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EDITORIAL
Year = :=20 2009  |  Volume : 46  | =20 Issue : 2  |  Page : = 79-81
 

Glioma: A continuing challenge and a = mystery?

D=20 Muzumdar
 Department = of=20 Neurosurgery, Seth Gordhandas Sunderdas Medical, College and = King=20 Edward VII Memorial Hospital, Mumbai, = India

Correspondence = Address:
D=20 Muzumdar
Department of Neurosurgery, Seth Gordhandas = Sunderdas=20 Medical, College and King Edward VII Memorial Hospital, = Mumbai=20
India

Source of Support: None, Conflict of = Interest:=20 None

DOI: 10.4103/0019-509X.49144



How to cite this = article:
Muzumdar=20 D. Glioma: A continuing challenge and a mystery?. = Indian J=20 Cancer 2009;46:79-81



Glioma=20 has no longer remained a primary neurosurgical disease. = Recent=20 advances in diagnostic radiology, neuropathology, and = molecular=20 biology have radically changed the current understanding of = glioma.=20 It is essentially an infiltrative disease. The entire = spectrum of=20 gliomas could be better described as 'Glial infiltrative = disease'=20 (GID). A multidisciplinary approach involving the = neuroradiologist,=20 neuropathologist, radiation oncologist, and medical = oncologist, in=20 the treatment of gliomas, has become the standard of care. = The=20 heterogeneity of gliomas is puzzling and a 'cure' for = gliomas still=20 appears out of sight. Glioma is a heterogenous tumor arising = from=20 the supporting glial cells of the brain and the spinal cord. = Although no underlying cause has been identified for a = majority of=20 malignant gliomas, there appears to be an association = between the=20 immunologic factors, gene polymorphism, and sequential = accumulation=20 of genetic aberrations. It is a genetic disease, the=20 manifestation of which is a function of time and has a = wide=20 range from birth till one becomes old. There is no method as = yet=20 that can predict the time of manifestation of glioma or the = time of=20 transformation of glioma to a higher grade. Usually, in = younger=20 patients it commences as a low-grade tumor and over a period = of time=20 evolves into a higher grade tumor. The eventual fatal = outcome is=20 almost a certainty. The time and rate of transformation into = a=20 higher grade variety is uncertain and unpredictable. They = may also=20 present as primary high -grade gliomas, especially = glioblastomas=20 occurring in patients older than 50 years, and the overall = outcome=20 is guarded in these patients in spite of the intense = treatment=20 protocols. [1] It is well known that the average = age (time=20 for transformation) for a low-grade glioma is about 7 to 10 = years=20 and the life span of a high-grade glioma patient = (glioblastoma=20 multiforme, GBM) is about two to three years, with the best = of=20 treatment protocols.

The major stride in = understanding the=20 gross behavior of glioma has been objectively possible due = to the=20 advances in magnetic resonance (MR) imaging including = special=20 sequences, namely, perfusion studies, functional studies, = and MR=20 spectroscopy. The primary status (low or high grade) of the = glioma,=20 the extent of involvement of the critical neural structures, = the=20 presence or absence of the preoperative seedling of = leptomeninges or=20 ventricles or spread to the spinal canal can be objectively=20 demonstrated. T2 flair studies have been particularly = informative in=20 mapping the extent of the disease. Advances in radiology can = now=20 reasonably distinguish between treatment-related effects, = namely,=20 postoperative changes, radiation-induced change or frank = necrosis=20 and pseudoprogression of disease following temozolomide=20 administration. The treatment paradigms have been = significantly=20 altered on a timely basis due to the significant inputs = obtained=20 from neuroradiology colleagues. The application and = interpretation=20 of neuroradiology advances such as MR spectroscopy and = perfusion=20 studies can sometimes be difficult and no definite = conclusion or=20 concrete recommendation can be derived. A high level of = training and=20 expertise is required to maintain accuracy.

