Towards the Real Interdisciplinary Approach in Treating ... · recent updates in neuro-oncology, more importantly we plan to arrive at consensus to develop local guidelines on diagnosis,

Article ID: WMC002381 ISSN 2046-1690

Towards the Real Interdisciplinary Approach inTreating Brain Tumors: Report from theNeuro-Oncology Scientific Club opening meeting -NOSC 2011-13 October- Mashhad, IR IranCorresponding Author:Dr. Kazem Anvari,Radiation Oncologist, Faculty member, Mashhad University of medical Sciences - Iran (Islamic Republic of)

Submitting Author:Dr. Mohammad Torabi Nami,MD, PhD Neuroscience, Institute for Cognitive Sciences Studies, Neuroscience Research Center,ICSS,17Pezeshkpour St., Valiasr Ave.(SBMU),Tehran - Iran (Islamic Republic of)

Other Authors:Dr. Gholamreza Bahadorkhan,Neurosurgeon, Faculty member, Mashhad University of medical Sciences - Iran (Islamic Republic of)

Dr. Sirous Nekooi,Radiologist, Faculty member, Mashhad University of medical Sciences - Iran (Islamic Republic of)

Dr. Ali Taghizadeh,Radiation Oncologist, Faculty member, Mashhad University of medical Sciences - Iran (Islamic Republic of)

Dr. Hamed Kheradmand,Neurosurgeon, Mashhad University of medical Sciences - Iran (Islamic Republic of)

Dr. Gholamhossein Nowferesti,Radiation Oncologist, Faculty member, Mashhad University of medical Sciences - Iran (Islamic Republic of)

Dr. Seyed Amir Aledavood,Radiation Oncologist, Faculty member, Mashhad University of medical Sciences - Iran (Islamic Republic of)

Dr. Mehdi Seilanian Tousi,Radiation Oncologist, Faculty member, Mashhad University of medical Sciences - Iran (Islamic Republic of)

Dr. Hossein Mashhadinejad,Neurosurgeon, Faculty member, Mashhad University of medical Sciences - Iran (Islamic Republic of)

Dr. Siavash Zahed Anaraki,Radiation Oncologist, Faculty member, Mashhad University of medical Sciences - Iran (Islamic Republic of)

Dr. Yasha Makhdoomi,Radiation Oncologist, Faculty member, Mashhad University of medical Sciences - Iran (Islamic Republic of)

Dr. Fatemeh Homaee,Radiation Oncologist, Faculty member, Mashhad University of medical Sciences - Iran (Islamic Republic of)

Dr. Mohammad Reza Ehsaee,Neurosurgeon, Faculty member, Mashhad University of medical Sciences - Iran (Islamic Republic of)

Dr. Azar Fani Pakdel,Radiation Oncologist, Faculty member, Mashhad University of medical Sciences - Iran (Islamic Republic of)

Dr. Fatemeh Varshoee Tabrizi,

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Radiation Oncologist, Faculty member, Mashhad University of medical Sciences - Iran (Islamic Republic of)

Dr. Soodabeh Shahidsales,Radiation Oncologist, Faculty member, Mashhad University of medical Sciences - Iran (Islamic Republic of)

Dr. Farhad Motlagh,Neurosurgeon, Farabi Hospital, Mashhad - Iran (Islamic Republic of)

Dr. Marjaneh Mirsadraie,Radiation Oncologist, Faculty member, Mashhad University of medical Sciences - Iran (Islamic Republic of)

Dr. Fahimeh Khoshroo,Radiation Oncologist, Faculty member, Mashhad University of medical Sciences - Iran (Islamic Republic of)

Dr. Reza Partoie,Radiation Oncologist, Faculty member, Mashhad University of medical Sciences - Iran (Islamic Republic of)

Dr. Mehdi Abili,Neurosurgeon, Faculty member, Mashhad University of medical Sciences - Iran (Islamic Republic of)

Dr. Saied Rahighi,Neurosurgeon, Mashhad University of medical Sciences - Iran (Islamic Republic of)

Dr. Amir Hooshang Yousefi,Radiation Oncologist, Bojnourd, Khorasan - Iran (Islamic Republic of)

Dr. Farzad Bidoyie,Radiation Oncologist, Mashhad University of medical Sciences - Iran (Islamic Republic of)

