THE PRESENT AND FUTURE MANAGEMENT OF MALIGNANT BRAIN TUMOURS: SURGERY, RADIOTHERAPY, CHEMOTHERAPY

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1 ii24 THE PRESENT AND FUTURE MANAGEMENT OF MALIGNANT BRAIN TUMOURS: SURGERY, RADIOTHERAPY, CHEMOTHERAPY See end of artile for authors affiliations Correspondene to: Professor R Rampling, Western Infirmary, Dumbarton Road, Glasgow G11 6NT; r.rampling@udf.gla.a.uk W R Rampling, A James, V Papanastassiou J Neurol Neurosurg Psyhiatry 2004; 75(Suppl II):ii24 ii30. doi: /jnnp hile the majority of malignant brain tumours remain ultimately inurable, a variety of intermediate outomes is nevertheless possible, depending on histologial tumour type and grade. A ommon treatment strategy obtains for most malignant brain tumours. Surgery followed by radiotherapy are the major treatment modalities, while hemotherapy provides adjuvant and palliative support. The most exiting areas of advane lie in the geneti targeting of onventional treatments and in applying biotherapies and agents speifially direted at moleular targets within the ell. We desribe the urrent status and future prospets for eah of these modalities. SURGERY Gliomas are the most frequently diagnosed lass of primary malignant brain tumour. Sine these tumours are inurable, the main emphasis is on symptom alleviation and prolongation of survival. In this ontext, neurosurgery has the distint but interrelated aims of providing histologial diagnosis, ytoredution, symptomati relief, and loal delivery of adjuvant therapy. 1 2 The surgial priniples used in managing other malignant tumours are similar, though in some for example, medulloblastoma extensive ytoredution may ontribute to ure. Histologial diagnosis In the great majority of ases of patients with newly diagnosed brain tumour it is imperative to obtain a preise histologial diagnosis. Guidane on prognosis, deisions on further management and patient ounselling will depend on the histologial type and grade of the lesion. It is important to ensure that the tissue samples on whih the final diagnosis is based are as representative as possible of the tumour as a whole. The diagnosti auray of various biopsy proedures depends on the amount of tissue obtained and the aurate targeting of areas of high diagnosti yield. This an be ahieved from an open biopsy or by a radiologially guided, stereotati proedure. To aquire a stereotati biopsy a rigid frame is attahed to the patient s head as an external oordinate referene system. Various imaging modalities (mainly omputed tomography (CT) but also magneti resonane imaging (MRI), positron emission tomography (PET), and single photon emission omputed tomography (SPECT)) an be integrated to produe biopsy target oordinates. This tehnique presently represents the gold standard as it ombines auray with a relatively low morbidity. Diagnosti pitfalls remain in tumours with pronouned heterogeneity or where small foi of high grade transformation exist in the bakground of a largely low grade lesion. In suh ases, onsideration should be given either to aquiring several target oordinates from various areas or to employing a more extensive approah, suh as raniotomy and open biopsy. Cytoredution A number of non-randomised studies and one prospetive trial have shown improved survival in patients undergoing raniotomy and resetion as ompared with those having a biopsy only. However, whether the surgery is responsible for this improvement remains unlear. A retrospetive audit of survival in 299 patients with newly diagnosed glioblastoma multiforme over the last five years at our institution has shown median survivals of 20, 38, and 53 weeks for patients undergoing biopsy, tumour debulking, and marosopi resetion, respetively. These figures orrelate well with a reent publiation from the glioma outome projet in the USA, whih reported median survivals of 21 and 45 weeks for biopsy and raniotomy, respetively, in 413 prospetively reruited patients. Patients with tumours situated in aessible, non-eloquent brain areas are andidates for an attempt at total marosopi resetion; interpreted as the removal of all visibly abnormal tissue. While this does not represent all tumour ells it does inlude the regions where tumour growth and neo-angiogenesis have resulted in blood brain barrier breakdown (enhanement on CT or MRI san). Attempts have been made to quantify the extent of resetion ahieved, mainly by J Neurol Neurosurg Psyhiatry: first published as /jnnp on 14 May Downloaded from on 1 September 2018 by guest. Proteted by opyright.

