs can alsoinfluence cognitive functioning. The conventional anticon-vulsants PB, PHT, CBZ, and VPA are all associated with cog-nitive side effects showing impairments in memory, mentalspeed, and attention with a less favourable cognitive profile ofPB as compared to other anticonvulsants [93–95]. Althoughthese side effects are mild or moderate [93], their impact canbe substantial if patients already suffer from cognitive dys-function due to space-occupying effects of the tumour or bythe sequelae of neurosurgery, radio-, and chemotherapy [96].As neurocognitive decline interferes with quality of life, suchchanges may have great impact on the daily life of patientsand family members [97].

In a group of 156 long-time survivors of low-grade gliomas, ahigher seizure frequency was associated with mental deterior-ation. The use of one of the conventional anticonvulsants ledto a worse performance in 6 out of 7 cognitive domains [98].Particularly, an inverse relationship was observed betweenanti-epileptic polytherapy with AEDs, ie, the number of anti-convulsants taken simultaneously had an unfavourable effecton executive and psychomotor functioning in patients withlow-grade gliomas and hypothalamic hamartomas [98–100].

In general, the newer AEDs like GBP, LTG, OXC, PGB, andLEV confer less pronounced cognitive side effects, with theexception of TPM (Table 4) [105–107]. A retrospective studycomparing TPM (n = 429), LTG (n = 336), and LEV (n = 301)in non-brain tumour-related epilepsy showed that almost halfthe patients using TPM discontinued its use because of mentalslowing in 27.8 % and dysphasia in 15 % [101, 108]. At thesame time, almost 10 % of patients on LTG experienced posi-tive cognitive effects like improved alertness, better emo-tional stability, or less irritability [108, 109]. In a study on 70patients with gliomas, patients on one of the conventionalAEDs suffered from more adverse events than those on OXC(42.9 % vs 11.4 %) and psychomotor slowness was only seenwith the traditional AEDs (21.7 %) [102]. In another study on40 patients with seizures and gliomas, switching to leveti-racetam monotherapy showed no negative effects on 6 do-mains of cognition. LEV might even have positive effects asthere were no signs of cognitive decline despite the presenceof a brain tumour or administration of ancillary anti-tumourtherapy [104]. Two smaller observational studies (including11 and 29 patients, respectively) showed mild cognitive im-pairment, it is unclear whether this is caused by the disease(ie, tumour progression) or by the use of LEV [14, 103].

Conclusion

Today, patients with brain tumours undergo intensive therapy,including neurosurgery, radiation therapy, and chemotherapy,at various stages of the disease. Besides, the majority of pa-tients needs anticonvulsants to control epileptic seizures, andoften glucocorticosteroids or other ancillary therapies to con-trol symptoms secondary to tumoural effects or to anti-tu-mour therapy. For these reasons, this multitude of co-treat-ments easily leads to a myriad of side effects in patients withbrain tumours, drugs used simultaneously may either aggra-vate or counteract each other. The use of anticonvulsant drugsillustrates each of these situations, thus – apart from seizurecontrol – a lot of attention is needed for avoiding or neutraliz-ing these side effects in patients with brain tumours. Obvi-ously, the first issue in prescribing anticonvulsants is to takeinto account pharmacokinetic properties and common sideeffects (Table 1). Another point of attention is the issue of rec-ognition of interactions with chemotherapy due to the en-zyme-inducing or -inhibiting effects of conventional AEDs(Table 2). The substantial effect that enzyme-inducing AEDScan have on the treatment of brain tumours is reflected by thelarge differences of dose regimens of chemotherapeuticagents, depending on whether or not patients receive an en-zyme-inducing AED. Prospective phase-I/II trials on CTDsdivided in strata with or without EIAEDs have produced cor-responding data on drug clearance, area-under-the-curve val-ues, and median or maximum tolerated doses of new canceragents, and illustrate the strong enzyme-inducing capabilitiesof phenobarbital, phenytoin, and carbamazepine (Table 3).

Nevertheless, these effects are not so easily detected as theyare mainly manifested by a potential inefficacy of chemothe-rapeutic or targeted drugs on the underlying tumour. As manytypes of brain tumours including low- and high-grade gliomasor systemic cancers often become resistant to anti-tumour-di-rected therapy, a poor response to therapy is easily accountedfor by ineffective therapy rather than by co-treatment with anenzyme-inducing agent. Likewise, chemotherapeutic agentsthemselves often have enzyme-inducing or -inhibiting prop-erties leading to either potential inefficacy or toxicity ofantiepileptic drugs.

By making use of pharmacokinetic data on drug interactions(Tables 2, 3), one may argue that potential adverse interac-tions can be prevented by a timely dose adjustment accordingto the anticipated effect of these interactions. To do so reli-ably, this will require therapeutic drug monitoring of the appliedchemotherapy as well as anticipating and accounting for adose amendment at each change of the AED regimen. To whatextent this approach is indeed feasible in daily practise is un-certain, as medical oncologists taking care of cancer treat-ment not seldom work in other hospitals than neurologistsprescribing and monitoring anticonvulsants. In practice, this,makes proper adjustment of medication difficult to pursue oreven elusive. Probably, the risks of harmful interactions takeplace on a much larger scale than we assume, as physiciansprobably often do not realise or are unaware of the possibilityof interactions.

Obviously, the use of anticonvulsants may lead to interactionsnot only with chemotherapeutic agents, but also with many



other kinds of drugs, for manyother conditions or co-morbidi-ties, which may accompany pa-tients with brain tumours. Onenoteworthy side effect is the oc-currence of severe dermatologicalcomplications, which is the result ofan intricate interaction betweenanticonvulsants and the adminis-tration of cranial radiotherapy,possibly related to co-medicationwith steroids and expression ofcertain HLA alleles.

Apart from interactions, manyanticonvulsants have side effectsthat can be extra damaging in pa-tients already at risk for organdysfunction like bone marrowsuppression or liver dysfunction.Compared to the second- andthird-generation anticonvulsants,the use of conventional anticon-vulsants PB, PHT, and CBZ moreoften leads to hepatic dysfunctionand, to a lesser extent, also to bonemarrow suppression.

Lastly, also the risk on neurotox-icity is of major importance in pa-tients with brain tumours and sei-zures, as both the need for anti-convulsants and the number ofanticonvulsants used are eachstronger contributing factors tothe severity of cognitive dysfunc-tion than having gone throughearlier neurosurgical excision orradiation therapy (Table 4). Al-though reviewing satisfactory sei-zure control is beyond the scopeof this paper, the risk of ineffec-tive cancer treatment, organ dys-function, and neurotoxicity illus-trates the importance of effectiveand well-tolerated anticonvulsantsthat do not interfere with cancertreatment. Fortunately, there is anumber of anticonvulsants thatpossess these properties. Oxcar-bazepine, lamotrigine, and topira-mate have only weak enzyme-in-ducing or -inhibiting properties.Although valproic acid can haveenzyme-inhibiting activity andcan lead to hepatic dysfunctionand thrombopenia, its histone-deacetylase-inhibiting activity mayhelp to control tumour progres-sion. Lastly, gabapentin, levetir-acetam, pregabalin, and lacosami-Ta

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23

de do all show no drug interactions. Future studies need toshow which of these agents or combinations would be the bestmatch to achieve effective seizure control together with goodtolerability.

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Chemotherapy and Polyneuropathies

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Chemotherapy and PolyneuropathiesWolfgang Grisold1, Stefan Oberndorfer2, Anthony J Windebank3

Received on September 23, 2011; accepted for publication on October 22, 2011;Pre-Publishing Online on December 15, 2011

From the 1Department of Neurology, Kaiser-Franz-Josef-Spital, Vienna; the 2Depart-ment of Neurology, Landesklinikum St. Pölten, Austria; the 3Department of Neuro-logy, Mayo Clinic, College of Medicine, Rochester, MN, USA

Correspondence to: Wolfgang Grisold, MD, Department of Neurology, Kaiser-Franz-Josef-Spital, A-1110 Vienna, Kundratstraße 3; e-mail: [email protected]

Introduction

Patients with oncological diseases need to receive the mosteffective anti-cancer therapy. To achieve this, usually a com-bination of surgery, radiotherapy (RT), and chemotherapy,also with biologicals with an increased use of targeted thera-pies, is applied. Like most other side effects of therapy, suchas nausea, haematotoxicity can be managed but the increaseduse of neurotoxic drugs and the development of CIPN are be-coming major dose-limiting factors.

Although the biological effects of all neurotoxic substanceclasses are known, the precise mode of action on the periph-eral nerves is not always clear, and much effort has to be madeto develop strategies of prevention and treatment of CIPN.The morphologic correlates of CIPN are depicted in Figure 1.This is of particular importance as the number of long-termsurvivors has increased due to the success of oncologic treat-ments and peripheral neurotoxicity becomes a major dose-limiting factor. Patients can be exposed to dysfunctions im-pairing their quality of life as well as to neuropathic pain. Toovercome this challenge several approaches are being made.

Several possibilities for common pathways and affected struc-tures of sensory neurons and peripheral nerves are being dis-cussed. The impairment of mitochondrial function (suggestedby the loss of mitochondrial mobility in bortezomib, pacli-taxel, and vinca alkaloid neuropathy) could be one of the keyfactors. Mitochondrial failure could be a mechanism causingaxonal injury either by a failure to maintain ionic concentra-tions, or by the fact that impaired mitochondrial motility re-sults in mitochondria being unable to move to areas of highcalcium concentration in the axon, resulting in axonal dam-

age. Mitochondria in aged persons could also be a factor indistal axonal degeneration.

Sensory neurons in the dorsal root ganglia (DRG) seem to beexposed to several pathologies:– The blood supply of the DRG by fenestrated capillaries that

allow passage of drugs into the extracellular space aroundDRG neurons (blood-nerve-barrier less well-expressed).

– Platinum binding to nuclear DNA appears to stimulatepost-mitotic neurons to enter a state resembling G1 of thecell cycle which might start processes resulting in apop-tosis.

– Cutaneous sensory fibres lose their glial ensheathment asthey approach the epidermis and are less protected contraryto motor fibres.

Abstract: Peripheral neuropathies induced bychemotherapy (CIPN) are an increasingly frequentproblem. Contrary to haematologic side effects,which can be treated with haematopoeticgrowth factors, neither prophylaxis nor specifictreatment is available, and only symptomatictreatment can be offered.

CIPN are predominantly sensory, duration-of-treatment-dependent neuropathies, which de-velop after a typical cumulative dose. Rarely mo-tor, autonomic, or CNS involvement occurs. Typi-cally, the appearance of CIPN is dose-dependentalthough in at least 2 drugs (oxaliplatin and

taxanes) immediate effects can appear, causedby different mechanisms. The substances thatmost frequently cause CIPN are vinca alkaloids,taxanes, platin derivates, bortezomib, and tha-lidomide. Little is known about synergistic neu-rotoxicity caused by previously given chemo-therapies, or concomitant chemotherapies. Therole of pre-existent neuropathies on the develop-ment of a CIPN is generally assumed, but notclear.

Neurologists are often called in as consult-ants for cancer patients suffering from CIPN andhave to assess whether the neuropathy is likely

to be caused by chemotherapy or other mecha-nisms, whether treatment needs to be modifiedor stopped due to CIPN, and what symptomatictreatment should be recommended.

Possible new approaches for the managementof CIPN could be genetic susceptibility, as thereare some promising advances with vinca alka-loids and taxanes. Eur Assoc Neurooncol Mag2012; 2 (1): 25–36.

Key words: chemotherapy, neurotoxicity, cen-tral nervous system, prevention, therapy

Figure 1. Morphologic correlates of CIPN. The DRGs can be the target of cumulativeneurotoxicity as in platinum compounds. Axons, rarely the myelin, can be damaged.At the neuromuscular transmission site (NMT), the acute toxicity of oxaliplatin oc-curs. Unmyelinated fibers and terminal nerve arbors are the sites of acute taxanetoxicity. An additional spinal mechanism at the alpha-2-delta-Typ1 subunit in neuro-pathic pain is assumed.



– Disruption of axonal transport also interferes with retro-grade transport of target-derived trophic factors, recycledmembrane, and other vesicular components. In the near fu-ture, based on databases containing cancer type, type, anddose of chemotherapy, phenotyping of patients with CIPNmight become more easily available and provide a basis forfuture strategic plans and even individualized therapies.

Concerning the severity and expression of neuropathies, aswell as the frequency of occurrence, there are major prob-lems. The characterization with scales and scores is heteroge-neous and is discussed by Cavaletti et al in this issue [1]. Thefrequency of neuropathy for each drug is even more complex,as most series rely on small studies or are the result of largermedical oncologic studies which report neuropathies only asside effects. Often, these figures provide no information onassociated diseases, pre-existing neuropathies, previous drugtreatments, and the combination of chemotherapies. Websitesrecording individually reported side effects reach large num-bers, and by and large they seem to list the distribution oftoxic effects, but are not sufficiently evaluated to determineneurotoxic effects. Several reviews on chemotherapy-inducedneuropathies exist, which rely on the available data [2–6].

Symptoms, Signs, and Investigations

Clinical SymptomsMost chemotherapy-induced neuropathies are sensory. As theCIPNs are duration-of-treatment-dependent, tingling ornumbness in the feet or fingers is an early sign. Patients alsoreport hypaesthesias, dysaesthesias or paraesthesias and neu-ropathic pain. Sensory symptoms such as numbness are usu-ally irritating. But also a “plus” of symptoms, such as tingling,itching, stabbing, or pain, may occur. When symptomsprogress, the sensory zone widens and progresses from thetips of the extremities to a stocking-glove-like distribution. Atthis stage, patients are usually already disabled: on the upperextremities by a loss of dexterity and development of clumsi-ness, on the lower extremities by an addition of instability,which leads to disturbed balance and falls. Neuropathic painis an issue in some CIPNs, allodynia may develop as well.Platin compounds can induce Lhermitte’s phenomenon,which can be troublesome. Rarely, also a Tinel-like electricshock can be induced when the feet touch the ground in a“stamping” manner, resembling a Hoffmann-Tinel sign.

Rarely encountered symptoms are pruritus, Raynaud’s phe-nomenon, and muscle pain, which have been observed par-ticularly in gemcitabine and taxanes. One neglected symptomis muscle cramps in small foot muscles, which are presumablya sign of distal motor involvement.

SignsThe signs usually consist of a loss of reflexes and disturbedsensory qualities such as touch, pinprick, and vibration (theRydel-Seiffert tuning fork is recommended) can be noted.Two-point discrimination is rarely performed but effective.Also monitoring of the progression with Semmes-Weinsteinelements is useful but may be time-consuming. Conventionaltests of coordination such as finger-to-nose, knee-to-shin, andthe Romberg test can become abnormal. A sensitive test is the

loss of stereotactile recognition of small figures such as coins,keys etc.

Motor function is usually not an issue in CIPN, apart fromvinca alkaloids, which can induce monopareses and dropfoot, and suramin which has a significant motor involvementbut is infrequently used.

Autonomic signs are rare but can be seen in vinca alkaloids,resulting in intestinal symptoms, even ileus, and have alsobeen noted in taxanes and platinum compounds.

Motor symptoms can occur as mononeuropathies or cranialnerve lesions in vinca alkaloids.

Some drugs cause muscle involvement (Table 1) with myal-gia, muscle cramps, or weakness [3, 7]. This can be a proxi-mal myopathy as seen in taxanes [8, 9] and vincristine [10].Myalgia has been observed in a combination of taxanes andgemcitabine [11]. Cramps rarely occur, but when they do,they occur in particular in small foot and hand muscles. Theradiation recall syndrome [12] has been described ingemcitabine and carboplatinum. Rhabdomyolysis has beenrarely attributed to chemotherapy [13, 14]. Sarcopenia, whichis a common phenomenon in advanced cancer, has also beenrelated to drug treatment [15]. In myelomas, muscle amyloi-dosis occurs as well [16, 17], which is characterized by a com-bination of weakness and pseudohypertrophic muscles.

Nerve Conduction Velocities (NCV)Nerve conduction velocity and EMG are the standard tests inclinical neurophysiology. In CIP, NCV usually shows axonalchanges often focused on sensory nerves. There is a correla-tion in axonal neuropathies with the NCV. The clinical corre-lation, however, has several caveats:– The correlation is weaker in drugs affecting the DRG, such

as platinum derivates, and also in small fibre type changes.– The correlation is poor with regard to temporal changes

within therapy.– In the clinical situation, the classical examination with a

history and findings is more significant than the NCV re-sults. The role of imaging of peripheral nerves in CIPN,such as magnetic resonance techniques and nerve ultra-sound, has not been determined.

There are some reports of mononeuropathies occurring withvinca alkaloids and CTS with aromatase inhibitors. For theselesions, it is suggested to use the common NCV criteria.

