Heesters, Martinus Adrianus Adolf Marie

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   University of GroningenRadiotherapy of brain gliomas. Diagnostic and therapeutic aspects.Heesters, Martinus Adrianus Adolf MarieIMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2001Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Heesters, M. A. A. M. (2001). Radiotherapy of brain gliomas. Diagnostic and therapeutic aspects. s.n.CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 07-06-2022SummaryWhen deep X-ray therapy became available it soon was used in the treatment ofsupratentorial gliomas. Presumably because surgely alone was a disappointingventure in high grade gliomas as the glioma rapidly recurred even after majorresections and because of the general notion of the effectivity of X-ray therapy inthe treatment of cancer. At the end of the 1970s and the beginning of the 1980s anumber of important advances took place lvhich form the basis of modernradiotherapy for gliomas. In the first place the technological improvement in thetools of radiotherapy as the introduction of computer technology with CTscanning, high energy radiation, computerized treatment planning which allowedfor accurate and reproducible treatment. Secondly, randonrized trials proved tlrevalue of radiotherapy in GBM by prolonging survival. In the third place theintroduction of histopathological classification systems such as the WHO systemresulted in the identification of groups of gliomas with different genesis andprognosis in which the role of radiotherapy was different.It was with basically these tools and knowledge that supratentorial gliomas weretreated since the end of the 1970s up until the present day. In this thesis theimpact on radiotherapy of several new developments in diagnostic andtherapeutic possibilities were studied.In chapter I a large patient series (n:839) with a supratentorial glioma treated inGroningen in the period 1979 until 1999 is analysed in relation to radiotherapy.The primary feature of the analysis is the histopathologic grading andclassification. It provides the most imporlant prognostic factor for survival and itdetermines the indication and outcome of radiotherapy. However otherprognostic factors also influence treatment decisions regarding radiotherapy suchas age and performance of the patient . To some extent these prognostic factorsare related to each other. In general low grade gliomas occur in younger patientsand the high grade gliomas in older patients. 'fherefore after histopathologicgrading age has lost some of its prognostic value. In the literature of the gliomathe role of radiotherapy is separately analysed for each histopathologic category.Therefore the same approach was follorved in this analysis.In GBM the place of radiotherapy is best documented. It doubles the MST withan optimum dose of 60 Gy in 6 weeks local field inadiation and is the standardtherapy after surgery. However radiotherapy in GBM is selectively applied inpatients with the best performance. In Groningen radiotherapy was applied in themajority of GBM patients excluding those with poor performance. Recentlyselection factors were used involving the introduction of short fractionationschemes e.g. l5 x 3 Gy with the reduction of overall treatment time of 3 weeksfor patients with less favourable prognostic factors such as age > 50 years andKarnovsky performance < 70.Presently in A there is no evidence that radiotherapy prolongs survival.Therefore in prognostically favourable patients with young age and goodperfonlance radiotherapy is withheld. ln symptomatic pal ients or in recurentt 38gliomas radiotherapy is applied also as a consequence of lack of therapeuticalternatives besides surgery and the evidence that A may respond to radiotherapy.In Groningen radiotherapy was widely applied in A although the timing ofradiotherapy was not evaluated (immediately after first surgery or afterrecurrence).Technological improvements in radiotherapy did not improve survival in glioma.This probably means that technically more precise radiotherapy does not affectlocal control in glioma as long as the biological effectiveness of radiotherapy isunchanged. However radiotherapy dose reduction to normal brain tissue likelyhas reduced radiation induced brain damage which is of benefit to patients with alonger survival.The problem in grading the astrocytic tumours is reflected in the definition of theAA and consequently also the role of radiotherapy. AA are treated as GBMalthough no separate data on the effectiveness of radiotherapy in AA exists.Histopathologically the AA cannot be sharply demarcated from A. This impliesthat some long term surviving AA patients are incorrectly graded