In spite = of the=20 major advances in the field of neurobiology and molecular = genetics,=20 the understanding of the nature and behavior of glioma still = remains=20 a mystery. Consequently, the therapy for glioma presents a=20 continuing challenge for the multidisciplinary team. Precise = neuropathological diagnosis is paramount to achieve optimum = results=20 of the therapy. The neuropathological interpretation can = have=20 interobserver bias and requires skill, expertise, and a good = understanding of the neurobiology of a glioma. A central = review of=20 the pathology is more likely to reduce the bias. = Histological=20 diagnosis is crucial and is the ultimate deciding factor for = the=20 institution of appropriate therapy. It is a formidable = challenge,=20 since with newer advances in immunohistochemistry, the=20 characterization and categorization of glioma have changed,=20 resulting in serial modifications and revision of the WHO=20 classification of gliomas. The World Helath Organaization = (WHO) has=20 coined several newer terminologies for which there are fewer = cases=20 and information in the literature. The decision to reoperate = or=20 observe, to deliver radiation or not or to administer = chemotherapy=20 is entirely dependent on the correct histological diagnosis. = In=20 spite of the advances in immunohistochemistry, the = importance of the=20 Hand E stained slide cannot be underestimated. As advances = in=20 neuropathology unfold, many variations and subtypes of = glioma,=20 whether they are completely benign, intermediate grade or = frankly=20 malignant, have been reported. It is sometimes difficult to=20 differentiate glioma from central nervous system = (CNS)=20 infections and demyelination.

The initial treatment = of a=20 glioma, low or high grade, is essentially surgical. It could = range=20 from a stereotactic biopsy to radical excision depending on = the=20 involvement or proximity to eloquent sites in the brain and = the=20 extent of infiltration. A safe radical excision is the goal. = However, subsequent therapy is largely guided by = neuropathological=20 diagnosis and the clinical neuro-oncologist. Re-exploration = for=20 recurrence of tumor is advocated in some cases, to enhance = the=20 quality of life or as a salvage measure. The modern day = neurosurgeon=20 is blessed to have state-of-the-art neurosurgical = microscopes with=20 neuronavigation compatibility, improved anesthesia = techniques with=20 provision for awake craniotomy, advanced = microinstrumentation,=20 better three dimensional understanding of the microanatomy = of the=20 brain, stereotaxy, functional mapping, and fiber tracking=20 technology. The primary aim of all the advances is directed = at=20 better understanding the pathology and biological behavior = of=20 glioma, thus enabling the surgeon to select the appropriate = surgical=20 strategy, trajectory, approach to the tumor, and = intraoperative=20 decision, to perform surgical excision ranging from biopsy = to=20 complete resection. Unlike surgery for extra-axial brain = tumors like=20 meningioma or neurinoma, intra-axial tumors, especially = gliomas,=20 pose a tremendous challenge for the neurosurgeon. The = surgery for=20 glioma is one of the most difficult neurosurgical problems, = as the=20 tumor cells can imperceptibly blend with the normal = functioning=20 tissue, which may not be appreciable even to the microscopic = eye.=20

Can glioma be completely excised? The so-called = 'complete=20 excision' is suggestive of a gross total excision and not a=20 'radical' excision as the descriptive terminology in cancer = therapy.=20 A 3 cm margin would not be plausible in brain considering = the=20 complex anatomy and eloquent nature of the brain. Since = glioma is=20 essentially an infiltrative disease, a certain component of = the=20 tumor, low grade or high grade, is likely to remain in the = vicinity=20 of the gross bulk of the tumor. The main aim of surgery is = to=20 provide tissue diagnosis and decompression without any = enhanced=20 neurological deficit. Symptomatic relief enhances the = quality of=20 life. The safety of surgery has been improved by advanced=20 neurosurgical technology including neuronavigation, = intraoperative=20 MRI, functional MRI, intraoperative mapping, as well as,=20 fluorescence-guided surgery. The relationship between=20 progression-free survival and the extent of removal of the = glioma=20 has been studied extensively by various groups. However, = there is no=20 general consensus whether the extent of surgical removal of = a glioma=20 significantly enhances the long-term survival of a glioma = patient,=20 but a modest survival advantage is reported. [2] In recurrent malignant gliomas = involving=20 inaccessible and deep-seated areas, 'no further treatment' = is also a=20 good option. In a majority of patients, the primary goal of = surgery=20 has been to relieve the symptoms of raised intracranial = pressure and=20 in turn enhance the quality of life for a short term. =