Skin BiopsyThe role of skin biopsy in CIPN is currently evolving [18].There are several reports describing small-fibre changes, in

Table 1. Muscle symptoms related to chemotherapy

Rhabdomyolysis CytarabineProximal weakness TaxanesRadiation recall phenomenon GemcitabineNecrotizing myopathy VincristineMyalgia Taxanes, gemcitabine, several

othersDistal cramps Vinca alkaloids (as neuropathy)



27

particular in taxane-related neuropathies. Punch skin biopsiesare classified as a minimally invasive procedure. Althoughloss of nerve fibre density is an end-stage phenomenon inneuropathy, early changes and hopefully future markers mayallow to identify prognostic factors. As yet, it can be classifiedas investigational in CIPN.

Nerve BiopsyAlthough most knowledge of the character of morphologicalchanges in CIPN derives from morphological studies, wholebiopsies for CIPN are not indicated unless a differential diag-nosis is required to rule out inflammatory, vasculitic, neoplas-tic, or amyloid neuropathy. Another exception is a biopsywithin a defined and approved study protocol.

Clinical Course and Development

Most CIPN are dose-dependent neuropathies, with the cumu-lative dose (Table 2) varying to some extent intraindividually.Usually, at the onset of chemotherapy throughout the first 1–3 cycles, CIPN symptoms appear. From cycle 3–4, usuallysymptoms develop. In some drugs, it has been observed thatafter a peak of neurotoxicity the increment of CIPN slows af-ter the 4th or 5th cycle [19, 20]. Due to the length-dependentmechanism, the feet are usually affected first.

General PhenomenaTwo drugs can produce an immediate toxicity, even after thefirst dose: (1) oxaliplatin, which has been studied extensively;its CIPN is caused by channelopathy-like mechanisms. (2)Acute, painful small-fibre lesions have been described intaxanes, which are attributed to mitochondrial and small-fibrechanges [21].

Once CIPN has developed and the patient suffers from symp-toms, the question is usually whether cessation or replace-ment of the drug is compatible with the oncologic strategy. Inthis setting, there are 2 other important aspects:

CoastingCoasting is an irritating phenomenon. It has been noted par-ticularly with platinum compounds; even after cessation ofthe neuropathy symptoms can progress and there is a consid-

erable time lag until improvement. Coasting can continue fora few weeks to months. Coasting has also been observed invinca alkaloids [22] but does not seem to be a frequent phe-nomenon in this drug.

PrognosisThe reversibility of CIPN is of increasing importance sinceactive chemotherapies prolong survival. Although there arefew long-term studies it must be assumed that CIPN is not al-ways completely reversible. A study with taxanes has shownthat even after several months to years some symptoms re-main. This is important information in the consultation withpatients.

Other Influential Factors

Pre-existing NeuropathiesThe influence of pre-existing neuropathies deriving from dia-betes mellitus, alcohol abuse, or from a pre-existing heredi-tary neuropathy on the development of CIPN is considerable.In older patients, also a small percentage of chronic idiopathicaxonal neuropathies occurs. Commonly, it is assumed thatpre-existing neuropathies, and in particular hereditary neuro-pathies, may predict a worse course of a neuropathy. In he-reditary neuropathies, even devastating effects have been ob-served in patients receiving chemotherapy.

Prior chemotherapy and combinations of chemotherapies arealso an issue, especially since patients often receive second- orthird-line therapies, also with varying drug combinations [23].

Assessment: Scales and Scores

There are several ways to classify the neurotoxic drugs causingCIPN. In clinical practice, it is equally important to note thatpatients receive non-neurotoxic toxic drugs as well for clinicaldecision-making and neurologic advice. For this review, welisted the substances according to common classifications.

For the clinical assessment, it has been agreed that the generaltoxicity scales used in general oncology are too imprecise forthe assessment of CIPN. On the other hand, more complexneurologic scales, such as the TNS, are too complicated and

Table 2. Cumulative doses. The cumulative dose per square metre is known for several drugs. For many drugs, large seriesare available. Acute side effects occur only in 2 drugs, other particular effects are mentioned in “other effects”.

Drug Cumulative dose Large series Acute effects Other effects

Cisplatin 300–400 mg/m2 + CoastingCarboplatin 600 mg/m2 +Oxaliplatin 800 mg/m2 Acute toxicity more often Acute toxicity!

described than cumulativeIfosfamide ? PainfulGemcitabine ? MyalgiaVincristine 5–15 mg/m2 + Addition: cranial nerve mononeuro-

pathies, autonomic symptoms,necrotizing myopathy

Paclitaxel 200 mg/m2 + Acute toxicity likely Myalgia, myopathyDocetaxel 400–600 mg/m2 + ?Bortezomib 1–1,3 mg/m2 + Painful, rarely demyelinatingThalidomide 20 g (total) +



time-consuming for non-neurologists, in particular medicaloncologists [6, 24–27]. In clinical practice, it would be help-ful for oncologists to have a small, easily applicable scale thathelps to identify patients with symptoms of neuropathy asearly as possible [19, 20]. Several scores are available such asthe NCI-CTC [24], ECOG [28], Ajani score, TNS [29], andthe modified TNS (sTNS). Patient observations and descrip-tions are increasingly used and differ from the physicians’ ob-servation. The frequently used numeric rating scales arebased on an ordinal setting, where differences amounting toone or two points can actually have dissimilar clinical signifi-cance. The CI-PeriNoms Study [30, 31] is an ongoing clini-metric study, which incorporates disability measures, vali-dates quality-of-life scales, and neurophysiological testing toascertain a better assessment of CIPN. An overview byCavaletti and the PeriNoms study group depicting this ap-proach can be found in this issue [1].

Substance Groups

1. Alkylators2. Antibiotics3. Antimetabolites4. Mitotic spindle inhibitors5. Topoisomerase inhibitors6. Proteasome inhibitors7. Others8. Biologicals

Alkylators

Platin DerivatesThree members of the drug family are currently used: cis-platin, carboplatin (mainly in lung, breast, and ovarian can-cers), and oxaliplatin (in metastatic colon cancer and under-going clinical trials for the treatment of other gastrointestinaltract malignancies).

The chemotherapeutic mechanism of platinum compounds issimilar to DNA-binding alkylating agents. If the DNA dam-age exceeds the ability to cell repair, the cell undergoes apop-totic cell death. Platinum compounds induce aberrant re-entryinto the cell cycle and apoptosis [32]. Platinum compoundshave a unique effect on neurons. Selective vulnerability ofDRG-sensory neurons depends presumably on the structureof the blood-nerve-barrier [33, 34]. Also binding of platinumto mitochondrial DNA has been considered a potential mecha-nism of cell death [35]. Cell death of the sensory neuron re-sults in permanent distal sensory loss.

Clinical FeaturesEach of the compounds produces dose-dependent sensorysymptoms and a sensory neuropathy in relation to the cumula-tive dose.

CisplatinFor cisplatin, the development of neuropathies is closely re-lated to the total cumulative drug dose [36, 37]. In the major-ity of patients who receive > 400–500 mg/m2 of cisplatin intypically 3–6 months [38, 39], the neuropathy is predomi-nantly sensory with initial complaints of paraesthesias in

the distal parts of the extremities. Although all sensory moda-lities are involved, a loss of large-fibre sensory function isprominent, which often results in sensory ataxia. Lhermitte’sphenomenon is common and probably an expression of spi-nal cord involvement. Coasting is a unique feature incisplatin, but can also be observed after spinal radiation.Many patients experience residual pain after some improve-ment in their neuropathy. This may last for several years af-ter discontinuation of the therapy and should be treated withstandard approaches for the management of neuropathicpain.

Motor involvement is rare, however, autonomic neuropathy isinfrequent and can cause dizziness, palpitations, or impotence[40].

Retreatment after previous cisplatin chemotherapy does notseem to be complicated by increased neurotoxicity [41].

Laboratory StudiesElectrophysiological features for platinum compounds aremostly axonal changes with a predominance of sensory fibres.Other laboratory studies are not informative. Nerve biopsystudies have shown a loss of large myelinated fibres [42]. Atypical constellation of clinical and electrophysiological find-ings is presented in Figure 2.

Prognosis and TreatmentNeuropathic symptoms can progress up to 2 months after ces-sation of therapy (“coasting”). Then, gradual improvementmay set in. However, because of the underlying pathology

Figure 2. Cisplatinum neuropathy. Clinical and electrophysiological features of a40-year-old male with an ataxic cisplatinum neuropathy. (a) Despite numbness andsensory ataxia no motor involvement with normal small-hand muscles. Nerve con-duction velocity (NCV) measurement shows normal motor NCV, (b) the sensory NCV isreduced to 1 uV (pathologic). (c) The feet appear normal, neither atrophy nor trophicchanges can be seen. (d) Knee-to-shin is pathologic, vibration perception is absent.(e) Motor NCVs of peroneal nerves are normal. The sural nerve sensory potential isabsent; (f) the F wave is normal.



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being a ganglionopathy, recovery may be incomplete, espe-cially in more severe cases.

CarboplatinCarboplatin is less neurotoxic [43]. In higher cumulativedoses, however, carboplatin also produces a sensory neuro-pathy, as does cisplatin [44]. In combination with paclitaxel,20 % of patients develop moderate or severe sensory neuropa-thies [45].

OxaliplatinIn addition to dose-dependent neuropathies, about 60–80 %of patients develop a cold-induced acute toxicity that involvesparaesthesias in the throat, mouth, face, and hands occurringwithin 30–60 min after application and also includes musclecramps and fasciculations.

The sensations are described as a tingling or burning inducedby contact with cold surfaces or cold liquids. They appearacutely and typically remit a few days after the infusion iscompleted. Also, EMG-spontaneous activity has been ob-served during the attacks [46].

Oxaliplatin affects voltage-gated sodium channels and inter-feres with axonal ion conductance [47]. Oxaliplatin is trans-formed into oxalate, which is an intracellular calcium chela-tor, which produces similar effects as seen in ethylene glycolpoisoning [48]. Oxalate, which is released intracellularily byoxaliplatin, chelates calcium and has an effect on inward so-dium channels [49–51]. Divalent cations modify voltage-gated sodium channels [52]. Based on this mechanism, iv cal-cium gluconate and magnesium sulfate lower acute oxali-platin symptoms [53].

Cumulative toxicity resembles cisplatin-induced neuropa-thies. Long-term use demonstrates that oxaliplatin is associ-ated with mild, sensory, and motor axon loss [54]. Oxcarba-zepine has been shown to be effective in prophylaxis [55].

Platinum HypersensitivityIn addition to neurotoxicity, other hypersensitivity reactionssuch as skin rash, flush, abdominal cramps, itching in thepalms, and severe cardiovascular reactions have been ob-served [56]. Usually, these will not be confused with neuro-toxicity, except for itching and pruritus.

Other Alkylating AgentsOther alkylating agents, such as nitrosoureas, procarbazine,and thiotepa, rarely cause neuropathies, except for ifosfamide.

IfosfamideNeuropathy occurs in about 8 % of patients [57–59]. The on-set is gradual, with paraesthesias and pain in the feet. The typeof sensory loss is panmodal. Pre-existent neuropathies are riskfactors [60]. Neuropathic pain can be an issue; tendon re-flexes are reduced; weakness is rare. Recovery after termina-tion of treatment is slow.

ProcarbazineProcarbazine is widely used in haematological malignanciesand in the treatment of brain tumours. Mild peripheral neuro-

pathy has been described but is rarely problematic [61].Myalgias have also been described.

ThiotepaThiotepa is an alkylating agent occasionally used to treat lep-tomeningeal metastases. Rarely, intrathecal thiotepa causes amyelopathy [62]. A motor neuropathy has also been describedafter intrathecal thiotepa chemotherapy [63]. On the whole,this is based on single observations and cannot be general-ized.

Cytotoxic AntibioticsSeveral antibiotics have antineoplastic effects. The mostprominent is doxorubicin, which is widely used in severalchemotherapies. Although doxorubicin can induce DRGchanges in animals, this is not an issue in clinical practice.

Other antibiotics, such as actinomycine, anthracyclines,daunorubicine, valrubicine, idarubicine, epirubicine, bleo-mycine, plicamycine, and mitamycine, rarely cause periph-eral neurologic complications.

AntimetabolitesAntimetabolites are compounds which inhibit the synthesis ofkey intermediary metabolites. Often, they are enzyme inhibi-tors and may block RNA or DNA synthesis. Most of the anti-metabolites are either analogues of nucleotide bases or inter-fere with folic acid metabolism. They are more commonlyassociated with central rather than peripheral neurotoxicity.CINP is generally not a major side effect.

MethotrexateMethotrexate (MTX) is a folate antagonist that inhibits dihy-drofolate reductase, a key enzyme in the synthesis of nucleo-tides. It is used alone or in combination chemotherapy forsolid tumours and haematological malignancies in a broadspectrum of dosages (low-to-high dose) and also timings(acute as well as permanent therapies). Peripheral neurotoxic-ity is rare. Although IT treatment is a routine procedure it canbe associated with complications, spinal arachnitis, and myelo-pathy.

Nelarabine is an analogue [64, 65] which does not seem to beinvolved in the development of CIPN.

Cytosine ArabinosideCytosine arabinoside (Ara-C) is a pyrimidine antagonist thatblocks synthesis of cytosine, thymidine, and uridine. Periph-eral neurotoxicity is rare. There are several case reports ofvarious neuropathies associated with the use of high-doseAra-C [66] and fludarabine combined with Ara-C [67]. Theseare only observational reports and the clinical relevance is notclear.

Depot Ara-C preparations (depocyte) are increasingly advo-cated for patients with meningeal carcinomatosis. Recent re-ports suggest that the drug may cause a cauda equina syn-drome [68, 69] in some patients. Repetitive IT drug applica-tion with cytarabine treatment caused demyelination in thethoracal roots, the cauda equina, and damage to the posteriorcolumns in a patient treated by the author (Figure 3).



GemcitabineGemcitabine is a deoxycytidine analogue structurally relatedto Ara-C. In many patients, it causes systemic symptoms oflow-grade fever, fatigue malaise, myalgia, and arthralgia withparaesthesia. In about 10 %, sensory neuropathy with par-aesthesias can develop. Autonomic involvement has also beenobserved.

Muscle symptoms can appear as myalgias or as “radiation re-call syndrome” in pre-radiated muscle. MRT can show oedemaof the affected muscle and CK can be elevated.

Gemcitabine is often used in combination with taxanes, plati-num compounds, or vinca alkaloids, all of which cause CINP,but does not seem to increase the risk of CIPN [70].

5-Fluorouracil5-Fluorouracil (5-FU) is a pyrimidine antagonist. It is used asa single agent or in combination regimens for the treatment ofmany tumours, especially in the gastrointestinal system. Asmall number of cases of CIPN have been reported after treat-ment with 5-FU (accompanied by radiation and levamisol)[71] and after 5-FU chemotherapy in combination with folinicacid and eniluracil [72].

The hand-foot syndrome appears in particular when treatmentconsisting of 5-FU and capecitabine is applied.

CapecitabineCapecitabine is metabolized to 5-FU. Except for observationsfrom single cases [72], CIPN are unlikely. Cranial nerve le-sions seem to appear rarely [73, 74].

The “hand-foot syndrome”, or “palmar plantar erythrodys-aesthesia” (PPE), has been observed in up to 10 % of patients

treated with capecitabine, but is not specific and also appearsin other drugs. Administration of the drug is followed withindays by palmar and plantar paraesthesias and itching followedby the development of an erythematous and occasionallybullous palmar and plantar rash. It is thought to be due to alocal skin reaction, but a relationship to neuropathy or dam-aged small skin nerves is postulated [75].

Mitotic Spindle Inhibitors

Vinca AlkaloidsVinca alkaloids are mitotic spindle inhibitors, such as taxanesand podophyllin analogues (etoposide and tenoposide). Thedrugs interfere with microtubule assembly and mitotic spindleformation. They also influence axonal transport [76], struc-ture, and function at many points. As with most toxic neuropa-thies, longer axons are more susceptible. Vinca alkaloids donot enter the blood-brain-barrier [77], which limits their usein neurological CNS disease.

Vinblastine, vincristine, and their semi-synthetic derivatives,vindesine and vinorelbine, are predominantly used for thetreatment of haematologic and lymphatic malignancies andseveral other conditions. All are given by intravenous infu-sion. Vinca alkaloids produce a dose-related sensorimotorneuropathy. Vincristine and vindesine cause the most severeneurotoxicity, while vinblastine and vinorelbine are lesstoxic. A combination of vinorelbine with taxanes can be se-vere in patients previously treated with paclitaxel and hasbeen observed in the course of a study monitoring [78].