2 NEUROLOGY IN PRACTICE alulating the proportion of preoperative enhaning tissue remaining in an early (, 72 hours), postoperative MRI san. A reent study has suggested that survival advantage is observed when. 98% of the enhaning tissue has been exised. Further developments in surgial tehnology (image guided surgery, intraoperative ultrasound, CT, and MRI), neuroimaging (PET/SPECT, MR spetrosopy, diffusion tensor imaging), and moleular biology (fluoresene/radioative labelling of tumour ells in situ) are intended to maximise tumour resetion while dereasing proedure related morbidity. Symptomati relief Surgery is a highly effetive means of reduing elevated intraranial pressure and relieving the loal mass effet aused by glioma. Moreover, major tumour deompression will allow prompt redution of steroid mediation, with the avoidane of the side effets produed by their long term use at high doses. The relative ease with whih intraranial pressure an be redued and neurologial symptoms alleviated in eah ase is balaned against the assoiated risks. Drainage of a ysti lesion or a polar lobe resetion, for example, are relatively low risk proedures, whih will produe rapid deompression and failitate a more extensive tumour resetion. The deision to operate in this situation is more straightforward than the removal of a diffuse, ill defined lesion lose to an eloquent brain area. Any surgial intervention is tailored to the patient s symptoms, linial ondition and needs, and prognosis, as well as to the requirements of any adjuvant treatments. Palliative surgery an also be used for patients with high grade glioma (HGG) that has re-grown after primary therapy (fig 1). The deision to operate may be even more diffiult and must take into aount the patient s performane status, the time interval from initial presentation and first line treatment, and the available treatment options, inluding linial trials. Delivery of adjuvant treatment The failure of inreasingly sophistiated onventional treatments (surgery and radiotherapy) to ontrol HGG demands the development of new therapeuti paradigms. Further, the delivery of drugs and maromoleules to the brain following systemi, intravasular administration is hindered by the existene of the blood brain barrier (BBB), the heterogeneity of HGG, and the unique environment of the entral nervous system (CNS), whih ause varied and unpreditable intraerebral drug distribution. Suh fators have led investigators to explore loo-regional routes of administration of new and onventional agents. 3 A onsistent theme running through strategies designed to overome these diffiulties has been the attempt to irumvent the BBB by the diret administration of agents into the extravasular spaes of the CNS. Tehniques involving neurosurgery have inluded parenhymal injetions, intraavitary instillation, slow release polymer implants, and intraventriular or intratheal administration. The latter two methods, while useful for aessing erebrospinal fluid (CSF) spaes, are similarly hindered by the presene of a CSF brain barrier. Some agents are introdued at the time of surgery for tumour resetion while others require the insertion of aess devies for subsequent administration. An example of the first approah is the reent introdution of parenhymal hemotherapy using biodegradable wafers impregnated with a nitrosurea. In a randomised double blind plaebo ontrolled trial, nitrosurea produed a statistially signifiant improvement in survival for patients with newly diagnosed HGG. The benefit was small, delivering an improvement of only two months in median survival (13.9 months for nitrosurea v 11.6 for plaebo). Other hemotherapy agents are urrently under investigation using similar tehnology. Aess devies, suh as indwelling atheters and reservoirs, have been used to deliver a variety of antineoplasti agents inluding radiolabelled monolonal antibodies, radioisotopes, and drugs, into the resetion avities of HGG. The main limitation of this approah is its reliane on the proess of diffusion within brain parenhyma for distribution. This is dependent on the onentration gradient (requiring very high values at the site of administration), the rate of tissue learane for the partiular agent, and the size of the administered moleule diffusion being inversely proportional to its moleular weight. It an therefore be a very slow proess with a limited volume of distribution. This is a major disadvantage when dealing with diffuse CNS disease suh as malignant glioma, where neoplasti ells may be entimetres away from the main tumour mass. A new and very promising approah explores the feasibility of using bulk flow within the brain extraellular fluid (ECF) spae for the intraerebral distribution of agents. This method has been alled onvetion enhaned delivery (CED) and involves the plaement within the brain parenhyma or tumour substane of one or more atheters that are subsequently onneted to ontinuous infusion pumps. The