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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