Dr. Jalal Mirshahi,Pharmacist, Behestan Group, Khorasan - Iran (Islamic Republic of)

Dr. Masoud Dehestani,Pharmacist, Mashhad - Iran (Islamic Republic of)

Dr. Masoud Noorifard,Pharmacist, Mashhad - Iran (Islamic Republic of)

Dr. Mohammad Afarid,MD, Behestan Group - Iran (Islamic Republic of)

Dr. Seyed Abdolreza Hejazi Farahmand,MD, Behestan Group - Iran (Islamic Republic of)

Article ID: WMC002381

Article Type: Faculty speak

Submitted on:26-Oct-2011, 12:55:16 PM GMT Published on: 27-Oct-2011, 02:36:54 PM GMT

Article URL: http://www.webmedcentral.com/article_view/2381

Subject Categories:ONCOLOGY

Keywords:Neuro-oncology working team, Interdisciplinary, Guideline definition, High grade glioma, Brain tumor,Mashhad

How to cite the article:Anvari K, Bahadorkhan G, Nekooi S, Taghizadeh A, Kheradmand H, Nowferesti G, et al.Towards the Real Interdisciplinary Approach in Treating Brain Tumors: Report from the Neuro-OncologyScientific Club opening meeting - NOSC 2011-13 October- Mashhad, IR Iran. WebmedCentral ONCOLOGY2011;2(10):WMC002381

Source(s) of Funding:

This communication in a form of a meeting has been made possible through funding support fromBehestandarou PJS.

Competing Interests:

NOSC ( The Neuro-Oncology Scientific Club) is a professional forum for the exchange of experts' experience andupdates on brain tumors in an interdiciplinary fashion. NOSC plans to act as a guideline definition group inMashhad and meanwhile has no competing interest to disclose.


http://www.webmedcentral.com/article_view/2381


Towards the Real Interdisciplinary Approach inTreating Brain Tumors: Report from theNeuro-Oncology Scientific Club opening meeting -NOSC 2011-13 October- Mashhad, IR IranAuthor(s): Anvari K, Bahadorkhan G, Nekooi S, Taghizadeh A, Kheradmand H, Nowferesti G, Aledavood S,Seilanian Tousi M, Mashhadinejad H, Zahed Anaraki S, Makhdoomi Y, Homaee F, Ehsaee M, Fani Pakdel A,Varshoee Tabrizi F, Shahidsales S, Motlagh F, Mirsadraie M, Khoshroo F, Partoie R, Abili M, Rahighi S, YousefiA, Bidoyie F, Mirshahi J, Dehestani M, Noorifard M, Afarid M, Hejazi Farahmand S, Torabi Nami M

Abstract

To strategize interdisciplinary approaches inneuro-oncology and guideline definitions, there hasalways been a room for having joint meetings inpractical fashion in our country. For forgingrelationship within various neuro-oncologyprofessional bodies in Mashhad, Khorasan Province,Iran, the original concept of Neuro Oncology ScientificClub (NOSC) was formed. The NOSC great emphasishas been placed on building bridges between differentgroups in the field (i.e Radiation Oncology,Neurosurgery, Neuroradiology, Neurology ,Pathologyand Molecular Genetics). Following comprehensiveround table discussions and “faculty speaks” wearrived at bottom line conclusions including:(1) Collecting and contemplating 10 year data of ourpatients so that to be incorporated in to the e-dataregistry.(2) Developing the initial format of the electronic dataregistry system for brain tumors in close conformitywith the needs of the Oncology Research Center(ORC), Mashhad Medical University.(3) More engaging experts from allied fields includingPsychiatry, Physical therapy and rehabilitation,Psychology and Nursing.The forthcoming NOSC session will have two mainissues on its agenda:(1) To discuss the preliminary draft of the localguideline (at least to define the diagnosis and referralalgorithm in a real interdisciplinary approach).(2): Having the web based brain tumor data registrysystem launched.