pumps must be able to deliver the very low infusion rates that are ritial for suessful fluid onvetion within the brain. Rates of infusion greater than a few ml/min will produe bakflow along the atheter and loss of pressure, while too low a pressure will lead to failure of delivery. An inreasing body of animal and, more reently, human data shows that a muh larger volume of distribution is ahieved ompared to previous delivery methods. CED is now the method of hoie in a variety of phase I through phase III linial trials investigating novel agents in CNS malignany. In summary, surgery plays a entral role in the initial diagnosis and symptom ontrol in patients with malignant brain tumours. All but the very elderly and the most infirm patients suspeted of having a primary brain tumour should be referred for an opinion from a neurosurgeon with a speialist tumour interest. In addition to its onventional role, neurosurgery is playing an inreasing role in novel treatment delivery, of whih some modalities have shown early promise in the management of these diseases. RADIOTHERAPY Radiotherapy an prolong survival in the majority of patients with malignant brain tumours, inluding high grade gliomas, and may be urative in others for example, medulloblastomas and germ ell tumours (the management of low grade gliomas is disussed by Whittle, p ii31). Our understanding of whih radiotherapeuti treatment to offer to whih patient has notably improved in reent years. 4 Numerous analyses have demonstrated that prognosti fators operate for patients treated for malignant glioma. In partiular these inlude age, performane status, tumour histology, extent of resetion, and possibly tumour size. It is possible to ombine suh fators into a prognosti guide to the value of radiotherapy in a partiular situation. Young ii25 J Neurol Neurosurg Psyhiatry: first published as /jnnp on 14 May Downloaded from on 1 September 2018 by guest. Proteted by opyright.

3 ii26 HGG Surgery & XRT Surveillane linial/imaging Reurrene? patients with good performane sores have a survival prognosis of longer than a year, provided optimal treatment is given. They merit radial treatment with radiation doses of, 60 Gy over periods of about six weeks. On the other hand, elderly infirm patients have prognoses of only a few months irrespetive of treatment and may be spared radiotherapy altogether. For those with intermediate status, shorter treatment shemes (for example, 30 Gy in two weeks using just six frations) an bring an appropriate level of survival benefit without overburdening the patient with large numbers of treatment frations and side effets. Suh shemes have gained wide aeptane. It has reently been suggested that age, per se, is not a prognosti fator independent of performane status and that high dose Good KS? Evidene of mass effet? Suitable for resetion Further resetion Unsure Thallium/tyrosine SPECT or PET Palliative are ±phase 1 studies Previous grade II/III? Consider 2nd line treatment ±phase 1/2/3 studies radiation therapy should be offered to older patients with otherwise good prognosti indiators. Beause high grade glioma ells are widely infiltrating through the oedematous white matter adjaent to tumour, and beyond, it is tempting to use very large radiation fields to over these ells. However, it has been demonstrated that in spite of wide volume radiotherapy the majority of tumours relapse within 2 m of the previous tumour s enhaning edge, or the resetion avity. Hene, until this problem is solved radiotherapy to large volumes of brain is not justified. Indeed muh attention is urrently being foused on using sophistiated radiotherapy planning tehniques, inluding onformal radiotherapy and intensity modulated radiotherapy, to redue the volumes of normal brain that are irradiated. This brings with it improvement in the side effets of treatment. In 1991, the Medial Researh Counil reported a study in whih two doses of radiotherapy (45 Gy v 60 Gy) were ompared in the treatment of malignant brain tumours. They learly showed improved survival in those patients reeiving the higher dose. This led to the prospet of further benefit from still higher doses. However, dose esalation studies using brahytherapy or stereotati radiotherapy/ radiosurgery have failed to show this improvement. Neither Re-biopsy Higher grade? Management based on grade Figure 1 Management algorithm for high grade glioma. HGG, high grade glioma; KS, Karnofsky performane sore; PET, positron emission tomography; SPECT, single photon emission omputed tomography; XRT, radiotherapy. Surgery: key points Tissue diagnosis is neessary for adequate management in the majority of ases Surgery may provide prompt symptomati relief but does not neessarily add to longevity Surgery offers prospets for novel treatment delivery NEUROLOGY IN PRACTICE J Neurol Neurosurg Psyhiatry: first published as /jnnp on 14 May Downloaded from on 1 September 2018 by guest. Proteted by opyright.

