Download - Advances in Clinical Neuroscience and Rehabilitation

More documents

Recommendations

Info

N E U RO S U RG E RY A RT I C L ETable 1: Differences between Primary and Secondary GBM’sPRIMARY (de novo)SECONDARYDefinition No clinical or pathological evidence of pre-existing lesion Malignant progression from lower grade tumourAge Typically older (mean 55 years) Typically younger < 45yrsGenetics Early EGFR overexpression Early p53 mutation and PDGF overexpression.V early IDH-1 mutationClinical Probably worse outcome Better survival (esp. if IDH-1 mutation)involving younger patients with a variableinterval between 1 to 10 years.Large numbers of genetic abnormalities havebeen found in gliomas. These genetic abnormalitiesincrease as the grade of glioma increases.Most of these abnormalities affect entry into cellcycle or inhibit apoptosis via multiple pathways,which is discussed in depth elsewhere. 36Recent data from the Cancer GenomeProject suggests genetic abnormalities canclassify GBM’s into four categories 37 :• CLASSICAL – amplification of EGFR• MESENCHYMAL – NF1 deletion• PRONEURAL – mutations of PDGFR-A andIDH-1• NEURAL – expressed neuronal markersThe proneural group showed improvedsurvival, but interestingly showed no survivaladvantage with chemoradiotherapy vs. radiotherapyalone. Further work is underway tounderstand the significance of this classificationfor individual patients.ManagementHGGs are best managed using a multi-disciplinaryteam (MDT) approach. Options formanagement span the spectrum from conservativetreatment, to surgery and adjuvanttherapy. The main thrust of management is diagnosisand prolongation of progression freesurvival.Dexamethasone is vitally important incontrolling cerebral oedema associated withtumours. The response to steroids can beextremely rapid. Failure to improve withsteroids suggests radical surgical resectionmay cause a worsening neurological deficit. 38The role of steroids, their complications anddosing in neuro-oncology has been recentlyreviewed elsewhere. 39Conservative management is a valid optionin patients with a poor prognosis as identifiedby age and poor performance status. In thissituation good palliative and supportive care isimportant.SurgerySurgery ranges from diagnostic biopsy toFigure 4: An intra-operative image of a resection of aglioblastoma under white light (upper panel) and blue light(bottom panel) after administration of 5-ALA. With bluelight the tumour can be seen as pink fluorescence in anarea that looked relatively normal with white light.debulking to gross total resection.1. Tumour BiopsyBiopsies are minimally invasive, well toleratedand suitable for lesions of any site or size.Biopsy is usually considered when the risks ofresection outweigh the benefit. 40 It is bestutilised in cases where initial diagnosis mayinfluence subsequent management. However,it has its pitfalls in the form of sampling errorespecially in small or heterogeneous samples.To reduce the risk of non-diagnostic biopsies,image-guidance is routinely used to guidebiopsies.2. Tumour ResectionDebulking surgery is beneficial in reducingthe tumour load and thus the side effects ofraised intracranial pressure and providing amore representative histological sample.Whether it provides an improvement insurvival is controversial. The Cochrane reviewof the literature has highlighted the lack ofquality studies in this area. 41 Retrospectivestudies have suggested that gross total resectionas defined by post operative MRI findingsof more than 98% tumour resection, has shownbetter quality of life and progression freesurvival. 42 The median survival, according toone study, improved from 8 months forsubtotal resection to 13 months after grosstotal resection (GTR). 43 This was reconfirmedby Pichlmeier et al whose RPA analysisrevealed survival benefit was greatest inpatients with higher RPA scores (i.e moresevere baseline disease based on age, performancestatus, neurology and mental status). Themedian survival for GTR vs incomplete resectionwas 17.7 vs 12.9 months for RPA IV and13.7 vs 10.4 months for RPA V. 44 The problemwith GTR remains balancing maximal resectionagainst potential neurological deficits.5-ALA is a new surgical adjuvant used toidentify glioma tissue under blue light (seeFigure 4). 