The faculty speaks at NOSC2011 - Mashhad, Iran

Introduction:This session was the first of a kind in our country

having experts from different disciplines involved in themanagements of brain tumors come together. Thisinterval meetings concept was proposed as a form of ascientific club (Neuro-Oncology Scientific Club/NOSC). This club is believed to be a facility to let then e u r o - o n c o l o g y e x p e r t s o f t h e f i e l d(Mashhad-Khorasan Province, Iran) discuss currenttopics in CNS tumors in a round table format andsharing ideas and experiences to more efficientlyapproach brain tumors in daily practice. The Novelty ofthis club is mainly its multidisciplinary character(Fig-1).The prospective aims that the interval meetings of theNOSC is heading for is something more than justhaving ser ies of ta lks and presentat ionscommunicated. Although one of our aims is to sharerecent updates in neuro-oncology, more importantlywe plan to arrive at consensus to develop localguidelines on diagnosis, treatment and follow-up ofCNS tumors through an interdisciplinary viewpoint.NOSC also plans to have all the communicateddiscussions composed as written reports forpublication to seek other domestic or internationalexperts’ comments. The communicated ideas in atransparent atmosphere will let us benefit from thereaders know-hows to improve this practice. This canalso have implications for health policy, practice,research and medical education.We would have the glial brain tumors as our initialfocus, however other kinds of CNS tumors with totallyseparate treatment paradigms can be discussed in ourfollowing sessions in long-term.The other idea is to arrive at the team work spirit inmanagement of CNS tumors. Experts from differentfields not limited to radiation oncology, radiology,neurosurgery, neurology, pathology, psychiatry,physical medicine and rehabilitation and nursing,would be involved to allow their standpoints be appliedin brain tumor patients’ health and quality of life.Consequently, we may be able to capture data fromthe field to form a databank for brain tumor patients in



our province, Khorasan. The data registry can be apivotal tool to design clinical trials and criticalresearches to come into new insights both infundamental and clinical aspects of neuro-oncology inMashhad. We also can work on a tissue bank as aplatform for molecular studies and so on.NOSC tries to stay unbiased when discussingtherapeutic options and other related issues. Allcomments are open to debates with no restrictions.Other than facilitation to run NOSC meeting which isby Behestandarou, NOSC has no conflict of interest todisclose. Having said this, NOSC above all, aims atimproving our brain tumor patients’ health and qualityof life through an interdisciplinary team work.Neuro-Oncology; A decade of experience withchemoradiation and beyond.Reviewing the clinical aspects of high grade gliomatreatment and its standard of care some conceptsworth to re-emphasize. High grad gliomas (HGG)mainly include grade III (anaplastic astrocytoma-AA)and grade IV (glioblastoma multiforme-GBM). GBMconstitute more than 50% of malignant gliomas andgenerally has a poor survival. One third of GBMpatients survive more than a year and only 5% liveover 5 years, while AA patients have a 5 year OverallSurvival (OS) of 27% [1-3]. The prognostic factors inmalignant gliomas which define the outcome includehistologic diagnosis (GBM with the worst prognosisfollowed by AA and other types of malignant glial braintumors), age and performance status (most trials arecarried out on patients with favorable PS) [2].Evidence show that over the past decade theprevalence of these malignant tumors are nearlydoubled. One reason could be a more widely use ofneuro-imaging which results in efficient diagnosis [4].There are two types of GBM: (1) Primary or de-novoGBM which arises from astrocytes within almost 3months in average, (2) secondary GBM whichoriginates from a low-grade astrocytomas. Thistransformation process may take 1-10 years [4, 5].Many molecular studies denote that these two types ofGBM should be considered as separate entities whileothers stress on the commonalities these two typeshave in nature [5].Imaging of GBM represents a distinct feature on MRI.GBM has a ring enhancement with gadolinium as wellas a central hypo-intensity representing necrosis onT1 weighted MRI. In radiation oncology T2 image isthe one used for planning. Since GBM has aninfiltrative nature, tumor cells nested in the edematousarea should be included in radiotherapy field [6].One of the crucial therapies for malignant glioma andGBM in particular is surgery. Surgical removal of thetumor is recommended in many instances and even if