4 NEUROLOGY IN PRACTICE have radiation sensitisers (for example, BudR) nor hypoxi ell sensitisers (for example, tirapazamine) brought any improvement. 4 The brain is sensitive not only to the total radiation dose but also to the radiation dose per fration. Numerous attempts have been made at modifying the frationation shedule for glioma treatment in order to gain therapeuti advantage. However, neither hyperfrationation, aelerated frationation, hypofrationation, nor any ombination of these, has produed any survival advantage. In view of all of the above, patients with high grade glioma should routinely be offered onventional doses of radiotherapy (60 Gy in 30 frations over six weeks) without radiation modifiers. Patients with major defiits may be offered shorter ourses of treatment, or none, espeially if elderly. In any event all patients should reeive best supportive are in addition to any radiotherapy. Whole neuraxis irradiation remains an integral omponent of urative treatment in patients, partiularly hildren, with tumours suh as medulloblastoma that have a propensity for CSF spread. Many of these tumours are also hemosensitive and this modality is used as a means of reduing the overall radiation dose without ompromising hane of ure. Although not onlusively baked by randomised trials, this approah has beome standard in medulloblastoma. Unfortunately, ependymoma does not seem to respond so well to this approah. Additional late onsequenes of whole neuraxis treatment inlude the late effets of irradiating nonneurologial tissues suh as growing bone and thyroid. Inreasingly hemotherapy is also used to treat germ ell tumours, with radiotherapy onfined to treating the primary lesion. 5 Compliations Radiotherapy is damaging to both tumour and to normal brain, and the potential onsequenes of treatment must be put in the ontext of any benefit. The priniple aute and intermediate ompliations are depilation, fatigue, and somnolene and are of greatest onern in patients with short prognoses. Mostly these symptoms are mild and improve with time from irradiation. Of greater onern in patients with long term survival prospets are vasular and white matter hange, inluding nerosis, neuronal fallout, endorine failure, and seond malignany. Late effets are related to the total delivered dose and the rate of delivery (dose per fration). While the effets on ognition of large radiation doses are well doumented, the effets of lower doses may have been overestimated, partiularly if delivered with small fration sizes. 5 Radiotherapy for patients with radio-urable tumours suh as medulloblastomas or germ ell tumours is quite different. These diseases have a propensity to disseminate throughout the CNS and raniospinal radiotherapy has been direted at this entire target, always using the highest dose that was safely possible. CHEMOTHERAPY Chemotherapy has three major roles in aner: as the primary treatment, as an adjuvant to the primary treatment (to prevent or delay relapse), or as palliative therapy to improve symptoms and prolong survival following primary treatment failure. Some rare neurologial onditions suh as primary CNS lymphoma, germ ell tumours, and primitive neuroetodermal tumours are hemo-responsive and hemotherapy Radiotherapy: key points Radiotherapy an prolong survival in the majority of patients with brain tumours Appliation of radiotherapy should be determined by performane and other prognosti fators Further progress in external beam radiotherapy is likely to ome from ombination with other treatment modalities plays a entral role in their management. However, the majority of brain tumours have been onsidered hemoresistant and the use of hemotherapy, partiularly as adjuvant treatment, is ontroversial. With the availability of newer drugs and a better understanding of the biology of brain tumours this situation is hanging, even for high grade gliomas. 