A. In thesepatients the application of high dose (60 Gy) irradiation after surgery is of noproven value. The appearance of an oligodendroglial component in a gliomawhether in case of a pure O or as a component in an A implies a better prognosisin comparison with the pure astrocytic tumours of corresponding grade ofmalignancy. Because these tumours are less frequent than A, the O tend to beincluded in low grade glioma sflrdies and AO in high grade glioma studies.Therefore evidence regarding the role ofradiotherapy in O is lacking. In generalthe same treatment approach is followed in O as in the astrocytic tumours ofcorresponding grade of malignancy. As O are biologically different from A withrespect to chemosensitivity, genetically and possibly radiosensitivity, separatestudies of O are needed in which the role of radiotheraov is defined.Further refinements of the classification and grading system came from tumourkinetic studies. Tumour growth rate depends on the balance of cell proliferationand cell death. The proliferation rate was studied by MIB-1 which is an antibodyagainst Ki-67 expressing non-G0 cells. This MIB-l labelling was possible onarchival paraffin embedded material allowing for large retrospective studies. Therate of cell death or apoptosis can also be measured on archival material usingTUNEL labelling, In chapter 2 both MIB-l labelling index and TLNEL labellingindex were used in a large retrospective patient series to assess their prognosticvalue. These indices were used within the current WHO classification system andnot as a substitute for classification and grading. Proliferation and apoptosis wereassessed within each histopathological category. It was found that the apoptoticrate appeared to be associated with the proliferation rate and was not anindependent prognostic marker. For radiotherapy purposes the relevantdistinction between A and AA is improved by using MIB-I. However from abiological point of view the distinction between A and AA is somewhat artificialas gliomas are regionally heterogeneous implying that the piece of tissue studiedmight not be representative for the tumour as a whole and in the course of timethe low grade glioma has a tendency to progress to higher grades of malignancy.1 3 9Another aspect concerns the oligodendroglial tumours with a higher proliferationrate compared to the astrocytic tumours although they had a better prognosis.This apparent discrepancy was already known in the concept that the number ofmitosis was of minor prognostic value in O. This points again to a differentbiology of oligodendroglial tumours and increases the uncertainty regarding therole of radiotherapy.With immunohistochemical analysis of protein products the activity of genesinvolved in the regulation of proliferation and apoptosis can be investigated. Inchapter 3 some of these proteins are studied in relation to the outcome ofradiotherapy. Some patients with a low grade glioma experience a long termrecurrence free survival (ttO years) and it was shown that the gliomas in thesecases had a low MIB-LI with low p53 protein expression possibly indicating non-mutated IP5-1. TP53 plays a central role in regulating cell proliferation ,differentiation , DNA repair and apoptosis. Mutations in TP 53 are stronglyassociated with progression of A to high grade astrocytomas. It is possible that inA low p53 immunoreactivity is associated with non-mutated TP 53 and isaccompanied by a low tendency to increase proliferation and progression rates.This is reflected by the low MIB LI and the long term progression free survivalfound in these tumours. These results further suggest that deregulation ofproliferation is the hallmark of glioma progression. The protein expression of thegenes involved in the apoptotic process did not differ between recurrent and non-recurring A. This suggests that the regulation of these apoptotic processes is notprimarily involved in glioma progression.In oligodendroglial tumours it is expected that O with detectable p53immunoreactivity progress more rapidly to a higher grade of malignancy.However, mutations in TP 53 are less frequent than in A. The analysis of pairs ofprimary and recurrent low grade gliomas showed an increase in proliferationparameters in the recurrent tumour compared to its primary. This is in accordancewith the progression in malignancy of low grade gliomas. However this studysuggest that radiotherapy plays no role in this process It may be hypothesizedthat some low grade gliomas are programmed to long term survival with orwithout radiotherapy and radiotherapy if applied does not increase proliferationand apoptosis in the recurrent tumour.Radiotherapy does not "cure" glioma but radiotherapy certainly