not successful in some cases, can provide adequatetissue for pathologic diagnosis. Patients’ symptomsarising from high ICP and pressure effect of thetumoral mass are improved post surgery. Somestudies postulated the benefit of surgery in survival.Tumor surgery has decreased the need for steroids inthe course of the tumor management [2,7, 8].In a prospective study data showed that surgery vs.biopsy can improve survival. based on this evidence,an optimal resection of the tumor bulk is nowconsidered as an important prognostic factor inpatients’ long-term outcome [9, 10].Due to the infiltrative character of GBM, surgery canhardly result in complete resection of the tumor with norisk of recurrence [8, 9].The other standard treatment of the malignant glialtumor is the external beam radiation which has beenproven to increase survival in prospective randomizedtrials [6, 11]. The conventional dose of radiotherapy isusually 6000 cGy-fraction; 200. All the efforts done todefine new radiotherapy protocols rather than theconventional, have failed to increased survival morethan what is achieved by the conventional RT[6].Methods such as brachytherapy or radiosurgeryboosts have added no value in terms of survivalcompared to conventional protocols of RT, howeverrecent advances in radiotherapy technology andplanning have significantly decreased the neurologicalconsequences caused by irradiation and this hasresulted in more efficient use of radiotherapy [12]. Thesystemic chemotherapy which is initially usedconcurrently with radiotherapy and then continued asadjuvant, had a marginal role before, but recently withthe availability of newer chemotherapeutic agents likeTemozolomide (TMZ), there has been a revolutionizedtrend in using chemotherapy in GBM treatment overthe past decade. Old trials were trying to evaluate theeffect of nitrosurea agents' benefits in improving GBMpatients OS and QOL. Many of these trials showed nosurvival benefit while few indicated minimally addedsurvival rate when nitrosurea regimens were added toRT [13, 14]. The glioma meta-analysis criticallyanalyzing data from 12 trials with cumulative patientnumber of over 3000, reported a 6% increase in oneyear median survival when older chemotherapyregimens were added to RT. Since these data werenot so impressive in terms of OS, other treatmentssuch as local systemic chemotherapies throughimplantation of BCNU wafers were tried. Theseimplants with sustained delivery of the chemo-agentsto tumors were first tried in recurrent GBM cases andwere shown to increase the OS [15]. Applying theseimplants for initially diagnosed GBM patients alsoshowed survival benefits. BCNU wafers were then



approved by FDA. Although these wafers are currentlyused in some centers, there is no global consensus ontheir routine use [16].There might be a need to use thestandard of care chemoradiation with TMZ, so therewill be cautions for TMZ interaction with BCNU. Basedon the above evidence, this protocol is yet far fromstandard in therapeutic decision making. Furthermore,core scientific panels such as NCCN have notrecommended this in high level category. Addition ofTMZ to RT vs. RT alone, gross resection vs. subtotalresection and the use of BCNU wafers could improvepatients' survivals in different levels (Fig-2).Over the recent years, a breakthrough alkylatingchemotherapeutic agent known as TMZ is introduced(Stupp etal. 2005) to be the standard of care regimenfor GBM and refractory AA patients who have afavorable PS and areThe final analysis of this study published in LancetOncology in 2009 reported the 5 year OS of thesepatients to be 10% compared to 2% in RT/TMZ vs. RTalone arm respectively [20].In a sub-analysis performed on the molecular basis ofthe tumor for an enzyme known as Methyl GuanineMethyl Transferase (MGMT), which plays a role inDNA repair, it was shown that positive methylationstatus of this enzyme causes a chemosensitivity toTMZ [20]. Although solid evidence indicate thesignificance of the impact of MGMT methylation statuson OS, current guidelines do not recommend routineassessment of this enzyme’s methylation status ineveryday practice (Fig-3) [18,19,20].There are other agents which are mainly used inrecurrent GBM. Bevacizumab as an anti vascularendothelial growth factor monoclonal anti body (antiVEGF MAb) has been approved for this indicationsince 2009. Other agents which can be used assalvage in recurrent GBM include TMZ, platinumbased regimens, PCV and Irinotecan [21]. There areongoing studies assessing the combination ofbevacizumab and TMZ with radiotherapy in recurrentGBM. Dose dense (21/28) use of low dose TMZ isalso under investigation. These are expected to beintroduced as available options while approachingrecurrent GBM.Frequently faced issues in high grade gliomamanagement. Looking for practical answers.There are consensus and controversies on somefrequently encountered issues while managing braintumors. For many of these questions there is nostraight forward reply or recommendation. In theEORTC-NCIC study by Stupp et al., which resulted indefinition of the standard regimen for the treatment ofGBM (75 mg/m2 daily ,7days per week from the first tothe last day of RT, up to a maximum of 49 days