6 For any hemotherapy agent to be effetive it must first penetrate to the aner and the seletive permeability of the BBB poses a partiular problem for brain tumours. Some drugs, beause of their small moleular size or high lipid solubility, naturally ahieve good BBB penetration (nitrosoureas, temozolomide) and high onentrations in tumour. This an be improved by bypassing the BBB using biodegradable wafers, BBB disruption, or ontinuous infusion methods. A limited number of drugs, suh as methotrexate and ytosine arabinoside, an be given safely by the diret intratheal route. However, apart from speial irumstanes, suh as hildhood aute lymphoblasti leukaemia, they have shown no effiay in brain tumours. Chemotherapy for relapsed disease The nitrosoureas (BCNU, CCNU) have historially played a entral role in the hemotherapy of gliomas. However, there are very few studies in whih either single agents or ombinations are ompared and optimum treatment is unlear. By ommon onsent the ombination of proarbazine, CCNU, and vinristine (PCV) has been adopted as the gold standard in spite of there being relatively little firm evidene for this. PCV has been shown to be more effetive than single agent nitrosourea in a prospetive randomised study in patients with anaplasti astroytoma. The same result did not reah statistial signifiane for patients with glioblastoma. Phase II trials have desribed response rates to PCV in the region of 20 40% for seleted patients with relapsed glioblastoma, though the appliability to the general population may be questioned. Median survival following hemotherapy for relapsed glioblastoma is 3 6 months. Four to six ourses of PCV are usual. Tablets are taken for 10 days with a single intravenous injetion every six weeks. The benefits of tumour ontrol must be balaned against the patient s tolerane of the treatment. Though generally well tolerated, the most ommon side effets are myelosuppression, whih may be umulative, and nausea. Vinristine an ause an unomfortable polyneuropathy, whih usually improves with essation of the drug. The possible interation of proarbazine with tyramine ontaining foods suh as red wine and ripe heese leads to speial dietary restritions. In general, the response to hemotherapy is better in younger patients, with lower grade tumours, good performane status, and longer progression-free interval. Temozolomide is a new alkylating agent whose ativity in patients with relapsed gliomas is similar to PCV. It is given ii27 J Neurol Neurosurg Psyhiatry: first published as /jnnp on 14 May Downloaded from on 1 September 2018 by guest. Proteted by opyright.

5 ii28 orally for five days every four weeks and is said to be better tolerated, and assoiated with a better quality of life, than proarbazine ontaining regimens. In many ountries it is used as primary treatment for relapsed glioma. In the UK, however, it is reommended only for seond line use though few patients survive long enough and remain well enough to be onsidered for it. A prospetive, randomised UK national study diretly omparing PCV with temozolomide (in two shedules) as first line treatment for high grade glioma at first relapse will assess whether there is a survival or quality of life advantage to the newer treatment. Any benefit will have to be onsidered against the higher ost of temozolomide. Other drugs that an be used in patients with relapsed glioma inlude arboplatin, etoposide, and dibromdulitol, though their role is not fully established and they are reserved as third line or experimental agents. Among the newer agents the topoisomerase 1 inhibitor, CPT11, has shown promise in some studies, partiularly in assoiation with temozolomide. Differential hemosensitivity in malignant glioma It has been reognised for some years that there is a differential hemosensitivity among different glioma lasses. Reently, however, moleular analysis has appeared to give partiular promise as a preditor of response. This leads to the exiting prospet of using moleular biology to improve upon standard pathologial methods in direting treatment. Cairnross and MDonald were the first to show that patients with relapsed anaplasti oligodendrogliomas demonstrated partiularly good response to hemotherapy with PCV. Moleular geneti studies then showed that the deletion of the long arm of hromosome 1 and the short arm of hromosome 19 (1p-, 19q-) is ommon in this group of tumours and, when present, was assoiated with pronouned hemosensitivity. Indeed patients in these studies enjoyed prolonged remissions, sometimes lasting several years. 