5-ALA is taken up and is convertedin the normal heme biosynthesis pathway. Intumours there is a deficiency of theferrochelatase enzyme that leads to the accumulationof the fluorophore protoporphyrin IXthat fluoresces under blue light. The use of 5-ALA enables more complete resections ofcontrast enhancing tumour, leading toimproved progression free survival in patientswith malignant glioma. Stummer et al showeda 29% increase in complete resections rates inthe 5-ALA group as opposed to the white lightgroup. The 5-ALA group also had a higher 6-month progression free survival than the whitelight group (41% vs 21.1%). 45Another adjuvant to surgery has been localtherapy with BCNU loaded wafers. Thesewafers provide a method of local delivery ofhigh concentration chemotherapeutic agentbypassing the blood brain barrier. The use ofthese agents remain controversial though, asquestions have been raised about their efficacyas well as side effects including CNS andwound infection rates as high as 28%. 46,47However, there is substantial evidence for theuse of BCNU wafers in adjuvant treatment. Aretrospective review on BCNU wafer implanta-MGMT methylation and mutation of the IDH-1 gene are both prognostic factorsassociated with better progression free survival and long term outcome26 > ACNR > VOLUME 12 NUMBER 4 > SEPTEMBER/OCTOBER 2012
N E U RO S U RG E RY A RT I C L ETable 2 Recursive partitioning analysis (RPA) of GBM survival based on Karnofsky performance status (KPS), the age of the patient, and treatment 53RPA class Definition Historical Median Survival Time Historical 1-Year SurvivalIII Age < 50, KPS ≥ 90 17.1 months 70%IV Age < 50, KPS < 90Age > 50, KPS ≥ 70, surgical removal with good neurologic function 11.2 months 46%V + VIAge ≥ 50, KPS ≥ 70, surgical removal with poor neurologic functionAge ≥ 50, KPS ≥ 70, no surgical removal 7.5 months 28%Age ≥ 50, KPS < 70Figure 5: An example of radiotherapy treatment volumes.The enhancing tumour is outlined as the gross tumourvolume (GTV). A 2.5cm margin is then applied to accountfor the infiltrating margin and is referred to as the clinicaltarget volume (CTV). A further 0.5 cm margin for set uperror is then applied, the patient target volume (PTV). Theareas outside the GTV will include normal brain at risk ofradiation injury. (Picture courtesy of Dr Neil Burnet,Addenbrooke’s Hospital, Cambridge).tion in combination with TMZ and radiotherapyin newly diagnosed GBM revealed amedian survival of 20.7 months with a twoyear median survival of 36%. 48RadiotherapyRadiotherapy has been the mainstay of adjuvanttherapy for high grade gliomas sincemultiple studies from the 1970s showed asurvival benefit. 49 However, attempts toimprove on the initial benefits by increasingdosage of radiation has failed to have anysuccess. Unfortunately the therapeuticwindow for radiotherapy to the brain is narrowand there is an increased incidence of radiationnecrosis with increased radiation dose.Part of the reason for this is the inability ofconventional imaging to identify infiltratingtumour. As a result radiotherapy planningoutlines the obvious tumour as the GrossTumour Volume (GTV). A 2.5cm margin isthen applied to form the Clinical TargetVolume (CTV). A 0.5cm margin is added toaccount for set up errors and patient movementto form the Planning Target Volume(PTV). In other words, a 3cm margin is appliedaround the tumour that will contain normalbrain. To reduce the risk of radiation necrosisthe dose is therefore limited (see Figure 5).Figure 6: An example of pseudoprogression in a patient with a glioblastoma being treated with concomitant Temozolomide andradiotherapy. Before starting the adjuvant phase the tumour appears to have enlarged in size. This is not true progression butpseudoprogression as continuation of adjuvant Temozolomide shows excellent