concomitantly with RT -RT/TMZ-,followed by monthlyadjuvant TMZ -5/28 days- for at least 6 cycles)(Fig-4)[22,23], one critical question can be about theoptimal duration of adjuvant TMZ treatment in GBM.To date, prolonged maintenance therapy with cytotoxicchemotherapeutic agents has not been shown toconfer a benefit in many diseases. In glioma patientseven though no trial has ever been designedspecifically to evaluate the duration of maintenancechemotherapy, the available data with Carmustine(BCNU) or PCV used for up to 12 months failed todemonstrate a significant survival advantage. Thosewho are with the idea of prolonged adjuvantchemotherapy in glioma, depend on the radiologicalresponse however response may also be seen aftertherapy has been discontinued. Stupp et al., who havei n t r o d u c e d t h e s t a n d a r d p r o t o c o l f o rchemoradiotherapy with TMZ, recommend not toexceed 6 maintenance doses [17, 26-30]. This is for anumber of reasons: (1) Although this treatment isusually well tolerated, cumulative bone marrow toxicitymay limit the possibility to administer subsequentsalvage chemotherapy in case of recurrence. (2)There is a theorical risk for development ofmyelodysplastic syndrome or secondary leukemiaafter chronic exposure to TMZ. This is like any otheralkylating agent. (3) Quality of life could be improvedfollowing a treatment free interval (less fatigue forinstance). (4) When adjuvant doses are withheld,patients can have the option of re-exposure to thesame treatment at a later stage. Currently theevidence to let the patients on 12 cycles rather than 6,in adjuvant chemotherapy in GBM is scant [23].Nevertheless and short of class I evidence,prolongation of TMZ maintenance for up to 12 cyclesis exceptionally used for patients who showcontinuous tumor response on MRI and a favorableclinical evolution [23]. Other than the Stupp protocolthere are suggested dose intense regimens whichallow a more intense exposure of the methyldiazonium ion to the DNA to more efficiently methylatethe promoter segment of the MGMT gene. Other thanthe standard adjuvant protocol (5/28d) there arerecommendations for dose intense regimens whichare out lined in the illustration (Fig-5) [26, 31-34].The rationale behind these suggested schedules ismore effective depletion of the repair protein MGMTfollowing the continuous exposure to TMZ. In a phaseII randomized trial by Greek et al., there has been noadded survival benefit of the intensified adjuvant TMZtherapy (150 mg/m2 for 5 days given every 2 weeksinstead of every 4 weeks) over the standard Stuppprotocol compared to RT alone. However cross trialcomparison should be made with caution [17, 27]. In



another ongoing trial the standard dose adjuvant TMZchemotherapy is being compared with a dose-denseregimen (75-100 mg/m2 daily for 21 days in a 28 daycycle). Although this study has reached to initialresults in 1100 patients, the final analysis is pending(EORTC 22033-26033).The main concern following the continuous exposureto TMZ in the induction of profound lymphocytopeniawith decreased CD4 count. Based on the above, theavailable experience does not warrant the use ofalternative TMZ regimens outside the widely acceptedprotocol [23].The next question is to whether administerprophylactic antibiotic for Pneumocystis CariniiPneumonia (PCP) in those receiving TMZchemotherapy. Lymphocytopenia associated withcontinuous exposure to TMZ may enhance the risk foropportunistic infections not limited to PneumocystisPneumonia but Candida, and Listeria specially inpatients receiving corticosteroids concomitantly [35,36].T h e p r o p h y l a x i s i s u s u a l l y w i t hTrimetoprim-Sulfametoxazol 1 tablet three times aweek. Other strategy could be to monitor patients'lymphocytes and CD4 count and to start antibioticsonce the counts dropped below 500 and 300/mm3respectively. There is another crucial question toaddress. Which setting of TMZ included treatment ismore important, concurrent (with RT) or adjuvant?In many of other solid tumors such as non-small celllung cancer, esophageal carcinoma and cervicalcancer, concommittant chemotherapy is shown toimprove outcome. Currently there is no availablereport comparing the privileges of concomitant overadjuvant TMZ and vice versa [37-39].There is an ongoing well designed trial (Van den Bentet al.) evaluating the efficacy of RT alone, concurrentRT/TMZ alone, adjuvant TMZ alone and standardprotocol arms in treating non 1p/19q deletedanaplastic astrocytoma and oligosstrocytoma. Theoutcome of this trial would reply to the above question.For the time being experts recommend to adhere tothe standard protocol without modifications in eitherdose or treatment duration.TMZ was initially studied in recurrent anaplasticastrocytoma and the results of the randomized studiesled to FDA approval for the use of TMZ in thesepatients. TMZ however is not yet studied for use inprimary setting of AA treatment. In a large randomizedtrial by the Medical Research Council (MRC), nobenefit of adjuvant PCV was documented compared toRT alone [40, 41].There are some recent works in place focusing onsome special subgroups of AA (i.e. those withco-deletion of 1p/19q, isocitrate dehydrogenase-IDH1-