The=20 cure for glioma is still a distant dream. The behavior of = the glioma=20 cell and molecular genetics is not fully elucidated. The = ultimate=20 answer to glioma treatment ('glioma magic pill') will come = from the=20 geneticist. Till then, the concept of 'curability' from = glioma will=20 be a controversial topic. The overall survival for glioma = has been=20 modest in spite of recent advances in treatment. Glioma stem = cells=20 may contribute to the resistance of malignant gliomas to = standard=20 treatments. [1] The term 'cure' should be = preferably not used=20 in the management of glioma, since the biological behavior = of a=20 glioma is still not fully understood. Radiation and = chemotherapy=20 measures have achieved considerable control rates and modern = techniques have been successful in enhancing the = progression-free=20 survival rate and reducing the treatment-related toxicity to = a=20 certain extent. However, with evidence-based guidelines for=20 treatment of low-grade and high-grade gliomas, new and more=20 challenging issues, such as, radiation-induced necrosis,=20 pseudoprogression following temozolomide administration, and = radiation-induced benign and malignant tumors need to be=20 addressed.

The current standard of therapy for GBM is = inadequate. There is certainly a need for better therapies. = There is=20 a wide heterogenity and complexity in the genetics of = gliomas in=20 general, particularly GBM. [1],[2] Targeted molecular therapies hold = promise for=20 the future. Activation of cell signaling pathways does = matter.=20 [1] However, effectively targeting cell = signaling=20 pathways is not simple. Critical targets exist in the tumor=20 microenvironment and are currently being explored. = Single-agent=20 targeted therapy does not always work and is likely to = evolve=20 resistance. Effective delivery of the targeted therapy is = paramount,=20 which includes adequate intratumoral concentration ensuring=20 confirmed target inhibition. Clinical trials involving=20 antiangiogenic agents that cause inhibition of VGEF and = integrins=20 have shown promising results. Glioblastoma multiforme is = complex=20 tumor to target, and selection of the right patient is vital = for=20 optimizing treatment response. Therapeutic strategies = effectively=20 targeting stem cells and overcoming their resistance to = treatment=20 will be necessary for eradication of malignant gliomas. = [1] The possibility of personalization = of=20 therapy, with better targets using gene-expression = signatures, based=20 on the patient's tumor genotype, also needs to be further=20 explored. [1],[2]

In a country like India, = the majority=20 of the population cannot afford the treatment expense since = there is=20 no standardization in medical insurance policy. With newer = advances=20 in molecular biology and therapeutics and novel drugs being = inducted=20 into clinical practice guidelines and standard of care, the=20 treatment for GBM can be prohibitively expensive, even for = the=20 higher and middle income group families. They would need = active=20 support from nongovernmental social organizations. The = approach to=20 treatment of gliomas should have a philosophical = inclination,=20 primarily involving the patient and the family interests at = the=20 core, since lifelong cure is still not a = certainty.

The=20 glioma patient requires to be treated with passion and care. = The=20 recommendation for treatment should help him lead a good = quality of=20 life. Appropriate measures such as surgery, radiation or=20 chemotherapy should be judiciously utilized. There has to be = a=20 general consensus amongst the neuro-oncology team, = exercising a=20 certain option for a glioma patient in a given clinical = scenario.=20 The spectrum of recommendation may range from observation, = surgery,=20 adjuvant treatment, resurgery or observation and palliative = adjuvant=20 therapy. The recommendations made by specialists should be = according=20 to scientific evidence, but sometimes they are more = influenced by=20 the specialty to which one belongs. [3] The patient and his family should = be apprised=20 about the pros and cons of the treatment and their consent = is=20 necessary. Good education, counseling, and rehabilitation = measures=20 are the key factors. The neurosurgeon's opinion in the = management of=20 complex recurrent or residual malignant gliomas is vital, = since=20 re-exploration has its own risks and potential = complications. The=20 justification for surgical treatment or adjuvant therapy in = small=20 recurrent or residual gliomas, which do not endanger the = quality of=20 life, is still difficult. Although an MR study may suggest a = postoperative or radiation-induced change, pseudoprogression = or=20 recurrence, it is still an evolving subject, with = recommendations=20 being 'suggestive' and may not be necessarily 'definitive'. = The=20 changes seen on radiological imaging should be correlated = with the=20 neurological picture to decide treatment-related issues. = There may=20 be a time when an honest advice of not treating a recurrent=20 high-grade glioma may arise or the patient and / or his = family=20 deferring further treatment needs sympathetic consideration. = The=20 role of the neurosurgeon in the management of gliomas has = been=20 primarily surgical. However, there is need for the present = day=20 neurosurgeon to be literate in molecular biology and = genetics, since=20 his role as a neurosurgeon-scientist, especially in the = basic=20 research on gliomas, is vital.