response after two more cycles.Although various radiotherapy regimeshave been proposed, traditionally two areused in HGG:1. Radical radiotherapy: gives 60 Gy doseover 30 daily fractions.2. Short Course/Palliative Radiotherapy:gives 30 Gy over two weeks in six fractions.As there is little planning patients can starttreatment very quickly and it is well tolerated.It is useful where patients are acutelydeteriorating.Cytotoxic ChemotherapyPCV was the standard adjuvant chemotherapeuticregime in use until the advent ofTemozolomide. PCV is nitrosurea basedchemotherapy providing a small survivalbenefit; a 5% increase in two year survivalrates. 50 The treatment involves a 10 day oralcourse of procarbazine, a single oral dose ofCCNU and a single intravenous infusion ofvincristine given in six weekly cycles.The introduction of Temozolomide hasprovided some improvement in survival. It isgiven orally over five consecutive days within a28 day cycle. Leucopenia and thrombocytopeniaare commonly associated side effectsof this treatment. The combination of radicalradiotherapy and daily, concomitantTemozolomide followed by six cycles of adjuvantTemozolomide has significantly alteredthe prognosis of GBM. Stupp et al. in a multicentretrial showed that at a median follow upof 28 months, the median survival was 14.6months in radiotherapy plus TMZ group ascompared to 12.1 months with radiotherapyalone. The two year survival rate was 26.5% vs10.4% while a five year review of the samepopulation has revealed 9.8% survival at fiveyears in the TMZ group compared to 1.9% inthe radiotherapy group. 29 This represents asignificant advance over previous survivalstatistics in high grade glioma. The MGMTstatus was found to be the single most importantpredictive factor for a favourableoutcome.It is now well recognised that MR appearancesimmediately after chemoradiotherapycan show apparent progression of disease–22% of patients in the study reported by Stuppet al did not receive the adjuvantchemotherapy phase due to presumed tumourprogression. Subsequent imaging shows thatthese changes either stabilise or improve. Thispseudoprogression is more commonly seen inpatients with methylated MGMT and is thoughtto represent a good prognostic sign of responseto therapy (see Figure 6).Treatment at Tumour ProgressionDespite the best management, virtually allpatients with HGG will develop recurrence oftumour at some point. Salvage therapies maybe considered depending on the patient’s clinicalcondition. These may include:1. Surgery: Re-operation is associated withhigher morbidity and mortality than for theoriginal operation. However, it is an optionin patients with a long progression freesurvival who have tumour that is maximallyresectable. Insertion of carmustinewafers at this stage has been shown toimprove survival. 512. Radiotherapy: There has been somesuggestion that the toxicity of re-irradiationhas been overestimated. Re-irradiation isACNR > VOLUME 12 NUMBER 4 > SEPTEMBER/OCTOBER 2012 > 27
Page 1: ISSN 1473-9348 VOLUME 12 ISSUE 4 SE
Page 4: F RO M T H E E D I TO R ...Martin T
Page 7 and 8: An element of changeA first-in-clas
Page 9 and 10: At the centre of managing epilepsy
Page 11 and 12: R E V I E W A RT I C L ELeft panel:
Page 13 and 14: R E V I E W A RT I C L EFigure 1: H
Page 15 and 16: S P E C I A L F E AT U R EThe EuroI
Page 17 and 18: R E H A B I L I TAT I O N A RT I C
Page 19 and 20: R E H A B I L I TAT I O N A RT I C
Page 21 and 22: N E U RO LO GY I N A RTAn Artist’
Page 23 and 24: NEUROSCIENCE NURSING FEATUREClinica
Page 25: N E U RO S U RG E RY A RT I C L Emu
Page 29 and 30: C O N F E R E N C E R E P O RT S39.
Page 31 and 32: C O N F E R E N C E R E P O RT SABN
Page 33 and 34: C O N F E R E N C E R E P O RT SThe
Page 35 and 36: Neuroradiology and Functional Neuro
Page 37 and 38: J O U R N A L R E V I E W SEditor
Page 39 and 40: N E W S R E V I E WFujifilm support

Download - Advances in Clinical Neuroscience and Rehabilitation

You also want an ePaper? Increase the reach of your titles

Delete template?

Save as template?