Clinical FeaturesCIPN present usually within the first 3 months of treatment.Early symptoms are paraesthesias and pain in the hands andfeet as well as distally accentuated hyperaesthesia. Weaknessmay also occur, in particular in wrist extensors and dorsi-flexors of the toes [79]. Tendon reflexes are lost early on.Muscle cramps in distal muscles (eg, feet) are frequent, oftenpersisting long after treatment cessation. Contrary to mostother CIPN, mononeuropathies (femoral, peritoneal nerves),cranial nerve lesions (with diplopia, vocal cord paralysis [80],facial nerve palsy, and sensoneurial hearing loss) have beendescribed [81, 82]. Autonomic changes can result in gas-trointestinal symptoms, such as paralytic ileus or megacolon[83]. Also bladder atony, impotence, orthostatic hypotension,and cardiac problems have been reported.

Rarely, severe neuropathy with quadriparesis occurs [84].Inherited neuropathies [85, 86] may aggravate the expressionof neuropathies and need to be considered before starting che-motherapy.

Laboratory StudiesNerve conduction studies show axonal neuropathies with areduced amplitude of motor and sensory action potentialswith mildly reduced conduction velocities.

Prognosis and TreatmentThere are no pharmacologic treatments to reduce or preventCIPN induced by vinca alkaloids. A pharmacological approachwith lacosamide has been proposed to reduce pain and allo-

Figure 3. Autopsy of the nerveroots, cauda equina and posteriorcolumns of a 74-year-old woman withbreast cancer and suspected menin-geal carcinomatosis. She receivedseveral cycles of intrathecal cyto-sine arabinoside (Depo-Cyt®). Themyelin appears blue with a Klüverstaining. (a) Cauda equina. Thenerve roots show loss of myelin witha patchy damage to nerve fascicles.(b) Spinal thoracic nerve. Diffusedemyelination. (c) Spinal cord andposterior column: Diffuse loss ofmyelinated fibres, ballooned dege-neration of myelinated fibres.



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dynia in animal models [87]. Reducing dose levels and fre-quency of application may ameliorate the development ofneuropathies. After cessation of therapy, coasting has also beendescribed [22]. In severe cases, improvement occurs overmonths to several years and may be incomplete. A decreasedrisk of neuropathy and a more rapid recovery may exist in Afri-can Americans with at least one CYP3A5*1 allele [88].

Physical therapy and orthoses minimize the effects of motordeficits. Skin protection and management of neuropathic painhelp patients with sensory deficits.

Inadvertent intrathecal injection of any of the vinca alkaloidsresults in severe ascending myeloencephalopathy that is usu-ally fatal [89, 90].

TaxanesBoth drugs, paclitaxel and docetaxel, are widely used alone orin combination for the treatment of breast, ovarian, lung, andmany other forms of cancer. Paclitaxel may produce moreneuropathies than docetaxel [91]. Taxanes are frequently usedin combination with other agents that cause CIPN. It is un-clear whether additive or synergistic neuropathy results fromthis combination. There are 2 important issues concerning thetransport vehicle of the drug: the transport mechanism iscremaphor [92], a non-ionic surfactant and a polysaturatedcastor oil which has side effects of its own, in particular aller-gic reactions; the other transport vehicle is abraxane, a pro-tein-bound paclitaxel, which avoids the side effects ofcremaphor but unfortunately causes CIPN in this preparation.Other preparations of paclitaxel are taxoprexin, a DHA pacli-taxel (omega-3 fatty acid), and xyotax, a PG paclitaxel (poly-[L]- glutamic acid).

Taxanes hyperstabilize microtubule subunit cross-linking.This has the effect of increased stability of microtubules anddecreased ability of the cell to dynamically reorganize thecytoskeleton. Also the formation of crystalline arrays of mi-crotubule subunits in the cell or axon [93] occurs, which dis-rupts the axonal transport, the retrograde transport of target-derived trophic factors, and other vesicular components. Bothprocesses interfere with axonal transport and result in neuro-pathy. In addition to microtubule changes, the ubiquitin-proteasome system (UPS) in axons with local activation ofcalpain/caspase cells and apoptosis may also be activated.Their mode of action is similar to epothilones.

Clinical FeaturesSensory symptoms are common and dose-related [94]. Bothdrugs induce paraesthesias, loss of sensation, and dysaes-thetic pain in the feet and hands. Activities of daily life, finemotor tasks, such as buttoning and writing, can be impaired.Gait unsteadiness can be a result of sensory ataxia.

At examination, the vibratory threshold increases and percep-tions of light, touch, and pin decrease in the feet more than inthe hands. Deep tendon reflexes at the ankle may be lost butmore proximal reflexes may be preserved.

Weakness is absent or mild, although motor neuropathieshave been observed [95]. Lhermitte’s phenomenon may ap-

pear. Autonomic symptoms have been described, gastrointes-tinal symptoms and cardiac arrhythmia may occur.

An acute toxicity, caused by mitochondrial damage andsmall-fibre type lesions with up-regulation of PGP9.5 in theLangerhans cells, has been described and can be attributed toacute CIPN toxicity [96]. As the lesions are restricted to theafferent axon’s terminal arbour, it was suggested to namethem “terminal arbour degeneration” [97].

Treatment with taxanes can also cause a proximal weaknesssyndrome independently of sensory symptoms. CK is normaland weakness improves after cessation of therapy. Myalgia/arthralgia syndromes are more frequent in paclitaxel and re-lated to drug treatment, beginning 2–3 days after administra-tion and lasting several days.

Laboratory StudiesElectrophysiological testing typically demonstrates that suralnerve potentials are reduced or absent in symptomatic pa-tients with signs of axonal neuropathy.

Concurrent cis-platinum or alcohol abuse increases the risk ofCIPN. ABCB1-allelic variation negatively influences the ef-fect of docetaxel treatment [98] and the onset of neuropathycan be delayed which will be possibly a predictive factor forthe development of CIPN.

Prognosis and TreatmentThe sensory symptoms can be troublesome and typically re-mit within several weeks after treatment has been completed.Lowering the dose and lengthening the treatment may reducedifficulties in more symptomatic patients. However, long-term follow-up examinations describe a prolonged effect ofCIPN in individuals with a negative effect on the quality oflife [99, 100].

Other Microtubule-Stabilizing AgentsEpithelonesEpithelones are a group of microtubule-stabilizing agents, in-cluding epothilone A, epothilone B [101], and epothilone D.Distal sensory and motor neuropathy, similar to taxanes, havebeen reported from phase-III clinical trials [102, 103]. Also aspecific effect on vibration perception has been described.

EribulinEribulin (eribulin mesylate) is a non-taxane microtubule dy-namics inhibitor with tubulin-based antimitotic activity. It isused in the treatment of patients with locally advanced ormetastatic breast cancer who have previously been treatedwith other chemotherapies. Peripheral neuropathy (incidence5 %) was the most common adverse event resulting in the dis-continuation of eribulin treatment. In animal experiments,eribulin seems less toxic compared to other drugs [104].

PodophyllinPodophyllin is an alkaloid extracted from the May Apple orAmerican Mandrake and is considered both a spindle inhibi-tor as well as a topoisomerase inhibitor.

Etoposide (VP 16) and teniposide (VM 26) are chemothera-peutic agents derived from podophyllin. They disrupt mitotic



spindle formation and inhibit topoisomerase II as well. The drugsare extensively used in many different forms of cancer, often incombination with drugs that cause CINP. Although peripheraltoxicity is generally accepted, usually by observations and casedescriptions [105], data from large studies are missing.

Topoisomerase InhibitorsTopoisomerase is an enzyme which interferes with repair ofDNA damage and facilitates apoptosis. Topoisomerase II cutsand unwinds DNA. Type-I topoisomerase inhibitors arecamptothecins (irinotecan and topotecan), and type-II inhibi-tors are amsacrine, etoposide, etoposide phosphate, andteniposide; they are used in several chemotherapies. For topo-tecan and teniposide, neuropathies of minor extent have beenreported [106, 107].

Proteasome InhibitorsBortezomid is a polycyclic derivative of boronic acid that inhib-its the mammalian 26S proteasome. The 26S proteasome is alarge complex that is part of the ubiquitin degradation pathway.It regulates the homoeostatic level of many intracellular pro-teins including those involved in cell-cycle regulation andapoptosis. The proteasome degrades the intracellular inhibitorof NFκB (IκB). Bortezomib increases the level of the inhibitorand decreases the activity of NFκB. This down-regulates theexpression of proteins that promote cell division and prolifera-tion and enhances apoptosis. Also, secretion of cytokines in thebone marrow is suppressed. It also enhances oxidative stress byup-regulation of p53, p21, p27, p38, MAPK, and JNK. Geneticfactors may be implicated in the susceptibility [108].

Carfilzomib is an irreversible proteasome inhibitor with lessneurotoxic side effects [109, 110].

Clinical FeaturesThe neuropathy is dose-related and cumulative. It is predomi-nantly sensory, distally accentuated, and depends on the dura-tion of treatment. It often causes neuropathic pain probablydue to small-fibre involvement. Patients experience sensoryloss (numbness) and, due to small-fibre loss, pain which isperceived as burning, sharp, cold, or electric. This painful as-sociation is particularly worrying [111, 112].

Also autonomic changes with postural hypotension have beenreported. Increased age is an additional risk factor. In trials,CIPN occurred in 37–44 % of patients with multiple myeloma[113]. Usually, it is a reversible duration-of-treatment-depen-dent neuropathy [114–116].

In a few cases, demyelinating neuropathies [117], which areprobably dysimmune [118], have been observed as well.

LaboratoryElectrophysiological changes demonstrate axonal loss as thedrug has become more widely used, more prevalent, and moresevere cases of neuropathy have been reported [119]. Pre-treatment with thalidomide is a serious risk factor for the de-velopment of CIPN.

A demyelinating neuropathy has also been observed [118],even in combination with thalidomide [119].

Others

Arsenic TrioxideArsenic trioxide has recently been introduced for the treat-ment of refractory forms of cancer [120]. It is an inorganicarsenic compound that has been known for many years tocause severe and sometimes fatal peripheral neuropathy. Arecent single-agent trial, however, described few neurotoxiceffects [121].

Thalidomide and LenalodimideThalidomide has a sad record of teratogenic effects due to itsuse in pregnant patients in the 1950s and 1960s. Since then ithas been used in erythema nodosum leprosum, and as a potentVEGF inhibitor in multiple myeloma, Waldenstrom’s macro-globulinaemia, myelodysplastic syndromes, acute myeloidleukaemia, myelofibrosis, graft versus host disease, prostatecancer, renal cell cancer, malignant brain tumours, Kaposisarcoma, and cancer.

The type of neuropathy is predominantly sensory, with numb-ness and pain in hands and feet. All sensory qualities are af-fected, reflexes may be preserved. Cramps of small footmuscles occur. Neuropathies develop in 20–40 % of patients[122, 123]. Frequency of neuropathy increases with age andcumulative doses or duration of treatment; vulnerability inaged persons is a also a major concern [124].

Lenalidomide is an analogue (alpha-3-aminophthalimidoglu-tarimide) and less neurotoxic in the PNS [125–127].

SuraminSuramin (polysulfonated naphthylurea) has been used for thetreatment of tropical parasitic diseases. It can cause nephropa-thy and, when used in cancer patients, 2 types of CIPN: a milddistal axonal neuropathy and an acute form resembling acutepolyradiculitis [128].

Biologicals

In addition to the “classical drugs” causing CIPN, some bio-logicals are also mentioned, usually when administered incombination with neurotoxic drugs, which makes it difficultto assess the true effect and incidence. Three antibodies havebeen mentioned to cause CIPN, and except for brentuximab,where sensory neuropathies have been described, bevacizu-mab and trastuzumab have been considered as well. An inter-esting approach to this question is made by http://www.ehealthme.com [129], where a total of side effects is listed for adefined period of time.

AntibodiesBevacizumabNeuropathy as a side effect of bevacizumab has not made it tothe “top ten” of its most frequent side effects [129]. As ofAugust 2011, 13,485 persons reported side effects; 16 indi-viduals (0.12 %) had a sensory neuropathy, which occurred inthe first month, which makes a cumulative effect unlikely.Other concomitant drugs were also used, which makes it diffi-cult to evaluate. A possible association with paclitaxel hasbeen observed. Presently, no clear evidence exists.



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Brentuximab Vedotin (SGN-35)Brentuximab vedotin is an anti-CD30 monoclonal antibody incombination with monomethyl auristatin E (an antitubulinagent). It is used in the treatment of Hodgkin’s lymphoma.Sensory neuropathies have been described [130]. A generalopinion can not be expressed presently.

TrastuzumabTrastuzumab was analyzed on http://www.ehealthme.com[129] with regard to reported side effects. As of August 2011,64,443 persons reported side effects, among them 8 indi-viduals (0.012 %) reported a sensory neuropathy. Contrary tobevacizumab, the neuropathy was most often observed afterone year (50 %) and 2 years (25 %), which makes a cumula-tive effect likely. Associated drugs were cyclophosphamide,gabapentine, and femara, but also other drugs, which makesthe interpretation difficult. In combination with conventionalchemotherapies, neuropathies have been described [131].

InterferonsInterferon-αInterferon-α is used in the treatment of leukaemia and lym-phoma as well as of hepatitis C. It can cause a distal symmet-ric sensory neuropathy, which can also cause pain and paraes-thesia, mild loss of pain and temperature perception [132].The NCV shows axonal loss.

HormonesHormonal treatment has been assessed in comparison withchemotherapy in breast cancer. A trial of primary endocrinetherapy using aromatase inhibitors (anastrozole and exemes-tane) in patients with ER-positive and/or PgR-positive breastcancer showed grade-2 neuropathies occurring in 30 % of pa-tients receiving chemotherapy, while hormonal treatment waswell-tolerated [133]. Focal neuropathies, such as the carpaltunnel syndrome, may increasingly occur during aromatasetherapy [134].

RadiosensitizersMisonidazoleMisonidazole has been used as an adjunct to radiation therapyas a radiosensitizer. It causes a sensory, often painful neuro-pathy and is dose-related (cumulative dose > 16–18 g)[135]. The incidence can be up to 30 % if the cumulativedose has been reached [135]. The newly used radiosensitizermotexafin gadolinium has not yet been reported to causeneuropathies.

VitaminsVitamin A and retinoid treatment are used in haematologicaldiseases. Not only muscle cramps and myalgia but also sen-sory symptoms have been reported. The mechanisms are notfully understood.

Conversely, in animal experiments, a protective effect ofretinoids in CIPN has been proposed [136].

TipifarnibTipifarnib is an oral non-peptidomimetic farnesyl transferaseinhibitor used in both solid tumours and haematological ma-lignancies such as acute myeloid leukaemia [137]. Toxicity is

predominantly haematological, mild neuropathies have beenreported [138].

Cancer Type and Neuropathy: Myeloma

Two types of malignancy – lung cancer (SCLC) and myeloma –have several types of disease-associated neuropathies. In lungcancer, it is a paraneoplastic, subacute sensory neuronopathy(SSN), which usually appears at the onset of malignancy priorto chemotherapy. Neuropathies in multiple myeloma can ap-pear at any time, due to several aetiologies, and have beensubject to reviews [139]. This is of importance as the currentdrug treatment has a high potential for the development ofneuropathies, and also because it is generally assumed that apre-existing neuropathy may increase the risk for a CIPN.Possible factors from myeloma and also genetic factors maybe responsible for the expression of a neuropathy [140, 141].

A neuropathy caused by therapy can be dose-limiting in up to10 % [142]. Although no specific treatment is available, dosemodification needs to be considered in case of paraesthesiasand pain. Treatment should be modified or reduced until tox-icity resolves. Treatment also consists of symptomatic man-agement of neuropathic pain, protection against sensory loss,and physical therapy. Elderly patients may be less able towithstand the side effects associated with newer treatmentregimens [143].

The rarely observed POEMS syndrome is associated withseveral types of neuropathies. Treatment results have beensummarized in a Cochrane review [144].

Differential Diagnosis

The differential diagnosis of CIPN is mainly based on the vi-tal question of what chemotherapy the patient has received sofar and if neurotoxicity can be expected from the substanceand its dose. Several drugs applied for chemotherapy do notcause CIPN, which can be an important factor in discussing apatient’s symptoms and signs at evaluation.

Differential diagnosis often considers paraneoplastic neuro-pathies, which tend to appear early in the course of the diseaseand often contribute to the detection of cancer.

Acute types of neuropathies, such as the Guillain-Barré syn-drome and CIDP, have been observed to appear in lymphomaand Hodgkin’s disease patients [145] and are related to thetumour type. Demyelinating neuropathies have been describedin suramin treatment, and also in rare cases of bortezombinadministration [117].