7 This hemosensitivity also appears to extend to other dugs suh as temozolomide. While the role of hemotherapy in relapse oligodendroglioma has been learly established, the value of PCV as treatment adjuvant to radiation is still under study. With optimisti antiipation of the outome, some workers have postulated that patients suffering from oligodendrogliomas arrying these hromosomal abnormalities may be better served by primary treatment with hemotherapy, reserving radiotherapy for relapse. In low grade oligodendroglioma, the assoiation of hemosensitivity with LOH1p, 19q status remains, but is not so strong. However, in patients with so alled oligoastroytoma the hemosensitivity appears to be predited by the 1p, 19q status. It is also lear that anaplasti astroytoma responds more favourably to hemotherapy than glioblastoma. Further, the geneti hanges marking progression of anaplasti astroytoma to glioblastoma are inreasingly understood. While the assoiation of hemosensitivity with the geneti profile is not so well established in malignant astroytoma, an aurate knowledge of tumour grade is learly required to allow rational hoie of treatment. These findings give real enouragement to searh for other moleular markers to improve targeting treatment for individual patients. NEUROLOGY IN PRACTICE vel delivery methods Although the BBB is partially disrupted in the viinity of a brain tumour, it is nevertheless pereived as a barrier to treatment. A variety of methods have been explored to bypass this problem. Neither osmoti BBB disruption, seletive BBB opening nor high dose treatment with marrow resue have shown any survival benefit over onventional treatment. The neurosurgial methods disussed above are, however, showing inreasing promise. Adjuvant hemotherapy Adjuvant hemotherapy has been suessful in some other tumour types (notably breast aner) in produing durable improvements in survival. Numerous randomised studies have attempted to demonstrate the same effet in patients with brain tumours. The most frequent study design has inorporated nitrosourea based hemotherapy as adjuvant to standard surgery and radiotherapy in omparison to standard treatment alone. Most studies were underpowered and failed to show any survival advantage. In 2002 the glioma metaanalysis trialist group 8 arried out a systemati review of individual patient data from 12 suh trials whose data were suffiiently homogeneous for the purpose. Radiotherapy doses ranged from Gy and volumes varied from whole brain to tumour only with a margin. All patients reeived a nitrosourea, some as single agent, others as ombination therapy. There was a statistially signifiant inrease in median survival from 10 to 12 months, equivalent to a 6% absolute improvement in survival at one year (from 40% to 46%). This was just sustained at two years but had effetively vanished at three years. The relative benefits were the same for glioblastomas and anaplasti astroytomas, though learly due to the shorter life expetany of the former, the absolute differene was less for this group of patients. Younger, fitter patients seemed to benefit most. The meta-analysis then learly demonstrates a statistially signifiant benefit to adjuvant hemotherapy in high grade gliomas. Should this be adopted therefore as standard pratie? Does a 6% improvement in one year survival justify several months of hemotherapy for all patients? An essential differene between this result and that in, say, breast aner, is that in the latter disease the improvement is durable. It an be argued that offering hemotherapy on progression, when patients have symptoms to palliate, is a better way of preserving a patient s quantity and quality of life. As yet adjuvant therapy has not been aepted as standard-of-are by most liniians in the UK. However, it an be argued that some young, fit, motivated patients with a good performane status after primary treatment should at least be offered the option of hemotherapy. Further there are enouraging nonrandomised data that suggest that temozolomide is muh more effetive in the adjuvant setting. Results of a European phase III study of adjuvant temozolomide are awaited. In summary, a signifiant role for adjuvant hemotherapy in the majority of malignant brain tumours is hard to demonstrate, although in individual histologial types suh as germ ell tumours or CNS lymphomas benefit is lear. Its major role in the treatment of high grade gliomas remains as a palliative option for reurrent disease with ongoing studies to determine the optimum regimen. With the introdution of moleular genetis as a routine linial tool in the future, it may beome possible to individualise patient are by offering hemotherapy earlier to those in whom there J Neurol Neurosurg Psyhiatry: first published as /jnnp on 14 May Downloaded from on 1 September 2018 by guest. Proteted by opyright.