mutation) which are shown to have more favorableresponse to therapy.There might raise a question regarding the value ofMGMT methylation status checking in routine practice.In Stupp trial, methylated MGMT was shown todrastically affect survival and treatment outcome ( riskof death was reduced by 55% in 2 years)[20], however,lack of reproducibility when interpreting the test plusinappropriateness of paraffin embedded blocks ratherthan fresh steriotactically obtained samples ,makeroutine evaluation of MGMT of a questionable value.Since currently there is no alternative treatmentavailable for those with unmethylated MGMT, globallyrenowned experts in neuro-oncology do notrecommend routine assessment of MGMT methylationstatus when deciding to treat GBM or recurrent AA.The role of molecular and chemical shift imaging in ourdecision making; the value of MRS.When brain tumors are primarily diagnosed andundergo treatment, the role of imaging will beevaluation of response to treatment vs. relapse. Inmany instances conventional imaging such as MRI isnot conclusive to document or rule out relapse of glialtumors (Fig-6) [42]. One of the applicable imagingmodalities to efficiently differentiate progression frompseudoprogression is Proton Magnetic ResonanceSpectroscopy (1H-MRS). This method can also beused in primary diagnosis of the tumors. MRS outputis a curve graph showing some peaks proportional toconcentration of distinct microelements in an identifiedvoxel [43]. The region of interest in MRI can be furtheranalyzed using these techniques. Since eachpathology changes the metabolites of a distinct regionin a specific way, MRS can be of diagnostic value fortumors, infections, so on [43, 44].MRS may succeed to decrease the need for biopsytaking in the future. That is the difference in protonspin larmor frequency which results in differentchemical signal ing in terms of metabol i teconcentration in MRS [44]. These differences are sosmall (0.0001%) that can be scaled as parts permillion (ppm). On the MRS curve graph horizontal axis,zero is on the right. On the left extreme is the 4 ppmconcentration.Like MRI, proton frequency is the basis for the routineMRS imaging (1H-MRS). MRS protocols which arebased on Na, K, and Ph. are more being used forresearch purposes [44].The micro-metabolites assessed in MRS include water(0-reference), Choline, Creatine, NAA (N-AcetylAspartate). There are few metabolites on MRS curvewhich are of diagnostic value in brain tumors. Theseare NAA (generated by normal neural cells), Choline(represents the cellular turn over. i.e. the higher the