delays tumourprogression by reducing tumour size and prolonging survival in GBM. Toachieve this goal radiotherapy has to be directed to the central tumour mass only,without the need to encompass all areas of tumour cell invasion. New imagingmodalities have been introduced. MRI with its superior soft tissue contrast and 3-dimensional depiction resulted in improved imaging of the glioma. Theconsequence of MRI for radiotherapy treatment planning was investigated inchapter 4. If the glioma showed no contrast enhancement e.g. in case of a lowgrade glioma, the observers had to rely on minor changes in density when usingCT. This leads to greater interobserver variation than when in the use of MRI T2weighted images for radiotherapy treatment field design. As the MRI T2 high140signal area encompasses the fumour area and because from within this region thelow grade glioma will progress it follows that in case of a non-contrast enhancingglioma MRI should be used lbr radiotherapy treatment planrring.Other new imaging modalities include PET and MRSI. In chapter 5 the IHspectroscopic imaging is introduced featuring some metabolic characteristics ofthe glioma. In the central tumour mass the NAA (parameter of functionalneurones) is depressed consistent with neuronal loss and replaced by an increaseof choline. Choline reflects the increased phosphocholine turnover in relation tomembrane biosynthesis of proliferating cells. Lactate was also found in somegliomas reflecting increased glycolysis which is a feature of the metabolism ofmalignant cells. Horvever, with the spectroscopic technique used, the lactatepeaks cannot be fully discriminated from free fatty acids.In chapter 6 tyrosine PET is validated as a method to visualize and quantifyprotein synthesis of the glioma. Regardless of the malignancy grade the gliomaexhibits an increased protein synthesis which can be measured with tyrosinePET. tn some cases the area of increased choline depicted with MRSI seemed toconelate with the area of increased PSR both indicatins the location of vitaltumour tissue.After radiotherapy the glioma will progress from within 2.5 cm of the outer rimof the contrast enhancing region in case of a GBM and from within the MRI T2region in case of a low grade glioma. Therefore using MRI and CT is adequatefor the purpose of treatment field design whereas metabolic imaging either withPET or MRSI is of no practical consequence for this purpose. On the other hand,PET and MRSI can be used for monitoring the radiotherapy treatment responseas CT and MRI cannot discriminate vital tumour from necrotic tumour tissue,radiation induced brain damage or effects of surgery. In chapter 7 protonspectroscopic imaging (MRSI) was used to monitor the response on radiotherapyof brain gliomas. To be certain that a true response of tumour metabolism wasmeasured only biopsied gliomas were investigated. Metabolic responses found inseveral gliomas were the decrease of choline and lactate was accompanied by ashrinkage of tumour diameter on MRI. In case of low grade gliomas this adds tothe evidence that although radiotherapy has no clear effect on survival it mayinduce tumour regression and tumour devitalization. The solid tumour mass ofthe glioma irreversibly has destroyed the existing brain parenchyma which isindicated by the irreversibly decreased NAA.With longer follow-up studies supported by histopathological verification thevalue of metabolic imaging could be further improved although in the case of abrain tumour the taking of multiple biopsies in time is a difficult aim to tealize.However, comparison of proton spectroscopy with histopathology has beenr41performed in other studies in the case of differentiating radionecrosis fromrecurrent brain glioma. Proton spectroscopy proved a useful tool for this purpose.In chapter 8 the response to radiotherapy in glioma was monitored with the useof tyrosine PET. The advantage of using tyrosine is the capacity to calculate thetrue PSR of the glioma before and after radiotherapy. The main results wereagain the response on radiotherapy of the volume of increased tyrosine uptakewith no decrease of the PSR in the remaining tumour. This probably means thatradiotherapy does not completely devitalize the glioma although it can inducetumour regression.ConclusiortsIn this thesis the radiotherapy of patients with brain gliomas is studied from aclinical point of view. Historically, radiotherapy was used as a treatmentmodality for these incurable tumours even before the evidence came out of thesurvival benefit for GBM patients with radiotherapy and before the introductionof "computerized radiotherapy" with treatment planning, CT imaging and highenergy inadiation. Using these modern