 
How to cite this = URL:
Muzumdar D.=20 Glioma: A continuing challenge and a mystery?. Indian = J Cancer=20 [serial online] 2009 [cited 2009 May 9];46:79-81. = Available from: http://= www.indianjcancer.com/text.asp?2009/46/2/79/49144
 =BB References   <= IMG=20 alt=3DTop=20 = src=3D"http://www.indianjcancer.com/images/arrow_top.gif"=20 border=3D0>

1. Wen PY, Kesari S. Malignant gliomas in adults. N = Engl J=20 Med 2008;359:492-507.  <= IMG=20 alt=3D"Back to cited text no. 1"=20 = src=3D"http://www.indianjcancer.com/images/ref_top.gif"=20 border=3D0>  [PUBMED]  [FULLTEXT]
2. Sanai N, Berger MS. Glioma extent of resection and = its=20 impact on patient outcome. Neurosurgery=20 2008;62:753-66.  <= IMG=20 alt=3D"Back to cited text no. 2"=20 = src=3D"http://www.indianjcancer.com/images/ref_top.gif"=20 border=3D0>  [PUBMED]  [FULLTEXT]
3. Linskey ME. The emergence of clinical practice = parameter=20 guidelines in neuro-oncology: Promise of utility = tempered with=20 caution. J Neurooncol 2008;89:359-62.  <= IMG=20 alt=3D"Back to cited text no. 3"=20 = src=3D"http://www.indianjcancer.com/images/ref_top.gif"=20 border=3D0>  [PUBMED]  [FULLTEXT]




 