mitosis rate, the higher the choline level is.), Creatine(corresponds to the baseline metabolism of the nervecell ) [44, 45].When imaging for the brain tumors, Choline and NAAare of special note. Increased choline in presence ofdecreased NAA can suggest a tumoral composition ofa point (Fig-7) [45]. Lactate is peaked when there is ananaerobic metabolism and lipid levels are increasedwhen we have necrosis [45]. Having all thesemetabolites assessed and interpreted, a clear pictureof the neurochemical composition of a voxel will be inhand. When at a distinct voxel, Choline in increased,NAA is decreased, Creatine is at mid level, withnoticeable level of lactate, the nectrotic nature of thetumoral tissue at that point is inferred. NAA is a markerfor glial tumors, so if at a given tumoral voxel no NAAis noted, the tumor is most probably non glial [45, 46].One of the cardinal implications for MRS is todifferentiate tumor relapse (true progression) from postradiation necrosis [43]. Normally to detect theprogression we apply Gad-MRI. Areas which areenhanced can represent progression; howeverradiation necrosis can likewise both induce a mass likepicture and enhancement. Currently the best modalityto mark a lesion as true or pseudoprogression of glialbrain tumor is either Positron Emission Tomography(PET) scan or MRS [43, 47] . MRS at thepseudoprogression zone does not show a cholinepeak. To differentiate glial brain tumors frommetastatic lesions following points should be noted: (1)in glioma, Choline spreads outside the enhancementborder. (2) In metastasis, we do not have a NAA peak.(3) Metastatic lesions do not have infiltrative extensionto their surrounding [46, 47].MRS can be done in a multi-voxel fashion, showingwhere we have tumoral infiltration and where we donot. MRS can also be color coded. For instance, therewould be a color mapping to localize where Ch/NAA isincreased (Tumor cells are nested) [47]. To specificallydefine pseudoporogression at a voxel, MRS ispreferred over the diffusion weighted MRI.Based on what stated earlier, in at least two conditionssuch as granulation tissue and radiation necrosis,conventional imaging is not informative enough andmolecular imaging modalities should address theunmet needs.On the bottom line, based on the literature, the mostpreferred methods to differentiate necrosis fromrecurrence are PET and MRS. Other imaging methodseven SPECT have their own shortcomings for thispurpose.There is a growing hope that an interdisciplinarycollaboration and better application of the state-of- the–art molecular imaging would result in better planning

for our brain tumor patients’ diagnostic and therapeuticmeasures.The interplay between neurosurgery, chemoradiationand radiodiagnosticsGetting to know how importantly neurosurgicalintervention may contribute to improving lives of braintumor patients, series of articles were briefly reviewedat NOSC and participants’ opinions were soughtaccordingly. Recent advances in brain surgicalprotocols as well as state-of-the-art functionalneuroimaging techniques such as fMRI hassignificantly contributed to better surgical outcome.Pre-surgical planning for brain tumors using fMRI andDiffusion Tensor Imaging (DTI) has helped todecrease damage to eloquent cortical brain areas (rendering competent higher cortical functions, andcognition) as well as subcortical tracts (playing majorroles in language and motor functions) [48].Efficient tumor resection along with chemoradiationplays a pivotal role in treating brain tumor patients, bywhich patients can experience longer survival andmore acceptable quality of life [20]. However only10-15% of patients may have complete resection andmajority of them have residual tumor and measurabledisease after surgery. For many of high grade gliomasand GBM in particular, radiotherapy (fractionated to60Gy) concurrently with TMZ (Stupp protocol [17]),followed by adjuvant TMZ is considered as thestandard of care. TMZ oral capsules are administeredat the dose of 75 mg/m2 concomitantly with RTforconsecutive 42 days, followed by adjuvant regimen(after 4 weeks of break) at 150-200 mg/m2 dose. Thisprotocol has not only shown to increase the 2 year OSof GBM patients (with WHO PS of 0 or 1 andappropriate hepatic and renal function) by 16% (26%vs.10% in RT/TMZ vs.RT alone arms respectively), butalso resulted in a higher 5 year OS compared to RTalone. A few patients in favorable prognostic categorycan survive longer than 5 years [20]. MGMT statusidentifies patients most likely to benefit from addition ofTMZ.Recursive Partitioning Analysis (RPA) with the EORTCsystem retains its prognostic significance over all aswell as in newly diagnosed GBM patients receiving RTwith or without TMZ. RPA class III patients are definedas those who are young, have intact cognitiveperformance, normal KPS and have experiencedgross tumor resection rather than biopsy only. To sumup what is inferred from the recently publishedevidence:(1) The survival advantages conferred by the additionof TMZ to RT in GBM remain significant and clinicallyrelevant with long-term follow up.(2) Observed a modest but significant proportion of



