Neurooncology current findings and challenges for

Authors: Silvia Hofer

Publish Date: 2013/06/22

Volume: 6, Issue: 4, Pages: 225-226

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Abstract

Primary central nervous system CNS tumors comprise approximately of 120 histological subtypes Thus it seems reasonable to concentrate primarily on some common entities Most primary CNS tumors of adults are of glial origin and if they belong to WHO grade II–IV they diffusely infiltrate the normal brain ab initio ie pretherapeutically With current standard treatment they cannot be cured And here lies an immense challenge for the neurooncology communityGliomas are defined by histomorphological criteria described in the fourth edition of the WHO classification published 2007 1 Histomorphology itself is able to precisely describe histological variants of CNS tumors and add new entities as soon as they are recognized by an international Working Group of 25 neuropathologists around the world However biological behavior of a certain tumor is only imperfectly predictable by histomorphological criteria aloneThere is now growing interest in the identification and validation of diagnostic prognostic and predictive molecular markers to divide brain tumors into biologically distinct categories in addition to histomorphological criteria Specific genetic changes eg IDH1 mutation LOH 1p/19q and MGMT methylation status segregate prognostic glioma subtypes and some have already proven useful in decision making to predict systemic treatment Apart from tissue and blood derived biomarkers “old” established and proven clinical prognostic factors such as age Karnofsky performance status extent of resection among others are easily available without any additional costs and are still the part of a clinicians armamentarium to guide treatment choicesFor anaplastic WHO grade III oligodendrogliomas the loss of 1p/19q LOH 1p/19q due to an unbalanced translocation improves both survival and the response to therapy and is thus both a prognostic and a predictive marker The most recent longterm followup from two large randomized Phase III trials 2 3 call for a routine testing of this marker with PCR or FISH technique in WHO grade III gliomas A marked overall survival benefit was achieved from the addition of chemotherapy to radiation confined to patients with anaplastic oligodendroglial tumors with versus without 1p/19q codeletionPromoter methylation of the MGMT gene causes epigenetic silencing of the methyltransferase which loses its gene repair activity if inactivated Evidence is now available for the growing population of elderly glioblastoma GBM patients unfit for postoperative concomitant radiation and chemotherapy to guide treatment decision upon MGMT methylation status A methylated MGMT promoter ie silenced gene is a powerful predictive biomarker for the benefit of postoperative chemotherapy with temozolomide alone For unmethylated tumors however radiation therapy alone is considered the standard in this patient population This has been clearly shown by two randomized trials with patients older than 65 and 60 years respectively 4 5 In the absence of alternative therapeutic strategies younger and fit patients with a GBM  70 years should be offered postoperative concurrent chemoirradiation without necessarily testing for the MGMT statusDetermination of the methylation status of the MGMT promoter however is technically demanding and requires reproducible and validated test procedures Various techniques are available and a generally accepted consensus is still pending Yet a methylationspecific polymerase chain reaction MSP seems appropriate for clinical routine testing with low sample numbersMutations of still another marker namely of the isocitrate dehydrogenase IDH genes have been identified as an early event in gliomagenesis These mutations are a typical feature of lowgrade glioma secondary transformed higher grade glioma and in a small cohort of GBM and are associated with a more favorable prognosis IDH mutations result in an oncometabolite called 2hydroxyglutarate 2HG Subsequent accumulation of this metabolite in the tumor tissue interferes with the epigenetic machinery and induces a CpG island methylator phenotype Recent advances have shown that magnetic resonance spectroscopy is able to detect 2HG in a noninvasive manner Ongoing research is aimed at targeting this enzyme for therapeutic purposes

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