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dotted; BORDER-TOP: #ffffff 3px dotted; = FONT-SIZE: 12px; MARGIN-LEFT: 2px; BORDER-LEFT: #ffffff 3px dotted; = COLOR: #000000; MARGIN-RIGHT: 2px; BORDER-BOTTOM: #ffffff 3px dotted; = FONT-STYLE: italic; FONT-FAMILY: Arial, verdana Helvetica, sans-serif; = BACKGROUND-COLOR: #cdd8ba } .splnote { BORDER-RIGHT: #a6adc4 1px solid; BORDER-TOP: #a6adc4 1px solid; = FONT-SIZE: 11px; BORDER-LEFT: #a6adc4 1px solid; LINE-HEIGHT: 135%; = BORDER-BOTTOM: #a6adc4 1px solid; FONT-FAMILY: Arial, Verdana, = Helvetica, sans-serif; BACKGROUND-COLOR: #e1f3ef } .jh { BACKGROUND-COLOR: #ffffff } .btm { BORDER-TOP: #eaead7 1px solid; BACKGROUND: = url(http://www.indianjcancer.com/images/btm.gif) #eaead7 no-repeat right = top; COLOR: #555555 } .ft { BACKGROUND: url(http://www.indianjcancer.com/images/ft.gif) } ------=_NextPart_000_0000_01C9D094.37562720 Content-Type: application/octet-stream Content-Transfer-Encoding: quoted-printable Content-Location: http://www.indianjcancer.com/templates/layer.js var link=3Dnew Array() var delay_hide=3D500 var menuobj; var menu; var default_menu_item; function lib_bwcheck(){ //Browsercheck (needed) this.ver=3Dnavigator.appVersion this.agent=3Dnavigator.userAgent this.dom=3Ddocument.getElementById?1:0 this.opera5=3Dthis.agent.indexOf("Opera 5")>-1 this.ie5=3D(this.ver.indexOf("MSIE 5")>-1 && this.dom && = !this.opera5)?1:0;=20 this.ie6=3D(this.ver.indexOf("MSIE 6")>-1 && this.dom && = !this.opera5)?1:0; this.ie4=3D(document.all && !this.dom && !this.opera5)?1:0; this.ie=3Dthis.ie4||this.ie5||this.ie6 this.mac=3Dthis.agent.indexOf("Mac")>-1 this.ns6=3D(this.dom && parseInt(this.ver) >=3D 5) ?1:0;=20 this.ns4=3D(document.layers && !this.dom)?1:0; this.bw=3D(this.ie6 || this.ie5 || this.ie4 || this.ns4 || this.ns6 || = this.opera5) return this } var bw=3Dnew lib_bwcheck(); function x(obj,visible) { this.evnt=3Dbw.dom? = document.getElementById(obj):bw.ie4?document.all[obj]:bw.ns4?document.lay= ers[obj]:0; if(!this.evnt) return false this.css=3Dbw.dom||bw.ie4?this.evnt.style:bw.ns4?this.evnt:0;=09 this.wref=3Dbw.dom||bw.ie4?this.evnt:bw.ns4?this.css.document:0;=09 this.css.visibility =3D visible; this.css.width=3D'100%'; } function showHideLayer(obj,visible){ =09 this.evnt=3Dbw.dom? = document.getElementById(obj):bw.ie4?document.all[obj]:bw.ns4?document.lay= ers[obj]:0; if(!this.evnt) return false this.css=3Dbw.dom||bw.ie4?this.evnt.style:bw.ns4?this.evnt:0;=09 this.wref=3Dbw.dom||bw.ie4?this.evnt:bw.ns4?this.css.document:0;=09 this.css.visibility =3D visible; this.css.top=3D'94px'; bw.ns4||bw.ns6?this.css.left=3D'-8px': this.css.left=3D'0px'; this.css.width=3D'100%'; this.css.position=3D"absolute"; } function writeSubmenu(obj,item){ =09 /* this.evnt=3Dbw.dom? = document.getElementById(obj):bw.ie4?document.all[obj]:bw.ns4?document.lay= ers[obj]:0; if(!this.evnt) return false this.css=3Dbw.dom||bw.ie4?this.evnt.style:bw.ns4?this.evnt:0;=09 this.wref=3Dbw.dom||bw.ie4?this.evnt:bw.ns4?this.css.document:0;=09 thecontent=3D(item=3D=3D-1)? "" : link[item] this.wref.innerHTML=3Dthecontent;*/ } function clearContent(obj){=09 =09 this.evnt=3Dbw.dom? = document.getElementById(obj):bw.ie4?document.all[obj]:bw.ns4?document.lay= ers[obj]:0; if(!this.evnt) return false this.css=3Dbw.dom||bw.ie4?this.evnt.style:bw.ns4?this.evnt:0;=09 this.wref=3Dbw.dom||bw.ie4?this.evnt:bw.ns4?this.css.document:0;=09 thecontent=3D(item=3D=3D-1)? "" : link[item] this.wref.innerHTML=3D""; } function clear_delayhide() { alert("asdASD"); if (window.delayhide) {onlpgld(default_menu_item) clearTimeout(delayhide) } } function contains_ns6(a, b)=20 { while (b.parentNode) if ((b =3D b.parentNode) =3D=3D a) return true; return false; } //// function navleftMouseOver(src) {=20 src.className=3D"leftnavcellover" }=20 function navleftMouseOut(src) {=20 