patients surviving at least 4-5 years with The RT/TMZregimen.(3) Patients in RPA III and with methylated MGMTbenefit most from RT/TMZ regimen.Important safety information for TMZ should be wellknown and observed in practice. These include but notrestricted to hypersensitivity reaction to any of itscomponents or DTIC, myelosuppression includingprolonged pancytopenia which may result in anaplasticanemia. Geriatric patients and women have beenshown in clinical trials to have a higher risk ofdeveloping myelosuppression. TMZ may carry fetalharm when administered to pregnant patients. Cautionshould be practiced when TMZ is administered tothose with severe renal and hepatic impairment. Mostof the constitutional untoward effects of TMZ areconsidered mild to moderate and well manageable.Where we stand with neuro-oncology in Mashhad andwhere we are planning to reach.Reviewing the general status of neuro-oncology inKhorasan province (North eastern Iran) where themeeting experts are currently practicing- below pointswere re-emphasized:The concept of the neuro-oncology working team andjoint clinics should be strengthened in real practice.Brain tumor is the 10th most common amongst allmalignancy types in Iran. In Khorasan province, CNSmalignancies are at the 6th rank. Given theirprevalence, we need to overcome pitfalls andchallenges in diagnosis, treatment and follow up ofthese tumors.The need for molecular and functional imaging,namely MRS, should be re-emphasized and theirapplication must be exercised in our setting whenindicated.Molecular studies in collaboration with molecularpathology experts can be an exciting realm forresearch which we should plan for.Stronger contribution of neurology, psychiatry,pathology, radioisotope, physical therapy,endocrinology and other allied disciplines experts inour future NOSC meetings should be moreencouraged.In relatively less common malignancies like braintumor, the prerequisite for any research is a sounddata registry system which allows data gathering andprocessing. This should be first launched in mainradiation oncology centers which are currently activein the city of Mashhad (Khorasan).NOSC’s first session conclusive remarks followingplenary and round table discussionsThe round table discussions went on to arrive at theconclusions outlined below. This was the groupconsensus of the first NOSC meeting in Mashhad.

A. NOSC, as an initiative step, is believed to be avaluable forum for lining up medium and long-terminterdisciplinary strategies in neuro-oncology.Participants would adhere to its vision throughparticipation in its interval meetings.B. This scientific club not only helps strategizing formaximal outcome in treatment of brain tumors but alsoserves as a scholarly forum which relatedneuro-oncology experts and trainees can benefit.C. NOSC above all aims at improving brain tumorpatients’ health and QOL through an interdisciplinaryteam workD. Other prospective aims that Mashhad NOSCshould be heading for are:1. Sharing updates on neuro-oncology in interval basis.2. Taking steps to define local practice guidelines inneuro-oncology (Interdisciplinary).3. Preparing databank with related tissue repertoire forneuro-oncology studies.4. Establishing a stronger spirit for the team work indiagnosis, treatment and follow-up of brain tumorpatients in khorasan province.5. Publishing the consensus outcome of each meetingin forms of expert opinions or consensus report papersin neuro-oncology literature and web based discussionforums.The panel later proposed to have the next NOSCmeeting in 3 months (Jan 2012).Main items on the following session agenda will be: (1)to discuss the preliminary draft of the local guideline(at least to define the diagnosis and referral algorithmin a real interdisciplinary approach). (2): having theweb based brain tumor data registry system launched.

Acknowledgment

The authors would like to thank medical affairs Behestan darou PJS for for scientific support,preparations and assistance at this meeting. Specialthanks go to Drs P.Dindoust, M.Pesyan,L.Mukhomorova (MSD) for their support.

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Illustrations

Illustration 1

Mashhad NOSC members, 2011

Illustration 2

Addition of TMZ to RT vs. RT alone, gross resection vs. subtotal resection and the use ofBCNU wafers could improve patients’ survivals in different levels. Reproduced from [16].



Illustration 3

Kaplan-Meier estimates of overall survival by MGMT status. Patients with methylated MGMT(A). Patients with unmethylated MGMT (B). Reproduced from [20]

Illustration 4

EORTC/NCIC treatment scheme for glioblastoma . Adapted and reproduced from [24,25].



Illustration 5

Standard and dose-dense temozolomide administration schedules, Adapted from [23].

Illustration 6

Clinical course of pseudoprogression in a 65-year-old patient with glioblastoma. (A)Presurgical MRI scan. (B) Postsurgical MRI scan. (C)MRI scan performed 1 month aftercombined TMZ/RT; adjuvant TMZ was continued. (D) Four months later, during administrationof maintenance TMZ. (E) Eight months later, during administration of maintenance.Reproduced from [23].



Illustration 7

A Normally expected MRS pattern (Right) An increased Ch/NAA ratio at a given point isproportional to tumoral cell composition (Left)



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