6 NEUROLOGY IN PRACTICE Chemotherapy: key points Chemotherapy has an established role in the palliation of patients with progressive brain tumours Adjuvant hemotherapy has yet to be proven as worthwhile in patients with high grade glioma Moleular profiling is showing promise in seleting appropriate patients for hemotherapy is a demonstrated abnormality known to onfer hemosensitivity, as seems possible for anaplasti oligodendrogliomas. NEW DIRECTIONS The outome for patients with malignant brain tumours following standard treatment is poor and new approahes are needed. The most promising are anti-aner treatments suh as antibodies or small inhibiting moleules, designed against speifi moleular targets rather than drugs derived from traditional empiri methods. Thus, for example, angiogenesis inhibitors or signal transdution inhibitors (STI) are designed to target moleules known to be ative in partiular aners. In some aners for example, breast and lung drugs, suh as traztuzamab and ZD1839 whih target the epidermal growth fator reeptor, are already entering linial usage though the results are somewhat mixed. Similar targets exist on gliomas and form the basis of ontemporary researh. 9 STI571 (imatinib mesylate) is an oral drug with several ations, inluding inhibition of tyrosine kinases ativated by the platelet derived growth fator reeptor (PDGFR). PDGFR, and its ligand PDGF, are frequently expressed in gliomas, and are thought to be important in promoting proliferation. PDGF/R are onsidered to work in an autorine loop fashion, stimulating glial ell division. STI571 has demonstrated the ability to inhibit this in vitro in ell lines, and in vivo in animal models. Phase I and II linial trials of STI571 have already been arried out in other tumours suh as hroni myeloid leukaemia and gastrointestinal stromal tumours with enouraging results, and trials are ongoing to investigate its role in glial tumours. Sine there are multiple aberrant elements in the ell yle ontrol of malignant gliomas it is likely that suh agents will be needed in ombination to be effetive in these diseases. This work is in its infany but has a ompelling logi and signifiant promise. A number of other highly innovative approahes in onology have been grouped under the term biotherapies, indiating their aim to ontrol aner either by manipulating biologial proesses or by utilising their produts as onolyti agents. They an be addressed under the headings of gene therapy, immunotherapy, onolyti viral therapy, and biologial toxins; all of whih have been applied to neuro-onology. Gene therapy The term aner gene therapy implies the manipulation of the tumour ell genome for therapeuti purposes. It is fair to say that gene therapy has failed to fulfil early expetations, probably beause these were set too high. Gene therapy an take on several different strategies: Suiide gene therapy Suiide gene therapy involves the inorporation into a tumour ell of a gene whose produt, either alone or in ombination with another agent, results in ell death. The most widely used paradigm is the introdution of nonhuman enzymes that are able to onvert non-toxi pro-drugs into ytotoxi metabolites. Two enzyme/pro-drug ombinations aount for the majority of human trials to date: Herpes simplex virus type 1 thymidine kinase (HSV-1-tk) and ganilovir Esherihia oli ytosine deaminase and 5-fluoroytosine. Modifying ontrol genes In this strategy the gene therapy ounterats a funtion of the tumour ell that is neessary for tumour growth and spread. Anti-angiogeni fators and tissue inhibitors of matrix metalloproteinases, important in the development, transformation, and invasiveness of HGG, have been evaluated in the laboratory and in pre-linial studies. Tumour suppressor genes This method attempts to restore the funtion of normal genes, in irumstanes where a prior mutation has rendered them ineffetive; as part of the arinogeni proess. These genes have been alled tumour suppressor genes even though they have very important physiologial funtions. The lassi examples are mutations to p53, whih ats both as a ell yle hekpoint swith and a trigger for apoptosis. Antisense strategies Antisense mehanisms interfere with the various steps of RNA proessing, a major omponent of gene expression, inluding transription, anabolism, and atabolism of mrna and translation. Ahieving tumour speifiity without interfering with normal ell funtion