Meningeal carcinomatosis rarely presents as a neuropathymimic, either as cauda equina presentation or rarely as an as-cending polyradicular form. Clinically, often the associationwith CNS symptoms is helpful. Cauda equina lesions involvethe sphincteric function as well, which is not the case in CIPN.As a rule, early pain appears.

Neurolymphomatosis [146] is a rare type of lymphomatousspread in lymphoma. It can occur either isolated in the periph-



eral nerves or in a combination of peripheral nerves and CSF,which is a matter of definition. The presenting signs can varyfrom a symmetric CIDP type to a multiplex type and solitaryperipheral nerve involvement. The diagnosis is difficult butimaging may help; finally, a biopsy is necessary. Also intra-vascular lymphoma can affect peripheral nerves [147].

NeuroleukaemiosisThis is a recently coined term [148] describing often symmet-ric and diffuse involvement of peripheral nerves. It has alsobeen noted to appear as a multifocal neuropathy in M4/M5leukaemia.

Historically, it appears that autopsy series in the pre-chemo-therapy era, were well aware of this phenomenon.

Cauda Equina SyndromeMalignant compression of the cauda equina may be caused bya tumour, vertebral collapse, lipomatosis following steroidtreatment, or chemical injury by intrathecal therapy and hasbeen reported as a side effect of cytosine arabinoside long-term application [68]. Usually, additional signs such as asphincter’s involvement or back pain make the diagnosislikely. Intramedullary metastases are extremely rare but theycan also mimic a sensorimotor neuropathy.

Prevention

Preventive drugs can potentially counteract cancer therapy.This has been the problem with several previously used pre-ventive therapies. Several drugs have been used, such as vita-mins (B and E) [149], gluthation, alpha lipicoic acid, acetyl-cysteine [150, 151], amifostine, calcium, magnesium, diethyl-dithiocarbamate [152], dithiocarbamate, Org 2766, oxcarba-zepine [153], or erythropoetin [154–157]. For platin drugs, aCochrane review states that chemoprotective agents do notseem to prevent CIPN [158].

Symptomatic Treatment

Despite the failure of drugs to prevent CIPN, several symp-tomatic treatments are available and should be considered ineach individual case.

Oxaliplatin’s Acute ToxicityThe treatment and prevention of acute oxaliplatin toxicityhave been an issue. Two basic avenues exist: (1) Ca and Mgadministration or (2) carbamazepine or oxcarbazepine, whichimpacts on the affected channels.

Neuropathic Pain and DysaesthesiaPain and paraesthesia can be a severe effect of some chemo-therapy regimens, in particular taxanes and bortezomib. Theuse of drugs directed against neuropathic pain with anti-convulsants, antidepressants, in severe cases opioids, and, re-cently, also topical local anaesthetics has to be decided on ac-cording to the symptoms of each patient.

PreventionThe question of whether the administration of anticonvulsantscan prevent neuropathies is increasingly discussed. Consider-

ing the concept of action of anticonvulsants this may not belikely; considering the effect that less grade-3 toxicities ap-pear during treatment, this effect of subjective improvementcan in a way be regarded as prevention of higher toxicity.

Physical and Occupational TherapiesCIPN, apart from sensory symptoms and pain, often have aloss of proprioception, which is a highly incommoding effectin ADLS and gait. These effects are often underestimated. It islikely that the amplified application of physical and occupa-tional therapies, which activate other senses (vision, hearing)as well, can compensate sensory deficits and might improvethem through systematic training [159].

Rehabilitation and Cancer Rehabilitation

Rehabilitation for cancer patients is increasingly offered [160].This is a tremendous success since, in the past, cancer in apatient often banned further rehabilitation. Without dwellingon the different types of cancer rehabilitation, neuropathies andsequelae of CIPN deserve particular attention [159]. Further,it is obvious from several studies (on taxanes) that often CIPNare not completely reversible and leave the patient distinctlydisabled [161].

Summary

CIPN caused by cancer treatment is gaining importance, asseveral effective therapies damage the peripheral nerves byvarious mechanisms. Despite different mechanisms of drugs,it is hoped that common mechanisms in the structure or func-tion of peripheral nerves may help to develop preventive strat-egies.

For the clinician, the knowledge of drugs given to the indi-vidual patient and the cumulative doses are important. In-creasingly, also other substances, in particular biological sub-stances, may play a role by influencing the metabolism.

Symptomatic treatment with regard to sensory and/or motorsymptoms and pain needs to be considered as well as conceptsof rehabilitation to improve a patient’s functions and qualityof life.

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141. Becker PS. Genetic predisposition forchemotherapy-induced neuropathy in multi-ple myeloma. J Clin Oncol 2011; 29: 783–6.142. Bang SM, Lee JH, Yoon SS, et al. A mul-ticenter retrospective analysis of adverseevents in Korean patients using bortezomibfor multiple myeloma. Int J Hematol 2006;83: 309–3.

143. Palumbo A, Mateos MV, Bringhen S, etal. Practical management of adverse eventsin multiple myeloma: can therapy be attenu-

ated in older patients? Blood Rev 2011; 25:181–91.144. Kuwabara S, Dispenzieri A, Arimura K,et al. Treatment for POEMS (polyneuropathy,organomegaly, endocrinopathy, M-protein,and skin changes) syndrome. CochraneDatabase Syst Rev 2008; (4): CD006828.145. Briani C, Vitaliani R, Grisold W, et al.Spectrum of paraneoplastic disease associ-ated with lymphoma. Neurology 2011; 76:705–10.146. Grisariu S, Avni B, Batchelor TT, et al.Neurolymphomatosis: an International Pri-mary CNS Lymphoma Collaborative Groupreport. Blood 2010; 115: 5005–11.147. Jiang QL, Pytel P, Rowin J. Disseminatedintravascular large-cell lymphoma with ini-tial presentation mimicking Guillain-Barrésyndrome. Muscle Nerve 2010; 42: 133–6.148. Aregawi DG, Sherman JH, Douvas MG,et al. Neuroleukemiosis: case report of leuk-emic nerve infiltration in acute lymphoblas-tic leukemia. Muscle Nerve 2008; 38: 1196–200.149. Argyriou AA, Chroni E, Koutras A, et al.Vitamin E for prophylaxis against chemo-therapy-induced neuropathy: A randomizedcontrolled trial. Neurology 2005; 64: 26–31.150. Bianchi G, Vitali G, Caraceni A, et al.Symptomatic and neurophysiological re-sponses of paclitaxel- or cisplatin-inducedneuropathy to oral acetyl-L-carnitine. EurJ Cancer 2005; 41: 1746–50.151. De Grandis D. Acetyl-L-carnitine for thetreatment of chemotherapy-induced periph-eral neuropathy: a short review. CNS Drugs2007; 21: 39–43.152. Gandara DR, Nahhas WA, Adelson MD,et al. Randomized placebo-controlled multi-center evaluation of diethyldithiocarbamatefor chemoprotection against cisplatin-inducedtoxicities. J Clin Oncol 1995; 13: 490–6.153. Lersch C, Schmelz R, Eckel F, et al. Pre-vention of oxaliplatin-induced peripheralsensory neuropathy by carbamazepine inpatients with advanced colorectal cancer.Clin Colorectal Cancer 2002; 2: 54–8.154. Kassem LA, Yassin NA. Role of erythro-poeitin in prevention of chemotherapy-inducedperipheral neuropathy. Pak J Biol Sci 2010;13: 577–87.

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Chemotherapy-Induced Peripheral Neuropathy Outcome Measures Standardization Study

37

The Chemotherapy-Induced PeripheralNeuropathy Outcome Measures Standardization(CI-Perinoms) Study: An Answer to the Unsettled

Question of Drug-Related Neuropathy Assessmentin Cancer Patients

Guido Cavaletti on behalf of the CI-PERINOMS Study Group*

* see contributor section

Received on October 10, 2011; accepted on October 11, 2011; Pre-PublishingOnline on November 3, 2011From the Dipartimento di Neuroscienze e Tecnologie Biomediche, Universitàdi Milano Bicocca, Monza, ItalyCorrespondence to: Guido Cavaletti, MD, Dipartimento di Neuroscienze eTecnologie Biomediche, Università di Milano Bicocca, I-20052 Monza, v. Cadore 48;e-mail: [email protected]

Abstract: Chemotherapy-induced peripheral neuro-pathy is a potentially severe and dose-limitingside effect of anticancer treatment. Despite itsclinical relevance several crucial aspects ofchemotherapy-induced peripheral neuropathy re-main unsolved. Among them, the proper assess-ment of the occurrence and severity of this sideeffect is one of the most important.

Chemotherapy-induced peripheral neuropathyseverity is generally assessed using commontoxicity criteria scales, but most of them mix ob-jective and subjective impairment and disabilityaspects. In addition, marked inter-observer dis-

agreement exists using these scales, leading tomisinterpretation of the results.

Various other scale types exist (eg, compositescales based on clinical and instrumental exami-nations; patient-reported outcome measures basedon self-administered questionnaires), but theseoutcome measures have never been subjected toformal clinimetric evaluation.

The Chemotherapy-Induced Peripheral Neu-ropathy Outcome Measures Standardization (CI-Perinoms) study is a collaborative effort of 20 Eu-ropean and US oncology and neurology centresspecifically designed to compare the validity and

reliability of different methods proposed for theassessment of chemotherapy-induced peripheralneuropathy in a formal way. The final aim of CI-Perinoms is to propose a standardized well-evaluated set of measures for optimal assess-ment of chemotherapy-induced peripheral neu-ropathy in future clinical studies. Eur Assoc ofNeuroOncol Mag 2012; 2 (1): 37–40.

Key words: chemotherapy, neuropathy, assess-ment, Rasch analysis, toxicity

Introduction

Chemotherapy-induced peripheral neurotoxicity (CIPN) is afrequent and sometimes severe side effect of several very ef-fective anti-cancer drugs [1, 2]. In fact, sensory impairment ispotentially dose-limiting in patients treated with platinumdrugs (cisplatin, oxaliplatin, less frequently carboplatin), tha-lidomide, or bortezomib, while sensorimotor CIPN is typicalwhen anti-tubulin drugs (taxanes, epothilones, and vinca al-kaloids) are administered [3]. Moreover, when several neuro-toxic anti-neoplastic drugs are used together in chemotherapyregimens, the incidence and severity of CIPN changes due tothe appearance of combined neurotoxicity.

Incidence

The incidence of CIPN has never been clearly established,largely due to methodological issues in its assessment [4–7].Outcome measures differ from one study to the other, andinterobserver disagreement has been described in the use ofvarious well-known neurotoxicity rating scales [7], making itdifficult to interpret literature data properly in terms of inci-dence and severity of CIPN. Moreover, several neurotoxicantineoplastic drugs are used together in chemotherapy sche-

dules for the treatment of selected kinds of solid or hae-matological cancers, with a subsequent possible increase inthe incidence and severity of CIPN and/or the appearance ofcombined neurotoxicity.

Toxicity

Although some aspects of CIPN are similar among the variousdrugs, every class of drugs has its characteristic toxicity pro-file [3]. Typically, platinum compounds produce a pattern ofsensory loss consistent with primary ganglionopathy and pro-prioceptive loss may result in ataxia leading to severe func-tional impairment [8, 9]. Besides its toxicity to the dorsal rootganglia and peripheral nerves, cisplatin is also toxic to thecochlea hairy cells leading to deafness [10]. Almost pure sen-sory impairment in pain, thermal and touch perception are themost common clinical features experienced by multiple my-eloma patients treated with bortezomib and/or thalidomide[11, 12]. All the various classes of anti-tubulins induce distalsensorimotor neuropathy, but reduced pain/thermal percep-tion and touch hypoaesthesia with non-painful paraesthesiasare always more severe than motor impairment [13, 14].

Patients often report neuropathic pain after the administrationof platinum drugs, paclitaxel, or vincristine [15], but it is par-ticularly severe in the case of bortezomib administration inthe treatment of multiple myeloma [12, 16–18].

Autonomic impairment is infrequent and may result in a widespectrum of symptoms, including orthostatic hypotension,constipation, sexual dysfunction, and micturition disorders.This can be clinically relevant particularly in vincristine-treated subjects [19].



CI-Perinoms

Since one of the main issues in the proper assessment of CIPNis represented by the absence of scientifically sound instru-ments (as depicted by Cavaletti et al [20]), we recently com-pleted the Chemotherapy-Induced Peripheral NeuropathyOutcome Measures Standardization (CI-Perinoms) study,based on the collaboration among 20 US and European oncol-ogy and neurology centres (see list of centres and principalinvestigators at the end of this article) [21].

The 2 fundamental and original objectives of the CI-Perinomsstudy are (1) the analysis of the current status of CIPN assess-ment and (2) the implementation of a rigorous clinimetric ap-proach [22], aiming to present a set of scientifically sound(valid and reliable) scales for the assessment of CIPN in fu-ture clinical studies.

It is now recognized that any useful scale to assess a medicaldisorder should be simple, valid, reliable, responsive, and itshould provide results that can be easily interpreted. Althoughthese concepts might appear quite obvious, some of them de-serve to be considered in detail. This is the case for validityand reliability, 2 fundamental methodological aspects whoseimportance is frequently underestimated. None of the mostwidely used scales to assess CIPN properly fulfill these re-quirements [23].

ValidityVarious types of validity are described.

– Face validity refers to the apparent sensibility of the meas-ure and its components. It indicates whether the scale ap-pears to be assessing the desired qualities and representsthe subjective judgement based on a review of the measureitself by one or more experts.

– Content validity consists of a judgement by experts evalu-ating whether an outcome measure captures all the relevantor important contents or domains of an illness.

– Construct validity is demonstrated by examining the rela-tions between a newly created test and other tests to showthat the new test measures the same “construct”. Evidencefor construct validity is gathered by undertaking a series ofstudies to determine convergent validity (the extent to which a measure corre-

lates with other measures of related entities), discriminant validity (the extent to which a measure does

not correlate with measures of different entities), and divergent validity (the extent to which a measure corre-

lates with measures of opposite entities).– Criterion-related validity is demonstrated by examining

the accuracy of a test compared with a “gold standard”.

ReliabilityRegarding reliability, a reliable measure is one that producesresults that are accurate, consistent, stable over time, and re-producible. There are 3 different types of reliability.

– Internal consistency is the extent to which items compris-ing a scale measure the same concept.

– Observer reliability is the agreement between observers orwithin an individual observer.

Inter-observer reliability is the agreement between ob-servations made by ≥ 2 raters on the same patient orgroup of patients while

intra-observer reliability is the agreement between ob-servations made by the same rater on 2 different occa-sions on the same patient or group of patients)

– Test-retest reliability is the agreement between observa-tions made for the same patient on 2 different occasions.

The main aim of CI-Perinoms is to propose a standardizedwell-evaluated set of measures for optimal assessment ofCIPN in future clinical studies starting from a series of instru-ments which have been used in daily practice and clinical tri-als in CIPN patients (Table 1).

In CI-Perinoms, the clinimetric assessment of CIPN was per-formed at 2 different levels of investigation: (1) the core studyrequired the evaluation of patients to be done with commondevices. As such, an evaluation can be performed at any medi-cal site. (2) The extended study included the use of additionalmethods of assessment, including specific devices (ie, gradu-ated tuning fork, 10 g monofilament) and nerve conductionstudies in order to ascertain whether this approach could givea more careful and clinically relevant estimate of CIPN. Pa-tients were also asked to complete a questionnaire to obtain aset of questions useful to develop a CIPN-specific OverallDisability scale specific to CIPN and based on the Raschanalysis (RODS-CIPN) [34, 35].

To assess inter- and intra-observer agreement 2 investigatorsin each participating centre applied the selected impairmentand activity limitation scales. Subjects were examined twicewithin a period of 3 weeks (visits 1 and 2) and the patient-re-ported outcome measures presented in Table 1 were com-pleted at both visits by each patient to allow a test-retest evalu-ation. A focused electrophysiological study was performedonly once at visit 1.

Since the National Cancer Institute Common Toxicity Criteriaversion 3 (NCI-CTC v.3) for neuropathy is still the most

Table 1. Selected outcome measures

Impairment measures Activity and partici- Quality ofpation measures life measures

NCS C-ODSS QLQ-CIPN20

TNSc TNSc QLQ-C30

10 g monofilament Qol-PS

mISS

Rydel-Seiffer tuning fork

NCI-CTC v.3 sensory andmotor

VAS

PI-NRS

NCS: nerve conduction studies; TNSc: Total Neuropathy Score, clinicalversion [24–27]; mISS: modified INCAT sensory sum score [28];C-ODSS: calibrated-overall disability sum score [29]; PI-NRS: 11-point-pain intensity numerical rating scale [30]; QLQ-CIPN20: EORTC 20items CIPN specific quality-of-life questionnaire [31]; QLQ-C30: EORTC30 item questionnaire for quality of life in cancer patients [32]; QoL-PS: quality of life personal score; VAS: visual analogue pain scale [33].