src.className=3D"leftnavcell" } function navtabMouseOver(src) {=20 src.className=3D"topBand1MO" }=20 function navtabMouseOut(src) {=20 src.className=3D"topBand2" } //// function navMouseOver(src,item) {=20 src.className=3D"topBand1MO" //writeSubmenu("submenu",item); //showHideLayer("submenu","visible");=09 =09 }=20 function navMouseOut(src,lyr) {=20 src.className=3D"topBand1"; // onlpgld(default_menu_item); =09 } function onload(item) { // writeSubmenu("submenu",item); // showHideLayer("submenu","visible"); =09 } function onlpgld(item) { default_menu_item=3Ditem;=09 writeSubmenu("submenu",item); showHideLayer("submenu","visible"); =09 } function navMouseOversUB(src) {=20 src.className=3D"topBand2MO" }=20 function navMouseOutsUB(src) {=20 src.className=3D"topBand2" } function navMouseBotOut(src) { src.className=3D"leftnavcell" } function navMouseBotOver(src) { src.className=3D"leftnavcellover" } function loadMenu(index) { writeMenu("menu",item); showHideLayer("menu","visible");=09 if (index >=3D 0) { onload(index) =09 } } function showMenu(e,f) { var ie4=3Ddocument.all&&navigator.userAgent.indexOf("Opera")=3D=3D-1 var ns6=3Ddocument.getElementById&&!document.all var ns4=3Ddocument.layers eventX=3Die4? event.clientX : ns6? e.clientX : e.x eventY=3Die4? event.clientY : ns6? e.clientY : e.y var rightedge=3Die4? document.body.clientWidth-eventX : = window.innerWidth-eventX var bottomedge=3Die4? document.body.clientHeight-eventY : = window.innerHeight-eventY var obj=3D"floatmenu"; this.evnt=3Dbw.dom? = document.getElementById(obj):bw.ie4?document.all[obj]:bw.ns4?document.lay= ers[obj]:0; if(!this.evnt) return false this.css=3Dbw.dom||bw.ie4?this.evnt.style:bw.ns4?this.evnt:0;=09 this.wref=3Dbw.dom||bw.ie4?this.evnt:bw.ns4?this.css.document:0;=09 this.css.visibility =3D "visible"; this.css.left=3Die4? document.body.scrollLeft+eventX : ns6? = window.pageXOffset+eventX : eventX if (bottomedge=3D 0 || pg.indexOf('changeaddress') >=3D 0 ) { var attributes =3D 'toolbar=3D0,location=3D0,directories=3D0,status=3D0, = menubar=3D0,scrollbars=3DYes,resizable=3D1,width=3D800,height=3D600,left=3D= 0,top=3D0'; } else { var attributes =3D 'toolbar=3D0,location=3D0,directories=3D0,status=3D0, = menubar=3D0,scrollbars=3D1,resizable=3D1,width=3D600,height=3D400,left=3D= 0,top=3D0'; } sealWin=3Dwindow.open(pg ,'',attributes);=20 self.name =3D pg;=20 } function valfld(field) { var valid =3D "0123456789"; // these are allowed values var ok =3D "yes"; var temp; if (field.value.length =3D=3D 0 ) { //alert("Invalid entry! please enter number"); field.value =3D "" field.focus(); field.select(); return false;=09 } for (var i=3D0; i'; t+=3D''; for(i=3D0;i'; } t+=3D''; document.write(t); var = bA=3D(ie)?document.all['blocks'+N]:document.getElementById('blocks'+N); bA.bar=3D(ie)?document.all['_xpbar'+N]:document.getElementById('_xpbar'+N= ); bA.blocks=3Dblocks; bA.N=3DN; bA.w=3Dw; bA.h=3Dh; bA.speed=3Dspeed; bA.ctr=3D0; bA.count=3Dcount; bA.action=3Daction; bA.togglePause=3DtogglePause; bA.showBar=3Dfunction(){ this.bar.style.visibility=3D"visible"; } bA.hideBar=3Dfunction(){ this.bar.style.visibility=3D"hidden"; } bA.tid=3DsetInterval('startBar('+N+')',speed); return bA; }} function startBar(bn){ var = t=3D(ie)?document.all['blocks'+bn]:document.getElementById('blocks'+bn); if(parseInt(t.style.left)+t.h+1-(t.blocks*t.h+t.blocks)>t.w){ t.style.left=3D-(t.h*2+1)+'px'; t.ctr++; if(t.ctr>=3Dt.count){ eval(t.action); t.ctr=3D0; }}else t.style.left=3D(parseInt(t.style.left)+t.h+1)+'px'; } function togglePause(){ if(this.tid=3D=3D0){ this.tid=3DsetInterval('startBar('+this.N+')',this.speed); }else{ clearInterval(this.tid); this.tid=3D0; }} function togglePause(){ if(this.tid=3D=3D0){ this.tid=3DsetInterval('startBar('+this.N+')',this.speed); }else{ clearInterval(this.tid); this.tid=3D0; }} document.write('