Weller, Michael

Wick, Wolfgang

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LETTER TO THE EDITOR‘‘Nanomania’’ ante portas of neurooncology?Michael Weller • Wolfgang WickReceived: 16 October 2010 / Accepted: 13 December 2010 / Published online: 25 December 2010 Springer Science+Business Media, LLC. 2010To the EditorThere is currently no standard of care for recurrent glio-blastoma. Accordingly, there is an urgent medical need fornew therapeutic approaches in this setting. Novel treatmentapproaches are often received with great hopes by patientsand relatives. Nevertheless, it is mandatory that all noveltreatment approaches, not only pharmacological treat-ments, are subjected to standardized evaluations of safetyand efficacy.In this regard, German neuro-oncologists have beenexposed to pressure from patients and relatives to introducethe new therapy referred to as intratumoral thermotherapy,developed by MagForce Nanotechnologies, for manyyears. Finally and fortunately, data of a ‘‘phase II trial’’were recently published in the Journal of Neuro-Oncology[1]. In contrast to the title of this article, we would like topoint out that neither safety nor efficacy weredemonstrated:(i) Safety was an issue. 15 patients experienced epilepticseizures in the context of the treatment. Even theauthors raise the possibility that patients might benefitfrom prophylactic anticonvulsants if they opt for thistreatment modality. From the quality of life perspec-tive, it is important to note that all metallic materialsincluding dental fillings, crowns and implants within40 cm of the treatment area had to be removed, forsafety reasons.(ii) Efficacy could not be demonstrated simply as aconsequence of the study design. The experimentaltreatment was combined with fractionated stereotac-tic radiotherapy at 30 Gy in 2 Gy fractions. Thecombination of an experimental treatment modalitywith an established treatment modality like stereo-tactic radiotherapy in an uncontrolled phase II trial isinappropriate to demonstrate efficacy.(iii) 24 of 59 patients had some treatment (resection 11,radiotherapy 2, chemotherapy 17) for the samerecurrence subsequently treated with intratumoralthermotherapy. No effort was made to dissect therole of the various treatment measures administeredat recurrence.(iv) The authors indicate that ‘‘data on any subsequenttreatments for tumor progression following thethermo/radiotherapy were not systematically col-lected’’. Accordingly, the impact of the experimentaltreatment on the overall survival estimate is impos-sible to evaluate. Progression-free survival was notassessed and cannot easily be addressed since thistreatment precludes further MRI monitoring for lifebecause of artefact. Yet, overall survival at 2 yearsfrom recurrence was the primary end point andadditional treatment measures at further recurrenceare likely to have influenced the treatment results.(v) The authors state that analysis was by intention totreat, but it remains unclear what happened to theseven patients that were included, but did not fulfilinclusion criteria. Curiously, analysis of efficacy isbased on 59 patients whereas analysis of safety is on66 patients.M. Weller (&)Department of Neurology, University Hospital Zurich,Frauenklinikstrasse 26, 8091 Zurich, Switzerlande-mail: michael.weller@usz.chW. WickDepartment of Neuro-Oncology, Heidelberg UniversityHospital, Im Neuenheimer Feld 400, 69120 Heidelberg,Germanye-mail: wolfgang.wick@med.uni-heidelberg.de123J Neurooncol (2011) 104:613–614DOI 10.1007/s11060-010-0508-ySome minor comments need to be made, too:(vi) The authors claim that randomization for recurrentglioblastoma is ‘‘extremely difficult’’ and that arandomized assessment of intratumoral thermother-apy was not possible. This statement is proven wrongby the series of randomized trials in that setting thathave been performed in the recent years, both usinglocal treatments such as immunotoxins or chemo-therapy, e.g. for cilengitide [2], erlotinib [3], enzas-taurin [4] or cediranib [5].(vii) The authors cite Stummer et al. [6] as a reference forthe value of surgery for recurrent glioblastomawhich is not the content of this work.(viii) The hypothesis that PET and SPECT are as good asMRI to monitor disease progression has never beenaddressed in a clinical study.Altogether, this trial has a study design that a priori didnot allow to draw conclusions regarding efficacy. Yet,substantial efforts are made in claiming efficacy in theDiscussion section, based on historical comparisons whichare inappropriate. This unjustified claim of efficacy isworrisome because two of the authors are employees ofMagForce Nanotechnologies. This is mentioned as a dis-closure, but the conflict of interest section says ‘‘none’’.Michael Weller, Zurich, SwitzerlandWolfgang Wick, Heidelberg, GermanyReferences1. Maier-Hauff K, Ulrich F, Nestler D, Niehoff H, Wust P, ThiesenB, Orawa H, Budach V, Jordan A (2010) Efficacy and safety ofintratumoral thermotherapy using magnetic iron-oxide nanoparti-cles combined with external beam radiotherapy on patients withrecurrent glioblastoma multiforme. J Neuro-Oncol. doi:10.1007/s11060-010-0389-02. Reardon DA, Fink KL, Mikkelsen T, Cloughesy TF, O’Neill A,Plotkin S, Glantz M, Ravin P, Raizer JJ, Rich KM, Schiff D,Shapiro WR, Burdette-Radoux S, Dropcho EJ, Wittemer SM,Nippgen J, Picard M, Nabors LB (2008) Randomized phase IIstudy of cilengitide, an integrin-targeting arginine-glycine-asparticacid peptide in recurrent glioblastoma multiforme. J Clin Oncol26:5610–56173. Van den Bent MJ, Brandes AA, Rampling R, KouwenhovenMCM, Kros JM, Carpentier AF, Clement PM, Frenay M, CamponeM, Baurain JF, Armand JP, Taphoorn MJB, Tosoni A, Kletzl H,Klughammer B, Lacombe D, Gorlia T (2009) Randomized phase IItrial of erlotinib versus temozolomide or carmustine in recurrentglioblastoma: EORTC brain tumor group study 26034. J ClinOncol 27:1268–12744. Wick W, Puduvalli VK, Chamberlain M, Van den Bent M,Carpentier AF, Cher LM, Mason W, Weller M, Hong S, Musib L,Liepa AM, Thornton DE, Fine HA (2010) Enzastaurin versuslomustine in the treatment of recurrent intracranial glioblastoma: aphase III study. J Clin Oncol 28:1168–11745. Batchelor TT, Mulholland P, Neyns B, Nabors LB, Campone M,Wick A, Mason W, Xu J, Liu Q, van den Bent M (2010) A phaseIII randomized study comparing the efficacy of cediranib asmonotherapy, and in combination with lomustine, with lomustinealone in recurrent glioblastoma patients. ESMO 2010, Milan, Italy,LBA 76. Stummer W, Pichlmeier U, Meinel T, Wiestler OD, Zanella F,Reulen HJ (2006) Fluorescence-guided surgery with 5-aminolev-ulinic acid for resection of malignant glioma: a randomisedcontrolled multicentre phase III trial. Lancet Oncol 7:392–401614 J Neurooncol (2011) 104:613–614123

"Nanomania” ante portas of neurooncology?

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