39

widely used method for assessing sensory neuropathy in moststudies of CIPN, this instrument was considered the clinicalstandard for the study, to be compared with the selected meth-ods for its effectiveness and appropriateness.

At the end of the enrolment period 281 patients were availablefor the analysis which is still ongoing.

We are convinced that CI-Perinoms, the first study ever per-formed to approach the CIPN assessment issue with a

clinimetric method, will eventually provide the basis for ananswer to a still unmet clinical need in the treatment of cancerpatients. The final aim is to provide a standardized set of out-come measures for future clinical studies in CIPN.


GC has no conflict of interest to declare.

The CI-PERINOMS Study Group

Steering CommitteeG Cavaletti, Dept of Neuroscience and Biomedical Tech-

nologies, University of Milan-Bicocca, Monza, Italy

D R Cornblath, Dept of Neurology, Johns Hopkins Univer-sity School of Medicine, Baltimore, MD, USA

T J Postma, Dept of Neurology, VU University MedicalCenter, Amsterdam, The Netherlands

I S J Merkies, Dept of Neurology, Spaarne Hospital, Hoofd-dorp/Maastricht University Medical Center, The Nether-lands

Group Sites and InvestigatorsA A Argyriou, Saint Andrew’s General Hospital of Patras,

Patras, Greece

W Boogerd, Dept of Neuro-Oncology, Netherlands CancerInstitute, Amsterdam, The Netherlands

C Briani, C Dalla Torre, M Campagnolo, M Lucchetta,Dept of Neurosciences, University of Padua, Padua, Italy

J Bruna, R Velasco, Dept of Neurology, Hospital Uni-versitari de Bellvitge, Hospitalet de Llobregat, Barcelona,Spain

D Cortinovis, M Cazzaniga, P Bidoli, Dept of Oncology, S.Gerardo Hospital, Monza, Italy

S G Dorsey, University of Maryland, MD, USA

M Eurelings, R J Meijer, Dept of Neurology, Spaarne Hos-pital, Hoofddorp, The Netherlands

B Frigeni, P Alberti, F Lanzani, L Mattavelli, M Piatti, Deptof Neuroscience and Biomedical Technologies, Univer-sity of Milan-Bicocca, Monza, Italy

C G Faber, Dept of Neurology, Maastricht University Medi-cal Centre, Maastricht, The Netherlands

R Grant, Edinburgh Centre for Neuro-Oncology, WesternGeneral Hospital, Edinburgh, UK

W Grisold, Dept of Neurology, Kaiser-Franz-Josef-Spital,Vienna, Austria

J J Heimans, Neurology Dept, VU University MedicalCenter, Amsterdam, The Netherlands

H P Kalofonos, University Hospital of Patras, Rion-Patras,Greece

S Koeppen, Dept of Neurology, University of Essen, Ger-many

M Leandri, Interuniversity Centre for Pain Neurophysiol-ogy, University of Genoa and National Cancer Institute,Genoa, Italy

A Mazzeo, M Russo, A Toscano, Dept of Neurosciences,Psychiatry and Anaesthesiology, University of Messina,Italy

A Pace, E Galiè, Dept of Neuroscience, National Cancer In-stitute Regina Elena, Rome, Italy

L Padua, Dept of Neurosciences, Università Cattolica,Rome & Fondazione Don Gnocchi, Italy

M Penas-Prado, C Domínguez González, Hospital Univer-sitario Doce de Octubre, Madrid, Spain

R Plasmati, F Pastorelli, Dept of Neurosciences, BellariaHospital, Bologna, Italy

D Psimaras, AP-HP, Groupe Hospitalier Pitie Salpetriere,Service of Neurology Mazarin, UPMC, Paris, France

D Ricard, Hôpital du Val-de-Grâce, Service de Neurologie,Paris, France

C Santos, R Salazar, Dept of Oncology, Hospital Duran iReynals, Institut Català d’Oncologia, Hospitalet de Llo-bregat, Barcelona, Spain

A Schenone, S Fabbri, Dept of Neuroscience and Ophtal-mology, University of Genoa, Italy

D J Storey, S Kerrigan, University of Edinburgh Cancer Re-search Centre and Edinburgh Centre for Neuro-Oncol-ogy, Western General Hospital, Edinburgh, UK

C Tomasello, G Altavilla, Dept of Medical Oncology, Uni-versity of Messina, Italy

Data Management and StatisticsS Galimberti, E Rossi, M G Valsecchi, Center of Biostatis-tics for Clinical Epidemiology, Department of ClinicalMedicine and Prevention, University of Milan Bicocca,Monza, Italy



References:

1. Cavaletti G, Alberti P, Marmiroli P. Chemo-therapy-induced peripheral neurotoxicity inthe era of pharmacogenomics. Lancet Oncol2011; 12: 1151–61.

2. Cavaletti G, Alberti P, Frigeni B, et al. Che-motherapy-induced neuropathy. Curr Treat Op-tions Neurol 2011; 13: 180–90.

3. Windebank AJ, Grisold W. Chemotherapy-induced neuropathy. J Peripher Nerv Syst2008; 13: 27–46.

4. Hughes R. NCI-CTC vs TNS: which tool isbetter for grading the severity of chemothe-rapy-induced peripheral neuropathy? NatClin Pract Neurol 2008; 4: 68–9.

5. Griffith KA, Merkies IS, Hill EE, et al.Measures of chemotherapy-induced periph-eral neuropathy: a systematic review of psy-chometric properties. J Peripher Nerv Syst2010; 15: 314–25.

6. Hausheer FH, Schilsky RL, Bain S, et al.Diagnosis, management, and evaluation ofchemotherapy-induced peripheral neuropa-thy. Semin Oncol 2006; 33: 15–49.

7. Postma TJ, Heimans JJ, Muller MJ, et al.Pitfalls in grading severity of chemotherapy-induced peripheral neuropathy. Ann Oncol1998; 9: 739–44.

8. Cavaletti G. Peripheral neurotoxicity ofplatinum-based chemotherapy. Nat Rev Can-cer 2008; 8: 1 p following 71.

9. Argyriou AA, Polychronopoulos P, Icono-mou G, et al. A review on oxaliplatin-induc-ed peripheral nerve damage. Cancer TreatRev 2008; 34: 368–77.

10. Schweitzer VG. Ototoxicity of chemo-therapeutic agents. Otolaryngol Clin NorthAm 1993; 26: 759–89.

11. Cavaletti G, Marmiroli P. Chemotherapy-induced peripheral neurotoxicity. Nat RevNeurol 2010; 6: 657–66.

12. Argyriou AA, Iconomou G, Kalofonos HP.Bortezomib-induced peripheral neuropathyin multiple myeloma: a comprehensive re-view of the literature. Blood 2008; 112:1593–9.

13. Argyriou AA, Marmiroli P, Cavaletti G,et al. Epothilone-induced peripheral neu-ropathy: a review of current knowledge. JPain Symptom Manage 2011; 42: 931–40.

14. Argyriou AA, Koltzenburg M, Polychrono-poulos P, et al. Peripheral nerve damage as-sociated with administration of taxanes inpatients with cancer. Crit Rev Oncol Hema-tol 2008; 66: 218–28.

15. Siau C, Xiao W, Bennett GJ. Paclitaxel-and vincristine-evoked painful peripheralneuropathies: loss of epidermal innervationand activation of Langerhans cells. ExpNeurol 2006; 201: 507–14.

16. Cavaletti G, Nobile-Orazio E. Bortezomib-induced peripheral neurotoxicity: still farfrom a painless gain. Haematologica 2007;92: 1308–10.

17. Velasco R, Petit J, Clapes V, et al. Neu-rological monitoring reduces the incidenceof bortezomib-induced peripheral neuropa-thy in multiple myeloma patients. J PeripherNerv Syst 2010; 15: 17–25.

18. Cavaletti G, Jakubowiak AJ. Peripheralneuropathy during bortezomib treatment ofmultiple myeloma: a review of recent stud-ies. Leuk Lymphoma 2010; 51: 1178–87.

19. Swain SM, Arezzo JC. Neuropathy asso-ciated with microtubule inhibitors: diagno-sis, incidence, and management. Clin AdvHematol Oncol 2008; 6: 455–67.

20. Cavaletti G, Frigeni B, Lanzani F, et al.Chemotherapy-induced peripheral neurotox-icity assessment: a critical revision of thecurrently available tools. Eur J Cancer 2010;46: 479–94.

21. CI-PERINOMS Study Group. CI-PERI-NOMS: chemotherapy-induced peripheralneuropathy outcome measures study. JPeripher Nerv Syst 2009; 14: 69–71.

22. van Nes SI, Faber CG, Merkies IS. Out-come measures in immune-mediated neu-ropathies: the need to standardize their useand to understand the clinimetric essentials.J Peripher Nerv Syst 2008; 13: 136–47.

23. Merkies IS, Hughes RA. The measure-ment of disease. J Neurol Neurosurg Psy-chiatry 2010; 81: 943.

24. Cornblath DR, Chaudhry V, Carter K, etal. Total neuropathy score: validation and re-liability study. Neurology 1999; 53: 1660–4.

25. Cavaletti G, Frigeni B, Lanzani F, et al.The Total Neuropathy Score as an assess-ment tool for grading the course of chemo-therapy-induced peripheral neurotoxicity:comparison with the National Cancer Insti-tute-Common Toxicity Scale. J Peripher NervSyst 2007; 12: 210–5.

26. Cavaletti G, Jann S, Pace A, et al. Multi-center assessment of the Total NeuropathyScore for chemotherapy-induced peripheralneurotoxicity. J Peripher Nerv Syst 2006; 11:135–41.

27. Cavaletti G, Bogliun G, Marzorati L, etal. Grading of chemotherapy-induced periph-

eral neurotoxicity using the Total Neuropa-thy Scale. Neurology 2003; 61: 1297–300.

28. Merkies IS, Lauria G. 131st ENMC inter-national workshop: selection of outcomemeasures for peripheral neuropathy clinicaltrials 10–12 December 2004, Naarden, TheNetherlands. Neuromuscul Disord 2006; 16:149–56.

29. van Nes SI, Vanhoutte EK, van DoornPA, et al. Rasch-built Overall DisabilityScale (R-ODS) for immune-mediated pe-ripheral neuropathies. Neurology 2011; 76:337–45.

30. Farrar JT, Young JP Jr, LaMoreaux L,et al. Clinical importance of changes inchronic pain intensity measured on an 11-point numerical pain rating scale. Pain 2001;94: 149–58.

31. Postma TJ, Aaronson NK, Heimans JJ,et al. The development of an EORTC qualityof life questionnaire to assess chemothera-py-induced peripheral neuropathy: the QLQ-CIPN20. Eur J Cancer 2005; 41: 1135–9.

32. Fayers P, Bottomley A. Quality of liferesearch within the EORTC-the EORTC QLQ-C30. European Organisation for Researchand Treatment of Cancer. Eur J Cancer 2002;38 (Suppl 4): S125–S133.

33. Chong MS, Bajwa ZH. Diagnosis andtreatment of neuropathic pain. J Pain Symp-tom Manage 2003; 25: S4–S11.

34. Humphry SM, Andrich D. Understandingthe unit in the Rasch model. J Appl Meas2008; 9: 249–64.

35. Andrich D. Controversy and the Raschmodel: a characteristic of incompatibleparadigms? Med Care 2004; 42: I7–I16.


Education

41

Report on aCompleted EANO Research Fellowship

Matthias Preusser

Department of Medicine I & Comprehensive Cancer-Center – CNS Tumors Unit, Medical University of Vienna, Austria

Recently, the EANO has launched a new fellowship programmespecifically aiming at supporting the mobility of young braintumour researchers within Europe. Motivated by the wish togain research experience abroad and to increase my profes-sional network in the field, I applied for such an EANO Fel-lowship Grant and am very proud to have been selected as thefirst awardee in early 2011. The EANO Fellowship Grant gaveme the opportunity to carry out the project “BRAF V600E muta-tions in brain metastases of solid cancers” from April to Sep-tember 2011 at the Department of Neuropathology, Ruprecht-Karl-University, Heidelberg, Germany (Chair: Dr Andreas vonDeimling), a distinguished laboratory well-known for itsgroundbreaking work on brain tumour neuropathology andbiology including the recent establishment of isocitrate dehy-drogenase 1 (IDH1) R132H immunostaining for neuropatho-logical work-up of gliomas.

In the funded project, we investigated expression of the mu-tated BRAF V600E protein in a large series of tumours frompatients with brain metastases of solid cancers. Brain meta-stases are common (up to 10 times more common than glio-mas), have a poor prognosis, and, surprisingly enough, are sofar grossly underrepresented in the scientific literature [1].Current treatment algorithms comprise mainly neurosurgeryand radiotherapy, while systemic therapies have not shownmuch efficacy so far. There is a strong need to single out noveltherapeutic targets and strategies for patients with brainmetastases. Activating mutations of the serine threonine ki-nase v-RAF murine sarcoma viral oncogene homolog B1(BRAF), most commonly of the V600E type, are found in awide range of tumours, and specific inhibitors targetingBRAF V600E protein have been developed [2]. Based on theavailable data on BRAF mutations in primary tumours, wehypothesized that a proportion of brain metastases also har-bours the mutation and therefore may be amenable to BRAF-inhibiting therapeutics. We analyzed BRAF V600E-mutantprotein expression using a recently generated mutation-specificantibody [3] in a series of 1120 tumour specimens (885 brainmetastases, 157 matched primary tumours, and 78 matchedextracranial metastases) of 874 brain metastasis patients. Theaim of our study was to define the target population forBRAF-inhibiting therapies among brain metastasis patientsand to analyze the tumoural expression patterns of BRAFV600E protein. In 85 cases, we performed validation of im-munohistochemical results by BRAF exon 15 gene sequenc-ing. BRAF V600E protein was found in brain metastases of55.3 % of melanoma cases, 6.7 % of ovarian cancer cases,5.5 % of colorectal cancer cases, 0.3 % of lung cancer cases,2/6 of thyroid cancer cases, and 1/2 chorioncarcinoma cases.BRAF V600E expression showed high intratumoural homo-geneity and was consistent among different tumour manifes-tations of individual patients, thus providing a rationale for

targeted BRAF inhibitor therapy in selected patients. VE1 im-munohistochemistry and BRAF exon 15 sequencing werecongruent in 97 % of cases. VE1 immunostaining was moresensitive than gene sequencing in our series, as it identifiedsmall BRAF V600E expressing tumour cell aggregates in 10/15 cases with inconclusive genetic results. In general, wefound homogenous anti-BRAF V600E immunostaining in-tensity throughout well-preserved tumour tissue. In none ofthe cases, we saw focal BRAF V600E expression, providingevidence for a monoclonal origin of BRAF V600E mutatedmetastases. However, we detected variability of immunostain-ing intensity among different tumours. It remains to be clari-fied whether these differences relate to tissue preservation,qualitative differences of the immunostaining reaction, orwhether they reflect true differences in BRAF V600E proteinexpression. It will be of interest to correlate immunostainingintensity to response to treatment with BRAF inhibitors withinclinical trials and we have begun to design appropriate trialsin cooperation with the European Organization for Researchand Treatment of Cancer (EORTC) Brain Tumour Group. In-terestingly, in our series, melanoma patients with BRAFV600E mutant protein expressing tumours were significantlyyounger at diagnosis of the primary tumour and at operationof brain metastases than patients with non-mutated tumours.From our work, we concluded that expression of BRAF V600Emutant protein is found in approximately 6 % of brain meta-stases and that immunohistochemical visualization of V600E-mutant BRAF protein is a promising tool for patient stratifica-tion for BRAF-inhibiting therapies and may facilitate molecu-lar tumour characterization in the clinical setting [4].

My research stay in Heidelberg was a very valuable and scien-tifically productive time. I could not only profit by increasingmy knowledge and scientific experience through the work andinteraction with my colleagues in Heidelberg, but am alsohappy to have made many new friends during my fellowship.Dr von Deimling and his colleagues made me feel very wel-come at their institute and were very supportive throughoutmy entire stay. I am very grateful for this and for the opportu-nity the EANO Fellowship Grant provided me with and trulyhope that the EANO continues this programme to support thecareers of more young scientists interested in the fascinatingfield of neuro-oncology. I feel that we need strong collabora-tive efforts to make more progress and to fight brain cancermore efficiently. To my mind, interaction and mobility of Eu-ropean researchers are pivotal for the establishment of strongnetworks for powerful scientific co-operations. Therefore, Istrongly encourage all brain tumour researchers interested ina research stay in another European laboratory to apply for anEANO Fellowship Grant and would be happy to share myexperience with the organisation of such an exchange or thedevelopment of the grant application.