remains a problem. Interferene with DNA expression is also a possibility, though the additional problem of intranulear delivery makes this less attrative. Immunotherapy (ellular and moleular) Immunotherapy enompasses a wide variety of treatment avenues aimed at reruiting the immune system and its omponents in either diret or indiret attak upon the tumour. Vaination with tumour ells (whole or gene modified tumour ells) Vaination against tumour assoiated antigens (for example, dendriti ell vaines) Lymphoyte therapy (allogenei or autologous lymphoytes with interleukin-2) Monolonal antibodies have been used both to stimulate immune response, for their diret anti-tumour effet, and to target therapeuti agents, suh as toxins and radioisotopes. Onolyti viral therapy (or virotherapy) The majority of viruses urrently used in gene therapy trials are repliation inompetent. One of their major limitations is the requirement that the virus be delivered to the majority of the tumour ells if it is to be effetive. Eah viral partile an at best only transfet one tumour ell. In reality, transfetion rates are nearer 10% than 100%. Even with the bystander effet (the killing of non-transfeted ells), there is still a onsiderable shortfall from what is needed for effetive tumour killing. The use of repliation ompetent viruses has the potential to irumvent this problem. A suessful infetion of a ell and the onsequent viral repliation results not only in the destrution of the infeted ell (viral onolysis) but also in the release of viral progeny to infet other ells in the viinity. This an initiate a hain reation, whih under the right onditions, ould potentially spread ii29 J Neurol Neurosurg Psyhiatry: first published as /jnnp on 14 May Downloaded from on 1 September 2018 by guest. Proteted by opyright.

7 ii30 New diretions: key points Cell yle targeted agents, gene therapy, immunotherapy, and onolyti viral therapy are all showing some early promise in the treatment of malignant brain tumours throughout the tumour. The mainstay of suessful aner virotherapy is the manipulation of the viral genome to allow repliation within tumour but not normal ells. This an be ahieved by the insertion of tumour speifi promoters or gene inativation to produe onditional repliation. The herpes simplex virus mutant HSV1716 has been the first in human trials in brain tumours. Biologial toxins A number of protein toxins have been evaluated in vitro and now in linial studies for their anti-tumour ativity, inluding diphtheria toxin, pseudomonas exotoxin, and riin. These have been onjugated to a variety of targeting moleules, either speifi to or over-expressed by tumour ells, suh as monolonal antibodies, and interleukins 4 and 13. These have entered linial trial, partiularly using CED for delivery, with reasonable promise.... Authors affiliations R Rampling, A James, Western Infirmary, Glasgow, UK V Papanastassiou, Southern General Hospital, Glasgow, UK REFERENCES NEUROLOGY IN PRACTICE 1 Laws ER, Parney IF, Huang W, et al. Survival following surgery and prognosti fators for reently diagnosed malignant glioma: data from the glioma outomes projet. J Neurosurg 2003;99: Westphal M, Giese A. Loal ontrol of gliomas: The next best step - a good step? Front Radiat Ther Onol 1999;33: Dunn IF, Blak PM. The neurosurgeon as loal onologist: ellular and moleular neurosurgery in malignant glioma therapy. Neurosurgery 2003;52: Rampling, R. Modern aspets of radiation therapy for glial tumours of the brain. FORUM Trends in Experimental and Clinial Mediine 1998;8: Rampling R. Central nervous system. In: Prie P, Sikora K, eds. Treatment of aner. London: Arnold, Arnold S, Pathell RA. Chemotherapy of primary brain tumors. In: Perry MC, ed. The hemotherapy soure book. Lippinott Williams & Wilkins, Cairnross JG, Ueki K, Zlatesu M, et al. Speifi geneti preditors of hemotherapeuti response and survival in patients with anaplasti oligodendrogliomas. J Ntl Caner Inst 1998;90: Stewart L and the Glioma Meta-analysis Trialists (GMT) Group. Chemotherapy in adult high-grade glioma: a systemati review and metaanalysis of individual patient data from 12 randomised trials. Lanet 2002;359: Basso U, Ermani M, Vastola F, et al. n-ytotoxi therapies for malignant gliomas. J Neuro-Onol 2002;58: J Neurol Neurosurg Psyhiatry: first published as /jnnp on 14 May Downloaded from on 1 September 2018 by guest. Proteted by opyright.