techniques two decades of radiotherapyfor glioma in Groningen were studied establishing the well known prognosticfactors for survival with histopathologic classification and grading as the mostimportant. Therefore the role of radiotherapy had to be studied for eachhistopathological category. Radiotherapy definitely improves survival in GBMalthough for the other histopathological categories the survival benefit is notproved. The lack of a curatjve opportunity with radiotherapy leads to the clinicalpolicy of withholding radiotherapy in patients with a poor performance and inlow grade glioma patients with prognostically favourable factors to avoidradiation-induced brain damage. The use of a grading system in astrocytictumours implies an uncertainty in the discrin,ination between A and AA whichhas its consequence for the indication of radiotherapy. In this field the mainadvantage of the use of proliferation markers e.g. the MIB-LI has beendemonstrated.This study emphasizes the importance of the proiiferation rate and not theapoptotic rate for the discrimination between high and low grade gliomas and theidentification of long term recurrence free gliomas. The p53 protein has a role inthe control of proliferation and apoptosis. This study suggests that long termprognosis in glioma depends on a norynal functioning of TP53 implying acontrolled low proliferation rate. Apoptosis does not seem to play a role.Furthermore this study suggests that radiotherapy does not influence changes inproliferation or apoptosis in recurrent low grade gliomas. New imagingmodalities changed the practice of radiotherapy but do not affect prognosis. MRIis to be preferred in the target definition of low grade gliomas. Metabolic imagingwith MRSI or tyrosine PET can be used to monitor radiotherapy response of theglioma but persistently shows increased metabolism which indicates vital tumourtissue surviving radiotherapy.142PerspectivesMolecular biology and genetics will provide new prognostic factors, refinementof the classification and grading system and predictive testing for planning oftreatment strategies. Some examples are the prognostic value of MIB-1 and p53as outiined in this thesis. Another example is the chromosomal aberration in lpand 19q predicting the response to chemotherapy in O.New conformal radiotherapy techniques with intensity modulated radiotherapy(IMRT), stereotactic conformal radiotherapy (SCRT) or proton therapy may beused in reduction of radiotherapy dose to certain eloquent brain areas possiblyleading to a decrease in radiation induced brain damage. An example is theavoidance of the brain areas containing proliferating and apoptosis sensitive stemcells e.g. the forebrain subependyma nd the dentate gyrus of hippocampus.New neuronavigation techniques in neurosurgery correlate the position ofneurosurgicai equipment during operation to its corresponding site on brainimages. This will allow a correlation between the site of tumour sampling onimaging with histopathology. This implies an integration of imaging andpathology reducing the problem of tumour heterogeneity. If this will be extendedto correlate metabolic imaging with histopathology new avenues will be openedin efforts to escalate the radiotherapy dose to areas of persistent vital tumourtissue. If these areas are smali enough no symptomatic radionecrosis is to beexpected obviating the need of repeated surgery. The idea of dose escalationwith IMRT, SCRT, proton therapy or radiosurgery is based on the concept of aspatial discrimination between the tumour and normal tissue. Although thisapproach will not cure the glioma because of the clonogenicity of the tumourcells widely invading into functional brain parenchyma. However, a meaningfulincrease in survival may be expected. To cure the glioma the therapy inevitablyhas to be directed to these migrating tumour cells. Recently this was attempted byusing neural stem cells. In a mouse model neural stem cells were engineered toproduce the therapeutic immunomodulator interleukin-4. After injection intobrain these therapeutic cells may travel along the white matter and potentiallytarget the brain invading neoplastic cells (Benetletti 5.,Pirola 8., Pollo 8., Mttgrassi L.,Crazia M., Rigamonti D. Cene therapy of etperimental brain tumors using neural progenitor cells.Nature Med. vol 6 aprit 2000 . 447-450). Perhaps some of these techniques can be furtherdeveloped to sensitize the invading tumour cells to low dose radiotherapy.t43

Radiotherapy of brain gliomas. Diagnostic and therapeutic aspects.

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Radiotherapy of brain gliomas. Diagnostic and therapeutic aspects.

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