Education

References:1. Kamar FG, Posner JB. Brain metastases.Semin Neurol 2010; 30: 217–35.2. Chapman PB, Hauschild A, Robert C, et al.Improved survival with vemurafenib inmelanoma with BRAF V600E mutation. NEngl J Med 2011; 364: 2507–16.3. Capper D, Preusser M, Habel A, et al.Assessment of BRAF V600E mutation status

by immunohistochemistry with a mutation-specific monoclonal antibody. Acta Neuro-pathol 2011; 122: 11–9.

4. Capper D, Berghoff AS, Magerle M, et al.Immunohistochemical testing of BRAFV600E status in 1120 tumor tissue samplesof patients with brain metastases. ActaNeuropathol 2012; 123: 223–33.

Correspondence to:Matthias Preusser, MDDepartment of Medicine I & Comprehensive Cancer Center –CNS Unit (CCC-CNS), Medical University of ViennaA-1090 ViennaWähringer Gürtel 18–20e-mail: [email protected]


Education

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Report of theEANO Educational Visit to Austria 2010

Eefje Sizoo

PhD Programme, VU University Medical Center, Amsterdam, The Netherlands

Background

In February 2008, I started a PhD programme at the VU Uni-versity Medical Center aiming to explore the end-of-life(EOL) phase of high-grade glioma (HGG) patients. The EOLphase begins when the patient’s condition deteriorates and nofurther tumour treatment is possible. Since there is to date nocure for high-grade glioma patients, everyone of them willeventually reach this phase. There is only limited data on thisEOL phase.

For this reason, we performed a retrospective chart study inthe Netherlands aiming to detect symptoms and problems inthe EOL phase [1]. Furthermore, we started a large, system-atic, historical cohort study interviewing relatives and physi-cians of deceased HGG patients who were diagnosed in 2005and 2006 in 3 Dutch hospitals (VUMC Amsterdam, MCHaaglanden The Hague, AMC Amsterdam). The aim of thisstudy was to further explore the EOL phase of HGG patientswith respect to symptoms, signs, quality of life, caregiver bur-den, quality of EOL care provided, and EOL decision-making.

Health care provisions in the EOL phase vary by country. Legis-lation and opinion regarding medical EOL decisions vary amongcountries and cultures. This underscores the importance of com-paring these issues among various countries and cultures.

In 2008, Dr Wolfgang Grisold and Dr Stefan Oberndorferfrom the Kaiser-Franz-Josef Hospital in Vienna published oneof the first papers examining the end-of-life phase of HGGpatients [2]. During the 2008 EANO conference in Barcelona,we discussed the extension of our project with 3 Austrian cen-tres, Kaiser-Franz-Josef (KFJ) Hospital, Vienna (Drs Grisoldand Oberndorfer), Vienna General Hospital (Dr ChristineMarosi), and Medical University of Innsbruck (Dr GünterStockhammer), as well as one Scottish centre (EdinburghCenter for Neuro-Oncology, Dr Robin Grant).

I applied for the EANO Educational Visit Grant to visit the 3Austrian centres participating in our international study. Mygoal was to help start up the project abroad, get better ac-quainted with our foreign colleagues, and gain insight into thecare in the EOL phase for Austrian patients. Furthermore, itwould add to my personal development to observe the care forneuro-oncological patients and the practice of neurologists ina foreign country.

Educational Visit

In August and September 2010, I visited Austria for 3 weeks.I spent the first week of my visit in Innsbruck visiting the cen-tre of Dr Stockhammer. Afterwards, I spent 2 weeks in Vienna,

visiting 2 different neuro-oncology groups: the group of DrsGrisold and Oberndorfer, neurologists at the KFJ hospital,and the group of Dr Marosi, oncologist at the Vienna GeneralHospital.

The International ProjectIn Innsbruck, I met the project participants, Dr Stockhammer,Dr Schauer-Mauer, Dr Holzner, and Dr Giesinger, to discussthe protocol and practical aspects of carrying out the study.During my visit, our study protocol was presented to the eth-ics committee and accepted conditionally. Drs Holzner andGiesinger, medical psychologists highly active in quality-of-life research, showed me some of the projects they are work-ing on which added to my knowledge on this research topic.

A central Viennese ethics committee had already approvedour study protocol and both centres started inclusion of rela-tives. At the KFJ hospital, the first questionnaires to relativeshad recently been sent out. Response was relatively low and itproved difficult to track relatives. We discussed how best toenhance the response rate. At the Vienna General Hospital, aPhD student (Dr Birgit Flechl) worked on the study and theinclusion process went quite well. It was helpful to share ex-periences and discuss (future) data analysis.

Neuro-Oncological Care in AustriaAt the 3 different neuro-oncological centres, I attended wardrounds, neuro-oncological outpatient clinics, and multidisci-plinary neuro-oncological tumour board meetings. Further-more, I joined a radiotherapist for a day at the KFJ hospital. Itwas interesting to compare the various tumour board discus-sions with our own tumour board at the VU University Medi-cal Center. Although the initial approach varies between hos-pitals, the decisions taken are quite similar. The same holdstrue for treatment of brain tumour patients at the various out-patient departments.

Social EventsThere was also time for social events: with Dr Marosi I visitedthe “Kunsthistorische Museum” and afterwards we had a tra-ditional Austrian dinner. On the last night of my visit in Inns-bruck, I was invited for the yearly barbecue with the neuro-oncology group on a mountain close to Innsbruck. A greatnight of Austrian hospitality!

Progress of the Study

In the meanwhile, the identification and inclusion of relativesand physicians of Austrian patients progressed well. By De-cember 1, 2011, the inclusion of relatives and physicians frompatients treated at the Medical University of Innsbruck was


Education

completed (Figure 1). The 2 Viennese centres completed theinclusion of relatives (Figure 2), the inclusion of physicians inVienna is still ongoing.

Furthermore, we are obtaining data from relatives and physiciansof patients treated at the Edinburgh Centre for Neuro-oncol-ogy, Edinburgh, Scotland. Comparative data analysis isplanned for the second half of 2012.

Conclusion

My visit to Austria was a great opportunity to get better ac-quainted with the colleagues involved in our internationalproject. I was able to help start up the project, share experi-ences, and discuss future directions. Data collection advancedin the year after my visit.

I saw different aspects of neuro-oncological care in variousAustrian hospitals, which added greatly to my personal andprofessional development. The health care system in Austriavaries from the Dutch system, and even in between the Aus-trian centres I noticed differences in approaches. However,there are many similarities as well and I think in the end, pa-tients are treated more or less the same in both countries.

Figure 1: Identification of subjects Figure 2: Inclusion of relatives in Vienna

Acknowledgements

Thanks to Dr Grisold, Dr Marosi, Dr Oberndorfer, and DrStockhammer for the invitation and hospitality. Specialthanks to J Egeter, B Flechl, and C Sax for their extensive ef-forts in approaching physicians and relatives. Finally, thanksto Dr M Taphoorn for his feedback on this report.

References:1. Sizoo EM, Braam AM, Postma TJ, et al. Symptoms and problems in the end-of-life phase ofhigh-grade glioma patients. Neuro Oncol 2010; 12: 1162–6.

2. Oberndorfer S, Lindeck-Pozza E, Lahrmann H, et al. The end-of-life hospital setting inpatients with glioblastoma. J Palliat Med 2008; 11: 26–30.

Correspondence to:Eefje M Sizoo, MDDepartment of NeurologyVU University Medical CenterPO Box 70571007 MB AmsterdamThe NetherlandsE-mail: [email protected]


A 52-Year-Old HIV-Seropositive Patient with Hodgkin’s Disease

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Case Report: A 52-Year-Old HIV-SeropositivePatient with Hodgkin’s Disease

Khê Hoang-Xuan1, Karima Mokhtari2, Laurent Capelle3

1Service de neurologie Mazarin, 2Service d’anatomopathologie 2 A orientation neurologique,3Service de neuro-chirurgie, CHU Hôpital Pitié-Salpêtrière, Paris, France

Case Report

An HIV-seropositive 52-year-old man presenting in June 1997with Hodgkin’s disease (grade II) was treated with an MOPPchemotherapy regimen (methylchlorethamine, vincristine,procarbazine, prednisone) followed by mediastinal radio-therapy with a total dose of 40 Gy at 1.8 Gy per fraction.

Ten years later, in 2007, he described a 2-year history ofparaesthesias in the feet bilaterally. Numbness and tinglinggradually progressed, ascending upward to include the legs,with a disturbance of pain and temperature sensation acrosshis upper abdomen and lower chest. In the weeks precedinghis admission, he had developed weakness in his lower andupper extremities as well as bladder sphincter dysfunction.An MRI was performed showing an enlargement of the cervi-cal and upper thoracic spinal cord with a hyperintense signalin a T2-weighted image from C3 to T7 (Figure 1), with an in-tramedullary contrast-enhancing lesion on C6.

What’s Your Diagnosis?

A spinal biopsy was performed and the pathological diagnosiswas a glioblastoma (WHO grade-IV astrocytoma). Because

this spinal tumour occurred in the field of a previous radio-therapy performed 10 years earlier, this glioblastoma mightbe a radiation-induced tumour, as previously described inHodgkin’s disease [1]. The main differential diagnosis wouldbe radiation-related myelitis (radionecrosis) but this diagnosiswas excluded by the biopsy. Doses below 45–50 Gy in 1.8–2-Gy fractions are considered safe and are rarely associatedwith injury to the spinal cord. However, several case reports ofradiation myelitis have been observed with such doses whengiven in conjunction with high-dose chemotherapy.

Reference:1. Riffaud L, Bernard M, Lesimple T, et al. Radiation-induced spinal cord glioma subsequent totreatment of Hodgkin’s disease: case report and review. J Neurooncol 2006; 76: 207–11.

Figure 1. Enlargement of the cervical and upper thoracic spinal cord with a hyperintense signal in a T2-weighted image from C3 to T7, with an intramedullary contrast-enhancing lesion on C6.

Correspondence to:Khê Hoang-Xuan, MDService de neurologie MazarinCHU Hôpital Pitié-Salpêtrière47–83 Boulevard de l’Hôpital75651 Paris Cedex 13, Francee-mail: [email protected]


Case Report

Rare Cerebellar Tumour ina Young Adult Bulging into the Fourth Ventricle

Karl Rössler1, Rolf Buslei2, Michael Buchfelder1

1Neurosurgical Clinic and 2Institute of Neuropathology, University Hospital of Erlangen, Germany

Case Presentation

A 38-year-old female was admitted with suddenly appearingprickling in both hands. The neurological examination de-

Figure 1.T2-weightedaxial image,depicting ahyperintensetumour withinthe fourthventricle andwithin thecerebellarpeduncles.

Figures 2, 3. T1-weighted axial and sagittal, gadolinium-enhanced images depicting a small enhancing tumour part.

Figure 2 Figure 3

monstrated no abnormalities. An MRI study of the headshowed a mass lesion within the upper und middle cerebellarpeduncles on the right side, measuring about 3 cm in diameter.The lesion bulged into the fourth ventricle and led to its partialocclusion. It appeared hypointense on T1-weighted imagesand exhibited a 1-cm slightly contrast-enhancing tumour part(Figures 1–3). Surgery was performed via median suboccipi-tal craniotomy through the fourth ventricle using intra-operative electrophysiological monitoring of the lower cranialnerves. The tumour was significantly firmer than CNS sub-stance und was removed gross-totally from the cerebellarpeduncles by means of microsurgical technique. The postope-rative course was uneventful besides transitory right-sideddysdiadochokinesia, intermittent dizziness, and vertigo.

Case Resolution: Rosette-Forming Glio-neuronal Tumour of the Fourth Ventricle(RGNT)

Histological examination of the tumour revealed a rosette-forming glioneuronal tumour of the fourth ventricle (RGNT),a benign (WHO grade I) tumour of young adults, arising in thefourth ventricular region (Figures 4, 5). This rare tumourentity first described by Komori et al in 2002 [1] was includedin the WHO classification of tumours of the central nervous


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system in 2007. Histologically, it consists of 2 distinct com-ponents, one with uniform neurocytes forming rosettes and/orperivascular pseudorosettes, the other being astrocytic in na-ture and resembling pilocytic astrocytoma. More than 40cases have been analysed and described since then. Mean ageof patients was found to be about 30 years with a female-to-male ratio of 2:1 [2]. Despite the benign histology and post-operative long-term stability of the patients without additionaltherapy, long-term follow-up is advisable in the face oflimited experience and seldomly reported recurrences.

Figure 4. H&E-stained histological slide, showing perivascular pseudorosetteswithin the tumour.

Figure 5. Synaptophysin immunoreactivity in the pericapallary space, confirmingneuronal differentiation.

References:1. Komori T, Scheithauer BW, Hirose T. A rosette-forming glioneuronal tumor of the fourthventricle: infratentorial form of dysembryoplastic neuroepithelial tumor? Am J Surg Pathol2002; 26: 582–91.

2. Solis OE, Mehta RI, Lai A, et al. Rosette-forming glioneuronal tumor: a pineal region casewith IDH1 and IDH2 mutation analyses and literature review of 43 cases. J Neurooncol 2011;102: 477–84.

Correspondence to:Karl Rössler, MDNeurosurgical ClinicUniversity Hospital of ErlangenSchwabachanlage 691054 ErlangenGermanyE-mail: [email protected]


Nurses

Neuro-oncology Nursing in EuropeHanneke Zwinkels

In Europe, nurses who provide care for cancer patients are found in a clinical or a palliative-care setting, like a hospice, anursing home, or in home care. To provide quality care for patients with cancer, education and evidence-based oncologynursing are of importance and should be accessible in every European country, through nursing schools, journals, associa-tions, congresses, and through the internet (e-learning). Education is aimed at several competences that oncology nursesneed regarding patient care: assessment of health status, diagnostic aspects of nursing care, and, as a result of that imple-mentation and evaluation of interventions, planning and coordinating care, and finally maintenance of a professional leveland competence.

Cancer Nursing

Regarding cancer nursing practice, there appears to be a greatvariety of competences, education, working conditions, andprofessional status between and even within European coun-tries [1]. A survey performed by the European OncologyNursing Society (EONS) among its national member societiesrevealed that oncology nursing programmes are found in 16of the 20 participating countries, with the duration of theseprograms ranging from 6–24 months (40–800 hours), and thatthese oncology nursing training programmes make use of thecore programmes of EONS in various ways. It became clearthat there is a high demand for oncology nurses in many Euro-pean countries. Oncology nursing is recognized as a special-ized area in 11 countries and all these countries except 3 havespecialized/expertise roles for nurses in palliative care. Thesurvey also showed that specialized roles for cancer protec-tion and prevention are gradually increasing. Senior positionsfor practicing nursing at the masters’ degree level exist in 4countries, nursing practices development units/departmentsare common in only a few countries, including England andSweden [2].

Knowledge and Skills

Because patient advocacy, provision of support, and infor-mation about disease and its treatment for patients and care-givers are important aspects of the coordinating role of theoncology nurse, it is recommended that nurses should becomeskilled communicators within the multidisciplinary team. Asa consequence, in many European countries the role of theoncology nurse has developed to the extent that in many cen-tres (neuro-) oncology nurses take a leading role in the care ofoncology patients. Specialization in oncology nursing isaimed at providing support for a specific group of cancer pa-tients and their families and to further develop care. So, thespecialized oncology nurse requires specialized knowledgeand skills [3].

Exchange of Knowledge

Admitting that neuro-oncology nursing is a specialty in on-cology care and cure has been the starting point of the motiva-tion for the contents of the nursing research and care pro-gramme at the next EANO conference. What could be the top-ics that address the demand of education for more or less

trained neuro-oncology nurses? What themes could be worth-while to be discussed that will add important skills and compe-tences to the understanding of oncology nurses and other healthcare personnel that result in optimal neuro-oncology care?

A colleague from Timone Hospital in Marseille, who startedas a neuro-oncology nurse in September 2011, came to visitme in the Netherlands for 2 weeks. The aim was to see how aneuro-oncology nurse offers psychosocial care to both pa-tients and caregivers and how coordination and continuationof care are being provided. In France, there is no national on-cology nursing programme. Compared to the Dutch Onco-logy Nursing Society with almost 3000 members, in France,the national oncology society counts about 200 members.Most French nurses end their jobs after 4–6 years, also be-cause there are limited ways to develop their nursing function.This colleague successfully conducted a newly started ad-vanced oncology programme for nurses with a duration of12 months, provided by institutions in Marseille and Paris.Hopefully, the programme will be continued.

During her visit, we discussed ideas about the content of thenursing session and came to the conclusion that there is muchknowledge to be obtained and spread for oncology nursesconcerning neuro-oncology, despite the fact that in the past 10years growing awareness has emerged within neuro-oncologycare and cure – awareness of the needs of patients and theirfamilies in guidance throughout their disease concerning pos-sible problems in coping, anxiety, fear, and depression, in ob-taining access to care and cure with a low threshold in case ofemergencies or sudden questions, and in shared responsibilityin treatment and end-of-life decision-making. But what aboutthe meaning (from a patient’s view) and the point (from a pro-fessional view) of rehabilitation, about end-of-life care, aboutcognitive disturbances and psychosocial disorders, cancercare disparities and patient access to health systems, clinicaltrials and effective cancer therapy, difficult ethical considera-tions in patients with a lack of insight? And last, but certainlynot least, patient advocacy: what are the rights of a patient toobtain good care and information? To address all these topics,we have created a programme with a multidisciplinary cha-racter: nurses, a physiotherapist, a speech and language pa-thologist, a neuropsychologist, a psychologist, physicians anda patient advocate will be presenting, enabling the attendinghealth care professionals to gain and share their knowledgeand experience with each other.


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Knowledge Enriches!

To increase access to education EANO offers oncology nursesa parallel session during the biannual European neuro-oncol-ogy conference, which will be held in Marseille from Septem-ber 6–9, 2012. It will take place on Friday, September 7, inParc Chanot, Marseille. During this parallel nursing session,French translation will be available. Furthermore, the EANOwebsite contains a special subsection for nurses – and otherhealth care professionals – with interesting educational mate-rials to advance and apply knowledge in neuro-oncology. Asurvey of psychosocial care of neuro-oncology patients inEurope to be found in this subsection will enlarge the insightof where we and our patients stand and could increase aware-ness of the need for neuro-oncology nurses. I would like

to invite everyone who delivers psychosocial support toneuro-oncology patients to submit the completed survey [email protected].

References:1. Fawcett-Henesy A. Foreword. In: Kearney N, Richardson A, Di Giulio P (eds). Cancer nursingpractice. Churchill Livingstone, Edinburgh, 2000; ix.

2. Glaus A. The status of cancer nursing – a European perspective. Eur Cancer Conference2003; 1: S363.

3. Kav S. Nursing of cancer patients: oncology nursing. Course book, 2006.

Correspondence to:Hanneke Zwinkels, RN, MA ANPMedical Center HaaglandenPO Box 432, NL-2501CK The Haguee-mail: [email protected]


Patient Issues

What You Don’t Know Won’t Hurt You ...Kathy Oliver

… or will it?

Each year, 200,000 people worldwide develop a primary ma-lignant brain tumour.

Although there are no statistics to show it, some of these peo-ple – as well as some of the tens of thousands of others whoare diagnosed annually with low-grade, benign, and meta-static brain tumours – will want to know everything abouttheir disease. The big picture, the truth, and nothing but thetruth.

Others won’t want to know.

In their paper on “psychosocial and supportive-care needs inhigh-grade glioma”, the authors Catt, Chalmers and Fallow-field state: “Active information seeking is an integral part ofcoping strategies for both patient and their relatives” [1].

It is the strong belief of some brain tumour patients, care-givers, and advocates that patients must have as much infor-mation as possible about their disease, its genetic characteris-tics, existing treatments, and emerging experimental ap-proaches if they are to make truly informed choices abouttheir care.

What you don’t know can hurt you, they argue.

A fledgling pilot project in Britain has the potential to armbrain tumour patients with an unprecedented level of knowl-edge. It is a patient information portal which will give patientsfree access to data about their care held by the UK NationalBrain Tumour Registry (UK NBTR).

Dr Jem Rashbass, director of the UK NBTR, said: “The ap-proach we propose will be incremental and designed tostrengthen the relationship and deliver considerable benefitsfor both patients and their clinical teams. A key element of thebrain tumour registry pilot will be to ensure that the technol-ogy, processes, and systems can easily be scaled to cover allcancer sites.”

Relying heavily on health information technology (“HIT” is“increasingly viewed as the most promising tool for improv-ing the overall quality, safety and efficiency of the health de-livery system” [2]), this potentially transformative project willgive brain tumour patients pioneering access to aspects oftheir datasets.

These datasets generally include full-text pathology, multi-disciplinary team data, Patient Administration System infor-mation (“PAS” data relates to hospital stays and activity), andsome imaging. There is also data on radiotherapy, PET-CT

imaging, vital status from the Office for National Statistics,and, from 2012, national chemotherapy data.

The pilot has the support of the National Brain Tumour Regis-try itself, the UK National Cancer Intelligence Network(NCIN), clinical groups, and a number of charities represent-ing the UK brain tumour patient community.

The project’s steering group recognises that the initiative isnot without controversy for it contains possible risks as wellas benefits for patients who choose to participate.

Among the benefits are: upholding an individual’s rights toaccess their own healthcare data; empowering patients to takea more active role in their treatments and care, thus improvingpatient experience; driving up data quality and context (pa-tients will be able to see, question, and comment on their owndata); patients being better prepared to discuss their care withtheir clinicians; and the opportunity to contribute to the regis-try longer-term information about their brain tumour journeyswhich has the potential to improve not only treatment butquality of survivorship as well.

So it will not only be a case of asking what your brain tumourregistry can do for you as the patient, but what you can also dofor your brain tumour registry.

Among the risks are: fear and anxiety potentially inflictedupon patients by obtaining information which they may noteasily understand or be able to appropriately interpret; the ef-fects that patients being privy to this information may have onthe clinician-patient relationship; and the potential for com-promised security of personal data. The steering group recog-nises that in order to allay any fear and anxiety for the patient,most users of the portal will require information to be accom-panied by professional interpretation so that medical termi-nology and data impact is correctly understood.

At the heart of this pilot programme are 2 important notions.The first is recognising patient ownership of their own medi-cal data. The second is the notion of personal choice, a tenetwhich is enshrined in the UK NHS (National Health Service)Constitution [3]. It will be completely up to a brain tumourpatient to choose whether he or she wishes to access their dataon the brain tumour registry.

This innovative project is one of a number of emerging initia-tives that focus on and support patients who wish to becomeexperts in their own care.

Another such initiative – not brain tumour-specific but fromwhich people with brain tumours can benefit – is the “Euro-pean Patients Academy on Therapeutic Innovation” (EUPATI;


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http://www.patientsacademy.eu). Launching in spring 2012by a consortium of 30 partners led by patient organisations,this is a multi-million Euro programme which aims to educatepatient advocates and the lay public about personalised andpredictive medicine, design and conduct of clinical trials,drug safety, risk/benefit assessment, pharmaco-economics,and drug development. EUPATI will provide educational ma-terial in 6 European languages targeting 11 European coun-tries [4].

Patient portals for rich but hitherto un-mined sources of datasuch as brain tumour registries, together with the opportunityto benefit from educational programmes such as EUPATI,have the potential to transform the brain tumour journey’slandscape.

References:1. Catt S, Chalmers A, Fallowfield L. Psycho-social and supportive-care needs in high-grade glioma. Lancet Oncol 2008; 9: 884–91.

2. http://en.wikipedia.org/wiki/Health_in-formation_technology [accessed November6, 2011].

3. NHS Constitution. http://www.nhs.uk/choiceintheNHS/Rightsandpledges/NHSConstitution/Pages/Overview.aspx [access-ed December 2, 2011].

4. http://www.eu-patient.eu/Initatives-Policy/Projects/EPF-led-EU-Projects/EUPATI/[accessed November 5, 2011].

Correspondence to:Kathy OliverInternational Brain Tumour AlliancePO Box 244Tadworth, Surrey KT20 5WQUnited Kingdome-mail: [email protected]


Calendar of Events

Calendar of Events2012

February 9–11 15th Biennial Canadian Neuro-Oncology Vancouver, BC, Canada http://www.cbtc.caMeeting

March 1–5 European Congress of Radiology Vienna, Austria http://www.myesr.org/cms/website.php?id=/en/ecr_2012.htm

March 8–10 International Congress on Amsterdam, http://www.tatcongress.org/tat12-home.htmlTargeted Anticancer Therapies The Netherlands

March 21–24 EBCC 8 Vienna, Austria http://www.ecco-org.eu

March 31 Spring Meeting EORTC Brussels, Belgium http://groups.eortc.be/brain/Brain Tumour Group

March 31– American Association for Chicago, IL http://www.aacr.org/home/scientists/meetings-April 4 Cancer Research Annual Meeting -workshops/aacr-annual-meeting-2012.aspx

April 25–28 3rd European Conference on Florence, Italy http://www.ecio2012.org/Interventional Oncology

April 26–17 8th European Oncology Nursing Geneva, Switzerland http://www.ecco-org.eu/sitecore/content/Society Spring Convention Home/Conferences/Conferences/EONS%208

May 9–13 ESTRO 31 Barcelona, Spain http://www.estro-events.org/Pages/ESTRO31.aspx

June 1–5 2012 ASCO Annual Meeting Chicago, IL, USA http://www.asco.org

June 4–8 13th Asian Oceanian Congress of Melbourne, Australia http://www.aocn2012.comNeurology

June 7–10 18. Jahreskongress der Deutschen Wiesbaden, Germany http://www.degro.org/degro2012Gesellschaft für Radioonkologie

June 9–12 22nd Meeting of the European Prague, Czech Republic http://www.congrex.ch/ens2012Neurological Society

June 21–24 19th International Brain Tumor Niagara Falls, ON, http://www.2012ibtrtc.caResearch and Therapy Conference Canada

June 24–27 15th International Symposium on Toronto, ON, Canada http://www.soc-neuro-onc.org/en/cev/66/Pediatric Neuro-Oncology

June 30–July 3 International Collaborative for Montpellier, France http://epi.grants.cancer.gov/btec/Brain Tumor Epidemiology

July 7–10 EACR 22 Biennial Congress Barcelona, Spain http://www.eacr.org

September 6–9 10th EANO Congress Marseille, France http://www.eano2012.eu/index.php

September 8–11 16th Congress of the European Stockholm, Sweden http://www2.kenes.com/efns/pages/Federation of the Neurological Societies home.aspx

September 19–21 ESSO 2012 Valencia, Spain http://www.ecco-org.eu

September 28– 37th ESMO Congress Vienna, Austria http://www.esmo.org/events/vienna-2012-October 2 congress.html

October 4–6 48th Annual Meeting of the Graz, Austria http://www.oegnc-jahrestagung.atAustrian Society for Neurosurgery

October 9–12 19th International Congress on Montréal, Canada http://www.palliativecare.ca/Palliative Care

October 13 Autumn Meeting EORTC Brussels, Belgium http://groups.eortc.be/brain/Brain Tumour Group

November 6–9 Molecular Targets and Cancer Dublin, Ireland http://www.ecco-org.euTherapeutics

November 15–18 17th Annual Scientific Meeting and Washington, DC, USA http://www.soc-neuro-onc.org/2012/Education of the Society forNeuro-Oncology

2013May 9–12 19. Jahreskongress der Deutschen Berlin, Germany

Gesellschaft für Radioonkologie

May 31–June 4 2013 ASCO Annual Meeting Chicago, IL, USA http://www.asco.org

2014May 30–June 3 2014 ASCO Annual Meeting Chicago, IL, USA http://www.asco.org

July 3–6 20. Jahrestagung der Deutschen Düsseldorf, GermanyGesellschaft für Radioonkologie


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On November 5, 2011, the first Italian Association for Neuro-Oncology (AINO) and Association des Neuro-Oncologuesd’Expression Française (ANOCEF) Joint Meeting was held inMilan during the 16th Annual Congress of the AINO. For thefirst time, a joint meeting between 2 national groups was or-ganized with the purpose of bringing together leading expertsfrom both countries to discuss similarities and differences inthe approach of specific tumour types. Low-grade gliomaswere chosen as the main topic and were addressed in all as-pects from biology to treatment modalities within 4 sessions.

The meeting was opened by Marie de Tayrac (Rennes) witha lecture on, “Molecular profiling of gliomas”, illustrating theusefulness of a multi-dimensional integrated analysis to iden-tify prognostic signatures.

In the first session, chaired by Carmine Carapella (Rome)and Marc Sanson (Paris), the role of molecular markers wasaddressed. Felice Giangaspero (Rome) illustrated the diag-nostic contribution of molecular markers, such as p53 muta-tions, 1p/19q co-deletion, alpha-internexine expression,IDH1/2 mutations, or BRAF alterations to conventional neu-ropathological tools for differential diagnosis. Marc Sansondiscussed the prognostic and predictive values of molecularmarkers in low-grade gliomas, particularly IDH-1/2 muta-tions, 1p19q co-deletion, and MGMT methylation/CIMP phe-notype.

The second session, chaired by Jean Yves Delattre (Paris)and Massimo Scerrati (Ancona), was devoted to neuroimag-ing techniques. Andrea Falini (Milan) reviewed the role ofMRI diffusion and DTI tractography for diagnosis, for pre-dicting the extent of surgical resection, and for monitoring theresponse to chemotherapy. Alberto Bizzi (Milan) reported aprospective study on monitoring the eloquent areas for lan-guage with both fMRI and neuropsychological tests. Finally,Eric Guedj (Marseille) reviewed the role of old (FDG) andnew (methionine, FLT) tracers for radiotherapy planning andmonitoring the response to treatments.

The third session, chaired by Giovanni Broggi (Milan) andXavier Muracciole (Marseille), addressed the role of surgery

and radiotherapy. Lorenzo Bello (Milan) and Hugues Duffau(Montpellier) discussed the role of intraoperative use of brainmapping techniques (intra-operative monitoring and awakesurgery) to maximize both the extent of resection and thefunctional integrity of eloquent areas. A survey on patterns ofcare within centres of radiotherapy in Italy and France waspresented by Ugo De Paula (Rome), Laura Fariselli (Milan)and Xavier Muracciole. Particular attention was paid to therespective roles of radio- and chemotherapy as upfront treat-ment for high-risk patients after surgery.

The fourth session discussed the role of chemotherapy: KhêHoang-Xuan (Paris) provided an exhaustive review of thestate of art, while Roberta Rudà (Turin) and Luc Taillandier(Nancy) described the ongoing Italian and French studies onnew strategies, such as dose-dense temozolomide, PCV andits sustained effect as a valuable alternative to TMZ, and pre-operative chemotherapy. Andrea Pace (Rome) addressed thetopic of epilepsy, supportive care, and cognitive rehabilita-tion. The last talk (Costanza Papagno, Milan) was focusedon quality of life and cognitive functions that are increasinglyrecognized as major endpoints in studies on low-grade glio-mas.

Olivier Chinot (Marseille) and Riccardo Soffietti (Turin),chairmen of the last session, closed the meeting with the hopeto strengthen, both in terms of future meetings and conjointstudies, the cooperation between the 2 countries. A joint ses-sion with AINO is planned at the next ANOCEF meeting inClermond-Ferrand, France.

Correspondence to:Roberta Rudà, MDDepartment of Neuro-OncologyUniversity and San Giovanni Battista HospitalVia Cherasco 1510126 TorinoItalyE-mail: [email protected]

National Societies:Joint Meeting AINO and ANOCEF

Roberta Rudà1, Marc Sanson2

1Department of Neuro-Oncology, University and San Giovanni Battista Hospital, Turin, Italy;2Department of Neurology, Pierre et Marie Curie University and Pitié-Salpêtrière Hospital, Paris, France

Association des Neuro-Oncologuesd’Expression Française


Patient Issues

National Societies:Dutch Society for Neuro-Oncology (LWNO)

Jaap Reijneveld, Roelien Enting

The Dutch Society for Neuro-Oncology, or Landelijke Werk-groep Neuro-Oncologie (LWNO), has approximately 100members, all physicians involved in the treatment of neuro-oncological patients, and 2 sub-committees for investigators(LWNO-i) and specialized nurses (LWNO-v).

The LWNO was founded in 1992; its main tasks are 4-fold.

Development and Maintenance of Natio-nal Clinical Neuro-OncologicalGuidelines and Treatment Protocols

The LWNO has developed guidelines on the diagnosis andtreatment of gliomas, parenchymal brain metastases, lep-tomeningeal metastases, and spinal epidural metastases ofsolid tumours. A working group on a guideline on the diagno-sis and treatment of meningioma has just been installed. Allguidelines are revised every 5 years and in between if newscientific evidence with sufficient impact on the diagnosisand/or treatment emerges. The guidelines are accessiblethrough the website “Oncoline” (http://www.oncoline.nl), thedigital oncological guideline database of the Dutch CancerCentre (IKNL). Apart from those guidelines, the LWNO hasdeveloped treatment protocols for rare tumours such asmedulloblastoma and germ cell tumours in adults.

Development of Quality Criteria for Careof Neuro-Oncological Patients

In close collaboration with Dutch advocacy groups of patientswith neurological diseases and patients with cancer, theLWNO currently works on a document that defines qualitativeand quantitative criteria for adequate care for neuro-oncologi-cal patients. These criteria will involve definitions of a suffi-ciently equipped hospital brain tumour multidisciplinaryboard and multidisciplinary outpatient clinic. Apart from that,we will provide guidelines for maximum intervals betweendiagnosis and start of treatment, and minimal numbers of pa-tients to be treated. This document will set the stage for fur-ther improvement of the quality of care for this patient groupthroughout the Netherlands.

Support of National Clinical andPre-Clinical Neuro-Oncological Studies

Dutch neuro-oncology has a longstanding reputation of excel-lent research, and members of the LWNO have played, andstill play, important roles in international neuro-oncologicalsocieties and research organisations, such as EANO, EORTC,and SNO. Apart from those international collaborations,which the LWNO actively endorses, the LWNO provides sup-port and a forum for the set-up of national clinical and pre-clinical studies, such as a randomised phase-II study onbevacizumab vs lomustine vs bevacuzimab/lomustine in re-current glioblastoma (BELOB study) and a randomised studyon the internet-based treatment of glioma patients with de-pression.

Providing a National Forum

The LWNO provides a national forum for medical profession-als involved in the research and treatment of neuro-oncolo-gical patients. The LWNO organizes meetings, such as ourannual scientific meeting and the regular plenary meetingsas well as meetings of the specific working groups andsubcommittees. At the annual scientific meetings, the“STOPHersentumoren.nl” and the “Ties Rudolphie” prizesare awarded to outstanding professionals in neuro-oncology.On an ad hoc basis, the LWNO advises Dutch governmentaland health organisations on neuro-oncological issues.

For more information please contact us via e-mail ([email protected]) or visit our website (http://iknl.ecom-many.com/Landelijk/werkgroepen/no_voor_leden/in-dex.php).

Correspondence to:Jaap C Reijneveld, MDDepartment of Neurology – HP 2F.35VU University Medical CenterPO Box 7057, 1007 MB AmsterdamThe Netherlandse-mail: [email protected]


Ongoing Trials

55

Interview with Dr James Perryabout the NCIC-CTG Elderly Glioblastoma Trial

Ufuk Abacioglu

From the Department of Radiation Oncology, Neolife Medical Center, Istanbul, Turkey

Q: Can you tell us about the ongoing “Elderly Glioblastoma”trial? What is the rationale and background for this trial?

A: Thank you for giving us the forum to discuss this interna-tional cooperative group study that addresses an importantunmet need in the management of older patients with glio-blastoma. We know from the EORTC/NCIC-CTG study thatthe addition of concurrent and adjuvant temozolomide (TMZ)to standard radiotherapy (60 Gy/30 fx) clearly improves sur-vival [1]. However, a trend-benefit analysis by the EORTCfound decreasing benefit with increasing age. We do not knowif this was due to the size of the subgroup of elderly patients inthe trial (and therefore a problem with statistical power) or ifthere is truly less benefit seen with increasing age. Therefore,a randomized trial testing the same clinical question (RT ±concurrent and adjuvant TMZ) was proposed for newly diag-nosed elderly patients. We learned from the Roa et al trial that40 Gy/15 fractions (ie, 3 weeks) of radiotherapy appears togive similar survival results to 60 Gy/30 fractions in the eld-erly [2]. We also learned from the ANOCEF trial that so-called “short-course” radiotherapy plus supportive care is su-perior to supportive care alone [3]. Therefore, this trial wasbuilt around the central premise that many older patients aregiven short-course radiotherapy in brain tumour centresacross the world; yet we do not know if the addition of concur-rent and adjuvant TMZ is of benefit.

Q: What are the design and inclusion criteria?

A: This is a randomized phase-III trial for patients over theage of 65 with newly diagnosed glioblastoma. Local patho-logical diagnosis is sufficient for study randomization but tis-sue is being collected for molecular companion analyses, es-pecially determination of MGMT promoter methylation sta-tus. Patients are stratified within predefined age groups, byPS, and by centre. There was one planned interim futilityanalysis and the independent DSMB has recommended pro-ceeding with the trial.

Q: What is your definition of the elderly? Why did you choose65 as cut-off?

A: Initially we designed this study with age restricted to 70and above. This “pure” approach would therefore not overlapwith patients who were in the previous EORTC/NCIC-CTGstudy and for whom level-1 evidence suggests treatment with“full-course” radiation plus chemotherapy. However, we feltthat the statistical power of the results over the age of 65 leftthe 65–70-year-old age group in an uncertain category and,after discussions with colleagues at the EORTC Brain com-mittee, we came to realize that many centres use shorter-course radiotherapy routinely over the age of 65. So this be-

came a pragmatic point in terms of maximizing accrual op-portunity. To date, the median age of patients in the study is 73years; so we believe that we are collecting an older cohort ofpatients (1/3 is 65–70, 1/3 is 71–75, and 1/3 is > 75). It is impor-tant to remember that the central question of this study is totest whether or not the addition of chemotherapy is importantfor patients who are recommended short-course radiation the-rapy. We expect that some centres will continue to offer 60Gy/30 fractions to suitably fit patients between 65 and 70; sothis study requires and allows for clinical judgement of thebest radiotherapy prescription on a case-by-case basis.

Q: Which groups, countries, and how many centres partici-pate in the trial?

A: The study is led by the National Cancer Institute of CanadaClinical Trials Group (NCIC-CTG) with major participationfrom the EORTC, the Trans-Tasman Radiation OncologyGroup (TROG), Japan, and most recently by the new Ameri-can cooperative group (ACTION). Accrual to date is NCIC-CTG 17 sites, n = 135; EORTC 27 sites, n = 122; TROG 14sites, n = 53, and Japan 2 sites, n = 6.

Q: Recent results from the German NOA-8 and Nordic trialsshowed somehow contradictory results on first-line treatmentwith radiotherapy or temozolomide [4, 5]. Taking into accountthose 2 other trials, how will your trial answer the question oftreatment for this population? Would you prefer to have athird arm with temozolomide alone within the trial?

A: These 2 important clinical trials did not show superiorityof radical radiotherapy in newly diagnosed elderly patientswith glioblastoma. Taken together with prior radiotherapystudies in the elderly we feel it is now reasonable to considershorter-course radiotherapy (such as 40 Gy/15 fx) as standardof care. These results fortuitously make the study question inour trial an important one. Our ongoing study will be the firstto test the efficacy and toxicity of concurrent and adjuvantTMZ added to this radiation scheme. We initially included achemotherapy-alone arm; however, this resulted in a verylarge sample size and, at that time, would have conflicted withthe ongoing European trials.

Q: Do you have any translational or biological investigationin this trial?

A: Tissue is being collected and a full translational analysiswill be coordinated and conducted through the NCIC-CTGheadquarters in Kingston, Ontario, Canada.

Q: How is the accrual and when do you expect to reach theaccrual goal? When can we get the first results?


Ongoing Trials

A: The addition of the EORTC provided a meaningful in-crease in accrual and we anticipate the participation of UScentres in early 2012. In order to have 90-% power to detect a25-% increase in the primary outcome of overall survival (in-creased MST from 6 to 8 months) between arms, using a 2-sided 5-% alpha, a minimum of 520 deaths must be observedprior to analysis. Total sample size is 560. As of September30, 2011, there were 316 patients randomized. The accrualrate is approximately 10–12 per month at present, so we esti-mate the trial will complete accrual by the end of 2013.

Thank you very much!

James Perry is NCIC-CTG study co-chair (along with DrNormand Laperriere) for the trial entitled “A randomizedphase III study of temozolomide and short-course radiationversus short-course radiation alone in the treatment of newlydiagnosed glioblastoma multiforme in elderly patients”.

Contact details:James R Perry, MD, FRCPCDivision of NeurologySunnybrook Health Sciences CentreUniversity of TorontoA402, 2075 Bayview AvenueToronto, Ontario, Canada M4N 3M5Phone: (001) 416-480-4766Fax: (001) 416-480-5054e-mail: [email protected]

References:1. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvanttemozolomide for glioblastoma. N Engl J Med 2005; 352: 987–96.

2. Roa W, Brasher PM, Bauman G, et al. Abbreviated course of radiation therapy in olderpatients with glioblastoma multiforme: A prospective randomized clinical trial. J Clin Oncol2004; 22: 1583–8.

3. Keime-Guibert F, Chinot O, Taillandier L, et al. Radiotherapy for glioblastoma in the elderly.N Engl J Med 2007; 356: 1527–35.

4. Wick W, Engel C, Combs SE, et al. NOA-08 randomized phase III trial of 1-week-on/1-week-off temozolomide versus involved-field radiotherapy in elderly (older than age 65) patientswith newly diagnosed anaplastic astrocytoma or glioblastoma (Methusalem). J Clin Oncol2010; 28 (18s): # LBA2001.

5. Malmstrom A, Grønberg BH, Stupp R, et al. Glioblastoma (GBM) in elderly patients:A randomized phase III trial comparing survival in patients treated with 6-week radiotherapy(RT) versus hypofractionated RT over 2 weeks versus temozolomide single-agent chemo-therapy (TMZ). J Clin Oncol 2010; 28 (18s): # LBA2002.

Correspondence to:Ufuk Abacioglu, MDDepartment of Radiation OncologyNeolife Medical CenterYucel Sok # 61. Levent, Besiktas34340 IstanbulTurkeye-mail: [email protected]


Hotspots

57

Hotspots in Neuro-OncologyMichael Weller

From the Department of Neurology, University Hospital Zurich, Switzerland

Peri-Ictal Pseudoprogression in Patientswith Brain Tumor

Rheims S, Ricard D, van den Bent M, et al. Neuro Oncol2011; 13: 775–82.

In the July issue of Neuro-Oncology, another chapter waspublished on the ongoing controversy of pseudoprogressionas a confounding factor when monitoring response to therapy:Rheims and colleagues reported on a series of 10 brain tu-mour patients who experienced pseudoprogression in the con-text of epileptic seizures. These interesting observations in asmall number of patients illustrate the need to carefully assesschanges in the MRI scans shortly after epileptic seizures inorder to avoid the false diagnosis of progression.

A Small-Molecule IAP Inhibitor Over-comes Resistance to Cytotoxic Therapiesin Malignant Gliomas In Vitro and In Vivo.

Ziegler DS, Keating J, Kesari S, et al. Neuro Oncol 2011; 13:820–9.

The August issue experienced a potential comeback of a cyto-toxic therapy approach to malignant glioma that attracted a lotof interest a few years ago, but gained much less attentionmore recently. Inhibitors of apoptosis proteins (IAP) areamong the cellular defence mechanisms to prevent the bio-chemical cascade of apoptosis involving caspase activation. Ithas been tried to block cytoprotective IAP function in variouscancer models including gliomas, using different agents anddelivery approaches. Here, Ziegler and colleagues demon-strate that the systemic treatment with a small-molecule IAPinhibitor is feasible and active, in the apparent absence of sig-nificant toxicity.

Infratentorial Craniospinal Irradiationfor von Hippel-Lindau: a RetrospectiveStudy Supporting a New Treatment forPatients with CNS Hemangioblastomas

Simone CB, Lonser RR, Ondos J, et al. Neuro Oncol 2011;13: 1030–6.

Treatment options for patients with von Hippel-Lindau dis-ease with diffuse CNS hemangioblastomas are very limited.

This report of 7 patients with 84 hemangioblastomas indicatesthat infratentorial craniospinal irradiation to 43.2 Gy in 24fractions offers a potentially reasonable treatment strategywith complete resolution of some lesions and a decrease in thegrowth rate and surgical interventions compared with histori-cal controls.

Morbidity and Mortality FollowingAcoustic Neuroma Excision in the UnitedStates: Analysis of Racial DisparitiesDuring a Decade in the Radiosurgery Era

McClelland S, Guo H, Okuyemi KS. Neuro Oncol 2011; 13:1252–9.

This article from the November issue is among the most pro-vocative articles published in Neuro-Oncology in 2011. In es-sence, data from a nationwide inpatient sample from 1994–2003 revealed a postoperative mortality rate following acous-tic neuroma surgery of 0.5 % and of an adverse discharge dis-position of 6.1 %. Patients had a better outcome when theywere operated by high-caseload surgeons, had private insur-ance, and were younger. There was a significant increase ofrisk of death among African Americans. These data call forreconsiderations of the current patterns of care of acousticneuromas in the US (and also for similar analyses in othercountries throughout the world).

Correspondence to:Michael Weller, MDDepartment of Neurology, University Hospital ZurichFrauenklinikstrasse 268091 Zurich, Switzerlande-mail: [email protected]


SNO News

News from the Society for Neuro-OncologyJ Charles Haynes

Society for Neuro-Oncology, Bellaire, TX, USA

The Society for Neuro-Oncology’s 16th Annual ScientificMeeting and Education Day took place November 17–20,2011, in Anaheim, California. In addition to the scientific andeducational sessions, there were several important interna-tional committee meetings at which members discussed ef-forts to increase cooperation between the various national andregional neuro-oncology organizations as well as initiatives toprovide outreach to developing regions of the world.

The first of these sessions was the inaugural meeting of theWorld Federation of Neuro-Oncology Societies (WFNOS).This new organization seeks to improve communication be-tween neuro-oncology societies and to coordinate and formal-ize the planning process for future quadrennial World Federa-tion of Neuro-Oncology (WNFO) conferences. The sessionenjoyed broad international participation, with representa-tives from North America, Europe, Japan, Korea, Australia,India, and China. As an initial first step, it was agreed that acharter should be drafted to outline the relationship betweenthe organizations as well as to codify a transparent process forselecting the locations for future WFNO meetings. It was gen-erally accepted that the location of WFNO meetings shouldrotate between North America, Europe, and Asia every 4years, and that there should be inclusive international repre-sentation within the scientific planning committee. The char-ter is currently being drafted and will be ready for dissemina-tion to the member organizations in early 2012. The nextWFNO meeting will take place November 20–24, 2013, at theMarriott Marquis Hotel in San Francisco, California.

With the goal of improving clinical and research activities inthe management of children and adults with brain tumours indeveloping regions of the world, the SNO International Out-reach Committee held an informative lunchtime session ad-dressing the global disparities that exist in neuro-oncologycare and treatment. Topics discussed included “Care in theMiddle East” (Mark Kieran), “Neuro-Oncology in Iraq” (Musta-fa Khasraw) and “Teleconferencing in North Africa” (EricBouffet). A highlight of the session was the introduction of DrJun-Ping Zhang, the recipient of the 2011 SNO InternationalOutreach Fellowship. Through a competitive applicationprocess, this fellowship provides a US$ 50,000 award to anindividual from a low-income or developing country to travelto the United States or Canada to study at a leading academicinstitution. Dr Zhang, a Chinese national, will be mentored by

Dr Patrick Wen at the Dana-Farber Cancer Institute in Boston,Massachusetts. Applications for the 2012 InternationalOutreach Fellowship are now being accepted, and membersof EANO are encouraged to refer potential applicants to theSNO website

http://www.soc-neuro-onc.org/international-outreach/

The deadline for applications is February 3, 2012.

Looking ahead, planning is now underway for a special sup-plemental issue of our official journal, Neuro-Oncology, thatwill focus on applied neuro-oncology and the practical as-pects of the care and treatment of patients with brain tumours.This exciting new initiative seeks to provide a forum for inter-national collaboration and an opportunity to share experi-ences across the various societies. The special issue will high-light the importance of evaluating the effects that the diagnos-is and treatment of brain tumours have on patients and care-givers with respect to clinical factors other than survival, andthe critical need to study this systematically through prospec-tive research efforts. Susan Chang will serve as editor-in-chiefof the supplement, with the assistance of co-editors from eachof the participating societies: Masao Matsutani (ASNO),Riccardo Soffietti (EANO), and Jeffrey Wefel (SNO). The co-editors will be responsible for soliciting the papers from theirrespective societies, with the goal of having the special issuecompleted in time for the next SNO meeting scheduled forNovember 15–18, 2012, at the Hilton Hotel in Washington,DC.

Finally, in an effort to further promote international educationand exchange, SNO and EANO are organizing reciprocal“meet the expert” sessions at their respective meetings in2012. A competitive application process for travel grants foryoung investigators will also be initiated in the New Year, anddetails will be posted shortly on the SNO and EANO websites.

Correspondence to:J Charles Haynes, JDSociety for Neuro-Oncology4617 Birch StreetBellaire, TX 77401-5509USAE-mail: [email protected]

For more information on the Society for Neuro-Oncology, please visit our website,

http://www.soc-neuro-onc.org


SNO News

59

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